THAT ARE NOT LOUILLOTTIUS009850268B2 (12 ) United States Patent ( 10) Patent No. : US 9 ,850 , 268 B2 Hoveyda et al. ( 45 ) Date of Patent: Dec . 26 , 2017 (54 ) METATHESIS CATALYSTS AND METHODS 17/ 269 (2013 . 01 ) ; C07C 17 /275 (2013 . 01 ) ; THEREOF C07C 17 /278 ( 2013 .01 ); C07C 17361 ( 2013 .01 ) ; C07C 37 /62 ( 2013 .01 ) ; C07C 41/ 30 (71 ) Applicants :Massachusetts Institute of ( 2013 .01 ) ; C07C 45 /63 ( 2013 . 01 ); C07C Technology , Cambridge , MA (US ) ; 67 /307 ( 2013 .01 ) ; C07C 67 /333 (2013 .01 ) ; Trustees of Boston College, Chestnut C07D 209 / 10 ( 2013 . 01 ) ; C07D 209 /48 Hill , MA (US ) ( 2013 .01 ) ; C070 333 /54 ( 2013 . 01) ; COFF 5 / 025 ( 2013 .01 ) ; CO7F 7 / 1844 ( 2013 .01 ) ; (72 ) Inventors : Amir H . Hoveyda , Lincoln , MA (US ) ; CO7F 7 / 1852 ( 2013 .01 ) ; C07 ) 9 /00 ( 2013 .01 ) ; Hanmo Zhang , Chestnut Hill, MA C07 ) 51/ 00 ( 2013 .01 ) ; B01J 2231/ 543 (US ) ; Ming Joo Koh , Chestnut Hill, ( 2013 . 01 ) ; B01 ) 2531 /64 ( 2013 .01 ) ; B01J MA (US ); Richard Royce Schrock , 2531/ 66 (2013 . 01 ); C07C 2601/ 14 ( 2017 .05 ); Winchester , MA (US ) C07C 2603/ 26 (2017 . 05 ) (58 ) Field of Classification Search (73 ) Assignees : Trustees of Boston College , Chestnut CPC ...... C07C 17 /275 ; C07C 45/ 63 ; C07C 37 /62 ; Hill , MA (US ) ; Massachusetts B01J 2231/ 543 ; B01J 2531/ 64 ; B01J Institute of Technology , Cambridge, 2531/ 66 ; B01J 31/ 2265 MA (US ) USPC ...... 548 /402 ; 514 / 408 , 184 ( * ) Notice: Subject to any disclaimer , the term of this See application file for complete search history . patent is extended or adjusted under 35 U .S .C . 154 (b ) by 0 days . ( 56 ) References Cited ( 21) Appl . No. : 14 /933 , 741 U . S . PATENT DOCUMENTS 2012/ 0323000 Al 12 /2012 Hoveyda et al . (22 ) Filed : Nov . 5 , 2015 2014 /0309388 Al 10 /2014 Schrock et al. (65 ) Prior Publication Data FOREIGN PATENT DOCUMENTS US 2016/ 0194343 A1 Jul. 7 , 2016 EP 0585887 3 / 1994 WO WO 2011008258 A2 * 1 / 2011 ...... B01J 31/ 1805 Related U .S . Application Data Wo 2011097642 8 / 2011 (60 ) Provisional application No .62 / 075 ,315 , filed on Nov . (Continued ) 5 , 2014 . OTHER PUBLICATIONS (51 ) Int. Ci. C07C 17 /275 ( 2006 .01 ) Dobereiner , et al ., " Catalytic Synthesis of n - Alkyl Arenes Through C07C 45 /63 ( 2006 . 01 ) Alkyl Group Cross -Metathesis ” , JACS , 135 , 2013 , 12572 -12575 . C07C 37 /62 ( 2006 .01 ) (Continued ) B01J 31/ 22 ( 2006 .01 ) CO7F 11 / 00 ( 2006 . 01 ) CO7D 333/ 54 ( 2006 . 01 ) Primary Examiner — Matthew Coughlin C07D 209 / 10 ( 2006 . 01 ) Assistant Examiner — Sagar Patel C07D 209 /48 ( 2006 .01 ) (74 ) Attorney, Agent, or Firm — Stoel Rives LLP CO7F 5 /02 ( 2006 .01 ) CO7F 7 / 18 ( 2006 . 01 ) ( 57 ) ABSTRACT C07C 17 / 266 ( 2006 .01 ) C07C 17 / 269 ( 2006 .01 ) The present application provides , among other things, com C07C 17 / 278 ( 2006 .01 ) pounds and methods for metathesis reactions . In some C07C 17 / 10 ( 2006 . 01 ) embodiments , the present disclosure provides methods for C07C 17 / 14 ( 2006 . 01 ) preparing alkenyl halide with regioselectivity and / or stereo C07C 171361 ( 2006 .01 ) selectivity . In some embodiments , the present disclosure CO7B 37 / 04 ( 2006 . 01 ) provides methods for preparing alkenyl halide with regiose C07C 17 /02 ( 2006 . 01 ) lectivity and Z - selectivity . In some embodiments , the pres C07J 9 / 00 ( 2006 .01 ) ent disclosure provides methods for preparing alkenyl halide C07 ) 51/ 00 ( 2006 . 01 ) with regioselectivity and E - selectivity. In some embodi C07C 671307 ( 2006 .01 ) ments , provided technologies are particularly useful for C07C 671333 ( 2006 .01 ) preparing alkenyl fluorides . In some embodiments , a pro C07C 41/ 30 (2006 . 01) vided compound useful for metathesis reactions has the ( 52 ) U . S . CI. structure of formula II - a . In some embodiments , a provided CPC ...... C07F 11/ 00 (2013 .01 ); B01J 31 /2265 compound useful for metathesis reactions has the structure ( 2013 . 01 ) ; CO7B 37 /04 (2013 . 01 ) ; C07C 17 / 02 of formula II - b . ( 2013 .01 ) ; C07C 17 / 10 ( 2013 .01 ) ; C07C 17 / 14 ( 2013 .01 ) ; C07C 17/ 266 ( 2013 .01 ); C07C 16 Claims, No Drawings US 9, 850 ,268 B2 Page 2 ( 56 ) References Cited FOREIGN PATENT DOCUMENTS wo 2014172534 10 / 2014 WO 2015136093 9 / 2015 OTHER PUBLICATIONS Fomine , et al. , “ Metathesis of Fluorinated Olefins by Ruthenium Alkylidene Catalysts . Fluorine Substituent Effects on a Ru -Carbene ( Alkylidene ) Complex Stability : A Computational Study ” , Applied Catalysis A : General, 355 , 2009 , 148 - 155 . MacNaughtan , et al. , “ Cross -Metathesis of Vinyl Halides. Scope and Limitations of Ruthenium - Based Catalysts” , Organometallics , 28 , 2009 , 2880 - 2887 . PCT/ US2015 / 059286 , International Search Report and Written Opinion , dated Mar. 14 , 2016 , 15 pages. Zhang , et al. , “ Preparation of Macrocyclic Z - Enoates and ( E , Z ) - or ( Z , E ) - Dienoates Through Catalytic Stereoselective Ring - Closing Metathesis ” , JACS , 136 , 2014 , 16493 - 16496 . * cited by examiner US 9 ,850 ,268 B2 METATHESIS CATALYSTS AND METHODS wherein : THEREOF M is molybdenum or tungsten ; R ! is an optionally substituted group selected from C1- 20 aliphatic , C1- 20 heteroaliphatic having 1 - 3 heteroatoms CROSS -REFERENCE TO RELATED independently selected from nitrogen , oxygen , or sulfur, APPLICATIONS phenyl, a 3 - 7 membered saturated or partially unsaturated carbocyclic ring , an 8 - 10 membered bicyclic saturated , The present application claims priority to the U . S . Pro partially unsaturated or aryl ring , a 5 - 6 membered mono visional Application No . 62 /075 , 315 , filed Nov. 5 , 2014 , the cyclic heteroaryl ring having 1 - 4 heteroatoms indepen entirety of which is incorporated herein by reference . dently selected from nitrogen , oxygen , or sulfur, a 4 - 7 10 membered saturated or partially unsaturated heterocyclic STATEMENT REGARDING FEDERALLY ring having 1 - 3 heteroatoms independently selected from nitrogen , oxygen , or sulfur, a 7 - 10 membered bicyclic SPONSORED RESEARCH OR DEVELOPMENT saturated or partially unsaturated heterocyclic ring having This invention was made with government support under 1 - 5 heteroatoms independently selected from nitrogen , Grant No. GM59426 awarded by the National Institute of oxygen , or sulfur, or an 8 - 10 membered bicyclic het Health and Grant No . CHE - 1362763 awarded by the eroaryl ring having 1 - 5 heteroatoms independently National Science Foundation . The U . S . government has selected from nitrogen , oxygen , or sulfur; or R is option certain rights in the invention . ally substituted 20 FIELD OF THE INVENTION (RX )p The present invention generally relates to metathesis reactions . 25 BACKGROUND each of R2 and R3 is independently R ', _ OR ', SR ', - N ( R ' ) 2 , OC ( O ) R ', - SOR ', — SO , R ', SO N ( R ') 2 , CO ) N ( R ') 2 , NR ' C (O ) R ', or - NR ' SO , R ', provided Catalytic metathesis has transformed chemical synthesis that R2 and R3 are not simultaneously hydrogen ; and offers exceptionally efficient pathways for the synthesis* 30 R * is R ' , or an optionally substituted group selected from of many commercially important chemicals including bio - 30 - Ar, C1- 20 aliphatic , C1- 20 heteroaliphatic having 1 -3 logically active molecules , oleochemicals , renewables , fine heteroatoms independently selected from nitrogen , oxy chemicals , and polymeric materials . There remains an unmet gen , or sulfur , phenyl, a 3 - 7 membered saturated or neneed for improved methods and catalysts for metathesis partially unsaturated carbocyclic ring , an 8 - 10 membered reactions, for example , in terms of better catalyst stability bicyclic saturated , partially unsaturated or aryl ring , a 5 - 6 and / or activity , efficiency and stereoselectivity . membered monocyclic heteroaryl ring having 1 - 4 het eroatoms independently selected from nitrogen , oxygen , SUMMARY or sulfur, a 4 - 7 membered saturated or partially unsatu rated heterocyclic ring having 1 - 3 heteroatoms indepen Among other things, the present disclosure recognizes 40 dently selected from nitrogen , oxygen , or sulfur, a 7 - 10 that it is particularly challenging to use alkenyl halides as membered bicyclic saturated or partially unsaturated het metathesis substrates to provide alkenyl halides efficiently erocyclic ring having 1- 5 heteroatoms independently and selectively . The present disclosure , among other things , selected from nitrogen , oxygen , or sulfur, or an 8 - 14 provides technologies, e . g . , compounds, compositions, membered bicyclic or tricyclic heteroaryl ring having 1 - 5 methods, etc . for preparing alkenyl halides through metath - 45 heteroatoms independently selected from nitrogen , oxy esis reactions with high efficiency , high regioselectivity and gen , or sulfur ; high Z - or E - selectivity . Ar is of the following formula : DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS 50 maan ( R ) to D ( R ) 1 . General Description of Certain Embodiments of YBY the Invention In some embodiments , a provided catalyst or metal com - 55 (R * )m plex is of formula II -a : wherein : m is 0 - 3 ; Il- a Ring B is an optionally substituted group selected from 60 phenyl or a 5 - 6 membered monocyclic heteroaryl ring having 1 -4 heteroatoms independently selected from Z=2– nitrogen , oxygen , or sulfur; p and q are independently 0 - 6 ; each of Ring C and Ring D is independently optionally R3 substituted groups selected from phenyl, a 3 - 7 mem bered saturated or partially unsaturated carbocyclic ring, an 8 - 10 membered bicyclic saturated , partially US 9 ,850 ,268 B2 unsaturated or aryl ring, a 5 - 6 membered monocyclic having 1 - 3 heteroatoms independently selected from heteroaryl ring having 1 - 4 heteroatoms independently nitrogen , oxygen , or sulfur , phenyl , a 3 - 7 membered selected from nitrogen , oxygen , or sulfur, a 4 - 7 mem saturated or partially unsaturated carbocyclic ring , an bered saturated or partially unsaturated heterocyclic 8 - 10 membered bicyclic saturated , partially unsaturated ring having 1 - 3 heteroatoms independently selected 5 or aryl ring , a 5 - 6 membered monocyclic heteroaryl ring from nitrogen , oxygen , or sulfur, a 7 - 10 membered having 1 -4 heteroatoms independently selected from bicyclic saturated or partially unsaturated heterocyclic nitrogen , oxygen , or sulfur, a 4 - 7 membered saturated or ring having 1 - 5 heteroatoms independently selected partially unsaturated heterocyclic ring having 1 - 3 heteroa from nitrogen , oxygen , or sulfur , or an 8 - 10 membered toms independently selected from nitrogen , oxygen , or bicyclic heteroaryl ring having 1 - 5 heteroatoms inde - 10 sulfur, a 7 - 10 membered bicyclic saturated or partially pendently selected from nitrogen , oxygen , or sulfur ; unsaturated heterocyclic ring having 1 - 5 heteroatoms each of R " , R ” , and R * is independently R ' ; independently selected from nitrogen , oxygen , or sulfur, R is halogen , OR , OR , - N ( R ') 2 , NR' C ( O ) R ', or an 8 - 14 membered bicyclic or tricyclic heteroaryl ring - NR ' C ( O )OR ', — NR ' C ( O ) N ( R ') 2 — NR 'SO , R ', having 1 -5 heteroatoms independently selected from - NR 'SO N (R ') 2, or — NR 'OR ', or an optionally substi - 15 nitrogen , oxygen , or sulfur ; and two RP are optionally tuted group selected from a 5 -6 membered monocyclic taken together with the oxygen atoms they are bound to heteroaryl ring having at least one nitrogen and 0 - 3 form a bidentate ligand ; and heteroatoms independently selected from nitrogen , oxy - Ar is of the following formula : gen , or sulfur, a 4 - 7 membered saturated or partially unsaturated heterocyclic ring having at least one nitrogen 20 and 0 - 2 heteroatoms independently selected from nitro warm gen , oxygen , or sulfur , a 7 -10 membered bicyclic satu rated or partially unsaturated heterocyclic ring having at (R™ ) + least one nitrogen and 0 - 4 heteroatoms independently selected from nitrogen , oxygen , or sulfur , or an 8 - 10 25 membered bicyclic heteroaryl ring having at least one ( R ) , nitrogen and 0 - 4 heteroatoms independently selected from nitrogen , oxygen , or sulfur; wherein : R is an optionally substituted group selected from C1- 20 tis 0 - 4 ; aliphatic , C1- 20 heteroaliphatic having 1 - 3 heteroatoms 30 p is 0 -6 ; independently selected from nitrogen , oxygen , or sulfur , each Ring B ' and Ring C ' is independently an optionally phenyl, a 3 - 7 membered saturated or partially unsaturated substituted group selected from phenyl, a 3 - 7 mem carbocyclic ring , an 8 - 10 membered bicyclic saturated , bered saturated or partially unsaturated carbocyclic partially unsaturated or aryl ring , a 5 - 6 membered mono ring , an 8 - 10 membered bicyclic saturated , partially cyclic heteroaryl ring having 1 - 4 heteroatoms indepen - 35 unsaturated or aryl ring , a 5 -6 membered monocyclic dently selected from nitrogen , oxygen , or sulfur, a 4 - 7 heteroaryl ring having 1 - 4 heteroatoms independently membered saturated or partially unsaturated heterocyclic selected from nitrogen , oxygen , or sulfur, a 4 - 7 mem ring having 1 - 3 heteroatoms independently selected from bered saturated or partially unsaturated heterocyclic nitrogen , oxygen , or sulfur, a 7 - 10 membered bicyclic ring having 1 - 3 heteroatoms independently selected saturated or partially unsaturated heterocyclic ring having 40 from nitrogen , oxygen , or sulfur, a 7 - 10 membered 1 - 5 heteroatoms independently selected from nitrogen , bicyclic saturated or partially unsaturated heterocyclic oxygen , or sulfur , or an 8 - 14 membered bicyclic or ring having 1 - 5 heteroatoms independently selected tricyclic heteroaryl ring having 1 - 5 heteroatoms indepen from nitrogen , oxygen , or sulfur, or an 8 -10 membered dently selected from nitrogen , oxygen , or sulfur ; and bicyclic heteroaryl ring having 1 - 5 heteroatoms inde each R ' is independently hydrogen or an optionally substi - 45 pendently selected from nitrogen , oxygen , or sulfur ; tuted group selected from C1. 20 aliphatic , phenyl, a 3 - 7 and membered saturated or partially unsaturated carbocyclic each RS is independently halogen , R ', _ OR ', SR ', ring , an 8 - 10 membered bicyclic saturated , partially - S (O ) R ', - S (O ) 2R ', OSI( R ') 3, - N (R ') 2, - NRC unsaturated or aryl ring , a 5 - 6 membered monocyclic ( O ) R ', NR ' C ( O )OR ', NR ' C ( O ) N ( R ' ) , heteroaryl ring having 1 - 4 heteroatoms independently 50 - NR 'SO R ', - NR 'SO , N ( R ' ) 2 , or — NR 'OR '. selected from nitrogen , oxygen , or sulfur, a 4 - 7 membered In some embodiments , a provided catalyst or metal com saturated or partially unsaturated heterocyclic ring having plex is of formula II - a , wherein : 1 - 3 heteroatoms independently selected from nitrogen , M is molybdenum or tungsten ; oxygen , or sulfur, a 7 - 10 membered bicyclic saturated or R is an optionally substituted group selected from C1- 20 partially unsaturated heterocyclic ring having 1 - 5 heteroa - 55 aliphatic , C1- 20 heteroaliphatic having 1 -3 heteroatoms toms independently selected from nitrogen , oxygen , or independently selected from nitrogen , oxygen , or sulfur, sulfur , or an 8 - 10 membered bicyclic heteroaryl ring phenyl, a 3 - 7 membered saturated or partially unsaturated having 1- 5 heteroatoms independently selected from carbocyclic ring , an 8 - 10 membered bicyclic saturated , nitrogen , oxygen , or sulfur, wherein : partially unsaturated or aryl ring , a 5 - 6 membered mono two R ' groups on the same nitrogen atom are optionally 60 cyclic heteroaryl ring having 1 - 4 heteroatoms indepen taken together with the nitrogen atom to form an dently selected from nitrogen , oxygen , or sulfur, a 4 - 7 optionally substituted 3 - 8 membered , saturated , par membered saturated or partially unsaturated heterocyclic tially unsaturated , or aryl ring having 1 - 4 heteroatoms ring having 1 - 3 heteroatoms independently selected from independently selected from nitrogen , oxygen , or sul nitrogen , oxygen , or sulfur , a 7 - 10 membered bicyclic fur ; 65 saturated or partially unsaturated heterocyclic ring having each R ? is independently an optionally substituted group 1 - 5 heteroatoms independently selected from nitrogen , selected from — Ar' , C1- 20 aliphatic , C1- 20 heteroaliphatic oxygen , or sulfur, or an 8 - 10 membered bicyclic het US 9 ,850 , 268 B2 eroaryl ring having 1 - 5 heteroatoms independently heteroatoms independently selected from nitrogen , oxy selected from nitrogen , oxygen , or sulfur ; gen , or sulfur, a 4 -7 membered saturated or partially each of R2 and R3 is independently R ', - OR ', SR ', unsaturated heterocyclic ring having at least one nitrogen - N ( R ') 2 , — OC ( O ) R ', - SOR ', - SO2R ', SO N (R ') 2 , and 0 - 2 heteroatoms independently selected from nitro - C ( O ) N ( R ') 2 , - NR ' C ( O ) R ', or — NR 'SO , R ', provided 5 gen , oxygen , or sulfur, a 7 - 10 membered bicyclic satu that R2 and R3 are not simultaneously hydrogen ; rated or partially unsaturated heterocyclic ring having at R4 is R², or an optionally substituted group selected from least one nitrogen and 0 - 4 heteroatoms independently - Ar, C1- 20 aliphatic , C1- 20 heteroaliphatic having 1 - 3 selected from nitrogen , oxygen , or sulfur, or an 8 - 10 heteroatoms independently selected from nitrogen , oxy membered bicyclic heteroaryl ring having at least one gen , or sulfur, phenyl, a 3 - 7 membered saturated or 10 nitrogen and 0 - 4 heteroatoms independently selected partially unsaturated carbocyclic ring, an 8 - 10 membered from nitrogen , oxygen , or sulfur; bicyclic saturated , partially unsaturated or aryl ring , a 5 - 6 R® is an optionally substituted group selected from C1- 20 membered monocyclic heteroaryl ring having 1 - 4 het aliphatic , C1- 20 heteroaliphatic having 1 - 3 heteroatoms eroatoms independently selected from nitrogen , oxygen , independently selected from nitrogen , oxygen , or sulfur, or sulfur, a 4 - 7 membered saturated or partially unsatuusatu 15 phenyl, a 3 - 7 membered saturated or partially unsaturated rated heterocyclic ring having 1 - 3 heteroatoms indepen carbocyclic ring , an 8 - 10 membered bicyclic saturated , dently selected from nitrogen , oxygen , or sulfur , a 7 - 10 partially unsaturated or aryl ring , a 5 -6 membered mono membered bicyclic saturated or partially unsaturated het cyclic heteroaryl ring having 1 - 4 heteroatoms indepen erocyclic ring having 1 - 5 heteroatoms independently dently selected from nitrogen , oxygen , or sulfur, a 4 -7 selected from nitrogen , oxygen , or sulfur, or an 8 - 14 20 membered saturated or partially unsaturated heterocyclic membered bicyclic or tricyclic heteroaryl ring having 1 - 5 ring having 1 - 3 heteroatoms independently selected from heteroatoms independently selected from nitrogen , oxy nitrogen , oxygen , or sulfur, a 7 - 10 membered bicyclic gen , or sulfur; saturated or partially unsaturated heterocyclic ring having Ar is of the following formula : 25 1 - 5 heteroatoms independently selected from nitrogen , oxygen , or sulfur, or an 8 - 14 membered bicyclic or more tricyclic heteroaryl ring having 1 - 5 heteroatoms indepen dently selected from nitrogen , oxygen , or sulfur; and ( R ), D (R ) q each R ' is independently hydrogen or an optionally substi BY 30 tuted group selected from C1- 6 aliphatic , phenyl, a 3 - 7 membered saturated or partially unsaturated carbocyclic (R *) m ring, an 8 - 10 membered bicyclic saturated , partially unsaturated or aryl ring , a 5 - 6 membered monocyclic wherein : heteroaryl ring having 1 - 4 heteroatoms independently m is 0 - 3 ; 35 selected from nitrogen , oxygen , or sulfur , a 4 - 7 membered Ring B is an optionally substituted group selected from saturated or partially unsaturated heterocyclic ring having phenyl or a 5 - 6 membered monocyclic heteroaryl ring 1 - 3 heteroatoms independently selected from nitrogen , having 1 -4 heteroatoms independently selected from oxygen , or sulfur , a 7 - 10 membered bicyclic saturated or nitrogen , oxygen , or sulfur; partially unsaturated heterocyclic ring having 1 - 5 heteroa p and q are independently 0 - 6 ; 40 toms independently selected from nitrogen , oxygen , or each of Ring C and Ring D is independently optionallyIntionally sulfur, or an 8 - 10 membered bicyclic heteroaryl ring substituted groups selected from phenyl, a 3 - 7 mem having 1 - 5 heteroatoms independently selected from bered saturated or partially unsaturated carbocyclic nitrogen , oxygen , or sulfur, wherein : ring , an 8 - 10 membered bicyclic saturated , partially two R ' groups on the same nitrogen atom are optionally unsaturated or aryl ring, a 5 - 6 membered monocyclic 45 taken together with the nitrogen atom to form an option heteroaryl ring having 1 - 4 heteroatoms independently ally substituted 3 - 8 membered , saturated , partially unsatu selected from nitrogen , oxygen , or sulfur, a 4 - 7 mem rated , or aryl ring having 1 - 4 heteroatoms independently bered saturated or partially unsaturated heterocyclic selected from nitrogen , oxygen , or sulfur ; and ring having 1 - 3 heteroatoms independently selected each R ? is independently an optionally substituted group from nitrogen , oxygen , or sulfur, a 7 - 10 membered 50 selected from — Ar' , C1- 20 aliphatic , C1- 20 heteroaliphatic bicyclic saturated or partially unsaturated heterocyclic having 1 - 3 heteroatoms independently selected from ring having 1 - 5 heteroatoms independently selected nitrogen , oxygen , or sulfur, phenyl, a 3 - 7 membered from nitrogen , oxygen , or sulfur, or an 8 - 10 membered saturated or partially unsaturated carbocyclic ring , an bicyclic heteroaryl ring having 1 -5 heteroatoms inde 8 - 10 membered bicyclic saturated , partially unsaturated pendently selected from nitrogen , oxygen , or sulfur ; 55 or aryl ring, a 5 - 6 membered monocyclic heteroaryl ring each of R * , Rº, and R ? is independently halogen , - OR ' , having 1 - 4 heteroatoms independently selected from - N ( R ') , NR ' C ( O ) R ', - NR ' C ( O )OR ', - NRC ( O ) nitrogen , oxygen , or sulfur, a 4 - 7 membered saturated or N ( R ' ) 2 , — NR 'SO2R ', — NR ' SO N ( R ') 2 , — NR 'OR ', or partially unsaturated heterocyclic ring having 1 - 3 heteroa an optionally substituted group selected from C1- 20 toms independently selected from nitrogen , oxygen , or aliphatic , C1- 20 heteroaliphatic having 1- 3 heteroatoms 60 sulfur, a 7 - 10 membered bicyclic saturated or partially independently selected from nitrogen , oxygen , or sul unsaturated heterocyclic ring having 1 - 5 heteroatoms fur ; independently selected from nitrogen , oxygen , or sulfur, RS is halogen , — OR ", OR , — N (R ') 2 , — NR ' C (O ) R ', or an 8 - 14 membered bicyclic or tricyclic heteroaryl ring - NR ' C ( O )OR ', NR 'C ( O ) N ( R ') 2 , - NR 'SO R ', having 1 - 5 heteroatoms independently selected from - NR 'SO N ( R ') 2, or — NR 'OR ', or an optionally substi - 65 nitrogen , oxygen , or sulfur; and two R ’ are optionally tuted group selected from a 5 - 6 membered monocyclic taken together with the oxygen atoms they are bound to heteroaryl ring having at least one nitrogen and 0 - 3 form a bidentate ligand ; and US 9 , 850 , 268 B2 Ar' is of the following formula : oxygen , or sulfur, or an 8 - 10 membered bicyclic het eroaryl ring having 1 - 5 heteroatoms independently selected from nitrogen , oxygen , or sulfur ; each of R² and R3 is independently R ', - OR ', SR ', (R )} @ 5 — N ( R ') 2 , OC ( O ) R ', - SOR ', - SO , R ', SO , N ( R ' ) 2 , - C (O ) N (R ') 2 , — NR ' C (O ) R ', or — NR 'SO , R ', provided that R2 and R3 are not simultaneously hydrogen ; ( R ) R4 is R ?, or an optionally substituted group selected from - Ar, C1- 20 aliphatic , C1- 20 heteroaliphatic having 1 - 3 wherein : 10 heteroatoms independently selected from nitrogen , oxy tis 0 -4 ; gen , or sulfur, phenyl, a 3 - 7 membered saturated or p is 0 -6 ; partially unsaturated carbocyclic ring , an 8 - 10 membered each Ring B ' and Ring C ' is independently an optionally bicyclic saturated , partially unsaturated or aryl ring , a 5 - 6 substituted group selected from phenyl, a 3 - 7 mem membered monocyclic heteroaryl ring having 1 - 4 het bered saturated or partially unsaturated carbocyclic 15 eroatoms independently selected from nitrogen , oxygen , ring , an 8 - 10 membered bicyclic saturated , partially or sulfur, a 4 - 7 membered saturated or partially unsatu unsaturated or aryl ring, a 5 -6 membered monocyclic rated heterocyclic ring having 1 - 3 heteroatoms indepen heteroaryl ring having 1 - 4 heteroatoms independently dently selected from nitrogen , oxygen , or sulfur, a 7 - 10 selected from nitrogen , oxygen , or sulfur, a 4 - 7 mem bered saturated or partially unsaturated heterocyclic 20 membered bicyclic saturated or partially unsaturated het ring having 1 - 3 heteroatoms independently selected erocyclic ring having 1 - 5 heteroatoms independently from nitrogen , oxygen , or sulfur , a 7 - 10 membered selected from nitrogen , oxygen , or sulfur, or an 8 - 14 bicyclic saturated or partially unsaturated heterocyclic membered bicyclic or tricyclic heteroaryl ring having 1 - 5 ring having 1 - 5 heteroatoms independently selected heteroatoms independently selected from nitrogen , oxy from nitrogen , oxygen , or sulfur, or an 8 - 10 membered 25 gen , or sulfur; bicyclic heteroaryl ring having 1 - 5 heteroatoms inde . Ar is of the following formula : pendently selected from nitrogen , oxygen , or sulfur ; and each R $ is independently halogen , R ', _ OR ', SR ', mm - S (O )R ', - S (O )2R ', - OSI( R ') 3 , N (R ') 2 , NR ' R3, - @ R ) C ( O ) R ', NR C ( O ) OR ', - NR ' C ( O ) N ( R ') 2 , 30 - NR 'SO , R ', - NR 'SO , N ( R ') 2 , or — NR 'OR '. In some embodiments , a provided catalyst or metal com ( R ) plex is of formula II -b : 35 wherein : II - b m is 0 - 3 ; Ring B is an optionally substituted group selected from phenyl or a 5 - 6 membered monocyclic heteroaryl ring having 1 - 4 heteroatoms independently selected from = 40 nitrogen , oxygen , or sulfur ; RS - M p and q are independently 0 - 6 ; O- each of Ring C and Ring D is independently optionally substituted groups selected from phenyl , a 3 - 7 mem wherein : bered saturated or partially unsaturated carbocyclic R2' and R3' are taken together with their intervening metal 45 ring , an 8 - 10 membered bicyclic saturated , partially atom to form an optionally substituted 3 - 8 membered unsaturated or aryl ring , a 5 -6 membered monocyclic saturated or partially unsaturated ring having, in addition heteroaryl ring having 1 - 4 heteroatoms independently to the intervening metal atom , 0 - 4 heteroatoms indepen selected from nitrogen , oxygen , or sulfur, a 4 - 7 mem dently selected from nitrogen , oxygen , or sulfur ; and bered saturated or partially unsaturated heterocyclic each of the other variables is independently as defined and 50 ring having 1 - 3 heteroatoms independently selected described for formula II -a . from nitrogen , oxygen , or sulfur, a 7 - 10 membered In some embodiments , a provided catalyst or metal com bicyclic saturated or partially unsaturated heterocyclic plex is of formula II - b , wherein : ring having 1 - 5 heteroatoms independently selected M is molybdenum or tungsten ; from nitrogen , oxygen , or sulfur, or an 8 - 10 membered R is an optionally substituted group selected from C1- 20 55 bicyclic heteroaryl ring having 1 - 5 heteroatoms inde aliphatic , C1- 20 heteroaliphatic having 1 -3 heteroatoms pendently selected from nitrogen , oxygen , or sulfur ; independently selected from nitrogen , oxygen , or sulfur, each of R * , Ry , and R2 is independently halogen , OR , phenyl, a 3 - 7 membered saturated or partially unsaturated - N (R ') 2, - NR ' C ( O ) R ', - NR 'C (O )OR ', - NR ' C (O ) carbocyclic ring , an 8 - 10 membered bicyclic saturated , N ( R ') 2 , NR 'SO , R ', - NR 'SO , N (R ') 2 , - NR 'OR ', or partially unsaturated or aryl ring , a 5 -6 membered mono - 60 an optionally substituted group selected from C1- 20 cyclic heteroaryl ring having 1 - 4 heteroatoms indepen aliphatic , C1- 20 heteroaliphatic having 1 - 3 heteroatoms dently selected from nitrogen , oxygen , or sulfur, a 4 - 7 independently selected from nitrogen , oxygen , or sul membered saturated or partially unsaturated heterocyclic fur ; ring having 1 -3 heteroatoms independently selected from RS is halogen , OR , OR ? , N ( R ') 2, NR 'C ( O ) R ', nitrogen , oxygen , or sulfur, a 7 - 10 membered bicyclic 65 — NR' C ( O )OR ', - NR 'C ( O ) N ( R ') 2 , - NR ' SO2R ', saturated or partially unsaturated heterocyclic ring having — NR 'SO , N ( R ') 2 , or — NR 'OR ', or an optionally substi 1 -5 heteroatoms independently selected from nitrogen , tuted group selected from a 5 -6 membered monocyclic US 9 ,850 ,268 B2 10 heteroaryl ring having at least one nitrogen and 0 -3 Ar' is of the following formula : heteroatoms independently selected from nitrogen , oxy gen , or sulfur , a 4 - 7 membered saturated or partially unsaturated heterocyclic ring having at least one nitrogen mm and 0 - 2 heteroatoms independently selected from nitro - 5 (RºR ' ) ,p - f© gen , oxygen , or sulfur, a 7 - 10 membered bicyclic satu rated or partially unsaturated heterocyclic ring having at least one nitrogen and 0 - 4 heteroatoms independently ( R ) selected from nitrogen , oxygen , or sulfur, or an 8 - 10 membered bicyclic heteroaryl ring having at least one 10 nitrogen and 0 - 4 heteroatoms independently selected wherein : from nitrogen , oxygen , or sulfur ; t is 0 - 4 ; R® is an optionally substituted group selected from C1- 20 p is 0 -6 ; aliphatic , C1- 20 heteroaliphatic having 1 - 3 heteroatoms each Ring B ' and Ring C ' is independently an optionally independently selected from nitrogen , oxygen , or sulfur, 15 substituted group selected from phenyl, a 3 - 7 mem phenyl, a 3 - 7 membered saturated or partially unsaturated bered saturated or partially unsaturated carbocyclic carbocyclic ring , an 8 - 10 membered bicyclic saturated , ring , an 8 - 10 membered bicyclic saturated , partially partially unsaturated or aryl ring , a 5 - 6 membered mono unsaturated or aryl ring , a 5 - 6 membered monocyclic cyclic heteroaryl ring having 1 - 4 heteroatoms indepen heteroaryl ring having 1 - 4 heteroatoms independently dently selected from nitrogen , oxygen , or sulfur, a 4 - 7 20 selected from nitrogen , oxygen , or sulfur , a 4 - 7 mem membered saturated or partially unsaturated heterocyclic bered saturated or partially unsaturated heterocyclic ring having 1 - 3 heteroatoms independently selected from ring having 1 - 3 heteroatoms independently selected nitrogen , oxygen , or sulfur, a 7 - 10 membered bicyclic from nitrogen , oxygen , or sulfur, a 7 - 10 membered saturated or partially unsaturated heterocyclic ring having bicyclic saturated or partially unsaturated heterocyclic 1 - 5 heteroatoms independently selected from nitrogen , 25 ring having 1 -5 heteroatoms independently selected oxygen , or sulfur , or an 8 - 14 membered bicyclic or from nitrogen , oxygen , or sulfur, or an 8 -10 membered tricyclic heteroaryl ring having 1- 5 heteroatoms indepen bicyclic heteroaryl ring having 1 - 5 heteroatoms inde dently selected from nitrogen , oxygen , or sulfur , and pendently selected from nitrogen , oxygen , or sulfur ; each R ' is independently hydrogen or an optionally substi and each RS is independently halogen , R ', _ OR ', tuted group selected from C1- 6 aliphatic , phenyl, a 3 - 7 30 SR ', - S ( O ) R ', - S ( O ) 2R ', OSi( R ') 3 , — N ( R ') 2 , membered saturated or partially unsaturated carbocyclic - NR ' C ( O ) R ' , — NR ' C ( O )OR ', — NR ' C ( O ) N ( R ') 2 , ring , an 8 - 10 membered bicyclic saturated , partially - NR 'SO , R ', - NR 'SO N ( R ') 2 , or — NR 'OR '. unsaturated or aryl ring , a 5 - 6 membered monocyclic In some embodiments , a provided catalyst or metal com heteroaryl ring having 1 - 4 heteroatoms independently plex , such as a compound of formula II - a or II - b , is useful selected from nitrogen , oxygen , or sulfur, a 4 - 7 membered 35 for metathesis reactions . In some embodiments , a provided saturated or partially unsaturated heterocyclic ring having catalyst or metal complex , such as a compound of formula 1 - 3 heteroatoms independently selected from nitrogen , II - a or II- b , is useful for olefin metathesis . In some embodi oxygen , or sulfur, a 7 - 10 membered bicyclic saturated or ments , a provided catalyst or metal complex is useful for partially unsaturated heterocyclic ring having 1 - 5 heteroa enyne metathesis . toms independently selected from nitrogen , oxygen , or 40 In some embodiments , the present disclosure provides sulfur, or an 8 - 10 membered bicyclic heteroaryl ring methods for metathesis reactions . In some embodiments , the having 1 - 5 heteroatoms independently selected from present disclosure provides a method , comprising : nitrogen , oxygen , or sulfur, wherein : reacting a first species comprising an olefin with a second two R ' groups on the same nitrogen atom are optionally species comprising an olefin in the presence of a taken together with the nitrogen atom to form an option - 45 catalyst or metal complex to provide at least one ally substituted 3 - 8 membered , saturated , partially unsatu product comprising an olefin , wherein : rated , or aryl ring having 1 - 4 heteroatoms independently each carbon atom of the olefin in the first species is selected from nitrogen , oxygen , or sulfur ; and substituted with at least one halogen ; and each R7 is independently an optionally substituted group the olefin in the at least one product comprises a carbon selected from — Ar' , C1- 20 aliphatic , C1- 20 heteroaliphatic 50 atom from the first species and a carbon atom from the having 1 - 3 heteroatoms independently selected from second species . nitrogen , oxygen , or sulfur, phenyl , a 3 - 7 membered In some embodiments , the present disclosure provides a saturated or partially unsaturated carbocyclic ring , an method , comprising: 8 - 10 membered bicyclic saturated , partially unsaturated reacting a first species comprising an olefin with a second or aryl ring , a 5 - 6 membered monocyclic heteroaryl ring 55 species comprising an alkyne in the presence of a having 1 - 4 heteroatoms independently selected from catalyst or metal complex to provide at least one nitrogen , oxygen , or sulfur, a 4 - 7 membered saturated or product comprising an olefin , wherein : partially unsaturated heterocyclic ring having 1 - 3 heteroa each carbon atom of the olefin in the first species is toms independently selected from nitrogen , oxygen , or substituted with at least one halogen ; and sulfur, a 7 - 10 membered bicyclic saturated or partially 60 the olefin in the at least one product comprises a carbon unsaturated heterocyclic ring having 1 -5 heteroatoms atom from the first species and a carbon atom from the independently selected from nitrogen , oxygen , or sulfur, second species . or an 8 -14 membered bicyclic or tricyclic heteroaryl ring having 1 - 5 heteroatoms independently selected from 2 . Definitions nitrogen , oxygen , or sulfur; and two R ’ are optionally 65 taken together with the oxygen atoms they are bound to Compounds of the present disclosure include those form a bidentate ligand ; and described generally herein , and are further illustrated by the US 9 ,850 , 268 B2 12 classes, subclasses , and species disclosed herein . As used ( e . g . , C7 -C20 for straight chain , C2- C20 for branched chain ), herein , the following definitions shall apply unless otherwise and alternatively , about 1 - 10 . In some embodiments , a indicated . For purposes of this disclosure , the chemical cycloalkyl ring has from about 3 - 10 carbon atoms in their elements are identified in accordance with the Periodic Table ring structure where such rings are monocyclic or bicyclic , of the Elements , CAS version , Handbook of Chemistry and 5 and alternatively about 5 , 6 or 7 carbons in the ring structure . Physics, 75th Ed . Additionally , general principles of organic In some embodiments , an alkyl group may be a lower alkyl chemistry are described in " Organic Chemistry " , Thomas group , wherein a lower alkyl group comprises 1 - 4 carbon Sorrell , University Science Books, Sausalito : 1999, and atoms (e . g ., C , -C4 for straight chain lower alkyls ). “ March ' s Advanced Organic Chemistry ” , 5th Ed ., Ed .: As used herein , the term “ alkenyl ” refers to an alkyl Smith , M . B . and March , J . , John Wiley & Sons, New York : 10 group , as defined herein , having one or more double bonds . 2001, the entire contents of which are hereby incorporated As used herein , the term “ alkynyl” refers to an alkyl by reference . group , as defined herein , having one or more triple bonds . The term “ aliphatic ” or “ aliphatic group ” , as used herein , The term " heteroalkyl” is given its ordinary meaning in means a straight -chain ( i. e ., unbranched ) or branched , sub - the art and refers to alkyl groups as described herein in stituted or unsubstituted hydrocarbon chain that is com - 15 which one or more carbon atoms is replaced with a heteroa pletely saturated or that contains one or more units of tom ( e . g . , oxygen , nitrogen , sulfur, and the like ) . Examples unsaturation , or a monocyclic hydrocarbon , bicyclic hydro - of heteroalkyl groups include , but are not limited to , alkoxy , carbon , or tricyclic hydrocarbon that is completely saturated poly ( ethylene glycol) - , alkyl- substituted amino , tetrahydro or that contains one or more units of unsaturation , but which furanyl, piperidinyl, morpholinyl, etc . is not aromatic ( also referred to herein as “ carbocycle , " 20 The term " aryl” used alone or as part of a larger moiety " cycloaliphatic ” or “ cycloalkyl" ) , that has a single point of as in “ aralkyl, " " aralkoxy , ” or “ aryloxyalkyl, ” refers to attachment to the rest of the molecule . Unless otherwise monocyclic or bicyclic ring systems having a total of five to specified , aliphatic groups contain 1 - 30 aliphatic carbon fourteen ring members , wherein at least one ring in the atoms. In some embodiments , aliphatic groups contain 1 - 20 system is aromatic and wherein each ring in the system aliphatic carbon atoms. In other embodiments , aliphatic 25 contains 3 to 7 ring members . The term “ aryl” may be used groups contain 1 - 10 aliphatic carbon atoms. In still other interchangeably with the term “ aryl ring .” In certain embodi embodiments , aliphatic groups contain 1 - 5 aliphatic carbon ments of the present disclosure, " aryl ” refers to an aromatic atoms, and in yet other embodiments , aliphatic groups ring system which includes , but not limited to , phenyl, contain 1 , 2 , 3 , or 4 aliphatic carbon atoms. Suitable ali - biphenyl, naphthyl, binaphthyl, anthracyl and the like, phatic groups include , but are not limited to , linear or 30 which may bear one or more substituents . Also included branched , substituted or unsubstituted alkyl, alkenyl, alky - within the scope of the term “ aryl, " as it is used herein , is a nyl groups and hybrids thereof such as ( cycloalkyl) alkyl , group in which an aromatic ring is fused to one or more ( cycloalkenyl) alkyl or ( cycloalkyl) alkenyl . non - aromatic rings , such as indanyl, phthalimidyl , naph The term “ cycloaliphatic ,” as used herein , refers to satu thimidyl , phenanthridinyl, or tetrahydronaphthyl, and the rated or partially unsaturated cyclic aliphatic monocyclic , 35 like . bicyclic , or polycyclic ring systems, as described herein , The terms " heteroaryl” and “ heteroar -, ” used alone or as having from 3 to 14 members, wherein the aliphatic ring part of a larger moiety , e . g . , " heteroaralkyl, ” or “ het system is optionally substituted as defined above and eroaralkoxy, ” refer to groups having 5 to 10 ring atoms ( i. e . , described herein . Cycloaliphatic groups include , without monocyclic or bicyclic ) , in some embodiments 5 , 6 , 9 , or 10 limitation , cyclopropyl, cyclobutyl, cyclopentyl, cyclopen - 40 ring atoms. In some embodiments , such rings have 6 , 10 , or tenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclohepte 14 u electrons shared in a cyclic array ; and having , in nyl, cyclooctyl, cyclooctenyl, norbornyl, adamantyl, and addition to carbon atoms, from one to five heteroatoms. The cyclooctadienyl. In some embodiments , the cycloalkyl has term “ heteroatom ” refers to nitrogen , oxygen , or sulfur, and 3 - 6 carbons. The terms " cycloaliphatic ,” may also include includes any oxidized form of nitrogen or sulfur, and any aliphatic rings that are fused to one or more aromatic or 45 quaternized form of a basic nitrogen . Heteroaryl groups nonaromatic rings, such as decahydronaphthyl or tetrahy - include , without limitation , thienyl, furanyl, pyrrolyl, imi dronaphthyl, where the radical or point of attachment is on dazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, the aliphatic ring . In some embodiments , a carbocyclic oxadiazolyl, thiazolyl , isothiazolyl, thiadiazolyl, pyridyl, group is bicyclic . In some embodiments , a carbocyclic group pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, is tricyclic . In some embodiments, a carbocyclic group is 50 naphthyridinyl, and pteridinyl. In some embodiments , a polycyclic . In some embodiments, " cycloaliphatic ” (or " car - heteroaryl is a heterobiaryl group , such as bipyridyl and the bocycle ” or “ cycloalkyl" ) refers to a monocyclic Cz -Co like . The terms "heteroaryl ” and “ heteroar- " , as used herein , hydrocarbon , or a C8- C10 bicyclic hydrocarbon that is com also include groups in which a heteroaromatic ring is fused pletely saturated or that contains one or more units of to one or more aryl, cycloaliphatic , or heterocyclyl rings , unsaturation , but which is not aromatic , that has a single 55 where the radical or point of attachment is on the heteroaro point of attachment to the rest of the molecule, or a C . - C , 6 matic ring . Non - limiting examples include indolyl, isoindo tricyclic hydrocarbon that is completely saturated or that lyl, benzothienyl , benzofuranyl, dibenzofuranyl, indazolyl , contains one or more units of unsaturation , but which is not benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinno aromatic , that has a single point of attachment to the rest of linyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H - quinoliz the molecule . 60 inyl , carbazolyl, acridinyl , phenazinyl, phenothiazinyl, phe As used herein , the term “ alkyl” is given its ordinary noxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, meaning in the art and may include saturated aliphatic and pyrido [ 2 , 3 - b ] - 1 , 4 -oxazin - 3 (4H ) -one . A heteroaryl group groups, including straight- chain alkyl groups , branched may be mono - or bicyclic . The term " heteroaryl” may be chain alkyl groups, cycloalkyl ( alicyclic ) groups , alkyl sub - used interchangeably with the terms " heteroaryl ring, " " het stituted cycloalkyl groups, and cycloalkyl substituted alkyl 65 eroaryl group ,” or “ heteroaromatic , ” any of which terms groups . In certain embodiments , a straight chain or branched include rings that are optionally substituted . The term “ het chain alkyl has about 1 -20 carbon atoms in its backbone eroaralkyl ” refers to an alkyl group substituted by a het US 9 ,850 ,268 B2 13 14 eroaryl, wherein the alkyl and heteroaryl portions indepen - detection , and , in certain embodiments , their recovery, puri dently are optionally substituted . fication , and use for one or more of the purposes disclosed As used herein , the terms " heterocycle ," " heterocyclyn, ” herein . " heterocyclic radical, ” and “ heterocyclic ring” are used Suitable monovalent substituents on a substitutable car interchangeably and refer to a stable 5 - to 7 -membered 5 bon atom of an “ optionally substituted ” group are indepen monocyclic or 7 - 10 -membered bicyclic heterocyclic moiety dently halogen ; (CH ) 4Rº; - (CH , ) - OR " ; that is either saturated or partially unsaturated , and having , O (CH ) - Rº, 0 (CH ). C ( O )OR° ; (CH ) . ACH in addition to carbon atoms, one or more , preferably one to (OR ) 2 ; (CH2 ) -4Ph , which may be substituted with Rº; four, heteroatoms, as defined above . When used in reference (CH , ) . . O (CH2 ) , Ph which may be substituted with Rº; to a ring atom of a heterocycle , the term “ nitrogen ” includes 10 CH = CHPh , which may be substituted with Rº ; a substituted nitrogen . As an example , in a saturated or (CH ) 0 -40 ( CH2) -1 -pyridyl which may be substituted partially unsaturated ring having 0 - 3 heteroatoms selected with Rº; — NO2; CN ; — N3 ; (CH2 ) - - N ( Rºz; from oxygen , sulfur or nitrogen , the nitrogen may be N (as (CH2 ) -4N (Rº ) C ( O ) Rº; — N (Rº ) C ( S ) Rº ; — ( CH2) - 4N in 3 ,4 -dihydro - 2H -pyrrolyl ) , NH (as in pyrrolidinyl) , or +NR (Rº )C ( O ) NRºz ; - N (Rº ) C (S )NR°2 ; (CH2 ) -4N (Rº ) C (O A ) ( as in N -substituted pyrrolidinyl ) . 15 OR°; - N (RºN ( R ) C ( O ) Rº ; — N (RºN (Rº ) C ( O )NR 2 ; A heterocyclic ring can be attached to its pendant group - N ( Rº) N ( R ) C ( O )OR° ; ( CH2) .- 4C ( O )Rº ; C ( S )Rº ; at any heteroatom or carbon atom that results in a stable (CH20 - 4C (O )OR° ; ( CH2) -4C (O )SR° ; (CH2 ) -4C structure and any of the ring atoms can be optionally ( O ) OSiRºz; - ( CH2) - 4C ( O )Rº ; OC ( O ) (CH2 ) . - 4SR — , substituted . Examples of such saturated or partially unsatu - SC ( S )SR° ; (CH2 ) . -4SC ( O ) Rº ; (CH2 ) - 4C ( O )NR°2 ; rated heterocyclic radicals include, without limitation , tet - 20 C (S )NRºz ; - C (S )SR° ; - SC ( S ) SR°, - (CH2 ) -40C (O ) rahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, NR°2 ; C (O )N (OR )Rº ; C (O ) C (O )Rº ; - C (O )CH C pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, (O )Rº ; C (NOR )Rº ; (CH2 ) .- 4SSR° ; ( CH2) - 4 decahydroquinolinyl, oxazolidinyl , piperazinyl, dioxanyl, S (O ), Rº ; (CH20 - 4S ( O )2OR° ; ( CH2) 0 - 40S ( O ) ,Rº ; dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholi - - S (O )2NR°2 ; (CH2 ) -4S (O )Rº ; — N (Rº ) S ( O ) 2NR°2; nyl, and quinuclidinyl. The terms " heterocycle ," " heterocy - 25 N ( RO ) S ( O ) Rº; - N (OR ) R°; C ( NH )NR°2 ; cly1, " " heterocyclyl ring, " " heterocyclic group , " " heterocy - P (O ) Rº; — P (O )Rºz ; OP ( O )Rºz ; OP (O ) (OR ) 2 ; clic moiety ," and " heterocyclic radical, ” are used — SiR ; - OSiRº ; ( C - 4 straight or branched alkylene ) interchangeably herein , and also include groups in which a O N (Rº ) 2; or (C1 - 4 straight or branched alkylene )C (O ) heterocyclyl ring is fused to one or more aryl, heteroaryl, or 0 N ( R ) , wherein each Rº may be substituted as defined cycloaliphatic rings, such as indolinyl, 3H - indolyl, chroma- 30 below and is independently hydrogen , C1- 6 aliphatic , nyl, phenanthridinyl, or tetrahydroquinolinyl . A heterocyclyl CH Ph , - O (CH2 ) - Ph , CH2- ( 5 - 6 membered het group may be mono - or bicyclic . The term " heterocyclylal- eroaryl ring ) , or a 5 - 6 -membered saturated , partially unsatu kyl” refers to an alkyl group substituted by a heterocyclyl, rated , or aryl ring having 0 - 4 heteroatoms independently wherein the alkyl and heterocyclyl portions independently selected from nitrogen , oxygen , or sulfur, or, notwithstand are optionally substituted . 35 ing the definition above , two independent occurrences of Rº, As used herein , the term “ partially unsaturated ” refers to taken together with their intervening atom ( s ) , form a 3 - 12 a ring moiety that includes at least one double or triple bond membered saturated , partially unsaturated , or arylmono - or The term " partially unsaturated ” is intended to encompass bicyclic ring having 0 - 4 heteroatoms independently selected rings having multiple sites of unsaturation , but is not from nitrogen , oxygen , or sulfur, which may be substituted intended to include aryl or heteroaryl moieties, as herein 40 as defined below . defined . Suitable monovalent substituents on Rº (or the ring The term " heteroatom ” means one or more of oxygen , formed by taking two independent occurrences of Rº sulfur, nitrogen , phosphorus, or silicon ( including , any oxi- together with their intervening atoms) , are independently dized form of nitrogen , sulfur, phosphorus , or silicon ; the halogen , ( CH2) - 2R , - (haloR ) , (CH2 ) 2 -20H , quaternized form of any basic nitrogen or ; a substitutable 45 ( CH2) -20R , - ( CH2) -2CH (OR ) 2; - O (haloR ), CN , nitrogen of a heterocyclic ring , for example N (as in 3 , 4 - N3, ( CH2) .- 2C ( O ) R , (CH2 ) . -2C ( O )OH , dihydro -2H -pyrrolyl ) , NH ( as in pyrrolidinyl) or NR * ( as in ( CH2) -2C ( O )OR , ( CH2) - 2SR , (CH2 ) o - 2SH , N - substituted pyrrolidinyl) ) . (CH2 ) - 2NH2, (CH2 ) o -2NHR , (CH2 ) 2 - 2NR 2 , The term “ unsaturated ,” as used herein , means that a — NO , — SiRz, OSiRz, - C (O ) SR , ( C , 4 straight or moiety has one or more units of unsaturation . 50 branched alkylene ) C ( O )OR ', or — SSR ' wherein each R ' is The term “ halogen ” means F , C1, Br, or I . unsubstituted or where preceded by “ halo ” is substituted As described herein , compounds of the disclosure may only with one or more halogens, and is independently contain " optionally substituted ” moieties . In general, the selected from C1- 4 aliphatic , CH , Ph , O ( CH2) .- Ph , or a term “ substituted ,” whether preceded by the term “ option 5 -6 -membered saturated , partially unsaturated , or aryl ring ally ” or not, means that one or more hydrogens of the 55 having 0 - 4 heteroatoms independently selected from nitro designated moiety are replaced with a suitable substituent. gen , oxygen , or sulfur . Suitable divalent substituents on a Unless otherwise indicated , an " optionally substituted ” saturated carbon atom of Rº include = 0 and — S . group may have a suitable substituent at each substitutable Suitable divalent substituents on a saturated carbon atom position of the group , and when more than one position in of an " optionally substituted ” group include the following : any given structure may be substituted with more than one 60 = O , = S , = NNR * 2, = NNHC ( O ) R * , = NNHC (O )OR * , substituent selected from a specified group , the substituent = NNHS (O ), R * , NR * , = NOR * , O (C (R * )) 2 -30 , or may be either the same or different at every position . S ( C ( R * _ ) ) 2 -35 % , wherein each independent occurrence Combinations of substituents envisioned by this disclosure of R * is selected from hydrogen , C - , aliphatic which may are preferably those that result in the formation of stable or be substituted as defined below , or an unsubstituted 5 - 6 chemically feasible compounds. The term “ stable , ” as used 65 membered saturated , partially unsaturated , or aryl ring hav herein , refers to compounds that are not substantially altered ing 0 - 4 heteroatoms independently selected from nitrogen , when subjected to conditions to allow for their production , oxygen , or sulfur. Suitable divalent substituents that are US 9 , 850 , 268 B2 15 16 bound to vicinal substitutable carbons of an “ optionally either an ( R ) enantiomer or an ( S ) enantiomer. Typically, substituted ” group include : - O (CR * , )2206 , wherein each chiral molecules lack a plane of symmetry . independent occurrence of R * is selected from hydrogen , The term “ achiral” is given its ordinary meaning in the art C V aliphatic which may be substituted as defined below , or and refers to a molecule that is superimposable with its an unsubstituted 5 - 6 -membered saturated , partially unsatu - 5 mirror image . Typically , achiralmolecules possess a plane of rated , or aryl ring having 0 -4 heteroatoms independently symmetry . selected from nitrogen , oxygen , or sulfur. As used herein , a ligand may be either monodentate or Suitable substituents on the aliphatic group of R * include polydentate . In some embodiments, a ligand is monodentate . In some embodiments , a ligand is bidentate . In some halogen , — R , -( haloR ), OH , OR , O (haloR )" , 10 embodiments , a ligand is tridentate . In some embodiments , CN , - C ( O ) OH , C ( O )OR " , - NH2, — NHR , - NR 2 , two or more monodentate ligands are taken together to form or — NO2, wherein each R * is unsubstituted or where pre a polydentate ligand . A ligand may have hapticity of more ceded by “ halo ” is substituted only with one or more than one . In some cases, a ligand has a hapticity of 1 to 10 . halogens, and is independently C1- 4 aliphatic , CH Ph , In some embodiments , a ligand has a hapticity of 1 . In some - O (CH2 ) , Ph , or a 5 -6 -membered saturated , partially 15 embodiments . a ligand has a hapticity of 2 . In some embodi unsaturated , or aryl ring having 0 - 4 heteroatoms indepen ments , a ligand has a hapticity of 3 . In some embodiments , dently selected from nitrogen , oxygen , or sulfur. a ligand has a hapticity of 4 . In some embodiments , a ligand Suitable substituents on a substitutable nitrogen of an has a hapticity of 5 . In some embodiments , a ligand has a " optionally substituted ” group include — R " , — NR " 2 , hapticity of 6 . For a ligand having hapticity greater than one , - C (O ) R ", - C ( O )OR ", C ( O ) C ( O )R " , - C (O )CH C (O ) 20 as sometimes done in the art, a single bond may be drawn R * , - S ( O ) R , - S (O )2NR * 2, C (S )NR * 2, C (NH )NR * 2 between the ligand and the metal. In some cases, a ligand is or — N ( R " ) S ( O ) 2R " ; wherein each R * is independently alkylidene . In some cases, a ligand is a nitrogen - containing hydrogen , C1- 6 aliphatic which may be substituted as defined ligand . In some cases , a ligand is an oxygen -containing below , unsubstituted — OPh , or an unsubstituted 5 - 6 -mem - ligand . In some cases, a ligand is a phosphorus - containing bered saturated , partially unsaturated , or aryl ring having 0 - 4 25 ligand . In some embodiments, a ligand comprises an unsatu heteroatoms independently selected from nitrogen , oxygen , rated bond , and the unsaturated bond is coordinated to a or sulfur, or, notwithstanding the definition above , two metal . In some embodiments , a ligand comprises a carbon independent occurrences of R , taken together with their carbon double bond , and the double bond is coordinated to intervening atom ( s ) form an unsubstituted 3 - 12 -membered a metal. In some embodiments , a ligand is an olefin . When saturated , partially unsaturated , or aryl mono - or bicyclic 30 an olefin double bond is coordinated to a metal , the chemical ring having 0 - 4 heteroatoms independently selected from bonding between the olefin and the metal can either be nitrogen , oxygen , or sulfur. depicted as a 3 -membered ring wherein the ring members Suitable substituents on the aliphatic group of R * are comprises the metal and both carbon atoms of the double independently halogen , — R , - (haloR ) , OH , OR , bond , or as a single bond between the metal and the double - O (haloR ), CN , - C (O )OH , C (O )OR , — NH2, 35 bond . - NHR , - NR 2 , or — NO , , wherein each R * is unsubsti - As used herein , a “ nitrogen - containing ligand ” may be tuted or where preceded by “ halo ” is substituted only with any species comprising a nitrogen atom . In some cases, the one or more halogens, and is independently C1- 4 aliphatic , nitrogen atom may bind to the metal atom . In some cases , - CH , Ph , O (CH , ) - Ph , or a 5 - 6 -membered saturated , the nitrogen - containing ligand may bind the metal center via partially unsaturated , or aryl ring having 0 -4 heteroatoms 40 a different atom . In some cases, the nitrogen atom may be a independently selected from nitrogen , oxygen , or sulfur. ring atom of a heteroaryl or heteroalkyl group . In some As used herein , the term " stereogenic metal atom " is cases, the nitrogen atom may be a substituted amine group . given its ordinary meaning, and refers to a metal atom It should be understood that , in catalyst precursors described coordinated by at least two ligands ( e . g . , at least four herein , the nitrogen - containing ligand may have sufficiently ligands ) , wherein the ligands are arranged about the metal 45 ionic character to coordinate a metal center , such as a Mo or atom such that the overall structure ( e . g . , metal complex ) W metal center. Examples of nitrogen - containing ligands lacks a plane of symmetry with respect to themetal atom . In include , but are not limited to , pyrrolyl, pyrazolyl , pyridinyl , some cases, the stereogenic metal atom may be coordinated pyrazinyl, pyrimidinyl, imidazolyl, triazolyl, tetrazolyl, by at least three ligands, at least four ligands, at least five oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, indolyl, inda ligands, at least six ligands , or more . In certain embodi- 50 zolyl, carbazolyl, morpholinyl, piperidinyl, oxazinyl, sub ments , the stereogenic metal atom may be coordinated by stituted derivatives thereof , and the like . For example, the four ligands . Metal complexes comprising a stereogenic nitrogen - containing ligand may be pyrrolide or 2 , 5 - dimeth metal center may provide sufficient space specificity at a ylpyrrolide . The nitrogen - containing ligand may be selected reaction site of the metal complex , such that a molecular to interact with an oxygen - containing ligand such that the substrate having a plane of symmetry may be reacted at the 55 oxygen - containing ligand can readily replace the nitrogen reaction site to form a product that is free of a plane of containing ligand in a precatalyst to generate a catalyst. In symmetry . That is , the stereogenic metal center of the metal cases where the catalyst composition may be generated in complex may impart sufficient shape specificity to induce situ in order to carry out a chemical reaction , the first, stereogenicity effectively , producing a chiral product. Such nitrogen -containing ligand may be selected such that , upon metal complexes may exhibit improved catalytic activity 60 replacement by an oxygen - containing ligand , the nitrogen and stereoselectivity, relative to previous systems, and may containing ligands or protonated versions thereof do not reduce undesired side reactions ( e . g ., dimerization or oli - interfere with the chemical reaction . In some embodiments , gomerization of the metal complex ) . the nitrogen - containing ligand may be chiral and the pre The term “ chiral” is given its ordinary meaning in the art catalyst may be provided as a racemic mixture or a purified and refers to a molecule that is not superimposable with its 65 stereoisomer . mirror image , wherein the resulting nonsuperimposable mir - In some embodiments, a nitrogen - containing ligand may ror images are known as " enantiomers ” and are labeled as also describe a ligand precursor comprising at least one US 9 , 850 , 268 B2 18 hydrogen atom directly bonded to a nitrogen atom , wherein of aldehydes and ketones, respectively . A “ Si protecting deprotonation of the at least one hydrogen atom results in a group ” is a protecting group comprising a Si atom , such as negatively charged nitrogen atom , which may coordinate to Si- trialkyl ( e . g . , trimethylsilyl, tributylsilyl, t - butyldimeth a metal atom . Exemplary such precursors include but are not ylsilyl) , Si- triaryl, Si- alkyl- diphenyl ( e . g ., t- butyldiphenyl limited to amines , amides, and pyrrole and its derivatives 5 silyl) , or Si- aryl- dialkyl ( e . g . , Si- phenyldialkyl ) . Generally , thereof. A nitrogen -containing ligand may be a heteroaryl or a Si protecting group is attached to an oxygen atom . The heteroalkyl group comprising at least one nitrogen ring field of protecting group chemistry has been reviewed atom . In some cases , the nitrogen atom may be positioned on (Greene , T . W . ; Wuts , P . G . M . Protective Groups in Organic a substituent of an alkyl, heteroalkyl, aryl, or heteroaryl Synthesis , 2nd ed .; Wiley : New York , 1991 ) . Such protect group . For example , a nitrogen - containing ligand may be an 10 ing groups ( and associated protected moieties ) are described amine - or amide - substituted aryl group , wherein the amine in detail below . or amide group is deprotonated upon coordination to the Protected hydroxyl groups are well known in the art and metal center. include those described in detail in Protecting Groups in As used herein , the term " oxygen - containing ligand ” may Organic Synthesis , T . W . Greene and P . G . M . Wuts , 3rd be used to refer to ligands comprising at least one oxygen 15 edition , John Wiley & Sons , 1999, the entirety of which is atom . In some cases, the oxygen atom binds to the metal incorporated herein by reference . Examples of suitably atom thereby forming an ether -linkage . In other cases, the protected hydroxyl groups further include, but are not lim oxygen - containing ligand may bind the metal center via a ited to , esters , carbonates, sulfonates , allyl ethers , ethers , different atom . The term " oxygen - containing ligand ” may silyl ethers , alkyl ethers , arylalkyl ethers , and alkoxyalkyl also describe ligand precursors comprising at least one 20 ethers. Examples of suitable esters include formates , hydroxyl group ( e . g . , a hydroxyl- containing ligand ) , acetates, proprionates, pentanoates, crotonates, and benzo wherein deprotonation of the hydroxyl group results in a ates. Specific examples of suitable esters include formate , negatively charged oxygen atom , which may coordinate to a benzoyl formate , chloroacetate , trifluoroacetate , methoxy metal atom . The oxygen - containing ligand may be a het - acetate , triphenylmethoxyacetate, p - chlorophenoxyacetate , eroaryl or heteroalkyl group comprising at least one oxygen 25 3 -phenylpropionate , 4 - oxopentanoate , 4 , 4 - ( ethylenedithio ) ring atom . In some cases , the oxygen atom may be posi- pentanoate , pivaloate ( trimethylacetate ) , crotonate , tioned on a substituent of an alkyl, heteroalkyl, aryl , or 4 -methoxy - crotonate , benzoate, p -benzylbenzoate , 2 , 4 , 6 heteroaryl group . For example, the oxygen - containing trimethylbenzoate . Examples of suitable carbonates include ligand may be a hydroxy - substituted aryl group , wherein the 9 - fluorenylmethyl, ethyl , 2 , 2 , 2 - trichloroethyl, 2 - ( trimethyl hydroxyl group is deprotonated upon coordination to the 30 silyl) ethyl , 2 - (phenylsulfonyl ) ethyl, vinyl , allyl, and p - ni metal center. trobenzyl carbonate . Examples of suitable silyl ethers In some embodiments , an oxygen - containing ligand may include trimethylsilyl, triethylsilyl, t - butyldimethylsilyl, also describe a ligand precursor comprising at least one t- butyldiphenylsilyl, triisopropylsilyl ether, and other tri hydroxyl group ( e . g ., a hydroxyl- containing ligand ) , alkylsilyl ethers . Examples of suitable alkyl ethers include wherein deprotonation of the hydroxyl group results in a 35 methyl, benzyl , p -methoxybenzyl , 3 , 4 -dimethoxybenzyl , tri negatively charged oxygen atom , which may coordinate to a tyl , t -butyl , and allyl ether, or derivatives thereof. Alkoxy metal atom . An oxygen - containing ligand may be a het alkyl ethers include acetals such as methoxymethyl, meth eroaryl or heteroalkyl group comprising at least one oxygen ylthiomethyl, ( 2 -methoxyethoxy )methyl , benzyloxymethyl, ring atom . In some cases, the oxygen atom may be posi beta - ( trimethylsilyl ) ethoxymethyl, and tetrahydropyran - 2 - yl tioned on a substituent of an alkyl , heteroalkyl, aryl, or 40 ether . Examples of suitable arylalkyl ethers include benzyl, heteroaryl group . For example , an oxygen - containing ligand p -methoxybenzyl (MPM ), 3 , 4 - dimethoxybenzyl , O - ni may be a hydroxy - substituted aryl group , wherein the trobenzyl, p - nitrobenzyl, p -halobenzyl , 2 , 6 - dichlorobenzyl , hydroxyl group is deprotonated upon coordination to the p -cyanobenzyl , 2 - and 4 - picolyl ethers . metal center. In some embodiments , an oxygen - containing Protected amines are well known in the art and include ligand is a neutral ligand . 45 those described in detail in Greene ( 1999 ) . Suitable mono As used herein , the term " phosphorus - containing ligand” protected amines further include , but are not limited to , may be used to refer to ligands comprising at least one aralkylamines , carbamates, allyl amines, amides, and the phosphorus atom . In some cases, the phosphorus atom binds like . Examples of suitable mono - protected amino moieties to the metal . In other cases , the phosphorus - containing include t -butyloxycarbonylamino NHBOC ) , ethyloxy ligand may bind to themetal center via a different atom (i . e ., 50 carbonylamino , methyloxycarbonylamino , trichloroethyl an atom other than the phosphorous) . The phosphorus - oxycarbonylamino , allyloxycarbonylamino ANHAlloc ) , containing ligand may have phosphorus atom of various benzyloxocarbonylamino ( NHCBZ ), allylamino , benzy oxidation states . In some cases the phosphorus- containing lamino ( NHBn ), fluorenylmethylcarbonyl ( NHFmoc ), ligand is phosphine . In some cases the phosphorus -contain formamido , acetamido , chloroacetamido , dichloroacet ing ligand is phosphite . In some cases the phosphorus- 55 amido , trichloroacetamido , phenylacetamido , trifluoroacet containing ligand is phosphate . The phosphorus- containing amido , benzamido, t- butyldiphenylsilyl , and the like . Suit ligand may be either monodentate or polydentate . In some able di- protected amines include amines that are substituted cases , two or more phosphorus atoms bind to the metal . In with two substituents independently selected from those some cases , one or more phosphorus atoms together with described above as mono - protected amines , and further one or more non - phosphorus atoms bind to the metal. In 60 include cyclic imides , such as phthalimide, maleimide , some embodiments , a phosphorus - containing ligand is a succinimide, and the like . Suitable di- protected amines also neutral ligand . include pyrroles and the like , 2 ,2 , 5 ,5 - tetramethyl- [ 1 , 2 , 5 ] The phrase " protecting group ," as used herein , refers to azadisilolidine and the like , and azide . temporary substituents which protect a potentially reactive Protected aldehydes are well known in the art and include functional group from undesired chemical transformations . 65 those described in detail in Greene (1999 ) . Suitable pro Examples of such protecting groups include esters of car - tected aldehydes further include , but are not limited to , boxylic acids, silyl ethers of alcohols , and acetals and ketals acyclic acetals , cyclic acetals , hydrazones, imines, and the US 9 ,850 , 268 B2 19 20 like. Examples of such groups include dimethyl acetal , electron -withdrawing group is — I . In some embodiments , diethyl acetal, diisopropyl acetal , dibenzyl acetal, bis ( 2 - hydrogen is used as reference and regarded as having no nitrobenzyl) acetal, 1, 3 -dioxanes , 1 ,3 -dioxolanes , semicar effect . bazones, and derivatives thereof. As used herein and in the claims, the singular forms “ a ” , Protected carboxylic acids are well known in the art and 5 " an ” , and “ the ” include the plural reference unless the include those described in detail in Greene ( 1999 ). Suitable context clearly indicates otherwise . Thus, for example , a protected carboxylic acids further include, but are not lim - reference to " a compound ” includes a plurality of such ited to , optionally substituted C - aliphatic esters , optionally compounds. substituted aryl esters, silyl esters , activated esters , amides, hydrazides , and the like. Examples of such ester groups 3 . Description of Certain Embodiments of the include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, Invention benzyl, and phenyl ester, wherein each group is optionally In some embodiments , M is molybdenum . In some substituted . Additional suitable protected carboxylic acids embodiments , M is tungsten . include oxazolines and ortho esters . 15 As defined generally above, Rl is an optionally substi Protected thiols are well known in the art and include tuted group selected from C a liphatic . C . heteroali those described in detail in Greene (1999 ) . Suitable pro phatic , phenyl, a 3 - 7 membered saturated or partially unsatu tected thiols further include, but are not limited to , disul rated carbocyclic ring, an 8 -10 membered bicyclic saturated , fides , thioethers , silyl thioethers , thioesters , thiocarbonates, partially unsaturated or aryl ring , a 5 -6 membered monocy and thiocarbamates , and the like . Examples of such groups 20 clic heteroaryl ring having 1 - 4 heteroatoms independently include , but are not limited to , alkyl thioethers , benzyl and selected from nitrogen , oxygen , or sulfur, a 3 - 7 membered substituted benzyl thioethers, triphenylmethyl thioethers, saturated or partially unsaturated heterocyclic ring having and trichloroethoxycarbonyl thioester, to name but a few . 1 - 3 heteroatoms independently selected from nitrogen , oxy Unless otherwise stated , structures depicted herein are gen , or sulfur, a 7 - 10 membered bicyclic saturated or par also meant to include all isomeric (e . g ., enantiomeric , diaste - 25 tially unsaturated heterocyclic ring having 1 - 5 heteroatoms reomeric , and geometric (or conformational) ) forms of the independently selected from nitrogen , oxygen , or sulfur, or structure ; for example , the R and S configurations for each an 8 - 10 membered bicyclic heteroaryl ring having 1 - 5 asymmetric center , ( Z ) and ( E ) double bond isomers , and ( Z ) heteroatoms independently selected from nitrogen , oxygen , and ( E ) conformational isomers . Therefore , single stereo or sulfur; or R is optionally substituted chemical isomers as well as enantiomeric , diastereomeric , and geometric (or conformational) mixtures of the present compounds are within the scope of the disclosure . ( R ) Unless otherwise stated , all tautomeric forms of the compounds of the disclosure are within the scope of the 2 disclosure . Additionally , unless otherwise stated , structures depicted In some embodiments . Rl is an optionally substituted group herein are also meant to include compounds that differ only selected from C , aliphatic , C , heteroaliphatic , phenyl, in the presence of one or more isotopically enriched atoms. a 3 -7 membered saturated or partially unsaturated carbocy For example , compounds having the present structures 40 clic ring , an 8 - 10 membered bicyclic saturated , partially except for the replacement of hydrogen by deuterium or unsaturated or aryl ring , a 5 - 6 membered monocyclic het tritium , or the replacement of a carbon by a ' C - or 13C - or eroaryl ring having 1- 4 heteroatoms independently selected 14C - enriched carbon are within the scope of this disclosure . from nitrogen , oxygen , or sulfur, a 3 - 7 membered saturated Such compounds are useful , for example , as analytical tools or partially unsaturated heterocyclic ring having 1 -3 het or probes in biological assays . 45 eroatoms independently selected from nitrogen , oxygen , or As used herein , the term " electron -withdrawing group ” is sulfur , a 7 - 10 membered bicyclic saturated or partially given its ordinary meaning in the art and refers to an atom unsaturated heterocyclic ring having 1 - 5 heteroatoms inde or group that draws electron density from a neighboring pendently selected from nitrogen , oxygen , or sulfur , or an atom or group , usually by resonance and/ or inductive 8 - 10 membered bicyclic heteroaryl ring having 1 - 5 heteroa effects. In some embodiments, an electron -withdrawing 50 toms independently selected from nitrogen , oxygen , or sul group withdraws electron density from an aromatic ring fur ; or R is optionally substituted system by resonance and /or inductive effects . In some embodiments , an electron -withdrawing group withdraws electron density from an aromatic ring system by resonance ( R %} p and inductive effects . In some embodiments , an electron - 55 withdrawing group lowers the electron density of an aro matic ring system such as phenyl. Exemplary electron withdrawing groups are extensively described in the art , including but not limited to halogen , carbonylmoieties ( e . g ., wherein each R ' is independently an electron - withdrawing aldehyde and ketone groups ) , COOH and its derivatives 60 group . In some embodiments , R ' is an optionally substituted ( e . g . , ester and amide moieties ) , protonated amines , quater - group selected from C1. 90 aliphatic , C1. 20 heteroaliphatic , nary ammonium groups, CN , - NO2, - S ( O ) - , and phenyl, a 3 - 7 membered saturated or partially unsaturated - S ( O )2 — . In some embodiments , an electron -withdrawing carbocyclic ring , an 8 - 10 membered bicyclic saturated , group is halogen . In some embodiments , an electron -with - partially unsaturated or aryl ring , a 5 -6 membered monocy drawing group is F . In some embodiments , an electron - 65 clic heteroaryl ring having 1- 4 heteroatoms independently withdrawing group is C1. In some embodiments , an elec - selected from nitrogen , oxygen , or sulfur, a 3 - 7 membered tron - withdrawing group is Br. In some embodiments , an saturated or partially unsaturated heterocyclic ring having US 9 , 850 , 268 B2 21 22 1 - 3 heteroatoms independently selected from nitrogen , oxy - phenyl or C6F5 . In some embodiments , R ' is substituted gen , or sulfur, a 7 - 10 membered bicyclic saturated or par - phenyl, wherein at least one substituent is an electron tially unsaturated heterocyclic ring having 1 - 5 heteroatoms independently selected from nitrogen , oxygen , or sulfur, or withdrawing group . In some embodiments, R ' is substituted an 8 - 10 membered bicyclic heteroaryl ring having 1 - 5 5 with at least one R ' group . In some embodiments , a sub heteroatoms independently selected from nitrogen , oxygen , stituent is a small group such as halogen . In some embodi or sulfur. In some embodiments , R ' is optionally substituted ments , each substituent at the 2 ' and 6 - positions, if any , is a small group such as halogen . 10 In some embodiments , Rl is R ', wherein R ' is not hydro gen . 4 In some embodiments , R is optionally substituted wherein each R ' is independently an electron -withdrawing 15 group . In some embodiments , R ' is an optionally substituted

w

20 In some embodiments , Rl is wherein each R ' is independently an electron -withdrawing group , and wherein each = CH - of the depicted phenyl 25 w ring , if any, is independent optionally substituted . In some embodiments , R ' is optionally substituted C1- 20 aliphatic . In some embodiments , R is optionally substituted C1- 20 cycloaliphatic . In some embodiments , R is optionally substituted C1- 12 aliphatic . In some embodiments, Rl is 30 In some embodiments , Rl is optionally substituted C1. 19 cycloaliphatic . In some embodi ments , R ' is optionally substituted C1- 12 cycloalkyl. In some embodiments , R is optionally substituted adamantyl . In some embodiments , R ' is adamantyl. In some embodiments , Rl is optionally substituted C - aliphatic . In some embodi- 35 ments , R is optionally substituted C1- 6 alkyl . In some RY, RYCY R ", embodiments , R is optionally substituted hexyl, pentyl, butyl, propyl, ethyl or methyl. In some embodiments , R ' is min min optionally substituted hexyl. In some embodiments , R ' is optionally substituted pentyl. In some embodiments , R ' is 40 Ry optionally substituted butyl. In some embodiments , Rl is optionally substituted propyl. In some embodiments , Rl is RY RY RV optionally substituted ethyl. In some embodiments, R ' is optionally substituted methyl. In some embodiments , R ' is hexyl. In some embodiments , R ' is pentyl. In some embodi- 45 ments , R is butyl. In some embodiments , R ' is propyl . In some embodiments , Rl is ethyl. In some embodiments , Rl is nun mi mun methyl. In some embodiments , R is isopropyl. In certain embodiments , Rl is optionally substituted phe R? nyl. In some embodiments , R is substituted phenyl. In some 50 embodiments , Rl is mono -, di- , tri- , tetra - or penta - substi RRY tuted phenyl. In some embodiments, Rl is mono -substituted phenyl. In certain embodiments , R is 2 ,6 - disubstituted phenyl. In some embodiments , R ' is tri - substituted phenyl. , Ry Y RY, RYO Y In some embodiments , Rl is tetra - substituted phenyl. In 55 some embodiments, R ' is penta -substituted phenyl. In some nu w embodiments , a substituent is a halogen . In some embodi ments , a substituent is F , and Rl is phenyl substituted with RY one or more — F . In some embodiments , R ' is pentafluoro phenyl. In some embodiments , a substituent is optionally 60 RRY substituted C - 4 aliphatic . In some embodiments , R ' is phe nyl disubstituted with halogen or C , a aliphatic . Such R1 groups include but are not limited to 2 ,6 -dichlorophenyl , RY. 2 , 6 -dibromophenyl , 2 ,6 -dimethylphenyl , 2 , 6 -di - tert- butyl phenyl, and 2 ,6 -diisopropylphenyl . In some embodiments , 65 min M R ! is not 2 , 6 - dichlorophenyl. In some embodiments , R is not — C6F5. In some embodiments , R is not 2 ,6 - dichloro US 9 , 850 ,268 B2 23 450. 68 3 24 -continued 3. - continued R R R R

5

1 , Rya R , RY 1 de

10 ??| R In some embodiments , Rl is other than R R

R , or Ry "

d don CCI andand CF .

M 20 In some embodiments , at least one R ’ is halogen or — CF3. In some embodiments , at least one R is — F . In some In some embodiments . Rl is other than embodiments , at least one R is CFs . In some embodi ments , each R? ' is F . In some embodiments , R ' is other?? 25 than | i ci , and CF . 30 | 30 or

01 SCI, F1 35 In some embodiments , R ' is other than vid Wii We FF ? Br Br CH

CI , Br Br , Pri - i - Pr , Br BT,

de WAN dr d

CF3

and CFG.

dr

dvar don

In some embodiments , R1 is other than

F. ??IF F 60

FY FF and CF3. CI , F 7 SF, and Mee Me ??Home 65 US 9 , 850 , 268 B2 25 26 In some embodiments , Rl is other than 15930 -continued Br CH

, H3C Y tButBu , wi nim i - Pr Y i - Pr, Br Y Br,

win 10

F 2?? F CF3, F Y

mun wi mi 20

CF ; 25

ci, Br Y Br, ci, Br Br, ci nu 30 6000in 35 CF3CFz andand Y CF3C3. CF3 mi

, F3C Y 40 ni of : 74F3C F3C In some embodiments , Rl is other than 45 CH3 F w I

50 F C FC

I

mun * Br, or 55 ????+wi In some embodiments , Rl is selected from :

Priwa wan US 9, 850 ,268 B2 27 28 In some embodiments , Rl is - continued CFz

CH Br F CI , F3C YF, ci y Cl. Br Y Br.

min 1010 mim

F3CFzC F3C CF3 CF3,

www 20 wir

F3C a F30

25 Bror F C C3 wi

30

32 wim nim 35

NO

40 In some embodiments , R ' is Bror

in mu

a Y F2 mi F3C.

In some embodiments , R ' is mi

Br F30

Bror Cl, Br V BI mi ma US 9 , 850 , 268 B2 29 30 In some embodiments , Rl is In some embodiments , Rl is

CH3

im 10

F3C F3C

Cl, or In some embodiments , Rl is w

FC 20 FC a CF3CF3..

Br.

25 mi

In some embodiments , Rl is In some embodiments , Rl is 30 F F F

35 F C CF3.

40 In some embodiments , Rl is In some embodiments , R ' is

45

C 50 CH3 mim ni

In some embodiments , Rl is 55 In some embodiments , Rl is Br F C

Br Br.

min US 9 , 850 , 268 B2 31 32 In some embodiments , R is electron -withdrawing substituent is independently halogen or substituted C - , alkyl comprising one or more halogen . In some embodiments , R ' is substituted phenyl comprising one F C or more electron -withdrawing substituents , wherein each 5 electron - withdrawing substituent is independently halogen or substituted C - , alkyl comprising one or more halogen . In some embodiments , each electron -withdrawing substituent is independently halogen or C - haloalkyl. In some embodi mi ments , each electron -withdrawing substituent is indepen dently — F or C1- 6 fluoroalkyl. In some embodiments , each 10 electron - withdrawing substituent is independently — F or C - perfluoroalkyl. In some embodiments , Rl is As defined generally above, each of R2 and R3 is inde pendently R ', - OR ' , SR ', - N ( R ') 2 , OC ( O ) R ', SOR ', SO , R ', SON ( R ') , C ( O ) N (R ' ) , — NR ' C ( O ) R ', or F3C — NR 'SO , R ' , provided that R2 and R3 are not simultane ously hydrogen . In some embodiments , one of R2 and R3 is hydrogen and the other is an optionally substituted group selected from Br. C1- 6 aliphatic , phenyl, a 3 - 7 membered saturated or partially mm 20 unsaturated carbocyclic ring, an 8 - 10 membered bicyclic saturated , partially unsaturated or aryl ring , a 5 -6 membered monocyclic heteroaryl ring having 1 - 4 heteroatoms inde pendently selected from nitrogen , oxygen , or sulfur, a 4 - 7 In some embodiments , Rl is membered saturated or partially unsaturated heterocyclic 25 ring having 1 - 3 heteroatoms independently selected from nitrogen , oxygen , or sulfur, a 7 - 10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1 - 5 heteroatoms independently selected from nitrogen , oxy gen , or sulfur, or an 8 - 10 membered bicyclic heteroaryl ring having 1 - 5 heteroatoms independently selected from nitro 30 gen , oxygen , or sulfur, — OR ', — SR ', — N ( R ') , , - OC ( O ) R ' , - SOR ', — SO , R ', — SO N ( R ') 2 , C ( O ) N ( R ') 2 , NR ' C ( O ) R ', or - NR 'SO , R '. In some embodiments , one of R2 and min R * is hydrogen and the other is an optionally substituted group selected from C1- 6 aliphatic , a 3 - 7 membered satu 35 rated or partially unsaturated carbocyclic ring , an 8 - 10 membered bicyclic saturated , partially unsaturated or aryl In some embodiments , Rl is an optionally substituted ring, a 5 -6 membered monocyclic heteroaryl ring having 1 -4 C1- 20 aliphatic , wherein R ' is a tertiary substituent, or R ' is heteroatoms independently selected from nitrogen , oxygen , substituted phenyl wherein at least one substituent is an or sulfur, a 4 - 7 membered saturated or partially unsaturated electron -withdrawing group . In some embodiments , R ' is an 40 heterocyclic ring having 1 - 3 heteroatoms independently optionally substituted C1- 20 aliphatic , wherein R ' is a tertiary selected from nitrogen , oxygen , or sulfur, a 7 - 10 membered substituent, or R1 is substituted phenyl wherein at least one bicyclic saturated or partially unsaturated heterocyclic ring substituent is an electron -withdrawing group selected from having 1 - 5 heteroatoms independently selected from nitro halogen and optionally substituted C1- 6 haloalkyl. In some gen , oxygen , or sulfur , or an 8 - 10 membered bicyclic embodiments , R ' is an optionally substituted tertiary C4. 20 45 heteroaryl ring having 1 - 5 heteroatoms independently aliphatic , or R1 is substituted phenyl wherein at least one selected from nitrogen , oxygen , or sulfur. substituent is an electron -withdrawing group selected from In certain embodiments , R2 or R3 is optionally substituted - F and optionally substituted C1- 6 perfluoroalkyl. In some C1-6 aliphatic . In some embodiments , R² or R * is optionally embodiments , R1 is an optionally substituted C , . o aliphatic , substituted C . , alkyl. In certain embodiments , R2 or R is wherein R is a tertiary substituent, or R is substituted 50 C1- 6 alkyl substituted with phenyl and one or two additional phenyl wherein each substituent is independently an elec - substituents . In certain embodiments , R2 or R * is a lower tron - withdrawing group. In some embodiments , R is an alkyl group optionally substituted with one or two methyl optionally substituted C1- 20 aliphatic , wherein R ' is a tertiary groups and phenyl. In certain embodiments , R2 or R3 is substituent, or Rl is substituted phenyl wherein each sub - C (Me ) , Ph . In certain embodiments , R² or R3 is C (Me ) z . stituent is independently an electron - withdrawing group 55 In some embodiments , each of R2 and R3 is independently selected from halogen and optionally substituted C - 6 R ', wherein at least one of R² and R * is not hydrogen . haloalkyl. In some embodiments, R is an optionally sub - In certain embodiments , R² is hydrogen and R * is R ', stituted tertiary C4 - 20 aliphatic , or RP is substituted phenyl - OR ', — SR ', - N (R ') 2 , OC ( O ) R ', — SOR ', - SOZR ', wherein each substituent is independently an electron -with - SO , N ( R ') 2 - C ( O ) N ( R ') , NR ' C ( O ) R ', or drawing group selected from F and optionally substituted 60 — NR 'SO , R ', wherein each R ' is independently as defined C1- 6 perfluoroalkyl. In some embodiments , R ' is an option - above and described herein . In certain embodiments , R2 is ally substituted adamantyl , or R is substituted phenyl hydrogen and R is R ' , wherein R ' is as defined above and wherein each substituent is independently an electron -with - described herein . In certain embodiments , R² is hydrogen drawing group selected from — F and optionally substituted and R3 is optionally substituted C1- 20 aliphatic . In some C1- 6 perfluoroalkyl. In some embodiments , R is optionally 65 embodiments , R2 is hydrogen and R is optionally substi substituted adamantyl, or substituted phenyl comprising one tuted C1 . 20 alkyl. In certain embodiments , R² is hydrogen or more electron - withdrawing substituents , wherein each and R3 is C . , alkyl substituted with phenyl and one or two US 9 ,850 ,268 B2 33 34 additional substituents . In certain embodiments , R2 is hydro eroatoms independently selected from nitrogen , oxygen , or gen and R is a lower alkyl group optionally substituted with sulfur. In some embodiments , Ring B ' is an optionally one or two methyl groups and phenyl. In certain embodi substituted 5 -6 membered saturated heterocyclic ring having ments , R2 is hydrogen and R3 is - C (Me ) , Ph . In certain 1 - 2 heteroatoms independently selected from nitrogen , oxy embodiments , R2 is hydrogen and R3 is - C (Me ) . 5 gen , or sulfur. In some embodiments , R4 is R². In some embodiments , R4 In some embodiments , Ring B ' is an optionally substituted is R7, wherein R ? is optionally substituted phenyl. In some 3 -7 membered partially unsaturated heterocyclic ring having embodiments , R4 is R7, wherein R7 is Ar' : 1 - 3 heteroatoms independently selected from nitrogen , oxy gen , or sulfur. In some embodiments , Ring B ' is an option 10 ally substituted 5 - 6 membered partially unsaturated hetero mm cyclic ring having 1 - 2 heteroatoms independently selected ( R ) + from nitrogen , oxygen , or sulfur. In some embodiments , Ring B ' is an optionally substituted 7 - 10 membered bicyclic saturated heterocyclic ring having 15 1 - 5 heteroatoms independently selected from nitrogen , oxy ( R $) . gen , or sulfur. In some embodiments , Ring B ' is an option ally substituted 8 - 10 membered bicyclic saturated heterocy In some embodiments , p is 0 -6 . In some embodimentsp , c lic ring having 1 - 2 heteroatoms independently selected is 0 - 5 . In some embodiments , p is 1 - 5 . In some embodi - from nitrogen , oxygen , or sulfur. ments , p is 1 . In some embodiments , p is 2 . In some 20 In some embodiments , Ring B ' is an optionally substituted embodiments , p is 3 . In some embodiments , p is 4 . In some 7 - 10 membered bicyclic partially unsaturated heterocyclic embodiments , p is 5 . In some embodiments , p is 6 . In some ring having 1 - 5 heteroatoms independently selected from embodiments , p is 2 or 3 . nitrogen , oxygen , or sulfur. In some embodiments , Ring B ' In some embodiments , t is 0 . In some embodiments , t is is an optionally substituted 8 - 10 membered bicyclic partially 1 - 4 . In some embodiments , t is 1 . In some embodiments, t 25 unsaturated heterocyclic ring having 1 - 2 heteroatoms inde is 2 . In some embodiments , t is 3 . In some embodiments , t pendently selected from nitrogen , oxygen , or sulfur. is 4 . In some embodiments , t is 0 - 2. In some embodiments , In some embodiments , Ring B ' is an optionally substituted t is 0 - 3 . 8 - 14 membered bicyclic or tricyclic heteroaryl ring having In some embodiments , Ring B ' is optionally substituted 1 - 5 heteroatoms independently selected from nitrogen , oxy phenyl. 30 gen , or sulfur . In some embodiments , Ring B ' is an option In some embodiments , Ring B ' is an optionally substituted ally substituted 8 - 10 membered bicyclic heteroaryl ring 3 - 7 membered saturated carbocyclic ring . In some embodi- having 1 - 5 heteroatoms independently selected from nitro ments , Ring B ' is an optionally substituted 5 - 6 membered gen , oxygen , or sulfur. In some embodiments , Ring B ' is an saturated carbocyclic ring . In some embodiments , Ring B ' is optionally substituted 8 membered bicyclic heteroaryl ring an optionally substituted 3 - 7 membered partially unsatu - 35 having 1 - 3 heteroatoms independently selected from nitro rated carbocyclic ring . In some embodiments , Ring B ' is an gen , oxygen , or sulfur. In some embodiments , Ring B ' is an optionally substituted 5 - 6 membered partially unsaturated optionally substituted 9 membered bicyclic heteroaryl ring carbocyclic ring. having 1 - 3 heteroatoms independently selected from nitro In some embodiments , Ring B ' is an optionally substituted gen , oxygen , or sulfur. 8 - 10 membered bicyclic saturated carbocyclic ring . In some 40 In some embodiments , Ring B ' is an optionally substituted embodiments , Ring B ' is an optionally substituted 8 - 10 10 membered bicyclic heteroaryl ring having 1 - 3 heteroa membered bicyclic partially unsaturated carbocyclic ring . In toms independently selected from nitrogen , oxygen , or sul some embodiments , Ring B ' is an optionally substituted 8 - 10 fur. In some embodiments , Ring B ' is a 10 - 14 membered membered bicyclic aryl ring . tricyclic heteroaryl ring having 1 - 5 heteroatoms indepen In some embodiments , Ring B ' is an optionally substituted 45 dently selected from nitrogen , oxygen , or sulfur. 5 - 6 membered monocyclic heteroaryl ring having 1 - 4 het . In some embodiments, Ring B ' is an optionally substituted eroatoms independently selected from nitrogen , oxygen , or group selected from : sulfur. In some embodiments , Ring B ' is an optionally substituted 5 - 6 membered monocyclic heteroaryl ring hav ing 1 - 2 heteroatoms independently selected from nitrogen , 50 oxygen , or sulfur. In some embodiments , Ring B ' is an optionally substituted 5 membered monocyclic heteroaryl ring having 1 - 4 heteroa or toms independently selected from nitrogen , oxygen , or sul fur. In some embodiments , Ring B ' is an optionally substi- 55 tuted 5 membered monocyclic heteroaryl ring having 1 - 2 heteroatoms independently selected from nitrogen , oxygen , or sulfur. In some embodiments , Ring B ' is an optionally substituted 6 membered monocyclic heteroaryl ring having 1 - 4 heteroa - 60 mi toms independently selected from nitrogen , oxygen , or sul mi fur. In some embodiments , Ring B ' is an optionally substi tuted 6 membered monocyclic heteroaryl ring having 1 -2 heteroatoms independently selected from nitrogen , oxygen , or sulfur. 65 wherein each | independently represents the point of attach In some embodiments , Ring B ' is an optionally substituted ment to Ring C ' or oxygen , and Ring B ' is optionally 3 - 7 membered saturated heterocyclic ring having 1 - 3 het substituted with 0 -4 RS. US 9 , 850 , 268 B2 35 36 In some embodiments , Ring C ' is optionally substituted In some embodiments , Ring C ' is an optionally substituted phenyl. 8 - 10 membered bicyclic saturated carbocyclic ring . In some In some embodiments , Ring C ' is an optionally substituted embodiments, Ring C ' is an optionally substituted 8 - 10 group selected from : membered bicyclic partially unsaturated carbocyclic ring . In 5 some embodiments , Ring C ' is an optionally substituted 10 membered bicyclic aryl ring . In some embodiments , Ring C ' is an optionally substituted 5 - 6 membered monocyclic heteroaryl ring having 1 - 4 het eroatoms independently selected from nitrogen , oxygen , or , or sulfur. In some embodiments , Ring C ' is an optionally mi ni m in substituted 5 - 6 membered monocyclic heteroaryl ring hav ing 1 - 2 heteroatoms independently selected from nitrogen , oxygen , or sulfur . ?? In some embodiments , Ring C ' is an optionally substituted wherein each l represents the point of attachment to Ring 5 membered monocyclic heteroaryl ring having 1 - 4 heteroa B ' ; wherein Ring C ' is optionally substituted with 0 - 6 R ' ; and toms independently selected from nitrogen , oxygen , or sul wherein each of Ring B ' and R * is independently as defined furfur. In some embodiments. , Ring C ' is an optionally substi above and described herein . tuted 5 membered monocyclic heteroaryl ring having 1 - 2 In some embodiments , Ring C " is optionally substituted 20 heteroatoms independently selected from nitrogen , oxygen , or sulfur . In some embodiments, Ring C ' is an optionally substituted mm 6 membered monocyclic heteroaryl ring having 1 - 4 heteroa toms independently selected from nitrogen , oxygen , or sul 25 fur. In some embodiments , Ring C ' is an optionally substi tuted 6 membered monocyclic heteroaryl ring having 1 - 2 heteroatoms independently selected from nitrogen , oxygen , ( R ) p , or sulfur . In some embodiments , Ring C ' is an optionally substituted bove and 30 4 - 7 membered saturated heterocyclic ring having 1 - 3 het wherein RS and p is independently as defined above and 30 eroatoms independently selected from nitrogen , oxygen , or described herein . sulfur. In some embodiments , Ring C ' is an optionally In certain embodiments , Ring C ' is of the following substituted 5 -6 membered saturated heterocyclic ring having formula : 1 - 2 heteroatoms independently selected from nitrogen , oxy 35 gen , or sulfur. n In some embodiments ,Ring C ' is an optionally substituted 4 - 7 membered partially unsaturated heterocyclic ring having DS 1 - 3 heteroatoms independently selected from nitrogen , oxy gen , or sulfur. In some embodiments, Ring C ' is an option 40 ally substituted 5 - 6 membered partially unsaturated hetero cyclic ring having 1 - 2 heteroatoms independently selected from nitrogen , oxygen , or sulfur. RS In some embodiments , Ring C ' is an optionally substituted 7 - 10 membered bicyclic saturated heterocyclic ring having wherein each R $ is independently as defined above and 45 1 - 5 heteroatoms independently selected from nitrogen , oxy described herein . gen , or sulfur . In some embodiments , Ring C ' is an option In certain embodiments , Ring C ' is of the following ally substituted 8 - 10 membered bicyclic saturated heterocy structure : clic ring having 1 - 2 heteroatoms independently selected from nitrogen , oxygen , or sulfur. 50 In some embodiments , Ring C ' is an optionally substituted 7 - 10 membered bicyclic partially unsaturated heterocyclic ring having 1 - 5 heteroatoms independently selected from iPriPr i iPrPr. nitrogen , oxygen , or sulfur. In some embodiments , Ring C ' is an optionally substituted 8 - 10 membered bicyclic partially 55 unsaturated heterocyclic ring having 1 - 2 heteroatoms inde pendently selected from nitrogen , oxygen , or sulfur. In some embodiments , Ring C ' is an optionally substituted iPr 8 - 10 membered bicyclic heteroaryl ring having 1 - 5 heteroa toms independently selected from nitrogen , oxygen , or sul In some embodiments , Ring C ' is an optionally substituted 60 fur. In some embodiments, Ring C ' is an optionally substi a 3 - 7 membered saturated carbocyclic ring . In some embodi- tuted 8 membered bicyclic heteroaryl ring having 1 - 3 ments, Ring C ' is an optionally substituted a 5 - 6 membered heteroatoms independently selected from nitrogen , oxygen , saturated carbocyclic ring. In some embodiments , Ring C ' is or sulfur. an optionally substituted a 3 - 7 membered partially unsatu - In some embodiments , Ring C ' is an optionally substituted rated carbocyclic ring . In some embodiments , Ring C ' is an 65 9 membered bicyclic heteroaryl ring having 1 -3 heteroatoms optionally substituted a 5 - 6 membered partially unsaturated independently selected from nitrogen , oxygen , or sulfur. In carbocyclic ring . some embodiments , Ring C ' is an optionally substituted 10 US 9 ,850 ,268 B2 37 38 membered bicyclic heteroaryl ring having 1 - 3 heteroatoms two or more substituents are F . In certain embodiments, at independently selected from nitrogen , oxygen , or sulfur. least one RS is selected from methyl, ethyl, propyl, or butyl . In some embodiments , each R $ is independently halogen , In certain embodiments , at least one R $ is isopropyl . In R , OR , SR , - S ( O ) R ', - S ( O ) , R ', OSi( R ') , , certain embodiments , at least one R is _ CFz. - N ( R ') ) . — NR ' C ( O ) R '. — NR 'C (O )OR '. — NR ' C ( O ) 5 In some embodiments , at least one R is hydrogen or an optionally substituted group selected from C - 6 aliphatic , N ( R ') 2 , NR ' SO2R ', — NR ' SO , N ( R ') 2 , or — NR 'OR ', phenyl, a 3 - 7 membered saturated or partially unsaturated wherein each R ' is independently as defined above and carbocyclic ring, an 8 - 10 membered bicyclic saturated , described herein . partially unsaturated or aryl ring , a 5 -6 membered monocy In some embodiments , RS is hydrogen . In some embodi clic heteroaryl ring having 1 - 4 heteroatoms independently mentsm , R $ is halogen . In some embodiments , RS is F . In 10 selected from nitrogen , oxygen , or sulfur, a 4 - 7 membered some embodiments , RS is - C1. In some embodiments, R * is saturated or partially unsaturated heterocyclic ring having - Br. In some embodiments , RS is — I . 1 - 3 heteroatoms independently selected from nitrogen , oxy In some embodiments , RS is R '. In some embodiments , RS gen , or sulfur, a 7 - 10 membered bicyclic saturated or par is optionally substituted C1- 6 aliphatic . In some embodi tially unsaturated heterocyclic ring having 1 - 5 heteroatoms ments, R is optionally substituted C1- 6 aliphatic , whereinein RSR . 1515 independentlyinde selected from nitrogen , oxygen , or sulfur, or comprises one or more halogen . In some embodiments , RS an 8 - 10 membered bicyclic heteroaryl ring having 1 - 5 is optionally substituted C1- 6 aliphatic , wherein RS com heteroatoms independently selected from nitrogen , oxygen , prises one or more — F . InIn some embodiments , Ris RS is C1Cic- 6 . or sulfur. perfluoroaliphatic . In some embodiments , RS is C - perfluo In some embodiments , at least one RS is OSi( R ') z , roalkyl. In some embodiments , R 18 – CF3. In some 20 wherein each R ' is independently as defined above and embodiments , RS is optionally substituted C1- 6 alkyl . In described herein . some embodiments , R® is optionally substituted linear C1 - 6 In some embodiments , at least one RS is -- OR ' wherein alkyl. In some embodiments , R $ is optionally substituted each R ' is independently as defined above and described branched C1- alkyl. In some embodiments , R * is optionally herein substituted phenyl . In some embodiments, Rºis phenyl. In 25 In some embodiments , at least one RS is selected from some embodiments , Rºis optionally substituted 8 - 10 mem - - SR '. - S ( O ) R '. _ S ( O ) R '. wherein each R ' is indepen bered bicyclic aryl. In some embodiments, R is optionally dently as defined above and described herein . substituted naphthyl. In some embodiments , R is optionally In some embodiments . R4 is optionally substituted Ar. substituted 1 - naphthyl. In some embodiments , R is option - wherein Ar is of the following structure : ally substituted 2 - naphthyl. In some embodiments , R is 30 1 - substituted naphthyl . In some embodiments , R * is 2 - sub stituted naphthyl . In some embodiments , R * is optionally w substituted 5 -6 membered monocyclic heteroaryl ring hav ing 1 - 4 heteroatoms independently selected from nitrogen , ( RO) , fo I D( R ) oxygen , or sulfur . In some embodiments , RS is optionally 35 substituted 8 - 10 membered bicyclic heteroaryl. In some embodiments , R * is an optionally substituted 4 - 7 membered ( R * ) m saturated or partially unsaturated heterocyclic ring having 1 - 3 heteroatoms independently selected from nitrogen , oxy gen , or sulfur . In some embodiments . Rs is an optionally 40 . As generally defined above , m is 0 - 3 . In some embodi substituted 7 - 10 membered bicyclic saturated or partially ments , m is 0 . In some embodiments, m is 1 - 3 . In some unsaturated heterocyclic ring having 1 -5 heteroatoms inde embodiments, m is 1 . In some embodiments , m is 2 . In some pendently selected from nitrogen , oxygen , or sulfur. In some embodiments , m is 3 . In some embodiments , m is 0 -2 . embodiments , RS is selected from SR ', - S ( O ) R ', In some embodiments , q is 0 -6 . In some embodiments , q . - S ( O ) 2R ', wherein each R ' is independently as defined 1545 1is 0 - 5 . In some embodiments , q is 1 - 5 . In some embodi above and described herein . ments , q is 1 . In some embodiments, q is 2 . In some In certain embodiments , at least one RS is independently embodiments , q is 3 . In some embodiments , q is 4 . In some halogen . In certain embodiments , at least one R * is indepen embodiments , q is 5 . In some embodiments , q is 6 . In some dently — F . In certain embodiments, at least one RS is embodiments , q is 2 or 3 . independently -- - C1. In certain embodiments, at least one RS 50 In some embodiments, p = q . In some embodiments, is independently — Br. In certain embodiments , at least one p = q = 2 . In some embodiments , p = q = 3 . RS is independently — I . As generally defined above , Ring B is an optionally tly substituted group selected from phenyl or a 5 -6 membered In certain embodiments , at least one RS is independently monocyclic heteroaryl ring having 1- 4 heteroatoms inde selected- OS ( R )from . . or R _', N ( ROR ') . , NRCSR ', ( O - ) RS ('. O ) _R 'NRIC, - S( (O O )OR ) , R ': , 55 pendently selected from nitrogen , oxygen , or sulfur. In some - NR ' C ( O ) N ( R ') 2 , NR 'SO , R ', — NR 'SO , N ( R ') 2 or embodiments, Ring B is of the following structure : - NR 'OR ', wherein each R ' is independently as defined above and described herein . In certain embodiments , at least one RS is R ' , wherein R ' mann is as defined above and described herein . In some embodi- 60 m ments , at least one R * is optionally substituted C . , aliphatic . In some embodiments , at least one R * is optionally substi tuted C1- 6 alkyl. In some embodiments , at least one R * is mi optionally substituted C - haloalkyl. In some embodiments , at least one R * is optionally substituted C1- 6 haloalkyl, 65 ( R *) m wherein one substituent is — F . In some embodiments , at least one R * is optionally substituted C1- 6 haloalkyl, wherein US 9 , 850 , 268 B2 39 40 wherein R * and m are as defined above and described herein . ethyl, propyl, or butyl. In some embodiments , R * is methyl. In some embodiments , Ring B is optionally substituted In some embodiments , R * is ethyl. In some embodiments , R * phenyl. In some embodiments , m = 0 . In some embodiments , is optionally substituted n - alkyl. In some embodiments , R * Ring B is is optionally substituted isoalkyl. In certain embodiments , 5 R * is isopropyl. In some embodiments , R * is optionally substituted tertiary aliphatic . In some embodiments, R * is optionally substituted tertiary alkyl. In some embodiments , w R * is t- butyl . In some embodiments , R * is adamantyl. In some embodiments , R * is optionally substituted 10 cycloalkyl. In some embodiments, R * is optionally substi tuted heteroaliphatic . In some embodiments , R * is optionally we substituted heterocyclyl . In some embodiments , R * is substituted , and at least one substituent is halogen . In some embodiments Ring B is an optionally substituted 15 In some embodiments , R * is substituted C1- 20 aliphatic In some embodiments , Ring B is an optionally substituted 15 andin C1some- 20 heteroaliphatic , wherein one or more substituent 5 -6 membered monocyclic heteroaryl ring having 1 -4 het are independently halogen . In some embodiments , R * is eroatoms independently selected from nitrogen , oxygen , or CF3 . In some embodiments , R * is – C2F5. In some sulfur. In some embodiments , Ring B is an optionally embodiments , R * is substituted linear , branched or cyclic substituted 5 -membered monocyclic heteroaryl ring having18 20 aliphatic or heteroaliphatic , wherein one or more substitu 1 - 4 heteroatoms independently selected from nitrogen , oxy ents are independently halogen . gen , or sulfur, and m is 0 - 2 . In some embodiments , Ring B In certain embodiments , R * is optionally substituted C1- 20 is an optionally substituted 6 -membered monocyclic het heteroaliphatic having 1 - 3 heteroatoms independently eroaryl ring having 1 - 4 heteroatoms independently selected selected from nitrogen , oxygen , or sulfur . from nitrogen , oxygen , or sulfur , and m is 0 - 3 . 25 In some embodiments , R * is optionally substituted phenyl . In some embodiments , Ring B is a 5 - 6 membered mono - In some embodiments , R * is phenyl. cyclic heteroaryl ring having 1 -4 heteroatoms independently In some embodiments, Ring C is optionally substituted selected from nitrogen , oxygen , or sulfur . In some embodi - phenyl. In some embodiments , Ring Cis substituted phenyl ments , Ring B is a 5 - 6 membered monocyclic heteroaryl comprising a 2 ' -substituent . In some embodiments , Ring C ring having 1 - 2 heteroatoms independently selected from 30 is substituted phenyl comprising a 6 '- substituent. In some nitrogen , oxygen , or sulfur. embodiments , Ring C is substituted phenyl comprising a 2 ' In some embodiments , Ring B is a 5 -membered mono and a 6 '- substituent . In some embodiments , Ring C is 2 '- and cyclic heteroaryl ring having 1 - 4 heteroatoms independently 6 - substituted phenyl. In some embodiments , Ring C is selected from nitrogen , oxygen , or sulfur. In some embodi substituted phenyl comprising a 4 ' - substituent. In some ments , Ring B is a 5 -membered monocyclic heteroaryl ring 35 embodiments , Ring Cis substituted phenyl comprising a 2 ' - , having 1 - 2 heteroatoms independently selected from nitro - a 4 ' - and a 6 -substituent . In some embodiments , Ring C is gen , oxygen , or sulfur. 2 '- , 4 ' - and 6 '- substituted phenyl. In some embodiments , In some embodiments , Ring B is a 6 -membered mono - Ring C is substituted phenyl comprising a 3 '- substituent . In cyclic heteroaryl ring having 1 - 4 heteroatoms independently some embodiments , Ring C is substituted phenyl comprising selected from nitrogen , oxygen , or sulfur . In some embodi - 40 a 5 ' - substituent. In some embodiments , Ring Cis substituted ments , Ring B is a 6 -membered monocyclic heteroaryl ring phenyl comprising a 3 ' - and a 5 '- substituent. In some having 1 - 2 heteroatoms independently selected from nitro - embodiments , Ring C is 3 '- and 5 ' -substituted phenyl. In gen , oxygen , or sulfur. some embodiments , each substituent is independently an Exemplary optionally substituted Ring B heteroaryl optionally substituted C1- 6 alkyl. In some embodiments , a groups include thienylene , furanyl, pyrrolyl, imidazolyl, 45 substituent is a primary substituent, e . g . , methyl, ethyl , pyrazolyl, triazolyl, tetrazolyl , oxazolyl , isoxazolyl, oxadi- trifluoromethyl, etc . In some embodiments , each substituent azolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, is a primary substituent. In some embodiments , a substituent pyridazinyl, pyrimidinyl, pyrazinyl, and the like . is a secondary substituent, e . g. , isopropyl, etc . In some In some embodiments , R * is Rs . In some embodiments, embodiments , each substituent is a secondary substituent. In each R * is independently halogen , — OR ', - N ( R ') , — NR 50 some embodiments , a substituent is a tertiary substituent, C ( O )R ', — NR ' C (O )OR ', - NR ' C ( O ) N (R ') 2, — NR 'SO , R !, e. g. , tert -butyl , etc . In some embodiments , each substituent - NR 'SO , N ( R ') , — NR 'OR ', or an optionally substituted is a tertiary substituent. In some embodiments, each sub group selected from C1- 20 aliphatic and C1- 20 heteroaliphatic stituent is independently an unsubstituted C1- 6 alkyl. In some having 1 -3 heteroatoms independently selected from nitro embodiments , each substituent is independently an unsub gen , oxygen , or sulfur. 55 stituted linear C1- 6 alkyl. In some embodiments , each sub In certain embodiments , R * is halogen . In some embodi - stituent is methyl. In some embodiments , each substituent is ments , R * is F . In some embodiments , R * is — C1. In some ethyl. In some embodiments , each substituent is indepen embodiments , R * is Br. In some embodiments , R * is — I. dently an unsubstituted branched C - alkyl . In some In certain embodiments , R * is independently selected embodiments , each substituent is isopropyl. In some from — OR ', — N ( R ' ) , — NR ' C ( O ) R ', — NR ' C ( O )OR ', 60 embodiments , each substituent is tert- butyl . In some — NR ' C ( O ) N ( R ') , — NR 'SO , R ', — NR 'SO , N ( R ' ) , embodiments , each substituent on Ring C is the same. - NR 'OR '. In some embodiments , Ring C is 2 - and 6 - substituted In certain embodiments , R * is optionally substituted C1- 20 phenyl, wherein each of the 2 '- and 6 - substituents is inde aliphatic . In certain embodiments , R * is optionally substi - pendently Cl- , alkyl. In some embodiments , Ring C is 2 tuted C1- 10 aliphatic . In certain embodiments , R * is option - 65 and 6 '- substituted phenyl, wherein each of the 2 '- and ally substituted C . aliphatic . In certain embodiments , R * is 6 '- substituents is methyl. In some embodiments , Ring C is alkyl. In certain embodiments , R * is selected from methyl, 2 - and 6 - substituted phenyl, wherein each of the 2 ' - and US 9 , 850 , 268 B2 41 42 6 - substituents is ethyl. In some embodiments , Ring C is 2 - In certain embodiments , Rº is independently selected and 6 '- substituted phenyl, wherein each of the 2' - and from - OR ', - N (R ') 2 , - NR ' C (O )R ', - NR ' C (O )OR ', 6 - substituents is isopropyl. In some embodiments , Ring C is — NR ' C ( O ) N ( R ') 2 , NR 'SOZR ', - NR 'SO , N ( R ') 2 , 2 ' - , 4 - and 6 - substituted phenyl , wherein each of the 2 ' - , 4 - NR 'OR '. and 6 '- substituents is independently C1- 6 alkyl. In some 5 In certain embodiments , R ” is optionally substituted C . 20 embodiments , Ring C is 2 '- , 4 ' - and 6 ' - substituted phenyl, aliphatic . In certain embodiments . RY is optionally substi wherein each of the 2 '- , 4 '- and 6 '- substituents is methyl . In tuted C1- 10 aliphatic . In certain embodiments , R ' is option some embodiments , Ring C is 2 '- , 4 ' - and 6 - substituted phenyl, wherein each of the 2 ' - , 4 ' - and 6 - substituents is ally substituted C -5 aliphatic . In certain embodiments , R ’ is ethyl. In some embodiments , Ring C is 2 '- , 4 ' - and 6 - sub - 101alkyl . In certain embodiments , R " is selected from methyl, stituted phenyl, wherein each of the 2 ' -, 4 ' - and 6 ' -substitu ethyl, propyl, or butyl. In some embodiments , R ' is option ents is isopropyl. In some embodiments , Ring C is 3 ' - and ally substituted primary C - alkyl. In some embodiments , 5 '- substituted phenyl, wherein each of the 3' - and 5 '- sub R ” is methyl. In some embodiments , Ry is ethyl. In some stituents is independently C - , alkyl. In some embodiments, embodiments , Ry is optionally substituted n - alkyl. In some Ring C is 3 ' - and 5 '- substituted phenyl, wherein each of the 15 embodiments, Ry is optionally substituted secondary C1 - 6 3 '- and 5 '- substituents is independently tertiary C1- 6 alkyl. In alkyl. In some embodiments , R is optionally substituted some embodiments , Ring C is 3 ' - and 5 ' - substituted phenyl, isoalkyl. In certain embodiments , Rºis isopropyl. In some wherein each of the 3 ' - and 5 ' -substituents is independently embodiments , R ' is optionally substituted tertiary aliphatic . tert- butyl . In some embodiments , R ' is optionally substituted tertiary In some embodiments , Ring C is 2 , 4 , 6 - trimethylphenyl. 20 C1- 6 alkyl . In some embodiments , R ' is t -butyl . In some In some embodiments, Ring C is 2 , 4 , 6 - triethylphenyl. In embodiments , Ry is adamantyl. some embodiments , Ring C is 2, 4 ,6 - triisopropylphenyl. In In some embodiments , Ry is optionally substituted some embodiments , Ring C is 3 , 5 -di ( tert -butyl ) phenyl . cycloalkyl . In some embodiments , R ” is optionally substi In some embodiments, Ring C is an optionally substituted tuted heteroaliphatic . In some embodiments , RÝis optionally group selected from phenyl, an 8 - 10 membered bicyclic aryl 25 substituted heterocyclyl. ring, a 5 -6 membered monocyclic heteroaryl ring having 1 - 4 In some embodiments , R¥ is substituted , and at least one heteroatoms independently selected from nitrogen , oxygen , substituent is halogen . In some embodiments, Rº is substi or sulfur, or an 8 - 10 membered bicyclic heteroaryl ring tuted C1 - 20 aliphatic and C1 - 20 heteroaliphatic , wherein one having 1 - 5 heteroatoms independently selected from nitro - or more substituent are independently halogen . In some gen , oxygen , or sulfur. In some embodiments , Ring C is an 30 embodiments , Rº is CF3. In some embodiments , R ' is optionally substituted group selected from phenyl or an 8 - 10 C , F5. In some embodiments , Ry is substituted linear, membered bicyclic aryl ring. In some embodiments , Ring C branched or cyclic aliphatic or heteroaliphatic , wherein one is optionally substituted phenyl. In some embodiments , Ring or more substituents are independently halogen . C is optionally substituted 8 - 10 membered bicyclic aryl. In In certain embodiments , R ' is optionally substituted C1- 20 some embodiments , Ring C is optionally substituted naph - 35 heteroaliphatic having 1 - 3 heteroatoms independently thyl. In some embodiments , Ring C is optionally substituted selected from nitrogen , oxygen , or sulfur. 1 - naphthyl. In some embodiments , Ring C is 1 - naphthyl. In In some embodiments , R ' is C1- 20 aliphatic , or heteroali some embodiments , Ring Cis optionally substituted 2 -naph - phatic having 1 - 3 heteroatoms independently selected from thyl . In some embodiments , Ring C is 2 - naphthyl . nitrogen , oxygen , or sulfur, optionally substituted with one In some embodiments , Ring C is an optionally substituted 40 or more halogen . In some embodiments , R ” is C . , ali 3 - 7 membered saturated or partially unsaturated carbocyclic phatic , or heteroaliphatic having 1 - 3 heteroatoms indepen ring. In some embodiments , Ring C is an optionally substi - dently selected from nitrogen , oxygen , or sulfur, optionally tuted 8 - 10 membered bicyclic saturated , partially unsatu - substituted with one or more halogen . In some embodi rated or aryl ring . In some embodiments , Ring C is an ments , R ” is C1- 6 aliphatic , or heteroaliphatic having 1 - 3 optionally substituted 5 - 6 membered monocyclic heteroaryl 45 heteroatoms independently selected from nitrogen , oxygen , ring having 1 - 4 heteroatoms independently selected from or sulfur , optionally substituted with one or more halogen . In nitrogen , oxygen , or sulfur. In some embodiments , Ring C is some embodiments , R ” is C1- 20 aliphatic optionally substi an optionally substituted 4 -7 membered saturated or par - tuted with one or more halogen . In some embodiments , R ” tially unsaturated heterocyclic ring having 1 - 3 heteroatoms is C1- 10 aliphatic optionally substituted with one or more independently selected from nitrogen , oxygen , or sulfur. In 50 halogen . In some embodiments , RÝis C ., aliphatic option some embodiments , Ring C is an optionally substituted 7 - 10 ally substituted with one or more halogen . membered bicyclic saturated or partially unsaturated hetero - In some embodiments , Ry is an electron -withdrawing cyclic ring having 1 - 5 heteroatoms independently selected group . In some embodiments , each Ry is independently an from nitrogen , oxygen , or sulfur. In some embodiments , electron - withdrawing group . In some embodiments , R¥ is Ring C is an optionally substituted 8 - 10 membered bicyclic 55 halogen or optionally substituted C1- 20 aliphatic . In some heteroaryl ring having 1 - 5 heteroatoms independently embodiments , Ry is halogen or substituted C o aliphatic , selected from nitrogen , oxygen , or sulfur. wherein one or more substituent is halogen . In some In some embodiments , Rºis Rº. In some embodiments , embodiments , R ” is halogen or substituted C1- 10 aliphatic , each Ry is independently halogen , — OR ', — N ( R ') , , — NR wherein one or more substituent is halogen . In some C ( O ) R ' , - NR ' C ( O )OR ', — NR ' C ( O ) N ( R ' ) , - NR 'SO , R ', 60 embodiments , Rºis halogen . In some embodiments , Ry is - NR 'SO , N ( R ') 2 , — NR 'OR ', or an optionally substituted — F . In some embodiments , R¥ is Cl. In some embodi group selected from C1. 20 aliphatic and C 2 heteroaliphatic ments , R ” is — Br. In some embodiments , RÝis — I. In some having 1 - 3 heteroatoms independently selected from nitro - embodiments , R ' is halogen or substituted C1- 20 aliphatic , gen , oxygen , or sulfur. wherein one or more substituent is halogen . In some In certain embodiments , R ' is halogen . In some embodi- 65 embodiments , R ' is halogen or substituted C1- 10 aliphatic , ments , RÝis — F . In some embodiments , Ry is - C1. In some wherein one or more substituent is halogen . In some embodiments , R ” is Br. In some embodiments , Ry is — I . embodiments , Ry is C1 .10 perhaloalkyl. In some embodi US 9 , 850 , 268 B2 43 44 ments , Rºis C1- 10 perfluoroalkyl . In some embodiments , R is naphthyl. In someember embodiments14 , is — CF3. In some embodiments , R ' is C2F5. In some embodiments , each R ' is independently halogen or substituted C1- 10 aliphatic , wherein one or more substitu ent is halogen . In some embodiments , each R ' is indepen (R™ ) , + D dently halogen or C1- 10 perhaloalkyl. In some embodiments , each R ” is independently halogen or C1- 10 perfluoroalkyl. In some embodiments , each R ' is independently halogen . In is 1 -naphthyl . In some embodiments , some embodiments , each R ' is F . In some embodiments , 10 each R ' is independently perfluoroalkyl. In some embodiments , each R ” is identical. In some embodiments , each R ” is different. In some embodiments , ( R ”) , ED two , three , four or five Rº are identical, and optionally mm verk15 different from another R ” . In some embodiments , R is optionally substituted phenyl. is 2 - naphthyl. In some embodiments . In some embodiments , R ' is phenyl. In some embodiments , 20 mot( R™) , + D os is 4 - tert -butyl ) phenyl . In some embodiments , is 2 , 4 , 6 - trimethylphenyl. In some embodiments , Rp(R™ ) - D 30 motw0 m0 ma is 3 , 5 - dimethphenyl. In some embodiments is 2, 4 ,6 - triethylphenyl. In some embodiments , 35 * (RI OH 40 is 3 ,5 -diphenylphenyl . an In some embodiments , Ring D is optionally substituted phenyl. In some embodiments , Ring D is substituted phenyl is 2 , 4 , 6 - triisopropylphenyl. In some embodiments , comprising a 2 ' - substituent . In some embodiments, Ring D is substituted phenyl comprising a 6 - substituent. In some 45 embodiments , Ring D is substituted phenyl comprising a 2 ' and a 6 - substituent . In some embodiments , Ring Dis 2 ' - and 6 '- substituted phenyl. In some embodiments , Ring D is (Rp substituted phenyl comprising a 4 '- substituent. In some min embodiments , Ring D is substituted phenyl comprising a 2 '- , 50 a 4 ' - and a 6 - substituent. In some embodiments, Ring D is 2 - , 4 '- and 6 -substituted phenyl. In some embodiments , is 3 , 5 -di ( tert- butyl) phenyl. In some embodiments , Ring D is substituted phenyl comprising a 3 ' - substituent. In some embodiments , Ring D is substituted phenyl compris ing a 5 ' - substituent . In some embodiments , Ring D is substituted phenyl comprising a 3 '- and a 5 '- substituent. In 55 some embodiments , Ring D is 3' - and 5 '- substituted phenyl. an In some embodiments , each substituent is independently an optionally substituted C - , alkyl. In some embodiments , a substituent is a primary substituent, e . g ., methyl, ethyl, trifluoromethyl, etc . In some embodiments , each substituent is phenyl. In some embodiments , 60 is a primary substituent. In some embodiments, a substituent is a secondary substituent, e . g ., isopropyl, etc . In some embodiments , each substituent is a secondary substituent . In some embodiments , a substituent is a tertiary substituent, (R ? ) p e . g ., tert -butyl , etc . In some embodiments , each substituent < > 0 65 is a tertiary substituent . In some embodiments , each sub stituent is independently an unsubstituted C1- 6 alkyl. In some embodiments , each substituent is independently an unsub US 9 , 850 , 268 B2 45 46 stituted linear C1- 6 alkyl. In some embodiments , each sub embodiments , Ring D is an optionally substituted 8 - 10 stituent is methyl. In some embodiments , each substituent is membered bicyclic heteroaryl ring having 1 -5 heteroatoms ethyl. In some embodiments, each substituent is indepen independently selected from nitrogen , oxygen , or sulfur . dently an unsubstituted branched C1- 6 alkyl . In some In some embodiments , R is R $. In some embodiments , embodiments , each substituent is isopropyl. In some 5 each R is independently halogen , - OR ', - N ( R ') . , NR ' embodiments , each substituent is tert- butyl . In some embodiments , each substituent on Ring D is the same. C ( O ) R ', - NR ' C ( O )OR ', - NR ' C ( O ) N ( R ') 2 , NR 'SO , R ', In some embodiments , Ring D is 2 ' - and 6 -substituted NR 'SO , N ( R ') 2 , - NR 'OR ', or an optionally substituted phenyl, wherein each of the 2 ' - and 6 - substituents is inde group selected from C1- 20 aliphatic and C1- 20 heteroaliphatic pendently C1- 6 alkyl. In some embodiments , Ring D is 2 '- 10 having 1 - 3 heteroatoms independently selected from nitro and 6 - substituted phenyl, wherein each of the 2 '- and gen , oxygen , or sulfur. 6 ' - substituents is methyl. In some embodiments , Ring D is In certain embodiments , R2 is halogen . In some embodi 2 '- and 6 '- substituted phenyl, wherein each of the 2' - and ments , R ’ is F . In some embodiments , R² is Cl. In some 6 - substituents is ethyl. In some embodiments , Ring D is 2 embodiments , R² is - Br. In some embodiments , R2 is - I . and 6 - substituted phenyl, wherein each of the 2 ' - and 15 In certain embodiments , R2 is independently selected 6 - substituents is isopropyl. In some embodiments. Ring D from - OR ', — N ( R ' ) 2 — NR ' C ( O ) R ', - NR ' C ( O )OR ' , is 2 ' -, 4 '- and 6 - substituted phenyl, wherein each of the 2 -, - NR ' C ( O ) N ( R ') 2 , — NR 'SO R ', — NR 'SO2N ( R ') 2 , 4 '- and 6 '- substituents is independently C1- 6 alkyl. In some - NR 'OR ' . embodiments , Ring D is 2 '- , 4 '- and 6 ' - substituted phenyl, In certain embodiments , R ? is optionally substituted C1- 20 wherein each of the 2 ' - . 4 ' - and 6 - substituents is methvl. In 20 aliphatic . In certain embodiments , R2 is optionally substi some embodiments , Ring D is 2 '- , 4 '- and 6 -substituted tuted C -10 aliphatic . In certain embodiments , R2 is option phenyl, wherein each of the 2 ' -, 4 '- and 6 '- substituents is ally substituted C1- 5 aliphatic . In certain embodiments, R ’ is ethyl. In some embodiments , Ring D is 2 '- , 4 '- and 6 '- sub alkyl . In certain embodiments, R2 is selected from methyl, stituted phenyl, wherein each of the 2 ' -. 4 ' - and 6 - substitu - ethyl, propyl, or butyl . In some embodiments, Rºis option ents is isopropyl. In some embodiments , Ring D is 3 '- and 25 ally substituted primary C1- 6 alkyl. In some embodiments , 5 ' -substituted phenyl, wherein each of the 3 ' - and 5 ' - sub - Ris methyl. In some embodiments , Ris ethyl . In some stituents is independently C , alkyl. In some embodiments, embodiments , R is optionally substituted n -alkyl . In some Ring D is 3 ' - and 5 '- substituted phenyl, wherein each of the embodiments , R ' is optionally substituted secondary C1- 6 3 ' - and 5 ' -substituents is independently tertiary C , alkyl. In alkyl . In some embodiments, R is optionally substituted some embodiments, Ring D is 3 ' - and 5 ' - substituted phenyl. 30 isoalkyl. In certain embodiments , R2 is isopropyl. In some wherein each of the 3 ' - and 5 ' - substituents is independently embodiments , R ’ is optionally substituted tertiary aliphatic . tert- butyl . In some embodiments , R2 is optionally substituted tertiary In some embodiments . Ring D is 2 . 4 .6 - trimethylphenyl. C1 - 6 alkyl. In some embodiments , R ? is t -butyl . In some In some embodiments , Ring D is 2 ,4 ,6 - triethylphenyl. In embodiments , R is adamantyl. some embodiments, Ring D is 2 , 4 , 6 - triisopropylphenyl. In 35 In some embodiments , R is optionally substituted some embodiments , Ring D is 3 , 5 - di ( tert - butyl) phenyl. cycloalkyl. In some embodiments, R is optionally substi In some embodiments , Ring D is an optionally substituted tuted heteroaliphatic . In some embodiments , R is optionally group selected from phenyl, an 8 - 10 membered bicyclic aryl substituted heterocyclyl . ring , a 5 - 6 membered monocyclic heteroaryl ring having 1 - 4 . In some embodiments , R ? is substituted , and at least one heteroatoms independently selected from nitrogen , oxygen , 40 substituent is halogen . In some embodiments , Ris substi or sulfur, or an 8 - 10 membered bicyclic heteroaryl ring tuted C1- 20 aliphatic and C1- 20 heteroaliphatic , wherein one having 1 - 5 heteroatoms independently selected from nitro - or more substituent are independently halogen . In some gen , oxygen , or sulfur. In some embodiments , Ring D is an embodiments , R is – CF3. In some embodiments, Ris optionally substituted group selected from phenyl or an 8 - 10 C2F5. In some embodiments , R2 is substituted linear, membered bicyclic aryl ring . In some embodiments , Ring D 45 branched or cyclic aliphatic or heteroaliphatic, wherein one is optionally substituted phenyl. In some embodiments , Ring or more substituents are independently halogen . D is optionally substituted 8 - 10 membered bicyclic aryl. In In certain embodiments, R is optionally substituted C1- 20 some embodiments , Ring D is optionally substituted naph heteroaliphatic having 1 - 3 heteroatoms independently thyl. In some embodiments , Ring D is optionally substituted selected from nitrogen , oxygen , or sulfur. 1 -naphthyl . In some embodiments , Ring Dis 1 -naphthyl . In 50 In someembodiments , R ' is optionally substituted phenyl. some embodiments , Ring Dis optionally substituted 2 -naph In some embodiments , R * is phenyl . thyl. In some embodiments , Ring D is 2 - naphthyl. In some embodiments , In some embodiments , Ring D is an optionally substituted 3 - 7 membered saturated or partially unsaturated carbocyclic ring . In some embodiments , Ring D is an optionally substi - 55 tuted 8 - 10 membered bicyclic saturated , partially unsatu rated or aryl ring . In some embodiments , Ring D is an optionally substituted 5 - 6 membered monocyclic heteroaryl not ring having 1 - 4 heteroatoms independently selected from nitrogen , oxygen , or sulfur. In some embodiments, Ring D 60 is 2 ,4 , 6 -trimethylphenyl . In some embodiments , is an optionally substituted 4 - 7 membered saturated or partially unsaturated heterocyclic ring having 1 - 3 heteroa toms independently selected from nitrogen , oxygen , or sul fur. In some embodiments , Ring D is an optionally substi tuted 7 - 10 membered bicyclic saturated or partially 65 unsaturated heterocyclic ring having 1 - 5 heteroatoms inde pendently selected from nitrogen , oxygen , or sulfur. In some US 9 , 850 , 268 B2 47 48 is 2 , 4 , 6 - triethylphenyl . In some embodiments , is 3 , 5 - dimethylphenyl. In some embodiments , 20 + ( R ), + D wa is 2 ,4 , 6 -triisopropylphenyl . In some embodiments , is 3 , 5 -diphenylphenyl . 10 In some embodiments , each R * is identical . In some embodiments , each R is identical. In some embodiments , each R is identical . In some embodiments, each of Ry and R ? is identical. In some embodiments , each of R *, R¥ and R2 ( K is identical. In some embodiments , Ring C and Ring D are 13 identical. In some embodiments , is 3 ,5 - di( tert- butyl) phenyl . In some embodiments, ( R * ) - C and ( R + D 20» + - - 01 ( R ) a are identical. 25 In some embodiments , Ar is of the formula : is phenyl. In some embodiments , mm

830 ( R ') tc fD + (R )a

moge( R )m is naphthyl. In some embodiments , 735 In some embodiments , Ar is of the formula :

mm (R )a + D + D + (R ) « © no 40 (R™ ), + 0 is 1 - naphthyl. In some embodiments , R *) m -45 In some embodiments , Ar is of the formula : mo( R2) , mm 450 (R™ ) , te ( + ( R ) is 2 - naphthyl. In some embodiments , tes 55 ot In some embodiments , Ar is of the formula : is 4 - tert- butyl ) phenyl . In some embodiments , mam Rp( tC -(( RDR ?) ? motmet · megye(R *) m US 9 , 850, 268 B2 49 50 In some embodiments , Ar is of the formula : In some embodiments , Ar is of the formula

RY RY R ? . ma Rp( D + ( R )

RZ Jonio(Rx )m 10 In certain embodiments wherein Ar is as depicted above , In some embodiments , Ar is of the formula : each R¥ and each R is independently optionally substituted C1- 20 aliphatic . In certain embodiments wherein Ar is as depicted above , each R ” and each R is independently optionally substituted C . 10 aliphatic . In certain embodi ments wherein Ar is as depicted above , each Ry and each R ? is independently optionally substituted C . , alkyl. In certain embodiments wherein Ar is as depicted above , each Ry and each R is independently optionally substituted primary or 20 secondary C1- 6 alkyl. In certain embodiments wherein Ar is as depicted above , each R ” and each R2 is independently optionally substituted primary C - alkyl. In certain embodi ments wherein Ar is as depicted above , each R ” and each R ? In some embodiments , Ar is of the formula : is independently optionally substituted secondary C . , alkyl. 25 In certain embodiments wherein Ar is as depicted above , each R¥ and each R is independently unsubstituted primary or secondary C1- 6 alkyl. In certain embodiments wherein Ar is as depicted above , each Ry and each R is independently Rp( - (R ) unsubstituted primary C1- 6 alkyl. In certain embodiments wherein Ar is as depicted above, each Ry and each R is 30 independently unsubstituted secondary Ci alkyl. Exem plary R™ and R ’ groups include methyl, ethyl, propyl, and ago butyl. In some embodiments , each R ” and each R2 is methyl. In some embodiments , each R¥ and each R ’ is ethyl. In some In some embodiments, Ar is of the formula : embodiments , each Ry and each R is isopropyl. 35 InIn sosome embodiments, Ar is of the formula

man RY R2

40 win aga ? ega RZ In some embodiments , Ar is of the formula : 45 In certain embodiments wherein Ar is as depicted above , each Ry and each R is independently optionally substituted C1- 20 aliphatic . In certain embodiments wherein Ar is as mimo 50 depicted above , each R ” and each R is independently optionally substituted C1- 10 aliphatic . In certain embodi ments wherein Ar is as depicted above , each R¥ and each R ? is independently optionally substituted C - alkyl. In certain ayo embodiments wherein Ar is as depicted above , each Ry and 55 each R ’ is independently optionally substituted primary or secondary C . , alkyl. In certain embodiments wherein Ar is In some embodiments, Ar is of the formula as depicted above , each R ” and each R2 is independently optionally substituted primary C1- 6 alkyl. In certain embodi ments wherein Ar is as depicted above , each R ” and each R ? R RZ 60 is independently optionally substituted secondary C1- 6 alkyl. ma In certain embodiments wherein Ar is as depicted above , each Ry and each R ' is independently unsubstituted primary or secondary C1- 6 alkyl. In certain embodiments wherein Ar is as depicted above, each R¥ and each R is independently Ry R2 65 unsubstituted primary C1- 6 alkyl. In certain embodiments Song wherein Ar is as depicted above , each Ry and each RP is independently unsubstituted secondary C1- 6 alkyl. Exem US 9 ,850 ,268 B2 51 52 plary Rº and R ? groups include methyl, ethyl, propyl, and In certain embodiments , Ar has the following structure: butyl. In some embodiments , each R ” and each R ? is methyl. In some embodiments , each R ' and each R * is ethyl . In some embodiments , each Rº and each R ? is isopropyl . Ph 5 In certain embodiments , Ar has the following structure : mm

Ph Ph . Me Me Me 10 nan d . In certain embodiments , Ar has the following structure : Me b Me 1515 In certain embodiments , Ar has the following structure :

20 Ph Et Et Et Et. wan - Ouvre In certain embodiments , Ar has the following structure : 25

Et t - Bu t - Bu. mm In certain embodiments , Ar has the following structure : 30 ayor

iPr iPr iPr. 35 In some embodiments, R4 is optionally substituted Ar, wanan wherein Ar is

iPr Pr 40 In certain embodimentsose, Ar has the following structure : 45 age Me Me In some embodiments , R4 is

man

50 ma Me bydh Me . ago In certain embodiments , Ar has the following structure : 55DS In some embodiments , R4 is t - Bu t - Bu

60 Me Me Me Me. ni wana

t - Bu * t - Bu .

65 Me Me US 9 , 850 , 268 B2 53 54 In some embodiments , R4 is In some embodiments , R4 is

Et a Et Et man u mi

myBuyEt Bato 10 In some embodiments , R4 is In some embodiments , R4 is iPrPr iPriPriPriPr iPr. 7Y wpwa Y t - Bu . t - Bu . mm

iPr gennaio20 In some embodiments , R * is In some embodiments , Me Me 25 In some embodiments , R4 is optionally substituted C1- 20 aliphatic . In some embodiments , R * is optionally substituted wa C1- 20 alkyl. In some embodiments , R * is C1- 20 alkyl. In some embodiments , R * is C1- 20 haloalkyl. Me. In some embodiments , R4 is optionally substituted C1- 20 Me heteroaliphatic having 1 - 3 heteroatoms independently selected from nitrogen , oxygen , or sulfur. In some embodi ments , R4 is optionally substituted C1-6 heteroaliphatic hav ing 1 - 3 heteroatoms independently selected from nitrogen , In some embodiments , R * is 35 oxygen , or sulfur. In some embodiments, R4 is optionally substituted phe t - Bu t - Bu nyl. In some embodiments , R4 is optionally substituted phenyl comprising a biphenyl moiety . In some embodi ments , R4 is substituted phenyl comprising a 2' - and a 40 6 -substituent . In some embodiments , R4 is substituted phe nyl comprising a 2 ' - and a 6 - substituent, each of which is t - Bu t - Bu . independently a cyclic group . In some embodiments , R4 is substituted phenyl comprising a 2 ' - and a 6 ' -substituent , each of which is independently an aromatic group . In some dovode embodiments , R4 is phenyl. In some embodiments , R4 is In some embodiments , R * is an optionally substituted 3 - 7 membered saturated or partially unsaturated carbocyclic Ph Ph ring . In some embodiments , R4 is an optionally substituted 50 8 - 10 membered bicyclic saturated , partially unsaturated or aryl ring . In some embodiments, R4 is an optionally substi tuted 5 - 6 membered monocyclic heteroaryl ring having 1 - 4 heteroatoms independently selected from nitrogen , oxygen , Ph Ph . or sulfur. In some embodiments , R4 is an optionally substi 55 tuted 4 - 7 membered saturated or partially unsaturated het erocyclic ring having 1 - 3 heteroatoms independently selected from nitrogen , oxygen , or sulfur. In some embodi Deze ments , R * is an optionally substituted 7 - 10 membered bicy In some embodiments , R4 is clic saturated or partially unsaturated heterocyclic ring hav wa ing 1 - 5 heteroatoms independently selected from nitrogen , oxygen , or sulfur . In some embodiments , R * is an optionally substituted 8 - 14 membered bicyclic or tricyclic heteroaryl ring having 1 - 5 heteroatoms independently selected from 65 nitrogen , oxygen , or sulfur. gueroPh In some embodiments , OR4 is an optionally substituted group selected from : US 9 , 850 , 268 B2 | 55 56 - continued A - Rs

R ' W

1 HowM

H" 1 ) " XXXXHA .

15 IN NoSi( R ') C oSi( R ') 3 N

| | M "WW 20) .T?' ? |

? ?

25 oSi.( R ') . OR ! ' Osi.( R ') ? XXXX30)

65666888888886?????????? R ! 35

' RS XXXX4 )

oSi( R '} 3 RS NoSi( R ') 3 45

N PUVVU RS WAH XXXX50) Om R ! Si( R ') 55 . ??? RS

M M M 65 " RS' US 9 , 850 , 268 B2 57 58 - continued R ' , wherein R ' is not hydrogen . In some embodiments , each RS R $ at the o - position of the oxygen bonded to M is indepen dently R ', wherein R ' is an optionally substituted cyclic group . In some embodiments , each R at the o -position of the SORI oxygen bonded to M is independently R ', wherein R ' is an m optionally substituted aromatic group . In some embodi ments , each RS at the o - position of the oxygen bonded to M e is independently R ', wherein R ' is an optionally substituted me tertiary group . In some embodiments , each R ' at the o -po RSV RS 10 sition of the oxygen bonded to M is independently an optionally substituted group selected from phenyl, a 3 - 7 membered saturated or partially unsaturated carbocyclic ring, an 8 - 10 membered bicyclic saturated , partially unsatu OSi ( R ') 3 -RRRRRRRRRRRR $ RS rated or aryl ring , a 5 - 6 membered monocyclic heteroaryl 15 ring having 1- 4 heteroatoms independently selected from nitrogen , oxygen , or sulfur, a 4 - 7 membered saturated or VM partially unsaturated heterocyclic ring having 1 - 3 heteroa toms independently selected from nitrogen , oxygen , or sul fur, a 7 - 10 membered bicyclic saturated or partially unsatu RS 20 rated heterocyclic ring having 1 -5 heteroatoms independently selected from nitrogen , oxygen , or sulfur, or an 8 - 10 membered bicyclic heteroaryl ring having 1 - 5 RS OR OSI( R ') ; heteroatoms independently selected from nitrogen , oxygen , DS w or sulfur. In some embodiments , each RS at the o -position of 25 the oxygen bonded to M is independently an optionally RRRRRRRRRRRRRRR ma substituted group selected from phenyl, an 8 - 10 membered de bicyclic aryl ring , a 5 - 6 membered monocyclic heteroaryl ring having 1 -4 heteroatoms independently selected from nitrogen , oxygen , or sulfur , a 4 - 7 membered saturated or 30 partially unsaturated heterocyclic ring having 1 - 3 heteroa toms independently selected from nitrogen , oxygen , or sul fur, a 7 - 10 membered bicyclic saturated or partially unsatu rated heterocyclic ring having 1 - 5 heteroatoms independently selected from nitrogen , oxygen , or sulfur, or , and 35 an 8 - 10 membered bicyclic heteroaryl ring having 1 - 5 RS heteroatoms independently selected from nitrogen , oxygen , or sulfur. In some embodiments , each R ' at the o -position of the oxygen bonded to M is independently an optionally substituted group selected from phenyl, an 8 - 10 membered 40 bicyclic aryl ring , a 5 -6 membered monocyclic heteroaryl mo ring having 1 - 4 heteroatoms independently selected from nitrogen , oxygen , or sulfur, or an 8 - 10 membered bicyclic heteroaryl ring having 1 - 5 heteroatoms independently selected from nitrogen , oxygen , or sulfur. In some embodi wherein each s represents the point of attachment to nedthe 45 ments , each R $ at the o -position of the oxygen bonded to M metal, M , and each of R $ and R ' is independently as defined 43 is independently optionally substituted phenyl . In some above and described herein . In some embodiments , R at the embodiments , each RS at the O - position of the oxygen 0 -position of the oxygen bonded to Mis Cl, Br, I , or bonded to M is independently optionally substituted 8 - 10 R ', wherein R ' is not hydrogen . membered bicyclic aryl ring . In some embodiments , each RS In some embodiments , R $ at the o -position of the oxygen 50 at the o - position of the oxygen bonded to Mis independently bonded to M optionally substituted 1 - naphthyl. In some embodiments , each RS at the o -position of the oxygen bonded to M is independently optionally substituted 2 - naphthyl. In some n embodiments , each R $ at the o -position of the oxygen 55 bonded to M is independently 1 -substituted naphthyl. In some embodiments , each RS at the o - position of the oxygen permu bonded to M is independently 2 - substituted naphthyl. In some embodiments , each R ' at the o - position of the oxygen bonded to M is independently optionally substituted 5 - 6 min 60 membered monocyclic heteroaryl. In some embodiments , each RS at the o - position of the oxygen bonded to M is is — C1, — Br, — I. In some embodiments , RS at the o - posi- independently optionally substituted 4 - 7 membered satu tion of the oxygen bonded to M is — C1. In some embodi- rated or partially unsaturated heterocyclyl. In some embodi ments , RS at the o - position of the oxygen bonded to M is ments , each RS at the o - position of the oxygen bonded to M — Br. In some embodiments , RS at the o -position of the 65 is independently optionally substituted 8 - 10 membered oxygen bonded to M is — I . In some embodiments , each RS bicyclic heteroaryl. In some embodiments , each RS at the at the o -position of the oxygen bonded to M is independently 0 -position of the oxygen bonded to M is independently US 9 ,850 ,268 B2 59 60 optionally substituted 7 - 10 membered bicyclic saturated or partially unsaturated heterocyclyl . As understood by a per son having ordinary in the art , an optionally substituted group , such as optionally substituted phenyl, can have one or two or more substituents . In some embodiments , the sub - 5 stituents are the same. In some other embodiments , the substituents are not all the same. In some embodiments , each substituent is different . wan In some embodiments , there is R $ at the 3 - or 3 ' -position 10 of R4 comprising a biaryl moiety

15

mun 20 mi mi

In some embodiments , there is Rs at the 3 -position of R4 comprising a biaryl moiety . In some embodiments , there is 25 R $ at the 3 '- position of R4 comprising a biaryl moiety. In some embodiments , there are R at the 3 - and 3 '- positions of R * comprising a biaryl moiety . In some embodiments , R ' is and R '. In some embodiments , R * is optionally substituted C1- 6 | , and aliphatic . In some embodiments , R is optionally substituted min C1- 6 aliphatic ,wherein R * comprises one or more halogen . In mu some embodiments , R is optionally substituted C1- 6 ali phatic , wherein RS comprises one or more — F . In some embodiments , R * is C1- 6 perfluoroaliphatic . In some embodi - 35 ments, R $ is C1- 6 perfluoroalkyl . In some embodiments , R?is - CF3. In some embodiments , R * is optionally substituted C1- 6 alkyl. In some embodiments , R is optionally substi tuted linear C1- 6 alkyl. In some embodiments , R * is option ally substituted branched C . , alkyl. In some embodiments , 40 mm RS is optionally substituted phenyl. In some embodiments , R is optionally substituted 8 - 10 membered bicyclic aryl. In some embodiments , R * is optionally substituted 1 -naphthyl . In some embodiments , R * is optionally substituted 2 - naph - In some embodiments, R * is R7, wherein R7 is Ar' , and Ar thyl. In some embodiments , RS is 1 - substituted naphthyl . In 45 is an optionally substituted group selected from : some embodiments , RS is 2 -substituted naphthyl. In some embodiments , RS is optionally substituted 5 - 6 membered monocyclic heteroaryl ring having 1 - 4 heteroatoms inde pendently selected from nitrogen , oxygen , or sulfur. In some embodiments , RS is optionally substituted 8 - 10 membered 30 bicyclic heteroaryl. In some embodiments , RS is an option m ally substituted 4 - 7 membered saturated or partially unsatu rated heterocyclic ring having 1 - 3 heteroatoms indepen dently selected from nitrogen , oxygen , or sulfur. In some mi embodiments , RS is an optionally substituted 7 - 10 mem bered bicyclic saturated or partially unsaturated heterocyclic ring having 1 - 5 heteroatoms independently selected from nitrogen , oxygen , or sulfur. In some embodiments , RS is selected from — SR ', - S ( O ) R ' , - S ( O ) , R ', wherein each R ' is independently as defined above and described herein . O In some embodiments , at least one _ OR4 is an asym , and metric ligand . In some embodiments , at least one — OR * is w a symmetric ligand . In certain embodiments , at least one - OR4 is a silyl- protected BINOL derivative. 65 In some embodiments , R4 is R7, wherein R7 is Ar' , and Ar is an optionally substituted group selected from : US 9 , 850 , 268 B2 In some embodiments , R4 is Ar. In some embodiments , nitrogen , oxygen , or sulfur, and an 8 - 10 membered bicyclic In some embodiments , R4 is heteroaryl ring having at least one nitrogen and 0 - 4 heteroa toms independently selected from nitrogen , oxygen , or sul fur, wherein the nitrogen atom is deprotonated and bonded 5 to M . In some embodiments , RS is optionally substituted min Nelli , 5 -membered heteroaryl having at least one nitrogen and 0 - 3 Me. heteroatoms independently selected from nitrogen , oxygen , or sulfur, wherein the nitrogen atom is deprotonated and bonded to M . In some embodiments , R is optionally sub Me Me 10 stituted pyrrolyl wherein the nitrogen atom is deprotonated ostro and bonded to M . In some embodiments , R is an optionally substituted In some embodiments , R4 is 5 -membered monocyclic heteroaryl ring having 1 - 2 nitrogen 15 atoms. In some embodiments , R is an optionally substituted 5 - membered monocyclic heteroaryl ring having 1 - 2 nitrogen I atoms, wherein R is bonded to M through a nitrogen atom . EtaEt Etm . In some embodiments , R is an optionally substituted 5 -membered monocyclic heteroaryl ring having 1 - 2 nitrogen atoms. In some embodiments , R is an optionally substituted Et Et 5 -membered monocyclic heteroaryl ring having one nitro gen atom . In some embodiments, Rºis optionally substituted pyrrolyl. In some embodiments , R is optionally substituted In some embodiments , R * is halogen . In some embodi - 1 -pyrrolyl . In some embodiments , R is an optionally sub ments, R is OR “. In some embodiments , R5 is OR ? 25 stituted 5 -membered monocyclic heteroaryl ring having two In some embodiments . R5 is — N ( R ') , — NR ' C ( O ) R ', nitrogen atoms. In some embodiments , R is optionally — NR ' C ( O )OR ', NR ' C ( O ) N ( R ' ) , , - NR 'SO , R ', substituted imidazolyl. In some embodiments , Rºis option - NR 'SO , N ( R ') 2 , or — NR 'OR ', or an optionally substituted ally substituted pyrazolyl. group selected from a 5 -6 membered monocyclic heteroaryl 30 In some embodiments , R? is optionally substituted pyr ring having at least one nitrogen and 0 -3 heteroatoms r olyl. In some embodiments , RS is optionally substituted independently selected from nitrogen , oxygen , or sulfur, a 1 -pyrrolyl . In some embodiments , R? is optionally substi 4 - 7 membered saturated or partially unsaturated heterocy - tuted pyrrolyl having the structure of clic ring having at least one nitrogen and 0 - 2 heteroatoms independently selected from nitrogen , oxygen , or sulfur, a 35 7 - 10 membered bicyclic saturated or partially unsaturated heterocyclic ring having at least one nitrogen and 0 - 4 heteroatoms independently selected from nitrogen , oxygen , mu or sulfur , or an 8 - 10 membered bicyclic heteroaryl ring having at least one nitrogen and 0 - 4 heteroatoms indepen - 40 dently selected from nitrogen , oxygen , or sulfur. In some embodiments , RS is — N (R ') 2 , - NR 'C ( O ) R ', - NR ' C (O ) wherein each of p and Rºis independently as defined above OR ', — NR ' C ( O ) N ( R ' ) 2 , — NR ' SOZR ', — NR 'SO N ( R ') 2 , or and described herein . In some embodiments, R * is disubsti - NR 'OR ', or an optionally substituted group selected from tuted pyrrolyl. In some embodiments , R is disubstituted a 5 -6 membered monocyclic heteroaryl ring having at least us45 pyrrolylP having the structure of one nitrogen and 0 - 3 heteroatoms independently selected from nitrogen , oxygen , or sulfur , a 4 - 7 membered saturated or partially unsaturated heterocyclic ring having at least one nitrogen and 0 - 2 heteroatoms independently selected from nitrogen , oxygen , or sulfur, a 7 - 10 membered bicyclic 50 ni saturated or partially unsaturated heterocyclic ring having at least one nitrogen and 0 - 4 heteroatoms independently selected from nitrogen , oxygen , or sulfur, or an 8 - 10 mem bered bicyclic heteroaryl ring having at least one nitrogen In some embodiments , RS is 2 , 5 - disubstituted pyrrolyl. In and 0 - 4 heteroatoms independently selected from nitrogen , 55 somethe embodiments , R is 2 , 5 - disubstituted pyrrolyl having oxygen , or sulfur, wherein R is bondedselected to M romvia nitrogen ., » the structure of In some embodiments ,R is - N ( R ') 2 . In some embodiments , R is an optionally substituted group selected from a 5 - 6 membered monocyclic heteroaryl ring having at least one nitrogen and 0 - 3 heteroatoms 60 mi independently selected from nitrogen , oxygen , or sulfur, and RY N RY. an 8 - 10 membered bicyclic heteroaryl ring having at least one nitrogen and 0 - 4 heteroatoms independently selected from nitrogen , oxygen , or sulfur. In some embodiments , RS is an optionally substituted group selected from a 5 - 6 65 membered monocyclic heteroaryl ring having at least one In some embodiments , R is 2 , 5 -disubstituted pyrrolyl hav nitrogen and 0 - 3 heteroatoms independently selected from ing the structure of US 9, 850 ,268 B2 63 64

ne N RY, 5 win wherein each of p and R ” is independently as defined above and described herein . In some embodiments , Ris disubsti wherein each R ” is independently R '. In some embodimentsS ,, 10 tuted imidazolyl. In some embodiments , R5 is disubstituted R® is 2 ,5 -disubstituted pyrrolyl having the structure of imidazolyl having the structure of

mi min NR" ,

In some embodiments , R is 2 , 5 - disubstituted imidazolyl. In wherein each R ’ is independently hydrogen or C1-4 aliphaticotic . 20 some embodiments , RS is 2 , 5 - disubstituted imidazolyl hav In some embodiments , R5 is 2 , 5 - disubstituted pyrrolvl hav - ing the structure of ing the structure of

25 winan NR" -Pr N i -Pr . 30 In some embodiments , R is 2 , 5 - disubstituted pyrrolyl hav In some embodiments , R is 2 , 5 - disubstituted pyrrolyl hav - ing the structure of ing the structure of 35

ni wi N RY, Ph , N , Ph . 40

wherein each R ' is independently R ' . In some embodiments , In some embodiments , R? is 85 RSR > is 2 ,5 - disubstituted pyrrolyl having the structure of

ma mi 50 RYN RY,

In some embodiments , R is 55 wherein each R ’ is independently hydrogen or C1- 4 aliphatic . In some embodiments , R is 2, 5 -disubstituted pyrrolyl hav ing the structure of

un

60 Me N Me. ni

i - Pr i - Pr. In some embodiments , R is optionally substituted imi - 65 dazolyl. In some embodiments , R is optionally substituted imidazolyl having the structure of US 9 ,850 ,268 B2 65 66 In some embodiments , R is 2, 5 -disubstituted pyrrolyl hav or partially unsaturated heterocyclic ring having 1 -3 het ing the structure of N eroatoms independently selected from nitrogen , oxygen , or sulfur, a 7 - 10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1 - 5 heteroatoms inde 5 pendently selected from nitrogen , oxygen , or sulfur, or an is 8 - 14 membered bicyclic or tricyclic heteroaryl ring having 1 - 5 heteroatoms independently selected from nitrogen , oxy Ph , N , Ph. gen , or sulfur; and two RP are optionally taken together with the oxygen atoms they are bound to form a bidentate ligand . 10 In some embodiments , each R ' is independently an option ally substituted group selected from - Ar' , C1- 20 aliphatic , In some embodiments , R is optionally substituted pyra - C1- 20 heteroaliphatic having 1 - 3 heteroatoms independently zolyl. In some embodiments , R is optionally substituted selected from nitrogen , oxygen , or sulfur, phenyl, a 3 - 7 pyrazolyl having the structure of 15 membered saturated or partially unsaturated carbocyclic ring, an 8 - 10 membered bicyclic saturated , partially unsatu rated or aryl ring , a 5 - 6 membered monocyclic heteroaryl ring having 1 - 4 heteroatoms independently selected from nitrogen , oxygen , or sulfur, a 4 - 7 membered saturated or 20 partially unsaturated heterocyclic ring having 1 - 3 heteroa toms independently selected from nitrogen , oxygen , or sul fur, a 7 - 10 membered bicyclic saturated or partially unsatu rated heterocyclic ring having 1 -5 heteroatoms wherein each of p and R ' is independently as defined above independently selected from nitrogen , oxygen , or sulfur, or and described herein . In some embodiments , R * is disubstiod 25 an 8 - 14 membered bicyclic or tricyclic heteroaryl ring tuted pyrazolyl. In some embodiments , RS is disubstituted 25 having 1 - 5 heteroatoms independently selected from nitro pyrazolyl having the structure of gen , oxygen , or sulfur. In some embodiments , R7 is Ar' . In some embodiments , R ' is optionally substituted C1- 20 30 aliphatic . In some embodiments , R ? is optionally substituted C1- 20 heteroaliphatic having 1 - 3 heteroatoms independently selected from nitrogen , oxygen , or sulfur . In some embodi w ments , R ' is optionally substituted phenyl. In some embodi ments , R ' is an optionally substituted 3 - 7 membered satu In some embodiments , R is optionally substituted C . 30 35 rated or partially unsaturated carbocyclic ring . In some aliphatic . In some embodiments , R? is optionally substituted embodiments , R ' is an optionally substituted 8 - 10 mem C1- 20 heteroaliphatic having 1 - 3 heteroatoms independently bered bicyclic saturated , partially unsaturated or aryl ring. In selected from nitrogen , oxygen , or sulfur. In some embodi- some embodiments , R ' is optionally substituted 8 - 10 mem ments , R is optionally substituted phenyl. In some embodi - bered aryl. In some embodiments , R ' is optionally substi ments , R™ is an optionally substituted 3 - 7 membered satu - 40 tuted 5 - 6 membered monocyclic heteroaryl having 1 - 4 het rated or partially unsaturated carbocyclic ring . In some eroatoms independently selected from nitrogen , oxygen , or embodiments , Rº is an optionally substituted 8 - 10 mem - sulfur. In some embodiments, R ' is an optionally substituted bered bicyclic saturated , partially unsaturated or aryl ring . In 4 - 7 membered saturated or partially unsaturated heterocy some embodiments , Rº is optionally substituted 8 - 10 mem clic ring having 1 - 3 heteroatoms independently selected bered aryl. In some embodiments, R is optionally substi - 45 from nitrogen , oxygen , or sulfur. In some embodiments , R ? tuted 5 - 6 membered monocyclic heteroaryl having 1 - 4 het is an optionally substituted 7 - 10 membered bicyclic satu eroatoms independently selected from nitrogen , oxygen , or rated or partially unsaturated heterocyclic ring having 1 - 5 sulfur. In some embodiments , Rºis an optionally substituted heteroatoms independently selected from nitrogen , oxygen , 4 - 7 membered saturated or partially unsaturated heterocy - or sulfur. In some embodiments , R ' is optionally substituted clic ring having 1 - 3 heteroatoms independently selected 50 8 -14 membered bicyclic or tricyclic heteroaryl having 1 - 5 from nitrogen , oxygen , or sulfur. In some embodiments , R heteroatoms independently selected from nitrogen , oxygen , is an optionally substituted 7 - 10 membered bicyclic satu - or sulfur. rated or partially unsaturated heterocyclic ring having 1 - 5 In some embodiments , each R ' is independently hydrogen heteroatoms independently selected from nitrogen , oxygen , or an optionally substituted group selected from C1- 20 ali or sulfur. In some embodiments , Rº is optionally substituted 55 phatic , phenyl, a 3 - 7 membered saturated or partially unsatu 8 -14 membered bicyclic or tricyclic heteroaryl having 1 - 5 rated carbocyclic ring , an 8 - 10 membered bicyclic saturated , heteroatoms independently selected from nitrogen , oxygen , partially unsaturated or aryl ring , a 5 - 6 membered monocy or sulfur. clic heteroaryl ring having 1 - 4 heteroatoms independently In some embodiments , each R ? is independently an selected from nitrogen , oxygen , or sulfur , a 4 - 7 membered optionally substituted group selected from Ar ', C1- 20 60 saturated or partially unsaturated heterocyclic ring having aliphatic , C , 2 heteroaliphatic having 1 - 3 heteroatoms inde - 1 - 3 heteroatoms independently selected from nitrogen , oxy pendently selected from nitrogen , oxygen , or sulfur, phenyl, gen , or sulfur, a 7 - 10 membered bicyclic saturated or par a 3 - 7 membered saturated or partially unsaturated carbocy tially unsaturated heterocyclic ring having 1 - 5 heterostoms clic ring , an 8 - 10 membered bicyclic saturated , partially independently selected from nitrogen , oxygen , or sulfur, or unsaturated or aryl ring, a 5 - 6 membered monocyclic het - 65 an 8 - 10 membered bicyclic heteroaryl ring having 1 - 5 eroaryl ring having 1 - 4 heteroatoms independently selected heteroatoms independently selected from nitrogen , oxygen , from nitrogen , oxygen , or sulfur, a 4 - 7 membered saturated or sulfur, wherein : US 9 ,850 ,268 B2 67 68 two R ' groups on the same nitrogen atom are optionally sulfur . In some embodiments , at least one R ' is optionally taken together with the nitrogen atom to form an substituted 4 - 7 membered saturated or partially unsaturated optionally substituted 3 - 8 membered , saturated , par heterocyclic ring having 1 - 3 heteroatoms independently tially unsaturated , or aryl ring having 1 - 4 heteroatoms selected from nitrogen , oxygen , or sulfur. In some embodi independently selected from nitrogen , oxygen , or sul - 5 ments , at least one R ' is optionally substituted 7 - 10 mem fur . bered bicyclic saturated or partially unsaturated heterocyclic In some embodiments , each R ' is independently hydrogen ring having 1 -5 heteroatoms independently selected from or an optionally substituted group selected from C1- 6 ali nitrogen , oxygen , or sulfur. In some embodiments , at least phatic , phenyl, a 3 - 7 membered saturated or partially unsatu one R ' is optionally substituted 8 - 10 membered bicyclic rated carbocyclic ring , an 8 - 10 membered bicyclic saturated , 10 heteroaryl ring having 1 - 5 heteroatoms independently partially unsaturated or aryl ring , a 5 - 6 membered monocy selected from nitrogen , oxygen , or sulfur. clic heteroaryl ring having 1 - 4 heteroatoms independently As generally defined above, R2' and R are taken together selected from nitrogen , oxygen , or sulfur, a 4 - 7 membered with their intervening metal atom to form an optionally saturated or partially unsaturated heterocyclic ring having substituted 3 - 8 membered saturated or partially unsaturated 1 - 3 heteroatoms independently selected from nitrogen , OxV - 15 ring having , in addition to the intervening metal atom , 0 - 4 gen , or sulfur , a 7 - 10 membered bicyclic saturated or par heteroatoms independently selected from nitrogen , oxygen , tially unsaturated heterocyclic ring having 1 - 5 heteroatoms or sulfur. In some embodiments , R2 and R3. are taken independently selected from nitrogen , oxygen , or sulfur, or together with their intervening metal atom to form an an 8 - 10 membered bicyclic heteroaryl ring having 1 - 5 optionally substituted 3 - 8 membered saturated ring having , heteroatoms independently selected from nitrogen , oxygenn ., 20 in! addition to the intervening metal atom , 0 -4 heteroatoms or sulfur, wherein : independently selected from nitrogen , oxygen , or sulfur. In two R ' groups on the same nitrogen atom are optionally some embodiments , R2 and R3 are taken together with their taken together with the nitrogen atom to form an intervening metal atom to form an optionally substituted 3 - 8 optionally substituted 3 - 8 membered , saturated , par membered metallocycloalkane ring . In some embodiments , tially unsaturated , or aryl ring having 1 - 4 heteroatoms 25 R2 and R * are taken together with their intervening metal independently selected from nitrogen , oxygen , or sul atom to form an optionally substituted 3 -4 membered met fur. allocycloalkane ring . In some embodiments , R2 and R3' are In some embodiments , each R ' is independently option taken together with their intervening metal atom to form an ally substituted C - 20 aliphatic . In some embodiments , each optionally substituted metallacyclopropane ring . In some R ' is independently optionally substitutedC aliphatic . In 30 embodiments , R and R are taken together with their some embodiments , each R ' is independently optionally intervening metal atom to form an optionally substituted substituted C1- 6 alkyl. In some embodiments , each R ' is metallacyclobutane ring . In some embodiments , each ring independently optionally substituted C1- 6 haloalkyl. In some carbon atom is independently optionally substituted . In embodiments , each R ' is independently optionally substi some embodiments, each ring carbon atom is unsubstituted . tuted C , haloalkyl, wherein one substituent is F . In some 35 In some embodiments , one or more ring carbon atoms are embodiments , each R ' is independently optionally substi - substituted . tutedC haloalkyl, wherein two or more substituents are In some embodiments , a provided catalyst or metal com - F . In certain embodiments , at least one R ' is independently plex is : selected from methyl, ethyl, propyl, or butyl. In certain embodiments, at least one R * is isopropyl. In certain embodi- 40 mentsm , at least one R ' is _ CFz . 2-T In some embodiments , at least one R ' is hydrogen . In some embodiments , at least one R ' is independently selected PS from an optionally substituted group selected from C1- 6 KMRS | SIG3. aliphatic , phenyl, a 3 - 7 membered saturated or partially 45 R40 unsaturated carbocyclic ring , an 8 - 10 membered bicyclic saturated , partially unsaturated or aryl ring , a 5 - 6 membered monocyclic heteroaryl ring having 1 - 4 heteroatoms inde - InII some embodiments , a provided metal complex is pendently selected from nitrogen , oxygen , or sulfur, a 4 - 7 membered saturated or partially unsaturated heterocyclic 50 ring having 1 - 3 heteroatoms independently selected from nitrogen , oxygen , or sulfur , a 7 -10 membered bicyclic G saturated or partially unsaturated heterocyclic ring having S=Z 1 - 5 heteroatoms independently selected from nitrogen , oxy R G3 gen , or sulfur, or an 8 - 10 membered bicyclic heteroaryl ring 55 R40 having 1 - 5 heteroatoms independently selected from nitro G2 gen , oxygen , or sulfur. In some embodiments , at least one R ' is optionallyally subsuh . In some embodiments , a provided metal complex is stitutedC aliphatic . In some embodiments , at least one R ' is optionally substituted phenyl. In some embodiments , at 60 least one R ' is optionally substituted 3 - 7 membered saturated 2 or partially unsaturated carbocyclic ring . In some embodi ments, at least one R ' is optionally substituted 8 - 10 mem bered bicyclic saturated , partially unsaturated or aryl ring . In RM G3 some embodiments , at least one R ' is optionally substituted 65 5 - 6 membered monocyclic heteroaryl ring having 1 - 4 het R* O * eroatoms independently selected from nitrogen , oxygen , or US 9 ,850 , 268 B2 69 Exemplary embodiments for G , G², G3, R3, R4, and R are 3 . R = described below , which can be optionally substituted . G -- Gº =any alkyl ( e. g. ,Me ) or aryl (e . g ., Ph ) G ', G2 and Gºmight be identical or any combination of the 5 above 1 . M = Mo or W 2 . R3 = 10 X Y X Z

t - Bu - N X Z N X y 15 0 . 020 PERN

20 N . NX N X

X Y XZ 22. 06 25 $ a od N N . Y N N

30 X , Y , Z and L might be identical, or four different substitu ents, or any 2 ( e. g ., X = Y or Y = Z ) or any 3 (e . g ., X = Y = 2 ) might be 35 identical y Nx 4 . OR4porno= momento I 40 ¢ + X 1 PO PO

of x 45 I 7888 N PO 50

55 X , Y , Z , L and Q might be identical , or five different PO substituents , or any 2 ( e . g . , X = Y or Y = Z ) or any 3 ( e . g . , X = Y = Z ) might be identical , or only one might be different than the other four. og X , Y , Z , L and Q might be H , F , Cl, Br, I, Me , Et, or any other n - alkyl, i- Pr or any other i- alkyl , Cy or any other cycloalkyl stor or heterocyclic , t -Bu , adamantyl or any quaternary carbon PO PO containing substituent . X , Y , Z , L and Q might be CF3, C2Fs as or any linear, branched , cyclic or heterocyclic halogenated substituent. US 9 ,850 ,268 B2 71 72 - continued alkyl , Ph , any mono - , di- , tri -, or tetra - substituted aryl ( all isomers ) with substituents being the same as for X / Y , 1 - or Y X 2 -substituted naphthyl or any 0 -, N -, or S -containing het erocycle . X and /or Y might be S -based ( sulfide , sulfoxide or 5 sulfone ). PO R®, R7, RS, R " , R10 ,R1 , R12 , R13 , and R14 = H , F , CI, Br, I, CF3, or any linear or branched hydrocarbon , Me, or any linear or branched alkyl, Ph , any mono - , di- , tri- , or tetra substituted aryl (all isomers ) with substituents , 1 - or 2 - sub 10 stituted naphthyl or any 0 - , N -, or S - containing heterocycle . R®, R7, R8, R9 , R10, R11 , R12 , R13 , and R14 might be S -based ?? ( sulfide , sulfoxide , or sulfone) . R ” , R7, RS, and Rº might be identical or different in any possible combination . The same identification field may apply as indicated with X and Y above . R10, R11, R12 , R13 and R 14 might be identical or different in RO any possible combination . The same identification field may enÃLA apply as indicated with X and Y above . PO L might be Ph , any mono - , di- , tri - , or tetra -substituted aryl pe R : 20 ( all isomers ) with substituents , 1 - or 2 - substituted naphthyl Rui RSR or any O - , N -, or S - containing heterocycle . Z , Q , and G might be identical, or three different substitu ents , or any 2 ( e . g . , Z = Q or Q = G ) might be identical. Po Y R12 Z , Q , and G might be H , F , C1, Br , I , CF3, or any linear or branched hydrocarbon , Me or any linear or branched alkyl, R : 21 R13 Ph , any mono -, di- , tri - , or tetra -substituted aryl ( all isomers ) R14R1 with substituents , 1 - or 2 - substituted naphthyl or any O - , N - , R11 or S -containing heterocycle . Z , Q , and G might be S -based Rio ( sulfide , sulfoxide or sulfone ). 30 In some embodiments , each of G ' , G , and G3 is inde R12 R12 pendently R '. In some embodiments , each of G ' , G², and Gº is independently an optionally substituted group selected from alkyl and aryl. In some embodiments , each of G !, G² , R13 R R13 and Gº is independently an optionally substituted group IN has - 35 selected from alkyl and phenyl. N In some embodiments , when R is part of an imido group Ril Rui as depicted above , R is R '. In some embodiments , R * is R10 Rio om optionally substituted tertiary aliphatic. In some embodi R12 R12R127 ments , R is optionally substituted tertiary alkyl such as L L 40 tert- butyl . In some embodiments , R3 is optionally substi tuted tertiary cycloalkyl. In some embodiments , R * is ada R13 mantyl . In some embodiments , R3 is optionally substituted R R N phenyl as depicted above . In some embodiments , R * is phenyl with 1 , 2 , 3 , 4 , or 5 substituents . In some embodi Q 45 ments, a substituent is X , Y , Z , L or Q . When multiple substituents are present, they can either all be the same, or RI some of them are the same, or each of them is different . In R 12 R12 some embodiments , two or three substituents are identical. L In some embodiments, four substituents are the same and are 50 different from the fifth one . R13 R13 As understood by a person having ordinary skill in the art , O R14 Z each of X , Y , Z , L and can independently be various TN suitable substituent groups . In some embodiments , X is Rs. In some embodiments , X Rul R 55 is R '. In some embodiments , X is optionally substituted C1- 6 aliphatic . In some embodiments , Y is optionally substituted R12 Ci- cycloaliphatic . In some embodiments, Y is optionally substituted C1- 6 cycloalkyl . In some embodiments , X is optionally substituted C - aliphatic , wherein Rs comprises R13 60 one or more halogen . In some embodiments , X is optionally R 14 substituted C1- 6 aliphatic , wherein R * comprises one ormore - F . In some embodiments , X is C - 6 perfluoroaliphatic . In some embodiments , X is C1- 6 perfluoroalkyl. In some embodiments , X is _ CFz. In some embodiments , X is X might be the same or different from Y . 65 optionally substituted C1- 6 alkyl. In some embodiments , X is X and/ or Y = H , F , C1, Br, I , CF3, or any linear or branched optionally substituted linear C1- 6 alkyl . In some embodi F -containing hydrocarbon , Me or any linear or branched ments , X is optionally substituted branched C1- 6 alkyl. In US 9 , 850 , 268 B2 73 74 some embodiments , X is optionally substituted phenyl. In partially unsaturated carbocyclic ring, an 8 - 10 membered some embodiments , X is optionally substituted 8 -10 mem - bicyclic saturated , partially unsaturated or aryl ring , a 5 - 6 bered bicyclic aryl. In some embodiments , X is optionally membered monocyclic heteroaryl ring having 1 -4 heteroa substituted 1 -naphthyl . In some embodiments , X is option toms independently selected from nitrogen , oxygen , or sul ally substituted 2 - naphthyl . In some embodiments , X is 5 fur, a 4 - 7 membered saturated or partially unsaturated het 1 -substituted naphthyl. In some embodiments , X is 2 - sub erocyclic ring having 1 - 3 heteroatoms independently stituted naphthyl. In some embodiments , X is optionally selected from nitrogen , oxygen , or sulfur, a 7 - 10 membered substituted 5 - 6 membered monocyclic heteroaryl ring hav ing 1 -4 heteroatoms independently selected from nitrogen , bicyclic saturated or partially unsaturated heterocyclic ring oxygen , or sulfur. In some embodiments, X is optionally 10 having 1 - 5 heteroatoms independently selected from nitro substituted 8 - 10 membered bicyclic heteroaryl. In some gen , oxygen , or sulfur , or an 8 - 10 membered bicyclic embodiments , X is an optionally substituted 4 - 7 membered heteroaryl ring having 1 - 5 heteroatoms independently saturated or partially unsaturated heterocyclic ring having selected from nitrogen , oxygen , or sulfur. In some embodi 1 - 3 heteroatoms independently selected from nitrogen , oxy ments , L is an optionally substituted group selected from ge n or sulfur. In some embodiments . X is an optionally 15 phenyl, an 8 -10 membered bicyclic aryl ring, a 5 -6 mem substituted 7 - 10 membered bicyclic saturated or partially bered monocyclic heteroaryl ring having 1 - 4 heteroatoms unnsaturated heterocyclic ring having 1 - 5 heteroatoms inde independently selected from nitrogen , oxygen , or sulfur, a pendently selected from nitrogen , oxygen , or sulfur. In some 4 - 7 membered saturated or partially unsaturated heterocy embodiments , X is selected from SR ', - S ( O ) R ', clic ring having 1 - 3 heteroatoms independently selected - S (O )2R ', wherein each R ' is independently as defined 20 from nitrogen , oxygen , or sulfur, a 7 - 10 membered bicyclic above and described herein . saturated or partially unsaturated heterocyclic ring having In some embodiments , Y is R $. In some embodiments , Y 1 -5 heteroatoms independently selected from nitrogen , oxy is R '. In some embodiments , Y is optionally substituted C1- 6 gen , or sulfur, or an 8 - 10 membered bicyclic heteroaryl ring aliphatic . In some embodiments , Y is optionally substituted having 1 - 5 heteroatoms independently selected from nitro Ci- cycloaliphatic . In some embodiments, Y is optionally 25 gen , oxygen , or sulfur. In some embodiments , L is an substituted C1- 6 cycloalkyl. In some embodiments , Y is optionally substituted group selected from phenyl , an 8 - 10 optionally substituted C1- 6 aliphatic , wherein R $ comprises membered bicyclic aryl ring , a 5 -6 membered monocyclic one or more halogen . In some embodiments , Y is optionally heteroaryl ring having 1 - 4 heteroatoms independently substitutedC aliphatic , wherein RS comprises one or more selected from nitrogen , oxygen , or sulfur , or an 8 - 10 mem - F . In some embodiments , Y is C , - perfluoroaliphatic . In 30 bered bicyclic heteroaryl ring having 1 - 5 heteroatoms inde some embodiments , Y is Cico perfluoroalkyl. In some pendently selected from nitrogen , oxygen , or sulfur. In some embodiments , Y is — CFz . In some embodiments , Y is embodiments , L is optionally substituted phenyl. In some optionally substituted C1- 6 alkyl. In some embodiments , Y is embodiments , L is optionally substituted 8 - 10 membered optionally substituted linear C1- 6 alkyl . In some embodi - bicyclic aryl ring . In some embodiments , L is optionally ments , Y is optionally substituted branched Ci , alkyl. In 35 substituted 1 - naphthyl. In some embodiments , L is option some embodiments, Y is optionally substituted phenyl. In ally substituted 2 - naphthyl. In some embodiments , L is some embodiments , Y is optionally substituted 8 - 10 mem - 1 -substituted naphthyl. In some embodiments , L is 2 - sub bered bicyclic aryl. In some embodiments , Y is optionally stituted naphthyl . In some embodiments , L is optionally substituted 1 - naphthyl. In some embodiments , Y is option - substituted 5 -6 membered monocyclic heteroaryl. In some ally substituted 2 - naphthyl. In some embodiments , Y is 40 embodiments , L is optionally substituted 4 - 7 membered 1 - substituted naphthyl. In some embodiments , Y is 2 - sub - saturated or partially unsaturated heterocyclyl. In some stituted naphthyl. In some embodiments , Y is optionally embodiments , L is optionally substituted 8 - 10 membered substituted 5 -6 membered monocyclic heteroaryl ring hav bicyclic heteroaryl. In some embodiments , L is optionally ing 1 - 4 heteroatoms independently selected from nitrogen , substituted 7 - 10 membered bicyclic saturated or partially oxygen , or sulfur. In some embodiments , Y is optionally 45 unsaturated heterocyclyl. substituted 8 - 10 membered bicyclic heteroaryl. In some Z , Q and G can each independently be any suitable embodiments , Y is an optionally substituted 4 - 7 membered substituents . In some embodiments , each of Z , Q and G is saturated or partially unsaturated heterocyclic ring having independently a substituent as described herein for X and /or 1 - 3 heteroatoms independently selected from nitrogen , oxy . Y . In some embodiments , each of Z , Q and G is indepen gen , or sulfur. In some embodiments , Y is an optionally 50 dently RS. Z , Q and G can either be the same or different substituted 7 - 10 membered bicyclic saturated or partially from one another. unsaturated heterocyclic ring having 1 -5 heteroatoms inde - R ", R ? , R8, R9, R1 , R1, R12 , R13 and R14 can each pendently selected from nitrogen , oxygen , or sulfur. In some independently be any suitable substituents . In some embodi embodiments , Y is selected from SR ', - S ( O ) R ', ments , each of R " , R7, R8, R " , R10 ,R1 , R12 , R13 and R14 is - S ( O ) 2R ', wherein each R ' is independently as defined 55 independently a substituent as described herein for X and / or above and described herein . Y . In some embodiments , each of R , R ? , R8, R9, R10 , R11 , In some embodiments , L is — Cl, Br, or — I. In some R12, R13 and R14 is independently RS. R " , R ? , R8, R9 , R10, embodiments , L is - C1. In some embodiments , L is — Br. R1, R12 , R13 and R14 can either be the same or different In some embodiments , L is — I . In some embodiments , L is from one another . R ' , wherein R ' is not hydrogen . 60 As understood by a person having ordinary skill in the art, In some embodiments , L is R ', wherein R ' is an optionally P can be any suitable group , for example but not limited to substituted cyclic group . In some embodiments , L is R ', any suitable protecting groups. In some embodiments , P is wherein R ' is an optionally substituted aromatic group . In Rø. some embodiments , L is R ' , wherein R ' is an optionally In some embodiments , each of the variables is indepen substituted tertiary group . 65 dently as described in US Patent Application Publication In some embodiments , L is an optionally substituted US2012 /0323000 , incorporated herein by reference , both group selected from phenyl, a 3 -7 membered saturated or individually and in combination . US 9 ,850 ,268 B2 75 76 Exemplary catalysts or metal complexes include but are -continued not limited to those listed below : F

a

N 11111 Ph , ? NIITTI .. Mo =

NUT . Mo , 11 | | Ph .

Br á

OTBS

F ? F

F Z

NIlllllllMot MilliPh NIIN . Mon til Ph ,

111 e O Me 30 Me Mellin Men 30

Me Me 35 F -

T

F 40

NI .. . Mon Ph NINI. Mo Ull Ph

45 Et OE Et Et EtlitustEt - Et,

Et 50 79 - F F

55 YE FF Y F

NINTE .. Mos " Ph M . Mon 11111 Ph 60

..1111li Wi- PriPr -Proin i -Pr - Pr, tBu - Bu ,

65 i - Pr i- Pr US 9 , 850 , 268 B2 77 78 provided method has the structure of a product from the - continued metathesis between the olefin of the first species and the olefin of the second species . In some embodiments, a first species of a provided olefin 5 metathesis method is an alkenyl halide , wherein each carbon FF Y of the alkene group is independently substituted with a halogen atom . In some embodiments , the two halogen atoms - N on the two carbon atoms of the double bond are cis . In some embodiments , the two halogen atoms on the two carbon NUT. . Mos ll Ph atomsof the double bond are cis , and the at least one product comprises a carbon atom from the olefin of the first species and the halogen atom attached to the carbon atom , and the at least one product is produced with Z - selectivity . In some embodiments , the olefin in the first species is Z with respect Me Me , to a halogen substituent on the first carbon atom of the olefin and a halogen substituent on the second carbon atom of the olefin . In some embodiments, the olefin in the first species is E with respect to a halogen substituent on the first carbon 20 atom of the olefin and a halogen substituent on the second carbon atom of the olefin . In some embodiments, the olefin in the first species is Z F with respect to a halogen substituent on the first carbon atom N of the olefin and a halogen substituent on the second carbon atom of the olefin . In some embodiments , a first species has MITTT .Mon till Ph the structure of ph

30 Ph Ph , and wherein each of X and Y is independently halogen . In some F embodiments , each of X and Y is _ C1. In some embodi ments , one of X and Y is — F and the other is C1. In some embodiments , one of X and Y is - F and the other is — Br. In some embodiments , the olefin of the second species comprises one or more substituents . In some embodiments , F each substituent is independent R ' , wherein R ' is an option ally substituted group selected from C1- 20 aliphatic , C1- 20 N 40 heteroaliphatic having 1 - 5 heteroatoms independently NITn .Mo , Ph selected from boron , silicon , phosphorus , nitrogen , oxygen , or sulfur, phenyl, a 3 - 7 membered saturated or partially tBu 11011ctBu unsaturated carbocyclic ring , an 8 - 10 membered bicyclic saturated , partially unsaturated or aryl ring, a 5 - 6 membered 45 monocyclic heteroaryl ring having 1 - 4 heteroatoms inde tBu tBu . pendently selected from boron , silicon , phosphorus, nitro gen , oxygen , or sulfur, a 4 - 7 membered saturated or partially unsaturated heterocyclic ring having 1 - 5 heteroatoms inde pendently selected from boron , silicon , phosphorus , nitro In some embodiments , the present disclosure provides 50 gen , oxygen , or sulfur, a 7 - 10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1 -5 het methods for metathesis reactions. In some embodiments , the eroatoms independently selected from boron , silicon , phos present disclosure provides a method , comprising : phorus , nitrogen , oxygen , or sulfur, or an 8 - 10 membered reacting a first species comprising an olefin with a second bicyclic heteroaryl ring having 1 - 5 heteroatoms indepen species comprising an olefin in the presence of a 55 dently selected from boron , silicon , phosphorus, nitrogen , catalyst or metal complex to provide at least one oxygen , or sulfur. In some embodiments , a second species of product comprising an olefin , wherein : a provided olefin metathesis method comprises a terminal each carbon atom of the olefin in the first species is olefin . In some embodiments , a second species has the structure of R - CH = CH2. In some embodiments , a second substituted with at least one halogen ; and 60 species has the structure of R - CH = CH2. In some the olefin in the at least one product comprises a carbon embodiments , a second species has the structure of atom from the first species and a carbon atom from the R1 _ CH = CH . , wherein R1 is an optionally substituted second species. group selected from C1- 20 aliphatic , C1- 20 heteroaliphatic In some embodiments , the present disclosure provides a having 1 - 3 heteroatoms independently selected from nitro method for olefin metathesis , comprising providing a cata - 65 gen , oxygen , or sulfur, phenyl , a 3 -7 membered saturated or lyst or metal complex has the structure of formula II - a or partially unsaturated carbocyclic ring , an 8 - 10 membered II -b . In some embodiments , the at least one product in a bicyclic saturated , partially unsaturated or aryl ring , a 5 - 6 US 9 ,850 ,268 B2 79 80 membered monocyclic heteroaryl ring having 1 - 4 heteroa eroatoms independently selected from boron , silicon , phos toms independently selected from nitrogen , oxygen , or sul phorus, nitrogen , oxygen , or sulfur, or an 8 - 10 membered fur, a 4 - 7 membered saturated or partially unsaturated het bicyclic heteroaryl ring having 1 - 5 heteroatoms indepen erocyclic ring having 1 - 3 heteroatoms independently dently selected from boron , silicon , phosphorus, nitrogen , selected from nitrogen , oxygen , or sulfur. a 7 - 10 membered 5 oxygen , or sulfur. In some embodiments , a second species of a provided olefin metathesis method comprises a terminal bicyclic saturated or partially unsaturated heterocyclic ring olefin . In some embodiments , a second species has the having 1 - 5 heteroatoms independently selected from nitro structure of R - CH = CH , . In some embodiments , a second gen , oxygen , or sulfur, or an 8 - 10 membered bicyclic species has the structure of R - CH CH , . In some heteroaryl ring having 1 - 5 heteroatoms independently embodiments , a second species has the structure of selected from nitrogen , oxygen , or sulfur. R - CH = CH , , wherein R is an optionally substituted In some embodiments , a first species of a provided olefin group selected from C1- 20 aliphatic , C1. 20 heteroaliphatic metathesis method is an alkenyl halide, wherein each carbon having 1 - 3 heteroatoms independently selected from nitro of the alkene group is independently substituted with a gen , oxygen , or sulfur, phenyl, a 3 - 7 membered saturated or partially unsaturated carbocyclic ring, an 8 - 10 membered halogen atom . In some embodiments , the two halogen atoms 15 bicyclic saturated , partially unsaturated or aryl ring , a 5 - 6 on the two carbon atoms of the double bond are cis . In some membered monocyclic heteroaryl ring having 1 - 4 heteroa embodiments , the two halogen atoms on the two carbon toms independently selected from nitrogen , oxygen , or sul atoms of the double bond are cis , and the at least one product fur , a 4 - 7 membered saturated or partially unsaturated het comprises a carbon atom from the olefin of the first species erocyclic ring having 1 - 3 heteroatoms independently and the halogen atom attached to the carbon atom , and the 20 selected from nitrogen , oxygen , or sulfur, a 7 - 10 membered at least one product is produced with Z - selectivity . In some bicyclic saturated or partially unsaturated heterocyclic ring embodiments , the two halogen atoms on the two carbon having 1 -5 heteroatoms independently selected from nitro atoms of the double bond are trans. In some embodiments , gen , oxygen , or sulfur, or an 8 - 10 membered bicyclic the two halogen atoms on the two carbon atoms of the heteroaryl ring having 1 - 5 heteroatoms independently double bond are trans , and the at least one product comprises 25 selected from nitrogen , oxygen , or sulfur. a carbon atom from the olefin of the first species and the In some embodiments, a provided exemplary method is halogen atom attached to the carbon atom , and the at least selected from a reaction described below : one product is produced with E - selectivity . In some embodiments , the olefin in the first species is E with respect to a halogen substituent on the first carbon atom 30 Mo- or of the olefin and a halogen substituent on the second carbon W -based X complex XO atom of the olefin . In some embodiments , a first species has x the structure of Mo- or W - based 01 - 02 X 35 X Y Q1 - Q2 complex X

Mo - or Q W - based complex wherein each of X and Y is independently halogen . In some X Y + 01 03 embodiments, a first species has the structure of 40

03 Mo- or on- l W -based complex 45 x y + ö-õ wherein each of X and Y is independently halogen . In some on - 1 embodiments, each of X and Y is Cl. In some embodi X * 01 Mo - or W -based complex ments , one of X and Y is — F and the other is Cl. In some 50 embodiments , one of X and Y is — and the other is — Br . In some embodiments , the olefin of the second species - In comprises one or more substituents . In some embodiments , each substituent is independent R ', wherein R is an option ally substituted group selected from C1- 20 aliphatic , C1- 20 55 heteroaliphatic having 1 - 5 heteroatoms independently selected from boron , silicon , phosphorus, nitrogen , oxygen , ------In or sulfur, phenyl, a 3 - 7 membered saturated or partially unsaturated carbocyclic ring , an 8 - 10 membered bicyclic In some embodiments , X and Y might be identical or saturated , partially unsaturated or aryl ring , a 5 - 6 membered 60 different; they may be H , F, C1, Br, I; they must not be H at monocyclic heteroaryl ring having 1 - 4 heteroatoms inde - the same time. In some embodiments , each of X is - C1 . pendently selected from boron , silicon , phosphorus, nitro - In some embodiments , Q1, Q², Q , . . . , 0 " - 1, Q ” , L ', L ?, gen , oxygen , or sulfur, a 4 -7 membered saturated or partially L ’ , . . . , L " - 1 , L " mightbe any secondary carbon containing unsaturated heterocyclic ring having 1 - 5 heteroatoms inde - substituent, tertiary carbon containing substituent, quater pendently selected from boron , silicon , phosphorus, nitro - 65 nary carbon containing substituent, aromatic groups, or O , gen , oxygen , or sulfur, a 7 - 10 membered bicyclic saturated N - , S - , Si- , B -, P - containing group , or heterocyclic substitu or partially unsaturated heterocyclic ring having 1 -5 het ent. US 9 , 850 , 268 B2 82 In some embodiments, n is an integer greater than 4 . In as the first species selectively82 produced some embodiments , n = 4 , 5 , 6 , . . . + 00 . In some embodi thefirst species sela ments, n is 4 - 10 . In some embodiments , n is 4 - 20 . In some !? embodiments , n is 4 -30 . In some embodiments , n is 4 -50 . In and some embodiments , n is 4 - 50 for Q . 55 In some embodiments , Z , Q , L might be any secondary carbon containing substituent, tertiary carbon containing over substituent, quaternary carbon containing substituent, aro matic groups, O , N - , S -, Si- , B -, P - containing group , or 10 R2 heterocyclic substituent. and In some embodiments , m is an integer . In some embodi ments , m = 0 , 1, 2 , 3 , . . . + 00 . In some embodiments , mis 0 - 10 . In some embodiments , m is 0 - 20 . 3)Šos In some embodiments , n is an integer . In some embodi ments , n = 0 , 1 , 2 , 3 , . . . too . In some embodiments , n is 0 - 10 for L . In some embodiments , n is 0 - 20 for L . and Š In some embodiments , a provided method is depicted below : 20 overover Y Ri R 2 Mo- or W -based complex R X R2 Y 25 and Š

In some embodiments , a provided method is depicted with below : 30

P Mo - or W -based complex * 35

X as the first species) . In some embodiments , provided meth ods selectively provide a product comprising a double bond , wherein one carbon atom of the double bond is the first 40 carbon atom of the olefin of the first species, wherein the halogen on the first carbon atom of the olefin of the first R , might be the same or different from R . X and / or Y = H , species is smaller than the halogen on the second carbon F , C1, Br, I ; they must not be H at the same time. In some atom of the olefin of the first species, and the other carbon embodiments , R1, R2= H or any linear or branched hydro atom of the double bond is the first carbon atom of the olefin carbon , Me, or any linear or branched alkyl, Ph , any mono - , 45 of the second species, wherein the substituent on the first di- , tri - , or tetra - substituted aryl ( all isomers ) with substitu carbon atom of the olefin of the second species is larger than ents , 1 - or 2 - substituted naphthyl or any O -, N -, or S - con the substituent on the second carbon atom of the olefin of the second species . In some embodiments , each olefin carbon taining heterocycle . In some embodiments , R1, R2 might be atom maintains its substituents after the reaction into prod N -, S - , Si- , B -, P -based group , e . g, in some embodiments , ucts . For example , in some embodiments , substituents on the the second species can be R ' . In some embodiments , each of 50 first and second carbon atoms of the olefins in the first R , and R , is independently R '. species and the second species do not change when such In some embodiments , provided methods provide regi carbon atoms are re - arranged to form products . In some oselectivity when the first carbon atom of the olefin in the embodiments , a second species comprises a terminal olefin first species has a different halogen substituent than the wherein the terminal double bond has only one unsubstituted second carbon atom of the olefin in the first species , and the 55 carbon atom ( CH2) , and provided methods selectively first carbon atom of the olefin in the second species has provide a product by replacing the = CH , moiety with the different substituents than the second carbon atom of the first carbon atom of the olefin in the first species and its olefin in the second species, in that, among all possible substituents , wherein the halogen on the first carbon atom of metathesis products , provided methods selectively provide the olefin of the first species is smaller than the halogen on products from one potential metathesis pathway . For 60 the second carbon atom of the olefin of the first species. For the above depicted reaction , in some embodiments , R , is example , the cross metathesis reaction depicted above with sterically larger than R2 . In some embodiments , R2 is hydro gen . In some embodiments , Y is sterically larger than X . In some embodiments , X is F . In some embodiments , Rj is 65 sterically larger than R2, and Y is sterically larger than X . In some embodiments , R , is hydrogen , X is — F , and Y is — C1 or - Br. In some embodiments , R , is hydrogen , X is F , US 9 ,850 ,268 B2 83 84 and Y is Cl. In some embodiments , R2 is hydrogen , X is In some embodiments , a second species has the structure of - F , and Y is - Br. When X is – F and Y is Cl or — Br, R ? — C = CH . In some embodiments , a second species has provided methods provide efficient synthesis of alkenyl the structure of R ? — C = CH , wherein Ri is an optionally fluoride. Such methods provide various benefits including substituted group selected from C1- 20 aliphatic , C1- 20 het but not limited to avoiding unstable and / or expensive sub - 5 eroaliphatic having 1 - 3 heteroatoms independently selected strates such as from nitrogen , oxygen , or sulfur, phenyl, a 3 - 7 membered saturated or partially unsaturated carbocyclic ring , an 8 - 10 membered bicyclic saturated , partially unsaturated or aryl ring , a 5 - 6 membered monocyclic heteroaryl ring having 1 - 4 10 hotheteroatoms independently selected from nitrogen , oxygen , or sulfur , a 4 - 7 membered saturated or partially unsaturated F heterocyclic ring having 1 -3 heteroatoms independently selected from nitrogen , oxygen , or sulfur, a 7 - 10 membered etc . bicyclic saturated or partially unsaturated heterocyclic ring In some embodiments , each carbon atom of the double 15 having 1- 5 heteroatoms independently selected from nitro bond in the second species has the same substitution pattern . gen , oxygen , or sulfur, or an 8 - 10 membered bicyclic In some embodiments , each carbon atom of the double bond heteroaryl ring having 1 - 5 heteroatoms independently in the second species has the same set of substituents . In selected from nitrogen , oxygen , or sulfur. In some embodi some embodiments , each carbon atom of the double bond in ments , a product comprises a conjugated diene . In some the second species is mono -substituted with the same sub - - embodiments , a diene is substituted with one or more stituent. In some embodiments, the second species is 1 . 2 - halogen . In some embodiments , a diene is useful as a disubstituted olefin . In some embodiments , a second species matmaterial for organic synthesis , e . g . , for Diels - Alder reaction . is R - CH = CH - R '. In some embodiments , a second spe In some embodiments , an exemplary provided method is cies is ( Z ) - R - CH = CH - R '. In some embodiments , a 75 depicteddepicted below : second species is ( E ) - R - CH = CH - R ". In some embodi ments , the two R are different . In some embodiments , a second species is asymmetric with respect to the center of its Mo- or W -based double bond . In some embodiments , the two R * are the same. - ++ R - = In some embodiments , a second species is ( E ) -Ph - CH = CH - 30 Ph . In some embodiments , a second species is symmetric with respect to the center of its double bond . + In some embodiments, the present disclosure provides a method , comprising : # reacting a first species comprising an olefin with a second 35 species comprising an alkyne in the presence of a catalyst or metal complex to provide at least one product comprising an olefin , wherein : each carbon atom of the olefin in the first species 1s In some embodiments. X and / or Y = H . E . C1. Br. 1 : they must substituted with at least one halogen ; and 40 not be H at the same time. In some embodiments , R , = H or the olefin in the at least one product comprises a carbon any linear or branched hydrocarbon , Me, or any linear or atom from the first species and a carbon atom from the branched alkyl, Ph , any mono -, di -, tri -, or tetra- substituted second species. aryl (all isomers ) with substituents , 1 - or 2 -substituted In some embodiments , the present disclosure provides a naphthyl or any O - . N , or S - containing heterocycle . R method for enyne metathesis , comprising providing a cata - 45 might be N - , S - , Si- , B - , P -based group . In some embodi lyst or metal complex has the structure of formula Il- a or ments . R is Rt. In some embodiments. R . is R ' . Il- b . In some embodiments , the at least one product in a In some embodiments , provided methods provide regi provided method has the structure of a product from the oselectivity . In some embodiments , provided methods pro metathesis between the olefin of the first species and the vide stereoselectivity . In some embodiments , provided alkyne of the second species . 50 methods provide regioselectivity and stereoselectivity . In In some embodiments , a first species of a provided enyne some embodiments , provided methods provide regioselec metathesis method is an alkenyl halide , wherein each carbon tivity and Z - selectivity . In some embodiments , provided of the alkene group is independently substituted with a methods provide regioselectivity and E -selectivity . halogen atom . In some embodiments , a first species has the In some embodiments , a provided catalyst or metal com structure of 55 plex , e . g . , a compound of formula II -a , a compound of formula II - b , etc . is isolated . In some embodiments , when used as a solid , a provided catalyst or metal complex , e . g . , a compound of formula II - a , a compound of formula II - b , etc . is purified and / or isolated . In some embodiments , when 60 used in a solution , a provided catalyst or metal complex , wherein each of X and Y is independently halogen . In some e . g ., a compound of formula II - a , a compound of formula embodiments , each of X and Y is – C1. In some embodi- II -b , etc . may not be isolated and may be generated in situ ments , one of X and Y is — F and the other is — Cl. In some and used without isolation from a solution . In some embodi embodiments , one of X and Y is — F and the other is — Br. ments , a provided catalyst or metal complex , e . g ., a com In some embodiments , a second species of a provided enyne 65 pound of formula II - a , a compound of formula II - b , etc . is metathesis method comprises an alkyne group . In some added as substantially pure form as a solid and /or solution . embodiments , a second species comprises a terminal alkyne . In some embodiments , the purity is greater than 50 % with US 9 ,850 , 268 B2 85 86 respect to the metal in that , for example , 50 % of the wherein each carbon atom of the olefin in the first species is metal- containing compound in the solid and /or solution is a substituted with at least one halogen , and R H or a salt compound of formula II -, when a compound of formula II - a thereof. In some embodiments , the present disclosure pro is used . In some embodiments , the purity is greater than vides a composition comprising a first species comprising an 60 % . In some embodiments , the purity is greater than 70 % . 5 olefin , wherein each carbon atom of the olefin in the first In some embodiments , the purity is greater than 80 % . In species is substituted with at least one halogen , and a metal some embodiments , the purity is greater than 85 % . In some complex comprising molybdenum or tungsten , R -OH or a embodiments , the purity is greater than 90 % . In some salt thereof, and RH or a salt thereof. In some embodi embodiments , the purity is greater than 91 % . In some ments , R -OH or a salt thereof, and /or RPH or a salt thereof, embodiments , the purity is greater than 92 % . In some is generated , or introduced , when preparing a metal com embodiments , the purity is greater than 93 % . In some plex , e . g . , a metal complex of formula II - a , a metal complex embodiments , the purity is greater than 94 % . In some of formula II - b , etc . In some embodiments, R - OH or a salt embodiments , the purity is greater than 95 % . In some thereof, and / or R H or a salt thereof, is generated when a embodiments , the purity is greater than 96 % . In some 16 metal complex , e . g . , a metal complex of formula II - a , a embodiments , the purity is greater than 97 % . In some metal complex of formula Il- b , etc . , degrades and / or is embodiments , the purity is greater than 98 % . In some quenched when a methathesis reaction reaches a desired embodiments , the purity is greater than 99 % . stage . In some embodiments , a first species is In some embodiments , the present disclosure provides a composition comprising 20

X Y In some embodiments , a first species is 25 and a catalyst or metal complex having the structure of formula II - a or II - b . In some embodiments , the present disclosure provides a composition comprising

30 X Y In some embodiments , X and Y are the same. In some embodiments , X and Y are different. In some embodiments , one of X and Y is — F , and the other is — Cl or — Br. In some 35 embodiments , one of X and Y is – F , and the other is Cl. and a catalyst or metal complex having the structure of In some embodiments , one of X and Y is - F , and the other formula II - a or II - b . In some embodiments , the present is — Br. In some embodiments , a metal complex comprising disclosure provides a composition comprising a diene hav - molybdenum or tungsten has the structure of formula II - a or ing the structure of formula I - a , and a catalyst or metal II - b . In some embodiments, a metal complex comprising complex having the structure of formula II - a or II - b . 40 molybdenum or tungsten has the structure of formula II - a . In In some embodiments , the present disclosure provides a some embodiments , a metal complex comprising molybde composition comprising a metal complex having the struc - num or tungsten has the structure of formula II - b . In some ture of formula II - a or II- b and a first species comprising an embodiments , a metal complex comprising molybdenum or olefin , wherein each carbon atom of the olefin in the first tungsten is a compound when another metal complex , e . g . , species is substituted with at least one halogen . In some 45 a metal complex of formula II - a , a metal complex of formula embodiments , the present disclosure provides a composition II - b , etc . , degrades and /or is quenched when a metathesis comprising a first species comprising an olefin , wherein reaction reaches a desired stage . Among other things, pro each carbon atom of the olefin in the first species is substi vided compositions are useful for preparing halogenated tuted with at least one halogen , and one or more species olefins with e . g ., high efficiency, high regioselectivity , high selected from a metal complex comprising molybdenum or 50 stereoselectivity , etc . tungsten , R - OH or a salt thereof, and RºH or a salt thereof. In some embodiments , a provided composition comprises In some embodiments , the present disclosure provides a CH = CHX . In some embodiments , a provided composition composition comprising a first species comprising an olefin , comprises CH2 = CHY. In some embodiments , a provided wherein each carbon atom of the olefin in the first species is composition comprises CH2 = CHX and / or CH2 = CHY. In substituted with at least one halogen , and a metal complex 55 some embodiments , a provided composition comprises comprising molybdenum or tungsten . In some embodi - CH2 = CHX or CH2 = CHY. In some embodiments , a pro ments , the present disclosure provides a composition com - vided composition comprises CH2 = CHX and CH2 = CHY. prising a first species comprising an olefin , wherein each In some embodiments , a provided composition comprises carbon atom of the olefin in the first species is substituted CH = CHX . In some embodiments , a provided composition with at least one halogen , and a species selected from R -OH 60 comprises CH = CHY . In some embodiments, a provided or a salt thereof, and RºH or a salt thereof. In some composition comprises CH2 = CHF. In some embodiments , embodiments , the present disclosure provides a composition a provided composition comprises CH = CHCl. In some comprising a first species comprising an olefin , wherein embodiments , a provided composition comprises each carbon atom of the olefin in the first species is substi - CH2 = CHBr. In some embodiments , a provided composi tuted with at least one halogen , and R -OH or a salt thereof. 65 tion comprises CH2= CHI. In some embodiments , the present disclosure provides a In some embodiments , a provided method generates composition comprising a first species comprising an olefin , CH2 = CHX . In some embodiments , a provided method US 9 ,850 ,268 B2 87 88 generates CH2 = CHY. In some embodiments , a provided provided in a molar ratio of less than about 1 . 2 : 1 to M . In method generates CH = CHX and / or CH = CHY . In some some embodiments, — OR4 is provided in a molar ratio of embodiments, a provided method generates CH2= CHX or less than about 1. 1 : 1 to M . In some embodiments , - OR * is CH2 = CHY. In some embodiments , a provided method provided in a molar ratio of more than about 2 : 1 to M . In generates CH = CHX and CH = CHY. In some embodi- 5 some embodiments , — OR4 is provided in a molar ratio of ments , a provided method generates CH = CHX . In some more than about 1 . 9 : 1 to M . In some embodiments , — OR + embodiments , a provided method generates CH = CHY . In is provided in a molar ratio of more than about 1 . 8 : 1 to M . some embodiments , a provided method generates In some embodiments, OR4 is provided in a molar ratio of CH2 = CHF. In some embodiments, a provided method more than about 1 . 7 : 1 to M . In some embodiments , — OR4 generates CH = CHC1. In some embodiments , a provided 10 is provided in a molar ratio of more than about 1 . 6 : 1 to M . method generates CH = CHBr. In some embodiments , a In some embodiments, - OR * is provided in a molar ratio of provided method generates CH2 = CHI. In some embodi more than about 1 .5 : 1 to M . In some embodiments , OR4 ments , a provided method provides surprisingly high regi - is provided in a molar ratio of more than about 1 . 4 : 1 to M . oselectivity , and selectively generates one of CH = CHX In some embodiments, OR4 is provided in a molar ratio of and CH – CHY over the other, when E - or Z - CHX — CHY 15 more than about 1 . 3 : 1 to M . In some embodiments , — OR4 is used as a metathesis substrate . In some embodiments, is provided in a molar ratio of more than about 1 . 2 : 1 to M . CH2= CHY is selectively generated over CH2= CHX , In some embodiments, _ OR * is provided in a molar ratio of wherein Y > X ( e . g ., as understood by a person having more than about 1 . 1 : 1 to M . ordinary skill in the art , I > Br > Cl > F ) . In some embodiments , Suitable conditions for performing provided methods the selectivity is greater than about 1 : 1 . In some embodi- 20 generally employ one or more solvents . In certain embodi ments , the selectivity is greater than about 2 : 1 . In some ments , one or more organic solvents are used . Examples of embodiments , the selectivity is greater than about 3 : 1 . In such organic solvents include , but are not limited to , hydro some embodiments , the selectivity is greater than about 4 : 1. carbons such as benzene , toluene , and pentane, halogenated In some embodiments , the selectivity is greater than about hydrocarbons such as dichloromethane, or polar aprotic 5 : 1 . In some embodiments , the selectivity is greater than 25 solvents , such as ethereal solvents including ether, DME , about 6 : 1 . In some embodiments , the selectivity is greater tetrahydrofuran ( THF ) , or dioxanes , or protic solvents , such than about 7 : 1 . In some embodiments , the selectivity is as alcohols , or mixtures thereof. In certain embodiments , greater than about 8 : 1 . In some embodiments , the selectivity one or more solvents are deuterated . is greater than about 9 : 1 . In some embodiments , the selec - In some embodiments , a single solvent is used . In certain tivity is greater than about 10 : 1 . In some embodiments , the 30 embodiments , a solvent is benzene . In certain embodiments , selectivity is greater than about 20 : 1 . In some embodiments, a solvent is ether . In some embodiments , a solvent is a the selectivity is greater than about 30 : 1 . In some embodi- nitrile . In some embodiments , a solvent is acetonitrile . ments , the selectivity is greater than about 40 : 1 . In some In some embodiments , mixtures of two or more solvents embodiments , the selectivity is greater than about 50 : 1 . In are used , and in some cases may be preferred to a single some embodiments , the selectivity is greater than about 35 solvent. In certain embodiments , the solvent mixture is a 60 : 1 . In some embodiments , the selectivity is greater than mixture of an ethereal solvent and a hydrocarbon . Exem about 70 : 1 . In some embodiments , the selectivity is greater p lary such mixtures include, for instance , an ether/ benzene than about 80 : 1 . In some embodiments , the selectivity is mixture . In some embodiments , an exemplary mixture is a greater than about 90 : 1 . In some embodiments , the selec - DME/ Toluene mixture . In some embodiments , an exem tivity is greater than about 100 : 1 . 40 plary mixture is DME / Toluene about 1 : 1 . Solvent mixtures In some embodiments , a ligand is provided in a molar may be comprised of equal volumes of each solvent or may ratio of about 10 : 1 , 9 : 1 , 8 : 1 , 7 : 1 , 6 : 1 , 5 : 1 , 4 : 1 , 3 : 1 , 2 : 1 , or 1 : 1 contain one solvent in excess of the other solvent or sol relative to the metal. In some embodiments , a ligand is vents . In certain embodiments wherein a solvent mixture is provided in a molar ratio of about 0 . 9 : 1 , 0 . 8 : 1 , 0 . 7 : 1 , 0 . 6 : 1 , comprised of two solvents , the solvents may be present in a 0 . 5 : 1 , 0 . 4 : 1 , 0 . 3 : 1 , 0 . 2 : 1 , or 0 . 1 : 1 relative to the metal . In 45 ratio of about 20 : 1 , about 10 : 1 , about 9 : 1 , about 8 : 1 , about certain embodiments , a ligand is provided in a molar ratio of 7 : 1 , about 6 : 1 , about 5 : 1 , about 4 : 1 , about 3 : 1 , about 2 : 1 , or about 1 : 1 relative to the metal. One of skill in the art will about 1 : 1 . In certain embodiments wherein a solventmixture appreciate that the optimalmolar ratio of ligand to metal will comprises an ethereal solvent and a hydrocarbon , the sol depend on , inter alia , whether the ligand is mono - or vents may be present in a ratio of about 20 : 1 , about 10 : 1 , polydentate . In some embodiments , a ligand or ligand pre - 50 about 9 : 1 , about 8 : 1 , about 7 : 1 , about 6 : 1 , about 5 : 1 , about cursor having the structure as described in formula II - a or 4 : 1 , about 3 : 1 , about 2 : 1 , or about 1: 1 ethereal solvent : II - b is provided in a molar ratio of about 1 : 1 to M . In some hydrocarbon . In certain embodiments , the solvent mixture embodiments , — OR is provided in a molar ratio of about comprises a mixture of ether and benzene in a ratio of about 1 : 1 to M . In some embodiments , OR4 is provided in a 5 : 1 . One of skill in the art would appreciate that other molar ratio of about 2 : 1 to M . In some embodiments , OR * 55 solvent mixtures and / or ratios are contemplated herein , that is provided in a molar ratio of less than about 2 : 1 to M . In the selection of such other solvent mixtures and / or ratios some embodiments , — OR is provided in a molar ratio of will depend on the solubility of species present in the less than about 1 . 9 : 1 to M . In some embodiments , — OR is reaction ( e . g . , substrates , additives , etc . ) , and that experi provided in a molar ratio of less than about 1 . 8 : 1 to M . In mentation required to optimized the solvent mixture and / or some embodiments , — OR * is provided in a molar ratio of 60 ratio would be routine in the art and not undue . less than about 1 . 7 : 1 to M . In some embodiments , OR * is Suitable conditions , in some embodiments , employ ambi provided in a molar ratio of less than about 1 . 6 : 1 to M . In ent temperatures . In some embodiments , a suitable tempera some embodiments , OR4 is provided in a molar ratio of ture is about 15° C ., about 20° C . , about 25° C ., or about 30° less than about 1 . 5 : 1 to M . In some embodiments, — OR is C . In some embodiments , a suitable temperature is from provided in a molar ratio of less than about 1 . 4 : 1 to M . In 65 about 15° C . to about 25° C . In certain embodiments , a some embodiments , — OR4 is provided in a molar ratio of suitable temperature is about 20° C ., 21° C ., 22° C ., 23° C . , less than about 1 . 3 : 1 to M . In some embodiments , - OR4 is 24° C . , or 25° C . US 9 ,850 ,268 B2 89 90 In certain embodiments , a provided method is performed about - 10° C ., about - 20° C . , about - 30° C . , about - 40° C . , at elevated temperature . In some embodiments, a suitable about - 50° C ., about - 60° C . , about - 70° C ., about - 80° C . , temperature is from about 25° C . to about 110° C . In certain about - 90° C . , and about - 100° C . embodiments, a suitable temperature is from about 40° C . to Suitable conditions typically involve reaction times of about 100° C . , from about 50° C . to about 100° C . , from 5 about 1 minute to about one or more days . In some embodi about 60° C . to about 100° C ., from about 70° C . to about ments , the reaction time ranges from about 0 . 5 hour to about 100° C ., from about 80° C . to about 100° C ., or from about 72 hours . In some embodiments , the reaction time ranges 90° C . to about 100° C . In some embodiments , a suitable from about 0 . 5 hour to about 48 hours . In some embodi temperature is about 80º C . In some embodiments , a suitable ments , the reaction time ranges from about 0 . 5 hour to about temperature is about 30° C . In some embodiments , a suitable 10 20 hours. In some embodiments , the reaction time ranges temperature is about 40° C . In some embodiments, a suitable from about 0 . 5 hour to about 15 hours . In some embodi temperature is about 50° C . In some embodiments , a suitable m ents , the reaction time ranges from about 1. 0 hour to about temperature is about 60° C . In some embodiments , a suitable 12 hours . In some embodiments , the reaction time ranges temperature is about 70° C . In some embodiments , a suitable from about 1 hour to about 10 hours . In some embodiments , temperature is about 80° C . In some embodiments , a suitable 15 the reaction time ranges from about 1 hour to about 8 hours . temperature is about 90° C . In some embodiments , a suitable In some embodiments, the reaction time ranges from about temperature is about 100° C . In some embodiments , a 1 hour to about 6 hours . In some embodiments , the reaction suitable temperature is about 110° C . time ranges from about 1 hour to about 4 hours . In some In certain embodiments , a provided method is performed embodiments , the reaction time ranges from about 1 hour to at temperature lower than ambient temperatures . In some 20 about 2 hours . In some embodiments , the reaction time embodiments , a suitable temperature is from about - 100° C . ranges from about 2 hours to about 8 hours . In some to about 10° C . In certain embodiments , a suitable tempera embodiments , the reaction time ranges from about 2 hours ture is from about - 80° C . to about 0° C . In certain to about 4 hours . In some embodiments , the reaction time embodiments , a suitable temperature is from about - 70° C . ranges from about 2 hours to about 3 hours . In certain to about 10° C . In certain embodiments , a suitable tempera - 25 embodiments , the reaction time is about 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , ture is from about - 60° C . to about 10° C . In certain 9 , 10 , 11 , 12 , 24 , 36 , 48 , 60 , 72 , 96 or 120 hours . In certain embodiments , a suitable temperature is from about - 50° C . embodiments , the reaction time is about 1 hour. In certain to about 10° C . In certain embodiments , a suitable tempera - embodiments , the reaction time is about 2 hours . In certain ture is from about - 40° C . to about 10° C . In certain embodiments , the reaction time is about 3 hours . In certain embodiments , a suitable temperature is from about - 30° C . 30 embodiments , the reaction time is about 4 hours . In certain to about 10° C . In some embodiments , a suitable tempera - embodiments , the reaction time is about 5 hours . In certain ture is below 0° C . In some embodiments , a suitable embodiments , the reaction time is about 6 hours . In some temperature is about - 100° C . In some embodiments , a embodiments , the reaction time is about 12 hours . In some suitable temperature is about - 90° C . In some embodiments, embodiments , the reaction time is about 24 hours . In some a suitable temperature is about - 80° C . In some embodi- 35 embodiments , the reaction time is about 36 hours . In some ments , a suitable temperature is about - 70° C . In some embodiments , the reaction time is about 48 hours . In some embodiments , a suitable temperature is about - 60° C . In embodiments , the reaction time is about 72 hours . In some some embodiments , a suitable temperature is about - 50° C . embodiments , the reaction time is about 96 hours . In some In some embodiments , a suitable temperature is about - 40° embodiments , the reaction time is about 120 hours . In C . In some embodiments , a suitable temperature is about 40 certain embodiments , the reaction time is less than about 1 - 30° C . In some embodiments , a suitable temperature is hour. In certain embodiments , the reaction time is about 5 , about - 20° C . In some embodiments, a suitable temperature 10 , 15 , 20 , 25 , 30 , 35 , 40 , 45 , 50 , or 55 minutes . In some is about - 10° C . In some embodiments , a suitable tempera - embodiments , the reaction time is about 5 minutes . In some ture is about 0° C . In some embodiments , a suitable tem - embodiments , the reaction time is about 10 minutes . In some perature is about 10° C . 45 embodiments , the reaction time is about 15 minutes . In some In some embodiments, a provided method is performed at embodiments , the reaction time is about 20 minutes . In some different temperatures . In some embodiments , temperature embodiments , the reaction time is about 25 minutes . In some changes in a provided method . In some embodiments , a embodiments , the reaction time is about 30 minutes . In some provided method involves temperature increase from a embodiments , the reaction time is about 35 minutes . In some lower suitable temperature to a higher suitable temperature . 50 embodiments , the reaction time is about 40 minutes . In some In some embodiments , a provided method comprises tem - embodiments , the reaction time is about 100 minutes . In perature increase from about - 80° C . , about - 70° C ., about some embodiments , the reaction time is about 110 minutes . - 60° C ., about - 50° C ., about - 40° C . , about - 30° C ., about In some embodiments , the reaction time is about 200 min - 20° C ., about - 10° C ., and about 0° C . to about 0° C . , about utes . In some embodiments , the reaction time is about 300 10° C ., about 20° C ., ambient temperature, about 22° C ., 55 minutes. In some embodiments , the reaction time is about about 25° C . , about 30° C ., about 40° C ., about 50° C . , about 400 minutes . 60° C ., about 70° C . , about 80° C . , about 90° C ., about 100° In some embodiments , a provided metal complex com C . and about 110° C . In some embodiments , a provided pound , e . g . a compound of formula II - a or II - b or an active method comprises temperature increase from about - 30° C . catalyst formed from a provided compound , is stable under to 22° C . In some embodiments , a provided method com - 60 metathesis conditions. In some embodiments , a provided prises temperature decrease from a higher suitable tempera - compound , or an active catalyst formed from a provided ture to a lower suitable temperature . In some embodiments , compound , decomposes under metathesis conditions . In a provided method comprises temperature increase from some embodiments , a provided compound, or an active about 110° C . , about 100° C . , about 90° C ., about 80° C ., catalyst formed from a provided compound , decomposes about 70° C . , about 60° C ., about 50° C ., about 40° C . , about 65 under metathesis conditions within about 1 hour. In some 30° C . , about 25° C . , about 22° C ., ambient temperature , embodiments , a provided compound , or an active catalyst about 20° C ., about 10° C ., and about 0° C . to about 0° C . , formed from a provided compound , decomposes under US 9 ,850 ,268 B2 91 92 metathesis conditions within about 2 hours . In some greater than about 3 : 1 , greater than about 4 : 1, greater than embodiments, a provided compound, or an active catalyst about 5 : 1 , greater than about 6 : 1 , greater than about 7 : 1 , formed from a provided compound , decomposes under greater than about 8 : 1 , greater than about 9 : 1 , greater than metathesis conditions within about 6 hours . In some about 95 : 5 , greater than about 96 : 4 , greater than about 97 : 3 , embodiments , a provided compound , or an active catalyst 5 greater than about 98 : 2 , or, in some cases , greater than about formed from a provided compound , decomposes under 99 : 1 , as determined using methods described herein ( e . g . , metathesis conditions within about 12 hours . In some HPLC or NMR ) . In some cases , about 100 % of the double embodiments , a provided compound , or an active catalyst bond produced in the metathesis reaction may have a E formed from a provided compound , decomposes under configuration . The E or trans selectivity may also be metathesis conditions within about 24 hours. In some 10 expressed as a percentage of product formed . In some cases , embodiments , a provided compound , or an active catalyst the product may be greater than about 50 % E , greater than formed from a provided compound , decomposes under about 60 % E , greater than about 70 % E , greater than about metathesis conditions within about 48 hours . In some 80 % E , greater than about 90 % E , greater than about 95 % E , embodiments, a provided compound , or an active catalyst greater than about 96 % E greater than about 97 % E , greater formed from a provided compound , decomposes under 15 than about 98 % E , greater than about 99 % E , or, in some metathesis conditions within about 96 hours . cases , greater than about 99. 5 % E . Some embodiments may provide the ability to selectively In some embodiments , a provided method requires an synthesize , via a metathesis reaction , products having a Z or amount of a provided compound ( e . g . , a metal complex E configuration about a double bond . Some embodiments having the structure of formula II - a or II - b ) such that the may provide the ability to selectively synthesize , via a 20 loading is from about 0 .01 mol % to about 20 mol % of the metathesis reaction , products having a Z configuration about provided compound relative to substrate ( e . g . , a first or a double bond . Some embodiments may provide the ability second double bond ) . In certain embodiments , a provided to selectively synthesize , via a metathesis reaction , products compound is used in an amount of between about 0 .01 mol having a E configuration about a double bond . In some % to about 10 mol % . In certain embodiments , a provided embodiments , a method of the present disclosure provides 25 compound is used in an amount of between about 0 .01 mol the ability to synthesize compounds comprising a Z - olefin . % to about 6 mol % . In certain embodiments , a provided In some embodiments , a method of the present disclosure compound is used in an amount of between about 0 .01 mol provides the ability to synthesize compounds comprising a % to about 5 mol % . In certain embodiments, a provided E -olefin . In some embodiments , such methods are useful compound is used in an amount of between about 0 . 01 mol when applied to a wide range of olefin substrates, including 30 % to about 4 mol % . In certain embodiments, a provided those having sterically small or large groups adjacent the compound is used in an amount of between about 0 . 01 mol olefin . In some embodiments , the substrate olefins are ter - % to about 3 mol % . In certain embodiments , a provided minal olefins. In some embodiments , one of the substrate compound is used in an amount of between about 0 .01 mol olefin is terminal olefin . % to about 1 mol % . In certain embodiments , a provided In some embodiments , the present disclosure provides 35 compound is used in an amount of between about 0 .01 mol methods for regioselective metathesis in that the methods % to about 0 . 5 mol % . In certain embodiments , a provided selectively provide products via one of the possible metath compound is used in an amount of between about 0 .01 mol esis pathways . In some embodiments , the present disclosure % to about 0 . 2 mol % . In certain embodiments , a provided provides methods for regioselective synthesis of alkenyl compound is used in an amount of about 0 . 05 % , 0 . 1 % , 0 . 2 % , fluoride using 1 - bromo - 2 - fluoroethylene or 1 -chloro - 2 - fluo - 40 0 . 5 % , 1 % , 2 % , 3 mol % , 4 mol % , 5 mol % , 6 mol % , 7 mol roethylene . In some embodiments , provided methods further % , 8 mol % , 9 mol % , or 10 mol % . provide Z - or E -selectivity . Exemplary reactions are In some embodiments , a method of the present disclosure described below . requires an amount of solvent such that the concentration of In some embodiments , the present disclosure provides a the reaction is between about 0 .01 M and about 1 M . In some method for Z - selective metathesis reactions. In some 45 embodiments , the concentration of the reaction is between embodiments , a provided method produces a double bond in about 0 .01 M and about 0 . 5 M . In some embodiments , the a Z : E ratio greater than about 1 : 1 , greater than about 2 : 1 , concentration of the reaction is between about 0 .01 M and greater than about 3 : 1 , greater than about 4 : 1 , greater than about 0 . 1 M . In some embodiments , the concentration of the about 5 : 1 , greater than about 6 : 1 , greater than about 7 : 1 , reaction is between about 0 .01 Mand about 0 .05 M . In some greater than about 8 : 1 , greater than about 9 : 1 , greater than 50 embodiments , the concentration of the reaction is about 0 .01 about 95 : 5 , greater than about 96 : 4 , greater than about 97 : 3 , M . In some embodiments , the concentration of the reaction greater than about 98 : 2 , or, in some cases , greater than about is about 0 .02 M . In some embodiments , the concentration of 99 : 1 , as determined using methods described herein ( e . g ., the reaction is about 0 .03 M . In some embodiments , the HPLC or NMR ) . In some cases, about 100 % of the double concentration of the reaction is about 0 . 04 M . In some bond produced in the metathesis reaction may have a Z 55 embodiments , the concentration of the reaction is about 0 . 05 configuration . The Zor cis selectivity may also be expressed M . In some embodiments , the concentration of the reaction as a percentage of product formed . In some cases , the is about 0 . 1 M . In some embodiments , the concentration of product may be greater than about 50 % Z , greater than about the reaction is about 0 . 3 M . 60 % Z , greater than about 70 % Z , greater than about 80 % Z In some embodiments , a method of the present disclosure greater than about 90 % Z , greater than about 95 % Z , greater 60 is performed at ambient pressure . In some embodiments , a than about 96 % Z , greater than about 97 % Z , greater than method of the present disclosure is performed at reduced about 98 % Z , greater than about 99 % Z , or, in some cases , pressure . In some embodiments, a method of the present greater than about 99. 5 % Z . disclosure is performed at a pressure of less than about 20 In some embodiments , the present disclosure provides a torr. In some embodiments , a method of the present disclo method for E - selective metathesis reactions . In some 65 sure is performed at a pressure of less than about 15 torr . In embodiments , a provided method produces a double bond in some embodiments , a method of the present disclosure is a E : Z ratio greater than about 1 : 1 , greater than about 2 : 1 , performed at a pressure of less than about 10 torr . In some US 9 ,850 ,268 B2 93 94 embodiments, a method of the present disclosure is per- ments, the ratio is greater than about 4 : 1 . In some formed at a pressure of about 9 , 8 , 7 , 6 , 5 , 4 , 3 , 2 , or 1 torr . embodiments , the ratio is greater than about 5 : 1 . In some In certain embodiments , a method of the present disclosure embodiments , the ratio is greater than about 6 : 1 . In some is performed at a pressure of about 7 torr . In certain embodiments , the ratio is greater than about 7 : 1 . In some embodiments , a method of the present disclosure is per - 5 embodiments , the ratio is greater than about 8 : 1 . In some formed at a pressure of about 1 torr . embodiments , the ratio is greater than about 9 : 1 . In some In some embodiments , a method of the present disclosure embodiments , the ratio is greater than about 10 : 1 . In some is performed at increased pressure . In some embodiments , a method of the present disclosure is performed at greater than embodiments , the ratio is greater than about 15 :1 . In some about 1 atm . In some embodiments , a method of the present 10 embodiments , the ratio is greater than about 20 : 1 . In some disclosure is performed at greater than about 2 atm . In some embodiments , the ratio is greater than about 30 :1 . In some embodiments , a method of the present disclosure is per embodiments , the ratio is greater than about 40 : 1 . In some formed at greater than about 3 atm . In some embodiments, embodiments , the ratio is greater than about 50 : 1 . In some a method of the present disclosure is performed at greater embodiments , a ratio is within a range , wherein the lower than about 5 atm . In some embodiments , a methodnethod of thethe 1615 end ratio is about 1 : 1 , 2 : 1 , 3 : 1 , 4 : 1 , 5 : 1 , 6 : 1 , 7 : 1 , 8 : 1 , 9 : 1 , present disclosure is performed at greater than about 10 atm . 10 : 1 , 11: 1 , 12 : 1 , 13 : 1 , 14 : 1 , 15 : 1 , 20 : 1 , 30 : 1 , 40 : 1 , or 50 : 1 , In some embodiments , a method of the present disclosure is and the higher end ratio is higher than the lower end ratio performed at about 2 atm . In some embodiments , a method and is about 2 : 1 , 3 : 1 , 4 : 1 , 5 : 1 , 6 : 1 , 7 : 1 , 8 : 1 , 9 : 1 , 10 : 1 , 11 : 1 , of the present disclosure is performed at about 3 atm . In 12 : 1 , 13 : 1 , 14 : 1 , 15 : 1 , 20 : 1 , 30 : 1 , 40 : 1 , or 50 : 1 . In some some embodiments , a method of the present disclosure is 20 embodiments , the lower end ratio is selected from about 1: 1, performed at about 5 atm . In some embodiments , a method 2 : 1 , or 3 : 1 , and the higher end ratio is selected from 20 : 1 , of the present disclosure is performed at about 10 atm . 30 : 1 , 40 : 1, or 50 : 1 . In some embodiments , the present disclosure recognizes In some embodiments , a provided catalyst or metal com that ratios of metathesis substrates have impact on the plex , or a reaction condition or selectivity , is independently reaction results , e . g ., yield , regioselectivity, stereoselectivity 25 as described in US Patent Application Publication US2012 / ( e . g . , Z - selectivity , E - selectivity , etc . ) , etc . In some embodi- 0323000 , incorporated herein by reference , both individu ments, provided technologies , e . g . , compounds, methods , ally and in combination . etc . provide high tolerance of molar ratio of substrates. In some embodiments , provided technologies deliver high As mentioned above , provided compounds are useful for yield and high selectivity ( e . g . , regioselectivity , stereoselec - 30 metathesis reactions. Exemplary such methods and reactions tivity , chemoselectivity , etc . , across a wide range of molar u are described below . ratios of substrates . In some embodiments , the present It will be appreciated that, in certain embodiments , each disclosure demonstrates that when too much first species is variable recited is as defined above and described in embodi used relative to a second species , product yield , regioselec ments , herein , both singly and in combination . tivity and / or stereoselectivity may decrease . In some 35 In some embodiments , the present disclosure provides the embodiments , the molar ratio of the first species to the following examples : second species is about 1 : 1 . In some embodiments , the ratio El. A method , comprising : is about 2: 1 . In some embodiments , the ratio is about 3 : 1. In reacting a first species comprising an olefin with a second some embodiments , the ratio is about 4 : 1 . In some embodi - species comprising an alkyne in the presence of a catalyst or ments , the ratio is about 5 : 1 . In some embodiments , the ratio 40 metal complex to provide at least one product comprising an is about 6 : 1 . In some embodiments , the ratio is about 7 : 1 . In olefin , wherein : some embodiments , the ratio is about 8 :1 . In some embodi- each carbon atom of the olefin in the first species is ments, the ratio is about 9 : 1 . In some embodiments , the ratio substituted with at least one halogen ; and is about 10 : 1. In some embodiments , the ratio is about 15 : 1 . the olefin in the at least one product comprises a carbon In some embodiments , the ratio is about 20 : 1 . In some 45 atom from the first species and a carbon atom from the embodiments , the ratio is about 30 : 1 . In some embodiments, second species . the ratio is about 40 : 1 . In some embodiments , the ratio is E2 . Themethod of example E1, wherein the second species about 50 : 1 . In some embodiments, themolar ratio of the first comprises a terminal alkyne . species to the second species is less than about 1 : 1 . In some E3 . The method of example E2, wherein the second species embodiments , the ratio is less than about 2 : 1. In some 50 has the structure of R - C = CH , wherein Rl is an optionally embodiments, the ratio is less than about 3 : 1 . In some substituted group selected from C1- 20 aliphatic , C1- 20 het embodiments , the ratio is less than about 4 : 1. In some eroaliphatic having 1 - 3 heteroatoms independently selected embodiments , the ratio is less than about 5 : 1 . In some from nitrogen , oxygen , or sulfur, phenyl, a 3 - 7 membered embodiments , the ratio is less than about 6 : 1 . In some saturated or partially unsaturated carbocyclic ring, an 8 - 10 embodiments , the ratio is less than about 7 : 1. In some 55 membered bicyclic saturated , partially unsaturated or aryl embodiments , the ratio is less than about 8 : 1 . In some ring , a 5 - 6 membered monocyclic heteroaryl ring having 1 - 4 embodiments, the ratio is less than about 9 : 1 . In some heteroatoms independently selected from nitrogen , oxygen , embodiments , the ratio is less than about 10 : 1 . In some or sulfur, a 4 - 7 membered saturated or partially unsaturated embodiments , the ratio is less than about 15 : 1 . In some heterocyclic ring having 1 -3 heteroatoms independently embodiments , the ratio is less than about 20 : 1 . In some 60 selected from nitrogen , oxygen , or sulfur, a 7 - 10 membered embodiments , the ratio is less than about 30 : 1 . In some bicyclic saturated or partially unsaturated heterocyclic ring embodiments , the ratio is less than about 40 : 1 . In some having 1 - 5 heteroatoms independently selected from nitro embodiments , the ratio is less than about 50 : 1 . In some gen , oxygen , or sulfur, or an 8 - 10 membered bicyclic embodiments , the molar ratio of the first species to the heteroaryl ring having 1 - 5 heteroatoms independently second species is greater than about 1 : 1 . In some embodi - 65 selected from nitrogen , oxygen , or sulfur . ments , the ratio is greater than about 2 : 1 . In some embodi E4 . The method of any one of the preceding examples, ments , the ratio is greater than about 3 : 1 . In some embodi- wherein the at least one product comprises a conjugated US 9 ,850 ,268 B2 95 96 diene, wherein the diene comprising two carbon atoms from wherein each of X and Y is independently halogen . the olefin of the first species , and two carbon atoms from the E15 . The method of any one of the preceding examples , alkyne in the second species . wherein X and Y are the same. E5 . The method of example E4 , wherein each of the two E16 . The method of any one of the preceding examples , carbon atoms from the olefin of the first species is indepen - 5 wherein the first species is dently substituted with at least one halogen as in the first species. E6 . The method of any one of the preceding examples , wherein the reaction is an enyne metathesis . E7. The method of any one of the preceding examples, 10 wherein the first species has the structure of: E17 . The method of any one of examples E9 - E14 , wherein X and Y are different . E18. The method of any one of examples E9 - E14 , wherein the first species is 15 wherein each of X and Y is independently halogen . E8 . The method of example E7, wherein the second species has the structure of R - C = CH , and the at least one product has a structure selected from : 20 E19 . The method of any one of the preceding examples, wherein the product is produced in a Z : E ratio greater than 80 : 20 . X Y E20 . The method of any one of the preceding examples , wherein the product is produced in a Z : E ratio greater than 25 85 : 15 . UDRi E21. The method of any one of the preceding examples , wherein the product is produced in a Z : E ratio greater than 90 : 10 . E22 . The method of any one of the preceding examples , R 30 wherein the product is produced in a Z : E ratio greater than 95 : 5 . E9 . A method , comprising: E23. The method of any one of the preceding examples , reacting a first species comprising an olefin with a second wherein the product is produced in a Z : E ratio greater than species comprising an olefin in the presence of a catalyst or 98 : 2 . metal complex to provide at least one product comprising an 355 E24 . The method of any one of examples E9- E11 , wherein olefin , wherein : the halogen substituent of the first carbon atom of the double each carbon atom of the olefin in the first species is bond in the first species and the halogen substituent of the substituted with at least one halogen ; and second carbon atom of the double bond in the first species the olefin in the at least one product comprises a carbon is trans . atom from the first species and a carbon atom from the 40 E25 . The method of any one of examples E9 - E11 , wherein second species . the halogen substituent of the first carbon atom of the double E10 . The method of example E9 , wherein the olefin in the bond in the first species and the halogen substituent of the at least one product is formed via a metathesis reaction second carbon atom of the double bond in the first species between the olefin in the first species and the olefin in the is trans , and the olefin in the at least one product comprises second species . 45 a carbon atom from the first species and a carbon atom from E11. The method of any one of the preceding examples, the second species is produced with E -selectivity . wherein each carbon atom of the double bond in the first E26 . The method of any one of examples E9 - E11 and species is substituted with no more than one halogen . E12 . The method of any one of the preceding examples, E24 - E25 , wherein the first species has the structure of: wherein the halogen substituent of the first carbon atom of the double bond in the first species and the halogen sub - 50 stituent of the second carbon atom of the double bond in the first species is cis . E13 . The method of any one of the preceding examples , wherein the halogen substituent of the first carbon atom of the double bond in the first species and the halogen sub - 55 stituent of the second carbon atom of the double bond in the wherein each of X and Y is independently halogen . first species is cis , and the olefin in the at least one product E27 . The method of any one of examples E9 - E11 and comprises a carbon atom from the first species and a carbon E24 -E26 , wherein X and Y are the same. atom from the second species is produced with Z -selectivity . E28 . The method of any one voof entender examples 1925E9 - E11 andand E14 . The method of any one of the preceding examples , 60 E24 -E26 , wherein the first species is wherein the first species has the structure of: Seneste

65 US 9 , 850 , 268 B2 97 98 E29. The method of any one of examples E9 -E11 and E45 . The method of any one of the preceding examples , E24 -E26 , wherein X and Y are different. wherein the halogen on the second carbon atom of the olefin E30 . The method of any one of examples E9 -E11 and of the first species is — Cl or — Br. E24 -E26 , wherein the first species is E46 . The method of any one of the preceding examples , 5 where in the second species comprises a terminal olefin . E47. The method of any one of the preceding examples , wherein the second species is R - CH = CH , . E48. The method of any one of the preceding examples , wherein the at least one product is R - CH = CHX , and is 10 regioselectively produced . E49. The method of any one of the preceding examples , E31 . The method of any one of examples E9 - E11 and wherein the other metathesis product together with E24 - E30 , wherein the product is produced in a E : Z ratio R ' - CH = CHX is CH = CHY, and is regioselectively pro greater than 80 : 20 . duced . E32 . The method of any one of examples E9 -E11 and 15 E50 . The method of any one of examples E36 - E49 , wherein E24 - E30 , wherein the product is produced in a E : Z ratio the first species is greater than 85 : 15 . E33. The method of any one of examples E9 -E11 and E24 - E30 , wherein the product is produced in a E : Z ratio greater than 90 : 10 . E34 . The method of any one of examples E9 -E11 and greaterE24 - E30the , methodwherein thethe produproduct is produced in a E : Z ratio X is - F , Y is _ Cl or — Br, and the at least one product is greater than 95 : 5 . produced with Z -selectivity . E35 . The method of any one of examples E9 - E11 and 25 E51. The method of any one of examples E36 -E49 , wherein E24 - E30 , wherein the product is produced in a E : Z ratio the first species is greater than 98 :2 . E36 . The method of any one of the preceding examples , wherein the product is formed with greater than 80 :20 regioselectivity 30 E37 . The method of any one of the preceding examples, wherein the product is formed with greater than 85 : 15 X is F , Y is — Br, and the at least one product is produced regioselectivity . Withwith Z Z- -selectivirselectivity Bt . ,and the at les E38. The method of any one of the preceding examples , E52 . The method of any one of examples E36 - E49, wherein wherein the product is formed with greater thanexamples 90 : 10. 35 the first species is regioselectivity . E39 . The method of any one of the preceding examples, wherein the product is formed with greater than 95 : 5 regi oselectivity . E40 . The method of any one of the preceding examples, 40 wherein the product is formed with greater than 98 : 2 regi oselectivity . E41. The method of any one of the preceding examples , X is – F , Y is C1 or Br, and the at least one product is wherein the product is formed with regioselectivity, wherein produced with E - selectivity . the at least one product is selectively produced and com - 45 E53 . The method of any one of examples E36 -E49 , wherein prises a double bond , wherein one carbon atom of the double the first species is bond is the first carbon atom of the double bond of the first species, wherein the halogen on the first carbon atom of the double bond of the first species is smaller than the halogen on the second carbon atom of the double bond of the first 50 species, and the other carbon atom of the double bond is the first carbon atom of the double bond of the second species , wherein the substituent on the first carbon atom of the double bond of the second species is larger than the sub - X is — F , Y is — C1, and the at least one product is produced stituent on the second carbon atom of the double bond of the 55 with E -selectivity . second species. E54 . The method of any one of examples E46 - E53 , wherein E42 . The method of any one of the preceding examples , the terminal olefin has the structure of R - CH = CH , , wherein the carbon atoms of the double bond in the at least wherein R is an optionally substituted group selected from one product have the same substituents as in the first and C1- 20 aliphatic , C1-20 heteroaliphatic having 1 -3 heteroatoms second species . 60 independently selected from nitrogen , oxygen , or sulfur, E43 . The method of any one of the preceding examples , phenyl , a 3 - 7 membered saturated or partially unsaturated wherein the halogen on the first carbon atom of the olefin of carbocyclic ring , an 8 - 10 membered bicyclic saturated . the first species is X , the halogen on the second carbon atom partially unsaturated or aryl ring , a 5 -6 membered monocy of the olefin of the first species is Y , and X < Y . clic heteroaryl ring having 1 - 4 heteroatoms independently E44 . The method of any one of the preceding examples, 65 selected from nitrogen , oxygen , or sulfur, a 4 - 7 membered wherein the halogen on the first carbon atom of the olefin of saturated or partially unsaturated heterocyclic ring having the first species is – F . 1 - 3 heteroatoms independently selected from nitrogen , oxy US 9 ,850 ,268 B2 99 100 gen , or sulfur, a 7 -10 membered bicyclic saturated or par each of R2 and R * is independently R ', OR , SR ', tially unsaturated heterocyclic ring having 1 - 5 heteroatoms — N ( R ') 2 , OC ( O ) R ', - SOR ', - SO , R ', SO , N ( R ') 2 , independently selected from nitrogen , oxygen , or sulfur, or C ( O ) N ( R ') 2 , - NR ' C ( O ) R ', or - NR' SOZR ', provided an 8 - 10 membered bicyclic heteroaryl ring having 1 - 5 that R2 and R3 are not simultaneously hydrogen ; heteroatoms independently selected from nitrogen , oxygen , 5 R4 is R7. or an optionally substituted group selected from or sulfur. E55 . The method of any one of examples E9- E45 , wherein - Ar, C1- 20 aliphatic , C1- 20 heteroaliphatic having 1 - 3 the olefin in the second species is an internal olefin . heteroatoms independently selected from nitrogen , oxy E56 . The method of any one of examples E9- E45 , wherein gen , or sulfur , phenyl, a 3 - 7 membered saturated or the olefin in the second species is an internal olefin within a partially unsaturated carbocyclic ring , an 8 - 10 membered ring. bicyclic saturated , partially unsaturated or aryl ring , a 5 -6 E57 . The method of any one of examples E9 - E45 and membered monocyclic heteroaryl ring having 1 - 4 het E55 - E56 , wherein the reaction is ring -opening cross metath eroatoms independently selected from nitrogen , oxygen , esis . or sulfur, a 4 - 7 membered saturated or partially unsatu E58 . The method of any one of examples E9 -E54 , wherein rated heterocyclic ring having 1 - 3 heteroatoms indepen the reaction is not ring - opening cross metathesis . dently selected from nitrogen , oxygen , or sulfur , a 7 - 10 E59 . The method of any one of examples E9 - E58 , wherein membered bicyclic saturated or partially unsaturated het the reaction is cross metathesis . E60 . The method of any one of the preceding examples, erocyclic ring having 1 - 5 heteroatoms independently wherein the first species and the second species are different. selected from nitrogen , oxygen , or sulfur, or an 8 - 14 E61. The method of any one of the preceding examples , 20 membered bicyclic or tricyclic heteroaryl ring having 1 - 5 wherein the olefin in the at least one product comprises a heteroatoms independently selected from nitrogen , oxy carbon atom substituted with at least one halogen from the gen , or sulfur; first species and a carbon atom from the second species. Ar is of the following formula : E62 . The method of example E61, wherein the at least one halogen is — C1. 25 non E63 . The method of any one of the preceding examples , wherein the first and second species is independently a ( R ” ) , AC ( D ( R ) compound as exemplified . E64 . The method of any one of the preceding examples, wherein the catalyst or metal complex is of formula II- a: 30 ( R™) m

II- a wherein : m is 0 - 3 ; — 35 Ring B is an optionally substituted group selected from phenyl or a 5 -6 membered monocyclic heteroaryl ring RSR = R ?, having 1 - 4 heteroatoms independently selected from R40 nitrogen , oxygen , or sulfur ; R3 p and q are independently 0 - 6 ; 40 each of Ring C and Ring D is independently optionally substituted groups selected from phenyl, a 3 - 7 mem wherein : bered saturated or partially unsaturated carbocyclic M is molybdenum or tungsten ; ring , an 8 - 10 membered bicyclic saturated , partially R ! is an optionally substituted group selected from C1- 20 unsaturated or aryl ring , a 5 - 6 membered monocyclic aliphatic , C1- 20 heteroaliphatic having 1 - 3 heteroatoms 4 heteroaryl ring having 1 - 4 heteroatoms independently independently selected from nitrogen , oxygen , or sulfur, selected from nitrogen , oxygen , or sulfur, a 4 -7 mem phenyl, a 3 - 7 membered saturated or partially unsaturated bered saturated or partially unsaturated heterocyclic carbocyclic ring , an 8 - 10 membered bicyclic saturated , ring having 1 - 3 heteroatoms independently selected partially unsaturated or aryl ring , a 5 - 6 membered mono from nitrogen , oxygen , or sulfur, a 7 - 10 membered cyclic heteroaryl ring having 1 - 4 heteroatoms indepen - so bicyclic saturated or partially unsaturated heterocyclic dently selected from nitrogen , oxygen , or sulfur, a 4 - 7 ring having 1 - 5 heteroatoms independently selected membered saturated or partially unsaturated heterocyclic from nitrogen , oxygen , or sulfur, or an 8 - 10 membered ring having 1 - 3 heteroatoms independently selected from bicyclic heteroaryl ring having 1 - 5 heteroatoms inde nitrogen , oxygen , or sulfur, a 7 - 10 membered bicyclic pendently selected from nitrogen , oxygen , or sulfur ; saturated or partially unsaturated heterocyclicYanic ring havingnaving 55se each of R *, Rº, and R is independently R?; 1 - 5 heteroatoms independently selected from nitrogen , R5 is halogen . _ OR6. _ ORT. - N ( R ') . . NR ' C ( O ) R ' . oxygen , or sulfur , or an 8 - 10 membered bicyclic het - NR ' C ( O )OR ', NR 'C ( O ) N ( R ') 2 , NR ' SO2R ', eroaryl ring having 1 - 5 heteroatoms independently - NR 'SO , N ( R ') 2 , or — NR 'OR ', or an optionally substi selected from nitrogen , oxygen , or sulfur; or R is option tuted group selected from a 5 - 6 membered monocyclic ally substituted 60 heteroaryl ring having at least one nitrogen and 0 - 3 heteroatoms independently selected from nitrogen , oxy gen , or sulfur, a 4 - 7 membered saturated or partially (R ) unsaturated heterocyclic ring having at least one nitrogen and 0 - 2 heteroatoms independently selected from nitro gen , oxygen , or sulfur, a 7 - 10 membered bicyclic satu mm rated or partially unsaturated heterocyclic ring having at least one nitrogen and 0 -4 heteroatoms independently US 9 ,850 , 268 B2 101 102 selected from nitrogen , oxygen , or sulfur, or an 8 - 10 Ar' is of the following formula : membered bicyclic heteroaryl ring having at least one nitrogen and 0 - 4 heteroatoms independently selected from nitrogen , oxygen , or sulfur; R® is an optionally substituted group selected from C1- 20 (R™ ) , + 0 aliphatic , C1- 20 heteroaliphatic having 1 -3 heteroatoms w€ ( R ) independently selected from nitrogen , oxygen , or sulfur, phenyl , a 3 -7 membered saturated or partially unsaturated carbocyclic ring, an 8 - 10 membered bicyclic saturated , wherein : partially unsaturated or aryl ring , a 5 -6 membered mono t is 0 - 4 ; p is 0 -6 ; cyclic heteroaryl ring having 1 - 4 heteroatoms indepen each Ring B ' and Ring C ' is independently an optionally dently selected from nitrogen , oxygen , or sulfur , a 4 - 7 substituted group selected from phenyl, a 3 - 7 mem membered saturated or partially unsaturated heterocyclic bered saturated or partially unsaturated carbocyclic ring , an 8 - 10 membered bicyclic saturated , partially ring having 1 - 3 heteroatoms independently selected from unsaturated or aryl ring , a 5 -6 membered monocyclic nitrogen , oxygen , or sulfur , a 7 -10 membered bicyclic heteroaryl ring having 1 - 4 heteroatoms independently saturated or partially unsaturated heterocyclic ring having selected from nitrogen , oxygen , or sulfur, a 4 - 7 mem bered saturated or partially unsaturated heterocyclic 1 - 5 heteroatoms independently selected from nitrogen , ring having 1 - 3 heteroatoms independently selected oxygen , or sulfur , or an 8 - 14 membered bicyclic or from nitrogen , oxygen , or sulfur , a 7 - 10 membered tricyclic heteroaryl ring having 1- 5 heteroatoms indepen bicyclic saturated or partially unsaturated heterocyclic ring having 1 - 5 heteroatoms independently selected dently selected from nitrogen , oxygen , or sulfur; and 25 from nitrogen , oxygen , or sulfur, or an 8 - 10 membered each R ' is independently hydrogen or an optionally substi bicyclic heteroaryl ring having 1 - 5 heteroatoms inde tuted group selected from C1- 20 aliphatic , phenyl, a 3 - 7 pendently selected from nitrogen , oxygen , or sulfur; membered saturated or partially unsaturated carbocyclic and ring, an 8 - 10 membered bicyclic saturated , partially each RS is independently halogen , R ', - OR ', SR ', - S (O )R ', - S ( O )2R ', OSi (R ' )3 , - N ( R ') 2 , - NRC unsaturated or aryl ring, a 5 - 6 membered monocyclic 30 ( O ) R ', NR ' C (O )OR ', — NR 'C (O )N ( R ') 2 , heteroaryl ring having 1 - 4 heteroatoms independently - NR 'SO , R ', - NR 'SO , N (R ') 2 , or — NR 'OR '. selected from nitrogen , oxygen , or sulfur, a 4 - 7 membered EOSE65 . The method of any one of examples 1 - 63 , wherein saturated or partially unsaturated heterocyclic ring having catalyst or the metal complex is of formula Il - b : 1 - 3 heteroatoms independently selected from nitrogen , oxygen , or sulfur , a 7 - 10 membered bicyclic saturated or 35 partially unsaturated heterocyclic ring having 1 - 5 heteroa II - b toms independently selected from nitrogen , oxygen , or sulfur, or an 8 - 10 membered bicyclic heteroaryl ring having 1 - 5 heteroatoms independently selected from = nitrogen , oxygen , or sulfur , wherein : 40 R3 - M two R ' groups on the same nitrogen atom are optionally - taken together with the nitrogen atom to form an optionally substituted 3 - 8 membered , saturated , par wherein : tially unsaturated , or aryl ring having 1 - 4 heteroatoms 45 R21 and R31 are taken together with their intervening metal independently selected from nitrogen , oxygen , or sul atom to form an optionally substituted 3 - 8 membered fur; saturated or partially unsaturated ring having , in addition each R ' is independently an optionally substituted group to the intervening metal atom , 0 - 4 heteroatoms indepen selected from — Ar' , C1- 20 aliphatic , C1- 20 heteroaliphatic dently selected from nitrogen , oxygen , or sulfur ; and having 1 -3 heteroatoms independently selected from 50 each of Rd , R4 and R is independently as defined in formula nitrogen , oxygen , or sulfur, phenyl , a 3 -7 membered II - a . saturated or partially unsaturated carbocyclic ring , an E66 . The method of any one of the preceding examples , 8 - 10 membered bicyclic saturated , partially unsaturated R1 is an optionally substituted group selected from C or aryl ring, a 5 - 6 membered monocyclic heteroaryl ring 55 aliphatic , C , heteroaliphatic having 1 - 3 heteroatoms having 1 - 4 heteroatoms independently selected from independently selected from nitrogen , oxygen , or sulfur, nitrogen , oxygen , or sulfur, a 4 - 7 membered saturated or phenyl, a 3 - 7 membered saturated or partially unsaturated partially unsaturated heterocyclic ring having 1 - 3 heteroa carbocyclic ring , an 8 - 10 membered bicyclic saturated , toms independently selected from nitrogen , oxygen , or partially unsaturated or aryl ring , a 5 - 6 membered mono sulfur , a 7 - 10 membered bicyclic saturated or partially 60 cyclic heteroaryl ring having 1 - 4 heteroatoms indepen unsaturated heterocyclic ring having 1 - 5 heteroatoms dently selected from nitrogen , oxygen , or sulfur, a 4 - 7 independently selected from nitrogen , oxygen , or sulfur, membered saturated or partially unsaturated heterocyclic or an 8 -14 membered bicyclic or tricyclic heteroaryl ring ring having 1 - 3 heteroatoms independently selected from having 1 - 5 heteroatoms independently selected from nitrogen , oxygen , or sulfur , a 7 - 10 membered bicyclic nitrogen , oxygen , or sulfur ; and two R ’ are optionally 65 saturated or partially unsaturated heterocyclic ring having taken together with the oxygen atoms they are bound to 1 - 5 heteroatoms independently selected from nitrogen , form a bidentate ligand ; and oxygen , or sulfur, or an 8 - 10 membered bicyclic het US 9 ,850 , 268 B2 103 104 eroaryl ring having 1 -5 heteroatoms independently heteroaryl ring having at least one nitrogen and 0 - 3 selected from nitrogen , oxygen , or sulfur ; heteroatoms independently selected from nitrogen , oxy each of R² and R3 is independently R ', — OR ', SR ', gen , or sulfur, a 4 - 7 membered saturated or partially - N ( R ') 2 , — OC ( O ) R ', - SOR ', - SO2R ', SO N (R ') 2 , unsaturated heterocyclic ring having at least one nitrogen C ( O ) N ( R ') 2 , - NR ' C ( O ) R ', or — NR 'SO , R ', provided 5 and 0 - 2 heteroatoms independently selected from nitro gen , oxygen , or sulfur, a 7 -10 membered bicyclic satu that R2 and R3 are not simultaneously hydrogen ; rated or partially unsaturated heterocyclic ring having at R4 is R², or an optionally substituted group selected from least one nitrogen and 0 - 4 heteroatoms independently - Ar, C1- 20 aliphatic , C1- 20 heteroaliphatic having 1 - 3 selected from nitrogen , oxygen , or sulfur, or an 8 - 10 heteroatoms independently selected from nitrogen , oxy membered bicyclic heteroaryl ring having at least one gen , or sulfur, phenyl, a 3 -7 membered saturated or nitrogen and 0 - 4 heteroatoms independently selected partially unsaturated carbocyclic ring , an 8 - 10 membered from nitrogen , oxygen , or sulfur ; bicyclic saturated , partially unsaturated or aryl ring , a 5 -6 R™ is an optionally substituted group selected from C1- 20 membered monocyclic heteroaryl ring having 1 - 4 het aliphatic , C1- 20 heteroaliphatic having 1 -3 heteroatoms eroatoms independently selected from nitrogen , oxygen , 15 independently selected from nitrogen , oxygen , or sulfur , or sulfur, a 4 - 7 membered saturated or partially unsatu phenyl , a 3 - 7 membered saturated or partially unsaturated rated heterocyclic ring having 1 - 3 heteroatoms indepen carbocyclic ring , an 8 - 10 membered bicyclic saturated , dently selected from nitrogen , oxygen , or sulfur , a 7 - 10 partially unsaturated or aryl ring , a 5 - 6 membered mono membered bicyclic saturated or partially unsaturated het cyclic heteroaryl ring having 1 - 4 heteroatoms indepen erocyclic ring having 1 -5 heteroatoms independently 20 dently selected from nitrogen , oxygen , or sulfur, a 4 - 7 selected from nitrogen , oxygen , or sulfur , or an 8 - 14 membered saturated or partially unsaturated heterocyclic membered bicyclic or tricyclic heteroaryl ring having 1 -5 ring having 1 - 3 heteroatoms independently selected from heteroatoms independently selected from nitrogen , oxy nitrogen , oxygen , or sulfur , a 7 - 10 membered bicyclic gen , or sulfur ; saturated or partially unsaturated heterocyclic ring having Ar is of the following formula : 25 1 - 5 heteroatoms independently selected from nitrogen , oxygen , or sulfur, or an 8 - 14 membered bicyclic or tricyclic heteroaryl ring having 1 - 5 heteroatoms indepen ma dently selected from nitrogen , oxygen , or sulfur; and (R4 ) , to D + (R ) each R ' is independently hydrogen or an optionally substi 30 tuted group selected from C1- 6 aliphatic , phenyl , a 3 - 7 membered saturated or partially unsaturated carbocyclic ring, an 8 - 10 membered bicyclic saturated , partially (R $) m unsaturated or aryl ring , a 5 - 6 membered monocyclic heteroaryl ring having 1 - 4 heteroatoms independently wherein : 35 selected from nitrogen , oxygen , or sulfur , a 4 - 7 membered m is 0 - 3 ; saturated or partially unsaturated heterocyclic ring having Ring B is an optionally substituted group selected from 1 - 3 heteroatoms independently selected from nitrogen , phenyl or a 5 - 6 membered monocyclic heteroaryl ring oxygen , or sulfur , a 7 - 10 membered bicyclic saturated or having 1 - 4 heteroatoms independently selected from partially unsaturated heterocyclic ring having 1 - 5 heteroa nitrogen , oxygen , or sulfur; 40 toms independently selected from nitrogen , oxygen , or p and q are independently 0 - 6 ; sulfur, or an 8 - 10 membered bicyclic heteroaryl ring each of Ring C and Ring D is independently optionally having 1 - 5 heteroatoms independently selected from substituted groups selected from phenyl , a 3 - 7 mem nitrogen , oxygen , or sulfur, wherein : bered saturated or partially unsaturated carbocyclic t wo R ' groups on the same nitrogen atom are optionally ring , an 8 - 10 membered bicyclic saturated , partially 45 taken together with the nitrogen atom to form an option unsaturated or aryl ring , a 5 - 6 membered monocyclic a lly substituted 3 - 8 membered , saturated , partially unsatu heteroaryl ring having 1 - 4 heteroatoms independently rated , or aryl ring having 1 - 4 heteroatoms independently selected from nitrogen , oxygen , or sulfur, a 4 - 7 mem selected from nitrogen , oxygen , or sulfur; and bered saturated or partially unsaturated heterocyclic each R ' is independently an optionally substituted group ring having 1 -3 heteroatoms independently selected 50 selected from — Ar' , C1- 20 aliphatic , C1- 20 heteroaliphatic from nitrogen , oxygen , or sulfur, a 7 - 10 membered having 1 - 3 heteroatoms independently selected from bicyclic saturated or partially unsaturated heterocyclic nitrogen , oxygen , or sulfur, phenyl, a 3 - 7 membered ring having 1 - 5 heteroatoms independently selected saturated or partially unsaturated carbocyclic ring , an from nitrogen , oxygen , or sulfur, or an 8 - 10 membered 8 - 10 membered bicyclic saturated , partially unsaturated bicyclic heteroaryl ring having 1 - 5 heteroatoms inde - 55 or aryl ring , a 5 - 6 membered monocyclic heteroaryl ring pendently selected from nitrogen , oxygen , or sulfur; having 1 - 4 heteroatoms independently selected from each of R * , R ' , and R is independently halogen , - OR ', nitrogen , oxygen , or sulfur, a 4 - 7 membered saturated or - N (R ') 2 , NR ' C ( O ) R ', - NR 'C (O )OR ' , - NR ' C (O ) partially unsaturated heterocyclic ring having 1 - 3 heteroa N (R ') 2, — NR 'SO , R ', — NR 'SO , N (R ') 2 , — NR 'OR ', or toms independently selected from nitrogen , oxygen , or an optionally substituted group selected from C1- 20 60 sulfur, a 7 - 10 membered bicyclic saturated or partially aliphatic , C1- 20 heteroaliphatic having 1 - 3 heteroatoms unsaturated heterocyclic ring having 1 - 5 heteroatoms independently selected from nitrogen , oxygen , or sul independently selected from nitrogen , oxygen , or sulfur, fur; or an 8 - 14 membered bicyclic or tricyclic heteroaryl ring R $ is halogen , - OR " , OR , — N ( R ' ) 2 , — NR' C ( O ) R ', having 1 - 5 heteroatoms independently selected from - NR ' C ( O )OR ', NR ' C ( O ) N ( R ') 2 , - NR ' SO R ', 65 nitrogen , oxygen , or sulfur; and two R ’ are optionally - NR ' SO2N ( R ') 2, or — NR 'OR ', or an optionally substi taken together with the oxygen atoms they are bound to tuted group selected from a 5 -6 membered monocyclic form a bidentate ligand ; and US 9, 850 ,268 B2 105 106 Ar' is of the following formula :

-

n

IR a weo EL

10 wherein : t is 0 - 4 ; E73. The method of any one of examples E1 - E66 , wherein p is 0 -6 ; R is optionally substituted C1- 20 aliphatic . each Ring B ' and Ring C ' is independently an optionally 1515 E73. The method of any one of examples E1 - E66 , wherein substituted group selected from phenyl, a 3 - 7 mem R ! is optionally substituted C1- 20 aliphatic , and R ! is a bered saturated or partially unsaturated carbocyclic tertiary substituent. ring , an 8 - 10 membered bicyclic saturated , partially E73a . The method of any one of examples E1 - E66 , wherein unsaturated or aryl ring , a 5 - 6 membered monocyclic Rl is adamantyl. heteroaryl ring having 1 - 4 heteroatoms independently - E74 . The method of any one of the preceding examples, selected from nitrogen , oxygen , or sulfur, a 4 - 7 mem - wherein one of R2 and R3 is hydrogen , and the other is bered saturated or partially unsaturated heterocyclic optionally substituted C1- 6 aliphatic ; or R ? and R ' are taken ring having 1 - 3 heteroatoms independently selected together with their intervening metal atom to form an from nitrogen , oxygen , or sulfur, a 7 - 10 membered 25 optionally substituted 3 - 4 membered saturated or partially bicyclic saturated or partially unsaturated heterocyclic unsaturated ring having , in addition to the intervening metal ring having 1 - 5 heteroatoms independently selected atom , 0 - 4 heteroatoms independently selected from nitro from nitrogen , oxygen , or sulfur, or an 8 - 10 membered gen , oxygen , or sulfur. bicyclic heteroaryl ring having 1 - 5 heteroatoms inde E75. The method of any one of the preceding examples , pendently selected from nitrogen , oxygen , or sulfur ; 30 wherein one of R2 and R3 is hydrogen , and the other is and optionally substituted C1- 6 aliphatic ; or R2 and R3' are taken each RS is independently halogen , R ', _ OR ', SR ', together with their intervening metal atom to form option - S (O )R ', - S (O ), R ', OSi( R ') 3, N (R ') 2, NR ' C ( O ) R ', - NR : C (O ) OR ', NR ' C ( O ) N ( R ') 2 , ally substituted metallacyclopropane or metallacyclobutane . NR 'SO , R ', - NR 'SO , N ( R ') , , or NR 'OR '. 35 E76 . The method of any one of the preceding examples, wherein one of R2 and R * is hydrogen , and the other is a E66 . The method of any one of the preceding examples , tertiary substituent and is substituted C - alkyl , or R2' and wherein M is Mo . R " are taken together with their intervening metal atom to E66a. The method of any one of the preceding examples, form metallacyclobutane. wherein M is W . E67 . The method of any one of the preceding examples , E77. The method of any one of the preceding examples , wherein Rl is optionally substituted phenyl or optionally wherein R4 is optionally substituted group selected from substituted C1- 20 aliphatic . phenyl , Ar' and Ar. E67. The method of any one of the preceding examples , E77 . The method of any one of the preceding examples, wherein R is optionally substituted phenyl. * 45 wherein R + is optionally substituted Ar' . E68 . The method of any one of the preceding examples , E78. The method of any one of the preceding examples , wherein R ' is substituted phenyl comprising one or more wherein R * is an optionally substituted group selected from : electron -withdrawing groups . E69 . The method of any one of the preceding examples, 50 wherein R is R ' is optionally substituted

(RV ) un met 55 m ni wherein p is not 0 . E70 . The method of example E69, wherein each R ” is 60 independently halogen or optionally substituted C1- 10 haloalkyl. E71. The method of example E69, wherein each Rºis mm independently halogen or C1- 10 perfluoroalkyl. 65 mu E72 . The method of any one of the preceding examples , wherein Rl is US 9 ,850 ,268 B2 107 108 - continued E81. The method of example E79 or E80 , wherein Ar is

?? RWRu RRZ ? - R2 5 n am

, and or

RY egyR2 atot 10 RY R RY R2

E82 . The method of example E79 or E80 , wherein Ar is

20 w R

mia

E78a . The method of any one of the preceding examples , 25 N wherein R4 is optionally substituted

30 E83 . The method of any one of the preceding examples , wherein R * is optionally substituted

mm nim 35

E78b . The method of any one of the preceding examples , 40 wherein R4 is optionally substituted E84 . The method of any one of the preceding examples , wherein R4 is optionally substituted phenyl. E85. The method of any one of the preceding examples , 45 wherein R4 is substituted phenyl comprising a 2 ' - and a 6 '- substituent . E86 . The method of any one of examples E1- E76 , wherein : R4 is – Ar; Ar is ni 50 RP RZ Ra ; wananRY RARE ; E79. The method of any one of the preceding examples , wherein R * is optionally substituted Ar. 55 E80 . The method of example E79, wherein Ar is RY RZ

mns 60 each of Rº and R ? is independently optionally substituted (R ? ) C1- 20 aliphatic . E87 . The method of example E86 , wherein each of Ry and R ? is methyl. E88 . The method of example E86 , wherein each of R ' and 65 R² is ethyl. E89 . The method of any one of the preceding examples , wherein each ofR and R is independently C1- 6 alkyl . wherein R4 is selected from US 9, 850 ,268 B2 109 110 -continued wa

añoPh PhPh t - Bu . t - Bu , and mm 10 Me Me Me wanan Me,

porMe Me mi

Et Et Et 20 man E90 . The method of any one of the preceding examples , wherein R is optionally substituted 5 - 6 membered het Et É 25 eroaryl having at least one nitrogen and 0 - 3 heteroatoms independently selected from nitrogen , oxygen , or sulfur, wherein the at least one nitrogen is bonded to M . iPriPr E91. The method of any one of the preceding examples , man wherein R? is optionally substituted 1 -pyrrolyl . E92. The method of any one of the preceding examples , wherein R is 1 -pyrrolyl . iPr iPr E93. The method of any one of the preceding examples , 35 whereinWhere RS is

Me Me mi Me 40 -Me . Me deye Me, . 45 E94 . The method of any one of the preceding examples , wherein the catalyst or metal complex is used in an amount of no more than about 15 mol % relative to the second t - Bu t - Bu species . E95 . The method of any one of the preceding examples , 50 wherein the catalyst or metal complex is used in an amount mm of no more than about 10 mol % relative to the second species . t - Bu t- Bu , E96 . The method of any one of the preceding examples , 55 wherein the catalyst or metal complex is used in an amount sa of no more than about 5 mol % relativea to the second species . E97 . The method of any one of the preceding examples, Ph wherein the catalyst or metal complex is used in an amount 60 of no more than about 3 mol % relative to the second ma species . E98. The method of any one of the preceding examples , wherein the catalyst or metal complex is one exemplified in ygun 65 the present application . E99 . The method of any one of the preceding examples , og de wherein the catalyst or metal complex is US 9, 850 ,268 B2 111 112

Mo - 3 Mo- E1 FF F . F Y F

Z LullPh Nuus MC N11111*is MO hallll Ph . tBu tBu 0 Me, MevawMe Me. 15 tBu tBu .

Me E103 . A compound of formula II- a or a compound of E100 . The method of any one of examples E1- E98 , wherein 20 formula II - b . the catalyst or metal complex is : E104 . A compound having the structure of Mo- 4 in example E100 . E104 . A compound having the structure of Mo- E1 in example E102 . Mo- 4 - E105 . A composition , comprising : F a first species comprising an olefin , wherein each carbon F atom of the olefin in the first species is substituted with at least one halogen ; and 2030 a metal complex comprising Mo or W . E106 . The composition of example E105 , wherein the first species has the structure of

NUD . MO aulPh FROM 35 Et v Et. wherein each of X and Y is independently halogen . E107 . The composition of example E105 , wherein the first Et 40 species has the structure of

E101 . The method of any one of examples E1- E98 , wherein the catalyst or metal complex is: 45

Mo- 5 wherein each of X and Y is independently halogen . F E108 . The composition of any one of examples E105 -E107 , 50 wherein X and Y are different. F E109 . The composition of any one of examples E105 -E107 , wherein X and Y are the same. E110 . The composition of any one of examples E105 -E109 , F wherein X is – F , Y is _ C1 or — Br. 55 E111 . The composition of any one of examples E105 -E109 , wherein X is F and Y is Cl. " Mo Ph E112 . The composition of any one of examples E105 -E109 , vi- Pro i- Pr , wherein X is — F and Y is — Br . i- Pr . E113 . The composition of any one of examples E105 - E113 , i- Pro 60 wherein the metal complex has the structure of formula II - a . E114 . The composition of any one of examples E105 - E113 , wherein the metal complex has the structure of formula II - b . 1 - Pr i - Pr E114 . The composition of any one of examples E105 - E113 , wherein the metal complex is as described in any one of 65 E64 -E104 . E102. The method of any one of examples E1- E98 , wherein E115 . The composition of any one of examples E105 -E112 , the catalyst or metal complex is : further comprising a second species comprising an olefin . US 9 , 850 , 268 B2 113 114 E116 . The composition of any one of examples E105 - E115 , E141. The compound of example E139, wherein wherein the metal complex promotes a metathesis reaction - CH = CHF has a E configuration . between the first species and the second species. E142 . The compound of any one of examples E139 -E141 , E117 . The composition of example E116 , wherein the wherein the bioactive molecule is an approved drug . metathesis reaction provides regioselectivity . 5 E142 . The compound of any one of examples E139 -E141 , E118 . The composition of example E116 or E117 , wherein wherein the bioactive molecule is or was in clinical trial. the metathesis reaction provides Z - selectivity . E143 . The compound of any one of examples E139 - E141 , E119 . The composition of example E116 or E117 , wherein wherein the bioactive molecule is a natural product . the metathesis reaction provides E - selectivity . E144 . A method for preparing a compound of any one of E120 . The composition of any one of theThe preceding 10 examples E139 -E143 , comprising a method of any one of examples , comprising R ' OH or a salt thereof. examples E1- E102 , wherein the second species is the bio active molecule . E121 . The composition of any one of the preceding E145 . A pharmaceutical composition , comprising a com examples, comprising R?H or a salt thereof. pound of any one of examples E139 -E143 , further compris E122 . The composition of any one of the preceding 15 ing a pharmaceutically acceptable carrier. examples , wherein the molar ratio of the first species and the metal complex is greater than about 2 : 1. EXEMPLIFICATION E123 . The composition of any one of the preceding examples , wherein the molar ratio of the first species and the Non -limiting examples were provided below . metal complex is greater than about 5 : 1 . 20 Stereochemically defined alkenes are ubiquitous in natu E124 . The composition of any one of the preceding ral occurring compounds and drugs and serve as substrates examples , wherein the molar ratio of the first species and the for numerous transformations in chemistry . Efficient proto metal complex is greater than about 10 :1 . cols for the stereoselective preparation of olefins are highly E125 . The composition of any one of the preceding desirable , particularly if they are promoted by catalysts that examples , wherein the molar ratio of the first species and the 25 control the identity of themajor product isomer . ( Füstner , A . metal complex is greater than about 20 : 1 . Science 2013, 341 , 1357 - 1364 . ) Alkenyl halides rank as one E126 . The composition of any one of the preceding of the most important classes of compounds in organic examples , wherein the molar ratio of the first species and the chemistry due to their occurrence in natural products as well metal complex is greater than about 30 : 1 . as the immense applications associated . ( ( a ) Guinchard , X . ; E127 . The composition of any one of the preceding 30 Roulland , E . Synlett . 2011 , 19 , 2779 - 2788 . (b ) Stanforth , S . examples , wherein the molar ratio of the first species and the P. Vinyl and Aryl Halides in Comprehensive Organic Func metalm complex is greater than about 40 : 1 . tional Group Transformations II ( ed . Katritzky , A . R . & E128 . The composition of any one of the preceding Taylor, R . J. K .) vol. 2 ( Elsevier, 2004 ). ) Traditionalmeth examples , wherein the molar ratio of the first species and the ods that afford Z -vinyl halides (e .g . , Stork - Zhao olefination ) metal complex is greater than about 50 : 1 . 35 (For a representative example , see: Stork , G .; Zhao , K . E129 . The composition of any one of the preceding Tetrahedron Lett. 1989 , 30 , 2173 - 2174 ) and their corre examples , comprising CH2 = CHY and / or CH2 = CHX . sponding E -diastereomers ( e . g ., Takai olefination ) (For a E130 . The composition of any one of the preceding representative example , see : Takai, K .; Nitta , K .; Utimoto , examples , comprising CH = CHY and CH2 = CHX , K . J. Am . Chem . Soc . 1986 , 108 , 7408 -7410 . ) offer moderate wherein each of X and Y is independently halogen , X < Y , 40 to high levels of selectivity depending on the relative steric and the molar ratio of CH = CHY and CH2 = CHX is size of the substrates and reagents employed . Other routes of greater than 1 : 1 . forming stereodefined vinyl halides frequently proceed E131 . The composition of example E130 , wherein the molar though an organometallic precursor before conversion to the ratio of CH2 = CHY and CH = CHX is greater than 2 : 1 . desired product with a halogen source . ( For a representative E132 . The composition of example E130 , wherein the molar 45 example , see : Morrill, C . ; Grubbs, R . H . J . Org . Chem . 2003 , ratio of CH2 = CHY and CH2 = CHX is greater than 3 : 1 . 68 , 6031 -6034 .) Despite these advances, there is a persisting E133 . The composition of example E130 , wherein the molar lack of catalytic protocols that directly furnish alkenyl ratio of CH = CHY and CH2= CHX is greater than 5 : 1. halides efficiently and stereoselectively, particularly those E134 . The composition of example E130 , wherein the molar that do not entail the generation of intermediates and stoi ratio of CH2= CHY and CH2= CHX is greater than 10 : 1 . 50 chiometric waste . In some embodiments , the present disclo E135 . The composition of example E130 , wherein the molar sure recognizes that stereoselective catalytic olefin metath ratio of CH2 = CHY and CH = CHX is greater than 20 : 1 . esis (OM ) with an appropriate vinyl halide cross - partner can E136 . The composition of any one of examples E105 -E135 , potentially provide a solution to the aforementioned chal comprising a metal complex comprising Mo or W , wherein lenge . However , previous reports have been limited to the metal complex is a degradation product of a compound 55 Ru -catalyzed protocols (( a ) Sashuk , V . ; Samoj?owicz , C .; of formula II - a or II - b . Szadkowska , A .; Grela , K . Chem . Commun . 2008 , 2468 E137 . The composition of any one of examples E105 - E136 , 2470 . ( b ) Macnaughtan , M . L . ; Gary, J . B . ; Gerlach , D . L . ; wherein the composition comprises no W . Johnson , M . J. A .; Kampf, J . W . Organometallics 2009 , 28 , E138 . The composition of any one of examples E105 -E136 , 2880 - 2887 ) which generally suffer from poor stereoselec wherein the composition comprises no Mo. 60 tivity ( E /Z mixtures ) and a narrow substrate range , likely as E139 . A fluorinated compound derived from a bioactive a result of the attenuated reactivity of the chloromethylidene molecule, wherein the bioactive molecule comprises a ter - species in OM and its susceptibility to various decomposi minal olefin , and the fluorinated derivative comprises a tion pathways . (Macnaughtan , M . L . ; Johnson , M . J . A . ; terminal olefin comprising — CH = CHF derived from the Kampf, J . W . J . Am . Chem . Soc. 2007 , 129 , 7708 - 7709 . ) terminal olefin of the bioactive molecule . 65 Herein , the present disclosure demonstrates that, among E140 . The compound of example E139, wherein other things , ring -opening / cross -metathesis (ROCM ) ( Ibra - CH = CHF has a Z configuration . hem , I . ; Yu , M . ; Schrock , R . R . ; Hoveyda , A . H . J . Am . US 9 , 850 , 268 B2 115 116 Chem . Soc. 2009, 131 , 3844 - 3845 ) and cross -metathesis - continued ( CM ) (Meek , S . J. ; O 'Brien , R . V .; Llaveria , J. , Schrock , R . R .; Hoveyda, A . H . Nature 2011 , 471, 461 -466 ) reactions involving suitable halogen - containing olefin cross - partners promoted by provided compounds, in some embodiments , 5 Me Y Me molybdenum -based monoaryloxide monopyrrolide (MAP ) N complexes, can deliver Z - alkenyl halides with high effi ciency and stereoselectivity . Nusta .MON 111 ] Ph We began by examining the ROCM reaction between 10 Z - cyclooctene 1 and 2 equivalents of commercially avail Br Br able Z - 1 , 2 -dichloroethylene in the presence of 5 mol % of various Ru carbenes and Mo alkylidenes (Scheme 1 ). TBSO 15 Scheme 1 ROCM of Z -cyclooctene and Z - 1 , 2 -dichloroethylene in the presence of various OM catalysts . Mo- 1 [Ru ] (5 mol %) , CH2Cl2, 22°C , 67 % conv, 4 -12 h 20 < 5 % conv to 2 Cl + or [Mo ] ( 5 mol % ) , C6H6, 22° C ., 2 h ( 2 equiv )

25

Ni ** * * MOI 111 Ph

Br

OTBS

Mo - 2 MesN NMes > 98 % conv, 75 % yield , > 98 : < 2 Z : E !!! DI * *395278 1t11*

- FF

Ru - 1 NII .. .Mon lll Ph < 5 % conv 0 Met , Me Ult Me

Me Me

MesNNMes Mo- 3 > 98 % conv , 63 % yield , 84 : 16 Z : E Clin, RWC 60 While ROCM was inefficient with Ru carbenes , Mo- based - Oi - Pr complexes Mo- 2 and Mo- 3 gave the desired product in moderate to good yields and Z - selectivities . Ru - 2 65 While there was minimal reaction with Ru - 1 (Koh , M . J . ; > 98 % conv, 13 % yield , 62 :38 Z : E Khan , R . K . M .; Torker, S .; Yu , M .; Mikus , M .; Hoveyda , A . H . , submitted ) and significant ring - opening metathesis US 9 ,850 ,268 B2 117 118 polymerization (ROMP ) of 1 with Ru - 2 (Garber , S . B . ; - continued Kingsbury, J . S . ; Gray , B . L . ; Hoveyda, A . H . J . Am . Chem . Soc . 2000 , 122 , 8168 -8179 ) and Mo - 1, (Meek , S . J .; O 'Brien , R . V . ; Llaveria , J .; Schrock , R . R .; Hoveyda, A . H . Nature 2011 , 471 , 461 -466 ) both Mo- 2 and Mo- 3 furnished 5 the desired ROCM product 3 in 75 % yield ( > 98 % Z -selec tivity ) and 63 % yield (84 % Z -selectivity ) within 2 hours , respectively . We next assessed the ability ofhigh oxidation NUM 11llllll state alkylidenes to promote the more challenging CM of 8 -bromo -1 - octene 4 and Z - 1 ,2 - dichloroethylene (Scheme 2 ). vi- Pro i- Pr, 5 was obtained in 60 % yield and complete Z -selectivity in i- Pr V ii- - Pr Pr the presence of 5 mol % of Mo- 3 within 4 hours . In contrast, I I CM was less efficient with other Mo- and W - based catalysts , and metathesis homocoupling of 4 was observed to be a 16 i - Pr i - Pr competitive side reaction in most cases . In some embodi W - 2 ments , the pentafluorophenylimido ligand of Mo- 3 was < 5 % conv partly responsible for promoting the CM reaction . F 20 Scheme 2 CM of 8 -bromo - 1 -octene and Z - 1 , 2 - dichloroethylene in the presence of various OM catalysts . [Mo ] or [ W ] -based complex F (5 mol % ) -Z= CI + Br 25 C6H6, 22° C ., 4 h ROMuun . W lulIPh Mo- 2 ( 5 equiv ) 4 60 % conv, 27 % conv to 5 , RO Mo- 1 > 98 : 2 Z : E 43 % conv , 30 mi < 5 % conv to 5 ( 11111 O F1 11 R = F 1111

eout35

a StaBr W - 3 43 % conv, < 5 % conv to 5 Mo- 3 40 CM of 8 - bromo - 1 -octene in the presence of excess Z - 1 , 2 87 % conv , 70 % conv to 5 , dichloroethylene was inefficient with W - based alkylidenes. 60 % yield , > 98 : < 2 Z : E Among the Mo - based complexes screened , best results were observed with Mo- 3 , which delivered the CM product in 50 % yield and complete Z - selectivity . Applicant recognizes that, in some embodiments , increas ing the size of the aryloxide ligand on M0 - 3 could poten tially prolong catalyst lifetime and improve reaction effi ciency . Mo- 4 gave 5 in 75 % yield and > 98 % Z -selectivity with minimal homocoupling side product . In some embodi ments , without the intention to be limited by theory , Appli 50 cant notes that the greater steric bulk most likely increases i - Pr i - Pr catalyst longevity , allowing the homodimer of 4 to further participate in reaction to regenerate the propagating alky NUS * . W lidene species for CM with Z - 1 , 2 -dichloroethylene . CM | | Ph with the sterically more encumbered Mo - 5 complex pro 55 ceeded to 62 % conversion within 4 hours. Increasing the Br reaction time to 12 hours resulted in almost complete Br conversion and 5 was obtained in 84 % yield , albeit with TBSO diminished Z - selectivity ( 93 % Z ) probably , without the intention to be limited by theory , as a result of post 60 metathesis isomerization . (Meek , S . J . ; O ' Brien , R . V . ; Llaveria , J. ; Schrock , R . R .; Hoveyda , A . H . Nature 2011, 471 , 461- 466 ) Applicant notes importance of tuning catalyst lifetime through ligand modification in order to achieve W - 1 optimal results in efficiency and stereoselectivity . Lowering 45 % conv , 65 the catalyst loading of Mo- 4 to 3 mol % was not detrimental 5 % conv to 5 , for the reaction , and 5 was obtained in 77 % yield and > 98 % Z -selectivity . US 9 ,850 ,268 B2 119 120 Exemplary optimal results were achieved with 5 mol % of Scheme 3 CM of 8 -bromo - 1 -octene and Z - 1 , 2 - dichloroethylene Mo - 4 , which gave the desired CM product in 75 % yield in the presence of various analogous of Mo - 3 . within 4 hours while preserving the high Z - selectivity . Reaction with the sterically more encumbered Mo - 5 pro ceeded to give the product in greater yield (84 % ) but with F plummeted stereoselectivity ( 93 : 7 Z : E ) after 12 hours , likely as a result of post -metathesis isomerization during late stages of the transformation . LE 10 With the catalysts (Mo - 3 and Mo- 4 ) in hand , we pro ceeded to investigate the generality of the CM protocol with ND . M il Ph a myriad of functionalized terminal alkenes , including branched allylic olefins and those that contain heterocyclic and /or Lewis basic functionalities (Scheme 4 ) . As demon Me 15 Mem JuveMe MelodMellin Me strated by examples herein , a broad scope of substrates can be used in provided methods . CM products were obtained in 41 - 80 % yield and 297 % Z - selectivity . The corresponding Me Me reactions with symmetric (14 ) and asymmetric ( 16 and 19 ) Mo - 3 20 Z - 1 , 2 - disubstituted olefins were similarly efficient and Z -se 4 h : lective , generating the desired products in 79- 91 % yield and 87 % conv, 70 % conv to 5 , 60 % yield , >98 :< 2 Z :E 94 : 6 - 97 : 3 Z : E ratios (Scheme 4 ). In addition , CM of vinyl F cyclohexane 21 with commercially available 1 , 2 - dibromo 25 ethylene (64 : 36 Z : E ratio ) was moderately efficient, afford FF ing 22 solely as the Z - isomer in 42 % yield ( Scheme 5 ) .

F F Scheme 4 CM of Z - 1 , 2 -dichloroethylene with terminal alkenes and Z - 1 , 2 - disubstituted internal alkenes . pr . . Mo IlPh Mo- 3 or Mo - 4 CI C1 + R ( 3 mol % ) .s111 Ex Et C6H6 ( 0 . 2 or Et VE 3 .3M ) 22° C ., ( 5 equiv ) 4 h

- OMe Mo - 4 4 h : 90 % conv, 88 % conv to 5 , OMe 75 % yield , > 98 : < 2 Z : E with 3 mol % M0 - 4 88 % conv, 61 % yield , > 98 : < 2 Z : E

N in . Mo III Ph NH

with 3 mol % Mo - 3 Ji- Pr i- Proin 86 % conv , 41 % yield , i - Pro i- Promi Wi i-- PrP 55 97 : 3 Z : E

i - Pr i - Pr

Mo - 5 4 h : 62 % conv, 41 % conv to 5 , 20 % conv to homodimer, 98 : 2 2 : 3 12 h : 95 % conv , 88 % conv to 5 , with 3 mol % M0- 4 84 % yield , 93 : 7 Z : E 81 % conv, 65 % yield , > 98 : < 2 Z : E US 9, 850 ,268 B2 121 122 - continued - continued CI - OTBS 17 CO2Me MeMeTV CI

17 18 with 3 mol % M0- 4 5 94 % conv , 91 % yield , 94 % conv , 86 % yield , 88 % conv, 80 % yield , 97 : 3 Z : E 97 : 3 Z : E > 98 : < 2 Z : E Cl . Me - ( 84G Mo- 4 (3 mol %) 60 i - Pr C6H6 22° C ., 4 h 10 (5 equiv ) O CI MeTV CI 20 18 Me > 98 % conv , 81 % yield , > 98 % conv , 79 % yield , 10 94 : 6 Z : E 94 :6 Z : E with 3 mol % M0 - 4 79 % conv, 73 % yield , Me > 98 : < 2 Z : E Me Me Mellit Me - Me Me

with 3 mol % Mo - 3 Me 84 % conv , 76 % yield , > 98 : < 2 Z : E 13549 G = wir

30 12 with 3 mol % M0- 3 CM promoted by Mo- 3 or Mo - 4 with a variety of terminal 89 % conv , 75 % yield , olefins were found to be efficient and stereoselective, gen > 98 : < 2 Z : E erating predominantly Z -products in 41 -80 % yield . Reac tions with symmetric and asymmetric Z - internal olefins 35 were significantly efficient and Z - selective in the presence of Mo - 4 as the catalyst .

13 Scheme 5 CM of 1 ,2 - dibromoethylene with vinylcyclohexane . with 3 mol % Mo- 3 6 82 % conv , 69 % yield , Br Br > 98 : < 2 Z : E Mo- 3 (5 mol % ) so C6H6 22°C . , 4 h OTBS ( 8 equiv ) Me

H TI eout 22 with 5 mol % M0- 4 61 % conv , 42 % yield , 75 % conv , 70 % yield , > 98 : 2 Z : E 95 :5 Z : E + MeTV 13 Me Mo- 4 (1 mol % ) CM of vinylcyclohexane and 1, 2 -dibromoethylene in the C6H6 22° C ., 4 h 55 presence of 5 mol % of Mo- 3 was moderately efficient but (5 equiv ) highly Z - selective , furnishing the desired Z - product in 42 % 2 CI Me yield .

15 60 Scheme 6 CM of 1 ,2 - dibromoethylene with alkenes. w 97 % conv , 85 % yield , 97: 3 Z : E Mo- 4 Br Br (5 mol % ) C Metz 177 CO2Me M0- 4 ( 3 mol % ) + R / Br. C6H6 22° C . , 4 h C6H6 65 ( 8 equiv , 64 % Z ) ( 0 . 2 or 3 . 3M ), (wizwa 5 equiv ) 16 22° C ., 4 US 9, 850 ,268 B2 123 124 - continued -continued Br D - OTBS F W = TIPS

23 28 95 % conv , 63 % yield , > 98 % conv , 72 :28 F :Br 88 : 12 Z : E 64 % yield of fluoride, > 98 : 2 Z : E Me Me Me Br - OTBS 10 Me Me 24 74 % conv , 57 % yield , 91 : 9 Z : E illlo 15 F The present disclosure , among other things , demonstrate that CM of 1 , 2 - dibromoethylene with alkenes was efficient and Z - selective when using provided technologies . In some embodiments , as evidenced by the examples herein , when both a Z isomer and an E isomer of an alkene are present , provided compounds and methods selectively promotes reactions with the Z - isomer to produce a Z - product . In some OMe 29 embodiments , both the Z isomer and the E isomer of 80 % conv , > 98 : 2 F : Br XCH = CHY are present, and provided compounds and os 63 % yield of Fluoride , methods selectively promotes reactions with the Z - isomer to > 98 : 2 Z : E produce a Z -product . As described above , the present disclosure, among other things , also provides technologies , e . g . , compound , meth ods , etc . , for regioselective synthesis of olefins such as vinyl 30 halides . In some embodiments, the present disclosure pro vides methods with both regioselectivity and stereoselectiv ity . In some embodiments , the present disclosure provides methods with both regioselectivity and Z -selectivity . Among other things, provided compounds and methods can provide 30 alkenyl fluoride with unexpectedly high regioselectivity 88 % conv , 95 : 5 F : Br and / or Z - selectivity . Non - limiting examples are presented in 66 % yield of Fluoride, Scheme 7 . 93 : 7 Z : E 40

Scheme 7 CM of Z - 1 - bromo - 2 - fluoroethylene with alkenes . OAC M0- 4 Br + R (5 mol % ) C6H6 (0 . 2 or 3 .3M ) , 22° C ., 4 h Me Me Me 31 94 % conv, 96 ; 4 F :Br OTBS 72 % yield of fluoride 94 :6 Z : E 26 . > 98 % conv . 96 : 4 F : Br 70 % yield (F ), > 98 :< 2 Z :E R = OMe, > 98 % conv . 93 . 7 F : Br 71 % yield ( F ), 95 :5 Z : E

HN HCI NH3

F GABA Inhibitor ( CM with TBS -amide ) with unique mode of action 27. 60 % conv , > 98 : 2 F : Br R = C1, 78 % conv , 96 : 4 F :Br 65 55 % overall yield of fluoride, 64 % yield?? ( F ) , 97 : 3 Z : E > 98 : 2 Z : E US 9 , 850 , 268 B2 125 126 -continued General Procedure for Preparation ofMo Complexes for Catalytic Reactions: In a Ny- filled glove box , an oven -dried 4 mL vial equipped with a magnetic stir bar was charged with Mo 5 bispyrrolide complex ( 1 . 00 equiv ) , phenol ( 1 . 00 equiv ) and C6H6, resulting in a dark red solution . The vial was capped and the mixture was allowed to stir for 2 hours at 22° C . , after which the catalyst solution was transferred to the Me reaction mixture by a syringe (dried at 65° C . ) . 10 2, 6 -( 2 ,4 ,6 -triethylphenyl ) Phenol 33 ' H NMR ( 400 MHz, CDC13 ) : 8 7 .09 - 7 . 06 ( 2H , m ) , 88 % conv , 91 : 9 F : Br 78 % yield of fluoride , 7 .04 - 7 . 01 (5H , br s ) , 4 .53 ( 1H , s ) , 2 .67 (4H , 9 , J = 7 . 6 Hz) , > 98 : 2 Z : E 15 2 . 46 - 2 .33 (8H , m ), 1 . 29 ( 6H , t, J = 7 .6 Hz) , 1 . 05 ( 12H , d , from perphenazine J = 7 . 6 Hz ) . anti- depressant Mo- 3 : Following the general procedure , an oven -dried 4 mL vial TU equipped with a magnetic stir bar was charged with Mo Me 20 bispyrrolide complex ( 59 . 8 mg, 0 . 1 mmol, 1 .00 equiv ) , 2 ,6 -Mes , Phenol (Mes = 2 , 4 ,6 -MezC6H2 ) (33 . 0 mg, 0 . 1 Me mmol, 1 .00 equiv ) and C . H . ( 1 mL ) , resulting in a dark red solution . The vial was capped and the mixture was allowed to stir for 2 hours at 22° C. ' H NMR ( 400 MHz, CD .) : 8 Me 25 11 .09 ( 1H , s ) . Mo - 4 : F Following the general procedure , an oven - dried 4 mL vial equipped with a magnetic stir bar was charged with Mo 34 bispyrrolide complex (59 . 8 mg, 0 . 1 mmol, 1 . 00 equiv ) , 86 % conv, > 98 : 2 F :Br 30 2 , 6 - ( 2 , 4 ,6 - triethylphenyl ) Phenol (41 . 5 mg, 0 . 1 mmol, 1 .00 80 % yield of fluoride, equiv ) and C . H . ( 1 mL ) , resulting in a dark red solution . The > 98 : 2 Z : E from sulbactam , vial was capped and the mixture was allowed to stir for 2 B - lactose inhibitor hours at 22° C . ' H NMR (400 MHz, CD ) : 8 11. 38 ( 1H , s ) . Me Experimental Procedure for Z -Selective ROCM and CM 35 General Procedure : Me In a N2- filled glove box , an oven - dried 8 mL vial equipped with a magnetic stir bar was charged with alkene substrate ( 1 . 0 equiv ) and Z - 1 , 2 - dichloroethylene ( 2 . 0 - 5 . 0 equiv ) . To this vessel, a solution of Mo- 2 , Mo- 3 or Mo- 4 in 40 benzene ( 1 - 5 mol % ) was added . The resulting solution was allowed to stir for 1 - 4 hours at 22° C ., after which the Me02C Me reaction was quenched by addition of wet CDC1z (percent 35 conversion is determined by 400 MHz 'H NMR analysis of 83 % conv , 94 : 6 F : Br 70 % yield of fluoride, the unpurified mixture ). Purification was performed through > 98 : 2 Z : E 45 silica gel chromatography . from isopimaric acid , K channel activator ( 12 , 9Z )- 1, 10 - dichloro - 1, 9 - decadiene ( 2 ) Following the general procedure , a solution of Mo- 2 in Experimental Procedure for In Situ Preparation of Mo - 50 benzene ( 0 . 1 M , 50 UL , 5 . 0 umol, 5 mol % ) was transferred Based MAP Complexes by syringe to an oven - dried vial containing Z - 1 , 2 -dichloro General Procedure for Preparation of Mo Complexes for ethylene ( 19 . 4 mg, 0 .2 mmol , 2 . 00 equiv ) , Z -cyclooctene NMR Analysis : In a N - filled glove box , an oven -dried 4 mL vial ( 11. 0 mg, 0 . 1 mmol, 1 . 00 equiv ) and benzene ( 450 uL ) . The equipped with a magnetic stir bar was charged with Mo resulting solution was allowed to stir for 2 hours at 22° C . bispyrrolide complex ( Yuan , J . ; Schrock , R . R . ; Müller , P .; 55 The reaction was quenched by addition of wet CDC1z and Axtell , J. C .; Dobereiner, G . E . Organometallics 2012 , 31 , analysis of the unpurified mixture revealed > 98 % consump 4650 -4653 ) ( 1 .00 equiv ) , phenol (Prepared in analogy to a tion of Z - cyclooctene . The resulting orange oil was purified previously reported procedure : Dickie. D . A : MacIntosh . I . by silica gel chromatography ( 100 % hexanes ) to afford 2 S . ; Ino , D . D . ; He, O . ; Labeodan , O . A : Jennings . M . C . : ( 15 . 6 mg, 0 .0753 mmol, 75 % yield ) in > 98 : < 2 Z : E ratio as Schatte , G . : Walsby , C . J .: Clyburne , J . A . C . Can . J. Chem . 60 colorless oil . ' H NMR ( 400 MHz , CDC1z ) : Z - isomer (ma 2008 , 86 , 20 -31 ) ( 1 .00 equiv ) and C Da, resulting in a dark jor ): 8 6 .01 ( 2H , dt, J = 7 . 2 , 1 . 6 Hz ) , 5 .75 ( 2H , 9 , J = 7 . 2 Hz ) , red solution . The vial was capped and the mixture was 2 . 22 ( 4H , qd , J = 7 . 6 , 1 . 6 Hz ), 1 . 42 - 1 . 32 ( 8H , m ) . allowed to stir for 2 hours at 22° C . , at which time it was transferred to a screw cap NMR tube by a pipette . The NMR ( Z ) - 8 - bromo - 1 - chloro - 1 -octene ( 5 ) tube was capped and sealed with Teflon tape . Note that for 65 in situ generated complexes , only the diagnostic signals of Following the general procedure, a solution of Mo - 4 in the a carbon of the syn - alkylidenes are shown . benzene (0 . 1 M , 30 uL , 3 .0 umol, 3 mol % ) was transferred US 9 ,850 , 268 B2 127 128 by syringe to an oven -dried vial containing Z - 1, 2 -dichloro - ratio as colorless oil. ' H NMR (400 MHz, CDC1z ): Z - isomer ethylene ( 48 . 5 mg, 0 . 5 mmol, 5 .00 equiv ) , 8 - bromo- 1 -octene (major ) : 87. 84 ( 1H , dd , J = 5 . 5 , 3 . 0 Hz) , 7 .71 ( 2H , dd , J = 5 . 4 , ( 19 . 1 mg, 0 . 1 mmol, 1 . 00 equiv ) and benzene (470 UL ) . The 3 . 1 Hz ), 6 .02 ( 1H , dt, J = 7 . 1 , 1 . 5 Hz) , 5 .73 ( 1H , q , J = 7 . 2 Hz) , resulting solution was allowed to stir for 4 hours at 22° C . 3 . 70 ( 2H , t, J = 7 . 2 Hz ), 2 . 28 (2H , qd , J = 7 . 4 , 1 . 5 Hz ) , The reaction was quenched by addition of wet CDC12 and 5 1 .77 - 1 .67 (2H , m ), 1 . 52 - 1 .44 ( 2H , m ) . analysis of the unpurified mixture revealed 90 % consump tion of 8 -bromo - 1 -octene . The resulting orange oil was ( Z ) -tert - butyl ( 8 - chloro -7 -octenyloxy )dimethylsilane purified by silica gel chromatography ( 100 % hexanes ) to (9 ) afford 5 ( 17 . 4 mg, 0 .0771 mmol, 77 % yield ) in > 98 : < 2 Z : E ratio as colorless oil. H NMR (400 MHz, CDC1z ) : Z -isomer 10 Following the general procedure , a solution of Mo - 4 in (major ) : 8 6 .02 ( 1H , dt, J = 7 . 2 , 1 . 6 Hz ) , 5 .74 ( 1H , q , J = 7 . 2 benzene ( 0 . 1 M , 30 UL , 3 . 0 umol, 3 mol % ) was transferred Hz) , 3 .41 ( 2H , t, J = 6 . 8 Hz ), 2 .23 ( 2H , qd , J = 7 . 2 , 1. 6 Hz ), by syringe to an oven - dried vial containing Z - 1 , 2 -dichloro 1 . 86 ( 2H , m ), 1 .49 - 1. 31 ( 6H , m ) . ethylene (48 . 5 mg, 0 . 5 mmol, 5 .00 equiv ) , tert- butyldim ethyl( 7 -octenyloxy ) silane ( 24 . 2 mg, 0 . 1 mmol, 1 .00 equiv ) ( Z ) - 4 - ( 3 - chloroallyl) - 1 , 2 - dimethoxybenzene ( 6 ) 15 and benzene ( 470 uL ) . The resulting solution was allowed to stir for 4 hours at 22° C . The reaction was quenched by Following the general procedure, a solution of Mo - 4 in addition of wet CDC12 and analysis of the unpurified mixture benzene ( 0 . 1 M , 30 UL , 3 . 0 umol, 3 mol % ) was transferred revealed 88 % consumption of tert -butyldimethyl ( 7 -octeny by syringe to an oven -dried vial containing Z - 1 , 2 - dichloro - loxy ) silane . The resulting orange oil was purified by silica ethylene (48 .5 mg, 0 .5 mmol, 5 .00 equiv) and 4 -allyl - 1, 2 - 20 gel chromatography (100 % hexanes ) to afford 9 ( 22 .2 mg, dimethoxybenzene ( 17 . 8 mg, 0 . 1 mmol, 1 .00 equiv ) . The 0 . 0802 mmol, 80 % yield ) in > 98 : < 2 Z : E ratio as colorless resulting solution was allowed to stir for 4 hours at 22° C . oil . ' H NMR (400 MHz, CDC1Z ): Z - isomer (major ) : 8 6 . 00 The reaction was quenched by addition of wet CDC1z and ( 1H , dd , J = 7 . 0 , 1 . 4 Hz) , 5 . 74 (1H , qd , J = 7 . 2 , 2 . 2 Hz) , 3 .60 analysis of the unpurified mixture revealed 88 % consumpnd - (2H , td , J = 6 . 5 , 2 . 2 Hz ) , 2 . 22 (2H , qd , J = 7 .0 Hz) , 1 . 55 - 1 .47 tion of 4 - allyl- 1 , 2 -dimethoxybenzene . The resulting orange 25 (2H , m ) , 1 . 44 - 1 . 29 (6H , m ) , 0 .89 ( 9H , d , J = 2 . 3 Hz) , 0 .04 oil was purified by silica gel chromatography ( 100 % (6H , d , J = 2 . 3 Hz) . hexanes to 10 % Et , in hexanes ) to afford 6 ( 13 . 0 mg, 0 .0611 mmol, 61 % yield ) in > 98 : < 2 Z : E ratio as colorless ( 15 , 2R , 4R )- 2 -( ( Z ) - 8 - chloro - 7 - octenyloxy ) - 1 - isopro oil. ' H NMR ( 400 MHz , CDC13 ): Z - isomer (major ) : d 6 .81 pyl- 4 - methylcyclohexane ( 10 ) ( 1H , d , J = 8 . 0 Hz) , 6 .77 - 6 . 72 ( 2H , m ), 6 . 15 ( 1H , ddd , J = 7 . 0 , 30 2 . 0 , 0 . 9 Hz ) , 5 . 95 ( 1H , q , J= 7 . 1 Hz) , 3 .87 (3H , s ), 3 . 86 ( 3H , Following the general procedure, a solution of Mo- 4 in s ), 3 .53 ( 2H , d , J = 7 . 2 Hz) . benzene ( 0 . 1 M , 30 UL , 3 . 0 umol, 3 mol % ) was transferred by syringe to an oven - dried vial containing Z - 1 , 2 -dichloro ( Z )- 3 -( 3 -chloroallyl ) - 1H - indole ( 7 ) ethylene ( 48 . 5 mg, 0 . 5 mmol, 5 . 00 equiv ) , ( 15 ,2R , 4R ) - 1 35 isopropyl- 4 -methyl - 2 - ( 7 - octenyloxy )cyclohexane ( 26 . 6 mg, Following the general procedure , a solution of Mo- 3 in 0 . 1 mmol, 1 . 00 equiv ) and benzene (470 uL ) . The resulting benzene ( 0 . 1 M , 30 uL , 3 . 0 umol, 3 mol % ) was transferred solution was allowed to stir for 4 hours at 22° C . The by syringe to an oven - dried vial containing Z - 1 , 2 - dichloro - reaction was quenched by addition of wet CDC1, and analy ethylene (48 . 5 mg, 0 . 5 mmol, 5 . 00 equiv ) and 3 -allyl - 1H - sis of the unpurified mixture revealed 79 % consumption of indole ( 15. 7 mg, 0 . 1 mmol, 1 . 00 equiv ) . The resulting 40 ( 19 , 2R , 4R ) - 1 - isopropyl - 4 -methyl - 2 - ( 7 -octenyloxy ) cyclo solution was allowed to stir for 4 hours at 22° C . The hexane . The resulting orange oil was purified by silica gel reaction was quenched by addition of wet CDC12 and analy - chromatography ( 100 % hexanes to 5 % Et 0 in hexanes) to sis of the unpurified mixture revealed 86 % consumption of afford 10 (22 . 1 mg, 0 . 0734 mmol, 73 % yield ) in > 98 : < 2 Z : E 3 -allyl - 1H - indole . The resulting orange oil was purified by ratio as colorless oil. ' H NMR (400 MHz , CDC1z ): Z -isomer silica gel chromatography (10 % EtoAc in hexanes to 15 % 45 (major ): 8 6 . 00 ( 1H , d , J = 7 . 0 Hz ) , 5 .75 ( 1H , qd , J = 7 .2 , 0 . 9 EtoAc in hexanes ) to afford 7 ( 7 . 9 mg , 0 . 0412 mmol, 41 % Hz ), 3 .65 - 3 .57 ( 1H , m ) , 3 . 25 ( 1H , dd , J = 15 . 8 , 6 . 8 Hz ) , 2 . 99 yield ) in 97 : 3 Z : E ratio as colorless oil. ' H NMR ( 400 MHz, ( 1H , td , J = 10 . 4 , 3 . 7 Hz ) , 2 . 26 - 2 . 17 ( 3H , m ), 2 . 13 - 1 . 94 ( 2H , CDC1z ) : Z - isomer (major ) : 8 7 . 95 ( 1H , brs ), 7 .62 ( 1H , d , m ) , 1 .68 - 1 .53 (3H , m ), 1 . 45 - 1 . 16 (11H , m ), 0 . 91 ( 3H , d , J = 7 .6 Hz ) , 7 .37 ( 1H , dt , J = 7 .6 , 1 . 2 Hz) , 7 . 21 ( 1H , td , J = 7 . 6 , J = 6 . 7 Hz) , 0 .89 ( 3H , d , J = 7 . 2 Hz) , 0 .77 (3H , d , J = 7 . 0 Hz ). 1 . 2 Hz ) , 7 . 14 ( 1H , td , J = 7 . 2 , 1 . 2 Hz) , 7 . 03 ( 1H , m ) , 6 . 14 ( 1H , 50 dt, J = 7 .2 , 1. 6 Hz ), 6 .03 ( 1H , q, J= 7 .2 Hz ), 3 .71 (2H , d , J = 7 .2 ( Z ) - 1 - chloro - 8 - ( 3 ,7 - dimethyl- 6 -octenyloxy ) - 1 Hz ) . octene ( 11 ) ( Z ) - 2 -( 6 - chloro - 5 - hexenyl) isoindoline - 1 , 3 - dione ( 8 ) Following the general procedure , a solution of Mo- 3 in 55 benzene ( 0 . 1 M , 30 UL , 3 . 0 umol, 3 mol % ) was transferred Following the general procedure , a solution of Mo - 4 in by syringe to an oven -dried vial containing Z - 1 , 2 - dichloro benzene ( 0 . 1 M , 30 uL , 3 . 0 umol, 3 mol % ) was transferred ethylene (48 . 5 mg, 0 . 5 mmol, 5 .00 equiv ) , 8 - ( 3 , 7 - dimethyl by syringe to an oven - dried vial containing Z - 1 , 2 -dichloro 6 -octenyloxy ) - 1 -octene (26 . 6 mg, 0 . 1 mmol, 1 . 00 equiv ) and ethylene (48 . 5 mg, 0 . 5 mmol, 5 . 00 equiv ) , 2 - ( 5 - hexenyl) benzene ( 470 UL ). The resulting solution was allowed to stir isoindoline - 1, 3 -dione (22 .9 mg, 0 . 1 mmol, 1 . 00 equiv ) and 60 for 4 hours at 22° C . The reaction was quenched by addition benzene ( 470 uL ). The resulting solution was allowed to stir o f wet CDC1 , and analysis of the unpurified mixture for 4 hours at 22° C . The reaction was quenched by addition revealed 84 % consumption of 8 - ( 3 , 7 - dimethyl- 6 - octeny of wet CDC12 and analysis of the unpurified mixture loxy )- 1 -octene . The resulting orange oil was purified by revealed 81 % consumption of 2 -( 5 -hexenyl ) isoindoline - 1 , 3 silica gel chromatography ( 100 % hexanes to 5 % Et20 in dione . The resulting orange oil was purified by silica gel 65 hexanes) to afford 11 (22 . 9 mg, 0 .0761 mmol, 76 % yield ) in chromatography ( 100 % hexanes to 10 % Et20 in hexanes) to > 98 : < 2 Z : E ratio as colorless oil . ' H NMR (400 MHz , afford 8 ( 17 . 2 mg, 0 . 0652 mmol, 65 % yield ) in > 98 : < 2 Z : E CDC13 ): Z - isomer (major ) : d 6 .01 (1H , d , J = 6 . 9 Hz) , 5 .74 US 9 ,850 ,268 B2 129 130 ( 1H , qd , J = 7 . 2 , 2 . 3 Hz ) , 5 . 10 ( 1H , t , J = 5 . 9 Hz) , 3 .45 - 3 . 35 The reaction was quenched by addition of wet CDC1 , and (4H , m ) , 2 .30 -2 . 16 ( 2H , m ), 2 .09 - 1 .88 ( 2H , m ), 1. 71 - 1. 55 analysis of the unpurified mixture revealed 94 % consump ( 3H , m ), 1 .68 (3H , s ), 1 .60 ( 3H , s ) , 1 .47 - 1 .08 ( 10H , m ) , 0 . 89 tion ofmethyl oleate . The resulting orange oil was purified by silica gel chromatography ( 100 % hexanes to 10 % Et , ( 3H , d , J = 6 . 5 Hz) . 5 in hexanes ) to afford 17 (20 .0 mg, 0 .0914 mmol, 91 % yield ) in 97 : 3 Z : E ratio as colorless oil and 18 ( 15 . 0 mg, 0 . 0859 ( Z ) - ( 2 - chlorovinyl ) cyclohexane ( 12 ) mmol, 86 % yield ) in 97 : 3 Z : E ratio as colorless oil . The spectral data for 18 were identical to those reported in the Following the general procedure , a solution of Mo- 3 in literature . (Okuyama , T . ; Takino , T . ; Sato , K . ; Oshima, K . ; benzene ( 0 . 1 M , 30 uL , 3 . 0 umol, 3 mol % ) was transferred Imamura , S .; Yamataka , H .; Asano , T. ; Ochiai, M . Bull by syringe to an oven -dried vial containing Z - 1 , 2 - dichloro - 10 Chem . Soc. Jpn . 1998 , 71 , 243 - 257 . ) ' H NMR (400 MHz, ethylene ( 48 . 5 mg, 0 . 5 mmol, 5 .00 equiv ) , vinylcyclohexane CDC1, ) for 17 : Z -isomer (major ) : 8 6 . 01 ( 1H , dd , J = 7 . 1 . 1 . 6 ( 11 . 0 mg , 0 . 1 mmol, 1 . 00 equiv ) and benzene (470 uL ) . The Hz ) , 5 .74 ( 1H , q , J = 7 . 1 Hz) , 3 .67 ( 3H , s ) , 2 . 30 ( 2H , t, J = 7 . 5 resulting solution was allowed to stir for 4 hours at 22° C . Hz ), 2 .21 ( 2H , qd, J = 7 . 2 , 1 . 4 Hz) , 1. 67 - 1 . 58 ( 2H , m ) , The reaction was quenched by addition of wet CDC12 and 1 .43 - 1 . 35 ( 2H , m ) , 1. 34 - 1 . 30 (6H , m ) . analysis of the unpurified mixture revealed 89 % consump - 15 tion of vinylcyclohexane . The resulting orange oil was ( Z ) - 10 - chloro - 9 -decenyl ( 3S ,89 , 9S , 10R , 13R , 143 , purified by silica gel chromatography ( 100 % hexanes ) to 17R ) - 10 , 13 - dimethyl - 17 - ( ( R ) - 6 -methyl - 2 -heptanyl ) afford 12 ( 10 .9 mg, 0 .0754 mmol, 75 % yield ) in > 98 : < 2 Z : E 2 , 3, 4 , 7 ,8 ,9 , 10 , 11, 12, 13 , 14 , 15 ,16 , 17 - tetradecahydro ratio as colorless oil . The spectral data for this compound 1H - 3 - cyclopenta [ a ]phenanthrenyl carbonate ( 20 ) & were identical to those reported in the literature. (Miller , R . 20 ( Z ) - 1 - chloro - 1 -decene ( 18 ) B . ; McGarvey, G . J . Org . Chem . 1978 , 43 , 4424 -4431 . ) Following the general procedure , a solution of Mo- 4 in benzene (0 .1 M , 30 uL , 3 .0 umol, 3 mol % ) was transferred ( Z ) - 4 - ( 2 -chlorovinyl ) - 1 -cyclohexene ( 13 ) by syringe to an oven - dried vial containing Z - 1 , 2 - dichloro 25 ethylene ( 48. 5 mg, 0 .5 mmol, 5 .00 equiv ), cholesteryl oleyl Following the general procedure , a solution of Mo -3 in 25 carbonate (68 . 1 mg, 0 . 1 mmol, 1 . 00 equiv ) and benzene ( 470 benzene (0 . 1 M , 30 uL , 3 .0 umol, 3 mol % ) was transferred uL ) . The resulting solution was allowed to stir for 4 hours at by syringe to an oven -dried vial containing Z - 1 , 2 - dichloro 22° C . The reaction was quenched by addition of wet CDC1z ethylene ( 48 . 5 mg, 0 . 5 mmol, 5 . 00 equiv ) , 4 - vinyl - 1 - cyclo and analysis of the unpurified mixture revealed > 98 % con hexene ( 11 . 0 mg, 0 . 1 mmol, 1 .00 equiv ) and benzene (470 sumption of cholesteryl oleyl carbonate . The resulting UL ) . The resulting solution was allowed to stir for 4 hours at 30 orange oil was purified by silica gel chromatography ( 100 % 22° C . The reaction was quenched by addition ofwet CDC1z hexanes to 5 % Et20 in hexanes) to afford 20 (49 . 0 mg, and analysis of the unpurified mixture revealed 89 % con - 0 .0812 mmol, 81 % yield ) in 94 : 6 Z : E ratio as colorless sumption of 4 - vinyl- 1 - cyclohexene . The resulting orange oil semi- solid and 18 ( 13 . 8 mg, 0 . 0790 mmol, 79 % yield ) in was purified by silica gel chromatography ( 100 % hexanes ) 94 : 6 Z : E ratio as colorless oil . The spectral data for 18 were to afford 13 ( 10 . 9 mg, 0 .0754 mmol, 75 % yield ) in > 98 : < 2 35 identical to those reported in the literature . (Okuyama , T . ; Z : E ratio as colorless oil. ' H NMR (400 MHz, CDC13 ) : Takino , T . ; Sato , K .; Oshima, K . ; Imamura , S . ; Yamataka , Z - isomer (major ) : 8 5 . 99 ( 1H , dd , J = 7 . 1 , 1 . 1 Hz ) , 5 .74 - 5 .62 H . ; Asano , T . ; Ochiai, M . Bull Chem . Soc . Jpn . 1998 , 71 , ( 3H , m ), 2 .94 -2 .81 (1H , m ), 2 . 20 - 2 .05 (3H , m ), 1. 87 - 1. 71 243 - 257. ) ' H NMR (400 MHz, CDC13 ) for 20 : Z -isomer (major ) : 8 6 . 01 ( 1H , d , J = 7 . 1 Hz ) , 5 .74 (1H , q , J = 7 . 1 Hz ) , ( 2H , m ) , 1 . 50 - 1 .42 ( 1H , m ) . 40 5 .39 ( 1H , d , J = 4 . 9 Hz ) , 4 .48 ( 1H , dt, J = 10 . 2 , 4 . 8 Hz ), 4 . 11 ( 2H , t , J = 6 . 7 Hz ), 2 . 43 - 2 . 35 (2H , m ) , 2 . 26 - 2 . 16 ( 2H , m ) , ( Z ) - 1 - chloro - 1 -hexene (15 ) 2 . 06 - 1 .77 (6H , m ) , 1 .70 - 1 .61 ( 3H , m ) , 1 . 53 - 1 . 22 (22H , m ) , Following the general procedure , a solution of Mo- 4 in 1. 17 - 1. 04 (7H , m ), 1. 01 (3H , s ), 0 . 91 ( 3H , d , J= 6 . 5 Hz) , 0 .86 benzene ( 0 . 1 M , 10 UL , 1 . 0 umol, 1 mol % ) was transferred (6H , dd , J = 6 .6 , 1 . 8 Hz) , 0 .68 ( 3H , s ). by syringe to an oven -dried vial containing Z - 1 , 2 - dichloro - 45 ethylene (48 .5 mg, 0 . 5 mmol, 5 .00 equiv ) and Z - 5 - decene ( Z ) -( 2 -bromovinyl ) cyclohexane (22 ) ( 14 . 0 mg, 0 . 1 mmol, 1 . 00 equiv ) . The resulting solution was Following the general procedure , a solution of Mo- 3 in allowed to stir for 2 hours at 22° C . The reaction was benzene ( 0 . 1 M , 30 uL . 3 . 0 umol. 3 mol % ) was transferred quenched by addition of wet CDC1z and analysis of the by syringe to an oven -dried vial containing 1, 2 -dibromoeth unpurified mixture revealed 97 % consumption of Z - 5 - de - 50 ylene (67 : 36 Z : E mixture , 148 . 7 mg, 0 . 8 mmol, 8 .00 equiv ) , cene . The resulting orange oil was purified by silica gel vinylcyclohexane ( 11. 0 mg, 0 . 1 mmol, 1 . 00 equiv ) and chromatography ( 100 % hexanes ) to afford 15 ( 20 .2 mg , benzene (470 uL ) . The resulting solution was allowed to stir 0 . 1703 mmol, 85 % yield based on substrate stoichiometry ) for 4 hours at 22° C . The reaction was quenched by addition in 97 : 3 Z : E ratio as colorless oil . The spectral data for this of wet CDC , and analysis of the unpurified mixture compound were identical to those reported in the literature 55 revealed 61 % consumption of vinylcyclohexane. The result ( Alami, M .; Crousse , B . ; Ferri , F . J . Organomet. Chem . ing orange oil was purified by silica gel chromatography 2001 , 624 , 114 - 123 .) ( 100 % hexanes) to afford 22 ( 7 . 9 mg, 0 .0418 mmol, 42 % yield ) in > 98 : < 2 Z : E ratio as colorless oil. The spectral data ( Z ) -methyl 10 -chloro - 9 -decenoate ( 17 ) & ( Z ) - 1 for this compound were identical to those reported in the chloro - 1 -decene ( 18 ) 60 literature. (Kuang , C .; Yang , Q . ; Senboku , H .; Tokuda , M . Tetrahedron 2005 , 61 , 4043 -4052 .) Following the general procedure , a solution of Mo- 4 in benzene (0 . 1 M , 30 °L , 3 .0 umol, 3 mol % ) was transferred ( Z ) -( ( 8 - Bromooct- 7 - en - 1 -yl ) oxy ) ( tert -butyl ) dimeth by syringe to an oven -dried vial containing Z - 1, 2 -dichloro ylsilane ( 23 ) ethylene ( 48 . 5 mg, 0 . 5 mmol, 5 .00 equiv ) , methyl oleate 65 (29 . 7 mg, 0 . 1 mmol, 1 . 00 equiv ) and benzene (470 UL ) . The Following the general procedure , a solution of Mo- 4 in resulting solution was allowed to stir for 4 hours at 22° C . benzene ( 0 . 1 M , 21 UL , 2 .1 umol, 5 mol % ) was transferred US 9 ,850 ,268 B2 131 132 by syringe to an oven - dried vial containing 1 , 2 - dibromoeth analysis of the unpurified mixture revealed > 98 % consump ene (61 . 0 mg, 0 . 330 mmol, 8 . 00 equiv ) , tert -butyldimethyl tion of 4 -methoxystyrene that resulted in the formation of a ( oct- 7 -en - 1 - yloxy ) silane ( 10 . 0 mg, 0 . 0410 mmol, 1 . 00 mixture of F - and Br- alkenes ( F :Br = 93 :7 ) . The resulting equiv ) . The resulting solution was allowed to stir for 4 hours orange oil was purified by silica gel chromatography ( 20 : 1 at 22° C . The reaction was quenched by addition of wet 5 hexanes/ Et, 0 ) to afford 26 ( 5 . 4 mg, 0 . 0355 mmol, 71 % CDC12 and analysis of the unpurified mixture revealed 95 % yield ) in 95 :5 Z : E ratio as pale yellow oil . The spectral data consumption of tert -butyldimethyl ( oct- 7 - en - 1 - yloxy ) silane . for this compound were identical to those reported in the The resulting orange oil was purified by silica gel chroma literature. (Zhu , L . ; Ni, C .; Zhao , Y . ; Hu, J. Tetrahedron 66 , tography (2 % Et, in hexanes to 5 % Et , in hexanes ) to 5089 -5100 ( 2010 ). ) afford 23 ( 8 . 3 mg, 0 .0260 mmol , 63 % yield ) in 88 : 12 Z : E 10 ratio as colorless oil . ' H NMR (400 MHz, CDC13) : Z - isomer ( Z ) - 1 -Chloro - 4 - ( 2 - fluorovinyl ) benzene ( 27) (major ) : 8 6 . 14 ( 1H , dt, J = 7 . 2 , 1 . 2 Hz ) , 6 .08 ( 1H , q , J = 6 . 8 Hz ), 3 .60 (2H , t , J = 6 . 4 Hz) , 2 . 19 ( 2H , q , J = 7 .2 Hz) , Following the general procedure , a solution of Mo- 4 in 1 .55 - 1 . 26 (8H , m ) , 0 .90 ( 9H , s ), 0 .05 (6H , s ) . benzene ( 0 .1 M , 36 UL , 3 .6 umol, 5 mol % ) was transferred 15 by syringe to an oven -dried vial containing Z - 1 -bromo -2 ( Z ) - ( 8 -Bromo - 2 , 6 - dimethyl- 7 - octen - 2 - yloxy) (tert fluoroethene ( 90 . 2 mg, 0 .722 mmol, 10 . 0 equiv ) and 4 - chlo butyl )dimethylsilane (24 ) rostyrene ( 10 . 0 mg, 0 .0722 mmol, 1 . 00 equiv ) . The resulting solution was allowed to stir for 4 hours at 22° C . The Following the general procedure , a solution of Mo - 4 in reaction was quenched by addition of wet CDC12 and analy benzene (0 . 1 M , 18 UL , 1 . 8 umol, 5 mol % ) was transferred 20 sis of the unpurified mixture revealed 78 % consumption of by syringe to an oven -dried vial containing 1 , 2 -dibromoeth - 4 -chlorostyrene that resulted in the formation of a mixture of ene (55 . 0 mg, 0 .296 mmol, 8 .00 equiv ) and tert -butyl ( 2 , 6 - F - and Br- alkenes ( 96 : 4 F : Br) . The resulting orange oil was dimethyl- 7 - octen - 2 - yloxy )dimethylsilane ( 10 . 0 mg, 0 .0370 purified by silica gel chromatography ( 100 % hexanes to 2 % mmol, 1 .00 equiv ). The resulting solution was allowed to stir Et 0 in hexanes) to afford 27 ( 7 . 2 mg, 0 .0460 mmol, 64 % for 4 hours at 22° C . The reaction was quenched by addition 25 yield ) in 97 : 3 Z : E ratio as colorless oil . The spectral data for of wet CDC1z and analysis of the unpurified mixture this compound were identical to those reported in the revealed 71 % consumption of tert -butyl ( 2 , 6 - dimethyl - 7 - literature . ( Emet, T .; Maulitz , A . H . ; Wurthwein , E . - U . ; octen - 2 -yloxy )dimethylsilane . The resulting orange oil was Haufe, G . J . Chem . Soc ., Perkin Trans 1 . 1929 - 1938 ( 2001) . ) purified by silica gel chromatography ( 100 % hexanes ) to afford 24 ( 7 . 4 mg, 0 .0212 mmol, 57 % yield ) in 91 : 9 Z : E 30 tert - Butyl( ( ( 8R , IS , 10R , 138 , 148 , 17R ) - 17 - ( ( Z ) - 3 ratio as colorless oil . ' H NMR (400 MHz, CDC13 ) : Z -isomer chloroallyl) - 13 -methyl - 2, 3 ,6 ,7 , 8 ,9 , 10 ,11 , 12, 13 ,14 , (major ): 8 6 .09 ( 1H , dd , J = 7 . 0 , 0 . 8 Hz ), 5 .85 ( 1H , dd , J = 9 .2 , 15 , 16 , 17 - tetradecahydro - 1H - cyclopenta [ a ] phenan 7 . 0 Hz ) , 2 . 76 - 2 .64 ( 1H , m ), 1 . 39 - 1 . 31 (6H , m ) , 1 . 17 (6H , s ) , thren - 17 - yl) oxy ) dimethylsilane 0 . 99 (3H , d , J = 6 .7 Hz ), 0 .85 ( 9H , s ), 0 .06 (6H , s ). 35 Following the general procedure, a solution of Mo - 4 in ( Z ) - tert -Buty ( (8 - fluoro - 2 ,6 -dimethyloct - 7 - en - 2 -yl ) benzene ( 0 . 1 M , 25 uL , 2 .5 umol, 5 mol % ) was transferred oxy ) dimethylsilane (25 ) by syringe to an oven -dried vial containing Z - 1 ,2 -dichlo roethene ( 24 .3 mg, 0 .251 mmol, 5. 00 equiv ) and (( (8R ,9S , Following the general procedure , a solution of Mo -4 in 10R , 138 ,148 , 17R )- 17 -allyl - 13 -methyl - 2 ,3 ,6 ,7 , 8, 9 , 10 ,11 , 12 , benzene ( 0 . 1 M , 25 uL , 2 . 5 umol, 5 mol % ) was transferred 40 13 , 14 , 15, 16 , 17- tetradecahydro - 1H - cyclopenta [ a ] by syringe to an oven -dried vial containing Z - 1 -bromo - 2 - phenanthren - 17 -yl ) oxy ) (tert -butyl ) dimethylsilane ( 20 . 7 fluoroethene (31 . 3 mg, 0 .251 mmol, 5 .00 equiv ) and tert - mg, 0 .0499 mmol, 1. 00 equiv ) . The resulting solution was butyl( 2 , 6 - dimethyl- 7 -octen - 2 -yloxy )dimethylsilane ( 13. 5 allowed to stir for 4 hours at 22° C . The reaction was mg, 0 .0499 mmol, 1 . 00 equiv ) . The resulting solution was quenched by addition of wet CDC1z and analysis of the allowed to stir for 2 hours at 22° C . The reaction was 45 unpurified mixture revealed 75 % consumption of ( ( (8R , IS , quenched by addition of wet CDC1z and analysis of the 10R , 13S , 148 , 17R ) - 17 - allyl - 13- methyl- 2 , 3 ,6 , 7 , 8 , 9 , 10 , 11, 12 , unpurified mixture revealed > 98 % consumption of tert- buty1 1 3 , 14 , 15 , 16 , 17 - tetradecahydro - 1H - cyclopenta [ a ]phenan ( 2 , 6 - dimethyl- 7 -octen - 2 -yloxy ) dimethylsilane that resulted thren - 17 - yl) oxy ) ( tert- butyl ) dimethylsilane . The resulting in the formation of a mixture of F - and Br- alkenes ( F :Br = 96 : orange oil was purified by silica gel chromatography ( 100 % 4 ) . The resulting orange oil was purified by silica gel 50 hexanes) to afford the product ( 15. 7 mg, 0 . 0349 mmol, 70 % chromatography ( 100 % hexanes ) to afford 25 ( 10 . 1 mg, yield ) in 95 :5 Z : E ratio as off- white solid . ' H NMR (400 0 .0350 mmol, 70 % yield ) in > 98 : < 2 Z : E ratio as colorless MHz, C , D ) : Z - isomer (major ): 8 5 . 97 ( 1H , q , J = 6 . 6 Hz) , oil. ' H NMR (600 MHz, CDC12 ): Z -isomer (major ) : 8 6 .41 5 . 81 ( 1H , dt , J = 7 . 1 , 1 . 9 Hz ), 5 .49 ( 1H , bs ), 2 .60 ( 1H , ddd , ( 1H , ddd , J = 86 . 0 , 4 . 8 , 0 . 8 Hz) , 4 .52 ( 1H , ddd , J = 43 . 9 , 9 . 8 , J = 16 . 4 , 6 . 1 , 1 . 2 Hz) , 2 . 47 ( 1H , ddd , J = 16 . 2 , 6 . 6 , 2 . 1 Hz) , 4 . 8 Hz ) , 2 .73 - 2 .63 ( m , 1H ) , 1 . 46 - 1 . 19 (6H , m ), 1 . 18 (3H , s ) , 55 2 . 30 - 2 .22 ( 1H , m ), 2 . 10 - 0 .80 ( 32H , m ) , 0 .63 - 0 .51 ( 1H , m ) , 1 . 17 ( 3H , s ) , 0 . 99 ( d , J = 6 . 8 Hz, 3H ) , 0 . 85 ( s , 9H ) , 0 .06 ( s , 0 . 12 (3H , S ) , 0 .09 (3H , s ) . 6H ) . ( Z ) - ( 10 - Fluorodec - 9 - en - 1 -yn - 1 - yl) triisopropylsilane (Z )- 1 -( 2 -Fluorovinyl ) - 4 -methoxybenzene ( 26 ) (28 ) 60 Following the general procedure , a solution of Mo- 4 in Following the general procedure , a solution of Mo - 4 in benzene ( 0 . 1 M , 25 uL , 2 . 5 umol, 5 mol % ) was transferred benzene ( 0 . 1 M , 30 uL , 3 . 0 umol, 3 mol % ) was transferred by syringe to an oven -dried vial containing Z - 1 -bromo - 2 - by syringe to an oven - dried vial containing Z - 1- bromo - 2 fluoroethene (62 . 5 mg, 0 . 500 mmol, 10 . 0 equiv ) and fluoroethene (62 . 5 mg, 0 .500 mmol, 5 .00 equiv ) and 9 - de 4 -methoxystyrene ( 6 . 8 mg, 0 . 0507 mmol, 1 .00 equiv ) . The 65 cen - 1 - ynyltriisopropylsilane (29 . 3 mg, 0 . 100 mmol, 1. 00 resulting solution was allowed to stir for 4 hours at 22° C . equiv ) . The resulting solution was allowed to stir for 4 hours The reaction was quenched by addition of wet CDC12 and at 22° C . The reaction was quenched by addition of wet US 9 ,850 ,268 B2 133 134 CDC12 and analysis of the unpurified mixture revealed > 98 % ing solution was allowed to stir for 4 hours at 22° C . The consumption of 9 -decen - 1 -ynyltriisopropylsilane that reaction was quenched by addition of wet CDC1 , and analy resulted in the formation of a mixture of F - and Br- alkenes sis of the unpurified mixture revealed 84 % consumption of ( F :Br = 72 :28 ). The resulting orange oil was purified by silica 4 -acetoxystyrene that resulted in the formation of a mixture gel chromatography ( 100 % hexanes ) to afford 28 in 74: 26 5 of F - and Br- alkenes ( F :Br = 96 : 4 ) . The resulting orange oil F : Br (70 % F - alkene by mass ) and > 98 : < 2 Z : E ratio (28 . 3 was purified by silica gel chromatography ( 10 :1 hexanes/ mg, 0 . 0638 mmol, 64 % yield ) as colorless oil. ' H NMR (600 Et, O ) to afford 31 ( 6 .5 mg, 0 .0361 mmol , 72 % yield ) in 94 :6 MHz, CDC1z : Z - isomer (major ): 8 6 .44 ( F -alkene , 1H , ddt, Z :E ratio as pale yellow oil. ' H NMR (600 MHz, CDC13 ): J = 86 . 0 , 4 . 7 , 1 . 5 Hz ), 6 . 17 - 6 .04 (Br - alkene, 2H , m ), 4 .71 Z - isomer (major ): 8 7 .52 ( 2H , d , J = 8 . 6 Hz ) , 7 .07 (2H , d , ( F - alkene , 1H , dtd , J = 43 . 5 , 7 .6 , 4 . 7 Hz ) , 2 .29 - 2 .04 (4H , m ) , 10 J = 8 . 7 Hz) , 6 .65 ( 1H , dd , J = 82 . 6 , 5 . 4 Hz) , 5 .60 (1H , dd , 1 .59 - 1 .20 (8H , m ), 1. 12 - 0 .97 (21H , m ). J = 44 .3 , 5 . 4 Hz ) , 2 . 30 ( 3H , s ). (4R ,59 ,6S ) -4 - (( Z )- 2 - Fluorovinyl) -2 - (4 -methoxyphe nyl) - 5 -methyl - 6 - ( ( S , E ) - 5 - phenylpent- 3 - en - 2 - yl) - 1 , 3 ( 2 ) -5 - ( 2 -Fluorovinyl ) pyrrolidin - 2 - one (32 ) dioxane (29 ) 15 Following the general procedure , a solution of Mo -4 in Following the general procedure , a solution of Mo- 4 in benzene ( 0 . 1 M , 89 UL , 8 . 9 umol, 10 mol % ) was transferred benzene ( 0 .1 M , 40 uL , 4 .0 umol, 10 mol % ) was transferred by syringe to an oven - dried vial containing Z - 1 - bromo- 2 by syringe to an oven - dried vial containing Z - 1 -bromo - 2 fluoroethene ( 55 . 4 mg, 0 .444 mmol, 5 .00 equiv ) and 1 - ( tert fluoroethene (25 . 0 mg, 0 . 200 mmol, 5 . 00 equiv ) and ( 4R , 20 butyldimethylsilyl) - 5 - vinylpyrrolidin - 2 - one ( 20 .0 mg, 5S ,6R ) - 2 - ( 4 -methoxyphenyl ) - 5 -methyl - 4 - ( ( R , E ) - 5 - phenyl 0 . 0887 mmol, 1 . 00 equiv ) . The resulting solution was pent- 3 -en -2 -yl ) - 6 -vinyl - 1 ,3 -dioxane (15 .1 mg, 0 .0399 allowed to stir for 12 hours at 40 OC . The reaction was mmol. 1 . 00 equiv ). The resulting solution was allowed to stir quenched by addition of wet CDClz and analysis of the for 4 hours at 22° C . The reaction was quenched by addition unpurified mixture revealed 60 % consumption of 1 - (tert of wet CDC1, and analysis of the unpurified mixture 25 butyldimethylsilyl) - 5 -vinylpyrrolidin - 2 - one that resulted in revealed 80 % consumption of (4R ,5S ,6R ) - 2 - ( 4 -methoxy - the exclusive formation of F -alkene ( > 98 : < 2 F : Br ). The phenyl) - 5 -methyl - 4 -( ( R , E )- 5 - phenylpent- 3 -en - 2 -yl ) - 6 -vi - mixture was concentrated and the unpurified residue was nyl- 1 , 3 - dioxane that resulted in the exclusive formation of re -dissolved in MeOH ( 1 . 0 mL ) and treated with an aqueous F -alkene . The resulting orange oil was purified by prepara - 1 .0M solution of HC1 ( 0 .25 mL ) . The solution was allowed tive thin layer chromatography ( 1 : 8 EtoAc /hexanes ) to 30 to stir for 2 hours at 22° C . The solution was diluted with afford 29 ( 10 . 0 mg, 0 . 0252 mmol, 63 % yield ) with > 98 : < 2 ETOAC ( 2 mL ) and H , O ( 2 mL ) and the organic layer was Z :E ratio as off -white solid . " H NMR (500 MHz, CDC13 ): separated . The aqueous layer was further extracted with Z - isomer (major ) : 8 7 .41 (2H , d , J = 8 . 7 Hz ), 7 . 33 - 7 .27 ( 4H . EtOAC ( 3x2 mL ), the organic layers were combined and m ) , 7 . 22 - 7 . 15 ( 2H , m ) , 6 . 89 ( 2H , d , J = 8 . 7 Hz ) , 6 . 66 ( 1H , dried over MgSO4. The volatiles were removed to afford ddd , J = 84 .2 , 4 . 9 , 1 . 1 Hz) , 5 .75 ( 1H , s ), 5 . 74 -5 .65 ( 1H , m ), 35 yellow oil, which was purified by silica gel chromatography 5 .60 ( 1H , dt, J = 15 . 3 , 6 . 6 Hz ) , 5 .40 ( 1H , ddd , J = 40 . 8 , 9 . 6 , 5 . 0 ( 30 % EtoAc in hexanes to 100 % EtOAC) to afford 32 (6 . 3 Hz) , 5 . 06 ( 1H , dd , J = 9 . 8 , 5 . 6 Hz ), 3 . 81 ( 3H , s ), 3 . 55 ( 1H , dd , mg, 0 . 0488 mmol, 55 % yield over two steps) with > 98 : < 2 J = 10 . 6 , 2 . 1 Hz) , 3 .38 ( 2H , d , J = 6 . 4 Hz) , 2 . 51 - 2 . 41 ( 1H , m ) , Z : E ratio as pale yellow oil. The spectral data for this 2 .34 -2 .24 (1H , m ), 1. 40 - 1. 19 (4H , m ) , 1 .16 ( 3H , d , J = 7 .0 compound were identical to those reported in the literature . Hz ), 0 .73 ( 3H , d , J = 7 . 0 Hz) . (Kolb , M . ; Barth , J. ; Heydt, J . - G . ; Jung , M . J . J . Med . Chem . ( Z ) - 1 - Bromo- 4 - ( 2 - fluorovinyl) benzene ( 30 ) 2007, 30 , 267 - 272 . ) Following the general procedure , a solution of Mo - 4 in ( S ,Z )- 2 -( 4 -( 3 - (2 -Chloro - 10H -phenothiazin - 10 -yl ) benzene (0 . 1 M , 27 uL , 2 .7 umol, 5 mol % ) was transferred 45 propyl) piperazin - 1 - yl) ethyl 6 - fluoro - 4 -methyl - 5 by syringe to an oven - dried vial containing Z - 1 -bromo - 2 hexenoate ( 33 ) fluoroethene (68 . 3 mg, 0 . 546 mmol, 10 . 0 equiv ) and 4 - bro mostyrene ( 10 . 0 mg, 0 .0546 mmol, 1 . 00 equiv ) . The result Following the general procedure, a solution of Mo- 4 in ing solution was allowed to stir for 4 hours at 22° C . The benzene ( 0 . 1 M , 10 uL , 1 . 0 umol , 5 mol % ) was transferred reaction was quenched by addition of wet CDC1 , and analy - 50 by syringe to an oven - dried vial containing Z - 1 -bromo - 2 sis of the unpurified mixture revealed 88 % consumption of fluoroethene ( 12 . 0 mg, 0 . 0970 mmol, 5 .00 equiv ) , ( S ) - 2 - ( 4 4 -bromostyrene that resulted in the formation of a mixture of ( 3 - ( 2 - chloro - 10H -phenothiazin - 10 - yl) propyl ) piperazin - 1 F - and Br- alkenes (95 : 5 F :Br ) . The resulting orange oil was yl ) ethyl 4 -methylhex -5 - enoate ( 10 .0 mg, 0. 0200 mmol, 1. 00 purified by silica gel chromatography ( 100 % hexanes to 2 % equiv ) and benzene (40 uL ) . The resulting solution was Et , in hexanes ) to afford 30 ( 7 . 2 mg, 0 . 0358 mmol , 66 % 55 allowed to stir for 4 hours at 22° C . The reaction was yield ) in 93 : 7 Z : E ratio as colorless oil . The spectral data for quenched by addition of wet CDC1 , and analysis of the this compound were identical to those reported in the unpurified mixture revealed 88 % consumption of ( S ) - 2 - ( 4 literature . ( Zhu , L .; Ni, C .; Zhao , Y .; Hu , J. Tetrahedron 66 , ( 3 - (2 -chloro - 10H - phenothiazin - 10 -yl ) propyl ) piperazin - 1 5089 - 5100 ( 2010 ). ) yl) ethyl 4 -methylhex - 5 -enoate that resulted in the formation 60 of a mixture of F - and Br- alkenes ( 91: 9 F : Br ) . The resulting ( Z )- 4 -( 2 -Fluorovinyl )phenyl acetate (31 ) orange oil was purified by silica gel chromatography ( 5 % MeOH in CH , C1, ) to afford 33 ( 8 . 3 mg , 0 .0156 mmol, 78 % Following the general procedure, a solution of Mo - 4 in yield ) with > 98 : < 2 Z : E ratio as colorless oil. ' H NMR (400 benzene ( 0 . 1 M , 25 uL , 2 . 5 umol, 5 mol % ) was transferred MHz, CDC13 ) : Z - isomer (major ) : 8 7 . 15 ( 1H , t , J = 7 . 6 Hz) , by syringe to an oven - dried vial containing Z - 1 - bromo - 2 - 65 7 . 11 ( 1H , d , J = 7 . 6 Hz ) , 7 . 01 ( 1H , d , J = 8 . 0 Hz ) , 6 . 94 - 6 . 84 fluoroethene (62 . 5 mg, 0 .500 mmol, 10 . 0 equiv ) and 4 -ac - (4H , m ), 6 .44 ( 1H , dd , J = 85 . 6 , 4 . 8 Hz) , 4 .51 ( 1H , dq, J = 43 . 2 , etoxystyrene ( 8 .1 mg, 0 .0499 mmol, 1 .00 equiv ) . The result - 4 . 8 Hz) , 4 . 18 (2H , t , J = 6 . 4 Hz) , 3 .89 (2H , t, J = 6 . 8 Hz ) , US 9 , 850 , 268 B2 135 136 2 .71 -2 .28 ( 15H , m ), 1 .94 ( 2H , quint, J= 7 .2 Hz ), 1. 76 - 1. 68 Science 2013 , 341, 1357 -1364 . ) Alkenyl halides rank as one ( 1H , m ), 1 . 55 - 1 .47 ( 1H , m ) , 1 . 02 ( 3H , d , J = 6 . 8 Hz) . of the most valuable classes of compounds in organic chemistry due to their occurrence in natural products as well ( Z ) - 4 - Fluoro - 2 -methyl - 3 -butenyl (2S ,5R ) - 3 , 3 - dim as the immense applications associated . ( (a ) Guinchard , X .; ethyl- 7 -oxo - 4 - thia - 1 - azabicyclo [ 3 . 2 . 0 ]heptane - 2 5 Roulland , E . Synlett . 2011 , 19 , 2779 - 2788 . ( b ) Stanforth , S . carboxylate 4 , 4 - dioxide ( 34 ) P . Vinyl and Aryl Halides in Comprehensive Organic Func tional Group Transformations II ( ed . Katritzky, A . R . & Taylor, R . J . K . ) vol. 2 (Elsevier , 2004 ) . ) Traditional meth Following the general procedure , a solution of Mo -4 in ods that afford E - alkenyl halides ( e . g . Takai olefination ) benzene (0 . 1 M , 10 uL , 1 .0 umol, 5 mol % ) was transferred ( ( For a representative example, see : Takai, K . ; Nitta , K . ; by syringe to an oven - dried vial containing Z - 1 - bromo- 2 - 10 Utimoto , K . J. Am . Chem . Soc. 1986 , 108 , 7408 - 7410 ) offer fluoroethene (20 . 7 mg, 0 . 166 mmol, 5 . 00 equiv ) and certain levels of selectivity depending on the relative steric 2 -methyl - 3 -butenyl (2S ,5R ) - 3 , 3 -dimethyl - 7 -oxo - 4 - thia - 1 size of the substrates , reagents and conditions employed . azabicyclo [ 3 . 2 . 0 ]heptane - 2 - carboxylate 4 , 4 - dioxide ( 10 . 0 Other routes of preparing these compounds frequently pro mg , 0 . 0332 mmol, 1 .00 equiv ). The resulting solution was ceed though multi - step synthesis routes . ( For a representa allowed to stir for 4 hours at 22° C . The reaction was 15 tive example , see : Morrill , C .; Grubbs, R . H . J. Org . Chem . quenched by addition of wet CDC1z and analysis of the 2003 , 68 , 6031 -6034 . ) There is a persisting lack of catalytic unpurified mixture revealed 86 % consumption of 2 -methyl - one - step protocols that directly furnish E -alkenyl halides 3 -butenyl ( 2S , 5R ) - 3 , 3 - dimethyl- 7 -oxo - 4 -thia - 1 -azabicyclo efficiently and stereoselectively , particularly those that do [ 3 . 2 . 0 ]heptane - 2 - carboxylate 4 , 4 - dioxide that resulted in the not entail the generation of unnecessary intermediates and exclusive formation of F - alkene ( > 98 : < 2 F : Br ). The result - 20 stoichiometric waste . Added to this problem is the inherent ing orange oil was purified by silica gel chromatography preference for 1 , 2 - disubstituted halogenated olefins to exist ( 10 % Et, in hexanes to 40 % Et , in hexanes ) to afford 34 as equilibrium mixtures of E / Z isomers, with the Z -diaste ( 8 . 5 mg, 0 .0266 mmol. 80 % yield ) with > 98 : < 2 Z : E ratio as reomer being thermodynamically more favored in several cases . (Craig , N . C .; Piper , L . G .; Wheeler, V . L . J . Phys . yellow oil . ÎH NMR ( 400 MHz , CDC13 ) : Z - isomer (major 16 ): 25 Chem . 1971, 75, 1453 - 1460 . ) Stereoselective catalytic olefin 86 .51 ( 1H , dd , J = 84 .4 , 4 . 6 Hz ) , 4 .64 -4 .59 ( 1H , m ), 4 .62 (1H , 25 metathesische (OM ) , in some embodiments , with an appropriate ddd , J = 41 . 8 , 9 . 5 , 4 . 6 Hz) , 4 . 43 - 4 . 37 ( 1H , m ), 4 .20 - 3 . 98 (2H , halogen - containing cross -partner , could potentially provide m ) , 3 .53 - 3 .42 ( 2H , m ) , 3 . 17 - 3 .03 ( 1H , m ) , 1 .62 ( 3H , s ) , 1 . 42 a solution to the aforementioned dilemma. However, previ (3H , s ), 1. 08 (3H , d , J = 3 .3 Hz ). ous reports have been limited to Ru - catalyzed protocols ( ( a ) Sashuk , V . ; Samoj ?owicz , C . ; Szadkowska , A . ; Grela , K . Methyl (1R ,4aR ,468 ,75 , 10aR ) - 7 -( ( Z )- 2 -fluorovi 30 Chem . Commun . 2008 , 2468 -2470 . ( b ) Macnaughtan , M . L . ; nyl) - 1 , 4a , 7 - trimethyl- 1 , 2 , 3 , 4 ,4a , 4b , 5 , 6 , 7 , 8 , 10 , 10a Gary, J . B . ; Gerlach , D . L . ; Johnson , M . J. A .; Kampf, J . W . dodecahydrophenanthrene - 1 - carboxylate (35 ) Organometallics 2009, 28 , 2880 - 2887 . ) which generally suffer from poor stereoselectivity ( E / Z mixtures ) and a Following the general procedure , a solution of Mo- 4 in narrow substrate range , in some cases as a result of the benzene ( 0 . 1 M , 27 UL , 2 . 7 umol, 10 mol % ) was transferred 35 attenuated reactivity of the chloromethylidene species in by syringe to an oven - dried vial containing Z - 1 - bromo - 2 OM and its susceptibility to various decomposition path fluoroethene ( 16 . 2 mg, 0 . 130 mmol, 5 .00 equiv ) and isopi ways. (Macnaughtan , M . L . ; Johnson , M . J . A . ; Kampf, J . W . maric acid methyl ester ( 8 . 2 mg, 0 .0259 mmol, 1 .00 equiv ) . J . Am . Chem . Soc . 2007 , 129, 7708 - 7709 . ) The present The resulting solution was allowed to stir for 4 hours at 22° disclosure recognizes that developing a catalyst -controlled C . The reaction was quenched by addition of wet CDC12 and 40 kinetically E -selective OM protocol in the context of alkenyl analysis of the unpurified mixture revealed 83 % consump - halides is a compelling challenge . In some embodiments , the tion of isopimaric acid methyl ester that resulted in the present disclosure present efficient and in some embodi formation of a mixture of F - and Br -alkenes (F : Br = 94 : 6 ) . ments kinetically , E - selective cross -metathesis (CM ) reac The resulting orange oil was purified by silica gel chroma tions involving suitable halogen - containing olefin reagents tography ( 1 : 1 hexanes/ benzene to 20 : 1 hexanes / Et , 0 ) to 45 promoted by provided compounds, for example , a com pound of formula II - a , a compound of formula Il - b , etc . In afford 35 (6 . 4 mg, 0 .0191 mmol, 70 % yield ) in > 98 : < 2 Z : E some embodiments , provided compounds are molybdenum ratio as colorless oil. ' H NMR ( 400 MHz , CDC1, ) : Z - isomer based monoaryloxide monopyrrolide (MAP ) complexes . (major ) : 8 6 . 26 ( 1H , dd , J = 85 . 0 , 5 . 4 Hz ) , 5 . 35 - 5 .28 ( 1H , m ) , We began by examining the CM of 4 -methoxystyrene and 4 .49 ( 1H , dd , J = 50 . 1 , 5 . 4 Hz) , 3 .64 ( 3H , s ) , 2 . 13 ( 2H , d , 10 equivalents of commercially available E - 1 , 2 -dichloroeth J = 2 . 1 Hz ) , 2 . 05 - 1 .66 (6H , m ), 1 .65 - 1. 45 (6H , m ), 1 .44 - 1 . 28 50 ene (E -DCE ) in the presence of 3 mol % of Mo- E1 to afford ( 1H , m ) , 1 . 26 ( 3H , d , J = 0 . 7 Hz) , 1 . 18 - 1 . 05 ( 1H , m ), 1 . 02 alkenyl chloride E1 (Scheme E1) . A direct comparison can (3H , S ), 0 . 89 (3H , m ) . As described previously , in some embodiments , the pres be made with the Ru -catalyzed results previously reported in ent disclosure provides technologies for E - selective synthe the literature . ( a ) Sashuk , V . ; Samoj?owicz , C . ; Szad sis of olefins. In some embodiments , the present disclosure 55 kowska , A .; Grela , K . Chem . Commun . 2008 , 2468 - 2470 . ( b ) provides technologies for E - selective synthesis of vinyl Macnaughtan , M . L .; Gary , J. B . ; Gerlach , D . L . ; Johnson , halides . In some embodiments , the present disclosure pro M . J . A . ; Kampf, J . W . Organometallics 2009, 28 , 2880 vides methods with both regioselectivity and E - selectivity . 2887. ) Among other things , provided compounds and methods can provide alkenyl fluoride with unexpectedly high regioselec - 60 Scheme E1 CM of 4 -methoxystyrene and E - DCE in the presence of tivity and /or E -selectivity . Ru - 1 and the recently developed complex Mo - E1 . Stereochemically defined alkenes are ubiquitous in natu ral occurring compounds and drugs and serve as substrates for numerous transformations in chemistry . Efficient proto cols for the stereoselective preparation of olefins are highly 65 desirable , particularly if they are promoted by catalysts that Meo control the identity of the major product isomer . ( Füstner , A . US 9, 850 ,268 B2 137 138 -continued - continued Cl 5 mol % Ru- E1 . C 5 mol % [Mo ] Ci C6H6, 50° C ., 24 h 01 C6H6, 22°C. , 2 h 100 equiv E -DCE ( 5 5 equiv

Me Me E1 Mew 32 % yielda 15 :85 E : Z OTBS Me F

Meo F L CI 3 mol % Mo- E1 C1 C6H6, 22° C ., 3 h 10 equiv N Cl20 ll Ph estaMO Meo vilEto EtIt º Et EtEt E1 25 > 98 % convo , 80 % yield 98 : 2 E : Z 92 % conv , 72 % conv to pdt Meskes C Mes 30 % yield ND , 80 : 20 E / Z F ou 2_ F

o 35 Y F

Ru - E1 TULIPh

40

45 N .. . llPh " " MO 96 % conv, 95 % conv to pdt Bu 95 % yield, 86 :14 E /Z 50 BiotBu tBu

Mo- E1 55 Yield was determined by GC . bIsolated yield . NI11 . HII Ph MOS Other provided metal complexes work as well : 60

Me Mev 65 52 % conv , 41 % conv to pdt OTBS Me % yield ND , 91: 9 E / Z US 9, 850 ,268 B2 139 140 - continued - continued

11

N LeclllPh N111111* * * MO 11| Ph 1111111 10 Mos

Ph

54 % conv, 25 % conv to pdt 50 % conv , 35 % conv to pdt % yield ND , 91 : 9 E / Z % yield ND , 85 : 15 E / Z

20 FF

F 25 Ph * Mos + 11 STILEWitBu F 30

tBu Bu LallPh N101 " MoreMO > 98 % conv , 93 % conv to pdt tBu 3535 98 % yield , 89: 11 E / Z tBu tBu with 20 equiv E - DCE 98 % yield , 93 : 7 E / Z While less than desired efficiency (32 % GC yield ) and 84 % conv, 79 % conv to pdt 40tº moderate stereoselectivity ( 15 :85 E : Z ) was obtained from 77 % yield , 90 : 10 E / Z Ru - E1 under forcing conditions (24 hours at 50 OC ), Mo- E1 and other exemplary provided compound furnished the desired product in good yield with unexpectedly high E 45 stereoselectivity (up to > 98 % E - isomer ) in much shorter reaction time at ambient temperature ( 3 hours at 22° C . ) . Furthermore, the Mo - catalyzed reactions were highly effi cient; a lower catalyst loading can be used to achieve complete consumption of the starting aryl alkene . F 50 As exemplified herein , a broad scope of olefins ( in some embodiments , second species in provided methods ) can be F used . For example , CM of a variety of olefins including e . g . , aryl, heteroaryl, alkyl , etc . , proceeded with high efficiency, high yield and high selectivity . In some embodiments, with F 3 . 0 - 5 . 0 mol % of Mo - E1 , CM products were obtained in 59 - 94 % yield in 93 : 7 to > 98 : 2 E : Z ratio (Scheme E2 ) . UllPh N111111111 MOMo ellit Scheme E2 60 a . CM of various alkenes and E -DCE in the presence ofMo - E1. a . CM between various olefins and E -DCE to acess E - alkenyl chlorides Me Me 3 mol % CiMoMo- E1 G + c C6H6 10 equiv 59 -94 % yield 78 % conv , 70 % conv to pdt 65 G = aklyl, aryl 22° C ., up to > 98 : 2 E : Z % yield ND , 90 :10 E /Z 4 h US 9 ,850 ,268 B2 141 142 -continued a slightly higher catalyst loading was required for 4 - trifluo CI romethylstyrene. Among other things, complex Mo - El is able to efficiently react with trans- stilbene to afford trans B - chlorostyrene in excellent yield and stereoselectivity . ACO As described , provided technologies , among other things , E2 > 98 % conv , 75 % yield provide regioselectivity , for example , when a first species >98 : 2 E :Z has different halogen substituents on the two carbon atoms of its olefin double bond . In some embodiments , the present 10 disclosure provides technologies for regioselective and ste reoselective synthesis of vinyl fluorides . As shown in Scheme E - 3 , the present disclosure , among other things, provides access to high - value alkenyl fluorides with surpris ingly high selectivity , in some embodiments , as single E3 > 98 % conv, 69 % yield 15 E -isomers . Again , a broad scope of alkenes can be used as > 98 : 2 E : Z substrate , including aryl alkenes , heteroaryl alkenes, etc . Sterically encumbered a -branched alkyl olefins can also be efficiently transformed to the corresponding E - alkenyl fluo rides ( e. g ., E9 and E10 ). The efficient reaction between the 20 methyl ester derivative of isopimaric acid (Imaizumi , Y .; Fzc Sakamoto , K . ; Yamada , A . ; Hotta , A .; Ohya , S . ; Muraki, K . ; E4 Uchiyama, M .; Ohwada , T . Mol. Pharmacol. 2002 , 62 , with 5 mol % Mo- E1 836 - 846 ) (potassium channel activator ) and 5 equivalents of 96 % conv , 59 % yield E - CFE affording E -E10 in 74 % yield as a single diaste > 98 : 2 E : Z 2 5 reomer highlights CM as an economical catalytic strategy for site - and stereoselective late - stage fluorination (Camp bell, M . G . ; Ritter , T . Org . Process Res. Dev. 2014 , 18 , 474 - 480 ) in alkene- tethered natural products and / or phar 30 maceuticals .

E5 Scheme E3 CM of various alkenes and E - CFE in the presence ofMo - E2 . 2 h > 98 % conv, 85 % yield 35 5 mol % > 98 : 2 E : Z F Mo - E2 G toluene , 59 - 79 % yield ( F ) TBSO G = alkyl, aryl 5 - 10 equiv 22°C . , up to 98 : 2 E : Z 4h Mé Me Me 40 E6 with 20 equiv , E - DCE 5 mol % Mo- E1, 15 min > 98 % conv, 94 % yield Br 93 : 7 E : Z 45 E7 10 equiv , E -CFE b . Efficient CM between two trans- 1 , 2 -disubstituted olefins > 98 % conv , 89 :11 F /CI 59 % yield ( F ) , > 98 :2 E : Z ( F ) Ps 1 C1 5 mol % Mo- E1 Ph + V C6H6 22° C . , 4 h 50 10 equiv

Ph , > 98 % conv 85 % yield 55 > 98 : 2 E : Z E8 10 equiv , E -CFE 95 % conv , 88 : 12 F /CI Excellent stereoselectivities were observed in all cases . A 66 % yield (F ), > 98 : 2 E : Z ( F ) slightly higher catalyst loading was necessary to obtain synthetically useful yields in the cases of highly electron - 60 TBSO . deficient aryl olefins such as 4 - trifluoromethylstyrene . b . CM of trans- stilbene with E -DCE . Efficient CM between é Me Me trans - stilbene , generally unreactive substrate in CM due to E9 its steric bulk and electron - deficiency . 5 equiv, E - CFE Electron - rich ( e . g ., E1 , E2, E5 , and E6 ) as well as 65 95 % conv , 90 : 10 F / CI electron - poor ( e . g . , E3 and E4 ) olefins serve well as sub 77 % yield (F ) , > 98 : 2 E :Z ( F ) strates in the above transformations. In some embodiments, US 9 , 850 , 268 B2 143 144 moselectivity , etc . In some embodiments , when a substrate - continuedMe comprises a terminal olefin and an internal olefin , provide F technologies selectively promote reactions at the terminal olefin . In some embodiments , when a substrate comprises an Me H 5 olefin and an alkyne , provided technologies selectively promote reactions at the olefin . In some embodiments , when a substrate comprises a terminal olefin and an alkyne , provided technologies selectively promote reactions at the terminal olefin . MeOC Me Exemplary Procedure for In Situ Preparation of Mo 10 Based MAP Complexes E10 from isopimaric acid General Procedure for Preparation of Mo Complexes for with 5 equiv . E -CFE NMR Analysis : 10 mol % Mo- E2 In a Ny- filled glove box , an oven - dried 4 mL vial 94 % conv , > 98 . 2 F / CI equipped with a magnetic stir bar was charged with Mo 74 % yield , > 98 : 2 E : Z 15 bis -pyrrolide complex ( Yuan , J . ; Schrock , R . R . ; Müller, P . ; B (pin ) Axtell, J . C . ; Dobereiner , G . E . Organometallics 2012 , 31 , 4650 - 4653) ( 1 . 00 equiv ) , phenol (Prepared in analogy to previously reported procedures : ( a ) Barder, T . E . ; Walker, S . D . , Martinelli, J . R . ; Buchwald , S . L . J . Am . Chem . Soc . 20 2005 , 127 , 4685 - 4696 . ( b ) Radlauer, M . R . ; Day , M . W . ; Agapie , T . Organometallics 2012 , 31 , 2231 - 2243 ) ( 1 .00 equiv ) and CD . , resulting in a dark red solution . The vial was capped and the mixture was allowed to stir for 2 hours at 22° C . , at which time it was transferred to a E11 25 screw cap NMR tube by a pipette . The NMR tube was > 98 % conv, 88 : 12 F : CI capped and sealed with Teflon tape . In some embodiments , 73 % yield ( F ) , > 98 : 2 E : Z for in situ generated complexes, the diagnostic signals of the F a carbon of the syn - alkylidenes were evaluated . General Procedure for Preparation of Mo Complexes for Catalytic Reactions : 30 In a Ny- filled glove box , an oven - dried 4 mL vial equipped with a magnetic stir bar was charged with Mo Y F bis -pyrrolide complex ( 1 .00 equiv ), phenol ( 1 . 00 equiv ) and C .Hg , resulting in a dark red solution . The vial was capped hrulll Ph and the mixture was allowed to stir for 2 hours at 22° C . , N1113* * MO 35 after which the catalyst solution was transferred to the reaction mixture by a syringe ( dried at 65° C . ) . 1111 Ex Ellen Et- - 2 ,6 -Bis ( 3 , 5 -di - tert - butylphenyl) phenol 40 H NMR (600 MHz, CDC1, ) : 8 7 . 45 ( 2H , t , J = 1 . 8 Hz) , 7 .39 (4H , d , J = 1 . 8 Hz) , 7 .30 ( 2H , d , J = 7 . 5 Hz) , 7 .06 ( 1H , t , Mo- E2 J = 7 .6 Hz ), 5 .55 ( 1H , s) , 1. 36 (36H , s ). Mo - E1: Following the Me general procedure , an oven - dried 4 mL vial equipped with a magnetic stir bar was charged with Mo bispyrrolide complex Me 45 (59 . 7 mg, 0 . 100 mmol, 1. 00 equiv ), 2 ,6 -bis ( 3 ,5 -di - tert Me OTBS butylphenyl ) phenol (47 . 1 mg, 0 . 100 mmol, 1. 00 equiv ) and with 5 mol % Mo- E1, with 5 mol % Mo- E2 , C .H . ( 1. 0 mL ), resulting in a dark red solution . The vial was 20 equiv 5 ( 2 h ) 20 equiv 5 ( 2 h ) capped and the mixture was allowed to stir for 2 hours at 22° 92 % conv , 81 : 19 F : CI 85 % conv, 86 : 14 F : CI C . ' H NMR ( 400 MHz, C . D . ): 8 11. 88 ( 1H , s ) . 82: 18 E : Z ( F ), 60: 40 E : Z ( CI) 90 : 10 E :Z (F ), < 2 : > 98 E : Z ( CI) 50 Experimental Procedure for E - Selective CM yield ND 69 % yield ( F ) General Procedure : In a Ny - filled glove box , an oven -dried 4 mL vial with 5 mol % Mo- E2 with 5 mol % Mo- E2 equipped with a magnetic stir bar was charged with alkene 5 equiv 5 ( 2 h ) 10 equiv 5 ( 2 h ) substrate ( 1. 0 equiv ) and E - 1 ,2 -dichloroethene ( 10 - 20 95 % conv , 20 : 10 F : C1 95 % conv , 88 : 12 F : CI 55 equiv ) or E - 1 - chloro - 2 - fluoroethene (5 - 10 equiv ) . To this > 98 :< 2 E : Z ( F ), < 2 : > 98 E : Z (CI ) 91: 9 E :Z (F ) , < 2 : > 98 E : Z (CI ) vessel, a solution of provided compound , e . g . , Mo- El or 77 % yield (F ) 75 % yield ( F ) Mo- E2 ( 3 . 0 - 10 . 0 mol % ) , was added . The resulting solution with 5 mol % Mo- E2 was allowed to stir for 15 minutes - 4 hours at 22° C ., after 40 equiv 5 ( 2 h ) which the reaction was quenched by addition of wet CDC12 56 % conv , 88 :12 F : CI 60 (percent conversion was determined by 400 or 600 MHz ' H 86 : 14 E : Z ( F ), < 2 : >98 E : Z (CI ) NMR analysis of the unpurified mixture ). Purification was yield ND performed through silica gel chromatography. As demonstrated in examples herein , provided technolo ( E ) - 1 -( 2 - Chlorovinyl) -4 -methoxybenzene (E1 ) gies , among other things , provide high functional group 65 tolerance , mild reaction conditions , high efficiency , and /or Following the general procedure , a solution of Mo- E1 in high selectivity , e . g ., regioselectivity , Z / E - selectivity , che - benzene ( 0 . 1 M , 30 uL , 3 . 0 mol, 3 mol % ) was transferred US 9 ,850 , 268 B2 145 146 by syringe to an oven -dried vial containing E - 1 , 2 -dichlo by syringe to an oven - dried vial containing E - 1 , 2 - dichlo roethene ( 96 . 9 mg, 1 . 0 mmol, 10 . 0 equiv ) and 4 -methox roethene (58 . 1 mg, 0 .600 mmol, 10 . 0 equiv ) and 3 - vinyl ystyrene ( 13 .4 mg, 0 . 100 mmol, 1 .00 equiv ). The resulting 1H - indole (8 .6 mg, 0 .0600 mmol, 1. 00 equiv ). The resulting solution was allowed to stir for 3 hours at 22° C . The reaction was quenched by addition of wet CDC12 and analy - 5 solution was allowed to stir for 2 hours at 22° C . The sis of the unpurified mixture revealed > 98 % consumption of reaction was quenched by addition of wet CDC12 and analy 4 -methoxystyrene . The resulting orange oil was purified by sis of the unpurified mixture revealed > 98 % consumption of silica gel chromatography (50 : 1 hexanes / Et , 0 ) to afford E1 3 -vinyl - 1H - indole . The resulting orange oil was purified by ( 13 . 5 mg, 0 .0801 mmol, 80 % yield ) in > 98 : 2 E : Z ratio as silica gel chromatography (5 : 1 hexanes/ Et, 0 ) to afford E5 off -white solid . IH NMR ( 400 MHZ. CDC1. ) : 87. 23 (2H . d . ( 9 . 1 mg, 0 .0512 mmol, 85 % yield ) in > 98 : 2 E : Z ratio as J = 8 . 3 Hz) , 6 . 86 ( 2H . d . J = 8 . 8 Hz) , 6 .77 ( 1H . d . J = 13 . 6 Hz ). 10 slightly yellow solid . ' H NMR ( 400 MHz, CDC12) : 8 8 . 12 6 . 50 ( 1H , d , J = 13. 6 Hz) , 3 .81 ( 3H , s ). ( 1H , s ) , 7 .73 ( 1H , ddt , J = 7 . 8 , 1 . 4 , 0 . 8 Hz ), 7 .41 - 7 .33 ( 1H , m ), 7 . 29 - 7 . 14 (3H , m ) , 6 . 99 ( 1H , dd , J = 13 . 6 , 0 .6 Hz) , 6 .64 ( E ) - 4 - 2 - Chlorovinyl) phenyl acetate ( E2 ) ( 1H , dd , J = 13 . 7 , 0 . 5 Hz) . Following the general procedure , a solution of Mo- E1 in 15 ( E ) - tert -Butyl ( (8 - chloro - 2 ,6 - dimethyloct - 7 - en - 2 -yl ) benzene ( 0 . 1 M , 24 uL , 2 . 4 mol, 3 mol % ) was transferred oxy )dimethylsilane ( E6 ) by syringe to an oven -dried vial containing E - 1 , 2 -dichlo roethene ( 77 .6 mg, 0 . 8 mmol, 10 . 0 equiv ) and 4 -acetoxysty - Following the general procedure , a solution of Mo- El in rene ( 13 . 0 mg, 0 .0800 mmol, 1. 00 equiv ). The resulting benzene (0 . 1 M , 25 uL , 2 . 5 umol, 5 mol % ) was transferred solution was allowed to stir for 4 hours at 22° C . The 20 by syringe to an oven - dried vial containing E - 1, 2 - dichlo reaction was quenched by addition of wet CDC1 , and analy roethene ( 96 . 9 mg, 1 .00 mmol, 20 . 0 equiv ) and tert -butyl sis of the unpurified mixture revealed > 98 % consumption of (( 2 ,6 -dimethyloct - 7 -en -2 -yl ) oxy )dimethylsilane (13 . 5 mg, 4 - acetoxystyrene . The resulting orange oil was purified by 0 . 0500 mmol, 1 . 00 equiv ). The resulting solution was silica gel chromatography ( 10 : 1 hexanes /Et20 ) to afford E2 allowed to stir for 15 minutes at 22° C . The reaction was ( 11 . 8 mg , 0 . 0600 mmol, 75 % yield ) in > 98 : 2 E : Z ratio as 25 quenched by addition of wet CDC1z and analysis of the off -white solid . ' H NMR (400 MHz, CDC1z ): 8 7 .30 (2H , d , unpurified mixture revealed > 98 % consumption of tert -butyl J = 8 . 8 Hz ) , 7 .06 ( 2H , d , J = 8 . 9 Hz ) , 6 .81 (1H , d , J = 13. 7 Hz) , ( ( 2, 6 -dimethyloct - 7 -en - 2 -yl ) oxy )dimethylsilane . The result 6 .60 ( 1H , dd , J = 13 . 7 Hz ), 2 . 30 ( 4H , s ) . ing orange oil was purified by silica gel chromatography ( E ) - 1 -Chloro - 4 -( 2 -chlorovinyl ) benzene ( E3 ) ( 100 % pentane ) to afford E6 ( 11 . 4 mg , 0 .0374 mmol, 94 % 30 yield ) in 93 : 7 E : Z ratio as colorless oil . ' H NMR (600 MHz, Following the general procedure , a solution of Mo - E1 in CDC1Z ) : E - isomer (major ) : 8 5 . 91 ( 1H , dd , J = 13 . 3 , 0 . 9 Hz ), benzene ( 0 . 1 M , 40 uL , 4 . 0 mol, 5 mol % ) was transferred 5 .78 ( 1H , d , J = 13 . 2 , 8 . 4 Hz ) , 1 .39 - 1 . 24 (6H , m ), 1. 17 (6H , by syringe to an oven - dried vial containing E - 1 , 2 -dichlo - s ), 1 .00 (3H , d , J = 6 . 7 Hz ) , 0 .85 ( 9H , s ) , 0 . 06 (6H , s ) . roethene (77 .6 mg, 0 .800 mmol, 10 .0 equiv ) and 4 - chlo rostyrene (11 . 1 mg, 0 .0800 mmol , 1. 00 equiv ). The resulting 35 ( E ) - 1 - Bromo- 4 - ( 2 - fluorovinyl) benzene (E7 ) solution was allowed to stir for 4 hours at 22° C . The reaction was quenched by addition of wet CDC12 and analy Following the general procedure , a solution of Mo- E2 in sis of the unpurified mixture revealed > 98 % consumption of benzene ( 0 . 1 M , 25 uL , 2 . 5 umol, 5 mol % ) was transferred 4 - chlorostyrene . The resulting orange oil was purified by by syringe to an oven -dried vial containing a solution of silica gel chromatography ( 100 % hexanes ) to afford E3 ( 9 . 6 40 E - 1 - chloro - 2 - fluoroethene in toluene ( 2 . 36 M , 218 uL , 0 .514 mg , 0 .0555 mmol, 69 % yield ) in > 98 : 2 E : Z ratio as off -white mmol, 10 . 0 equiv ) and 4 -bromostyrene ( 9 . 4 mg, 0 .0514 solid . ' H NMR ( 400 MHz, CDC12) : 87 .58 ( 4H , d , J = 7 . 8 Hz) , mmol, 1 .00 equiv ) . The resulting solution was allowed to stir 7 .40 (2H , d , J = 8 .0 Hz ), 6 .87 (2H , d , J = 13. 7 Hz ) , 6 . 76 (2H , for 2 hours at 22° C . The reaction was quenched by addition d , J = 13 . 7 Hz ). of wet CDC1, and analysis of the unpurified mixture 45 revealed > 98 % consumption of 4 -bromostyrene that resulted ( E ) - 1 - ( 2 - Chlorovinyl) - 4 - ( trifluoromethyl) benzene in the formation of a mixture of F - and C1- alkenes ( 89 : 11 ( E4) F :Cl ) . The resulting red oil was purified by silica gel chromatography ( 100 % hexanes ) to afford E7 ( 6 . 1 mg, Following the general procedure , a solution of Mo - El in 0 .0303 mmol, 59 % yield ) in > 98 : 2 E : Z ratio as colorless oil. benzene ( 0 . 1 M , 30 uL , 3 . 0 mol, 5 mol % ) was transferred 50 H NMR (400 MHz, CDC12 ) : 8 7 . 41 ( 2H , d , J = 8 . 4 Hz ), 7 . 15 by syringe to an oven -dried vial containing E - 1 , 2 -dichlo ( 1H , dd , J = 82 .6 , 11 . 4 Hz) , 7 . 10 ( 2H , d , J = 8 .6 Hz) , 6 . 32 ( 1H , roethene (58 . 1 mg, 0 .600 mmol, 10 . 0 equiv ) and 4 - trifluo - dd , J = 18 . 9 , 11 . 4 Hz ) . romethylstyrene ( 10 . 3 mg, 0 . 0600 mmol, 1 .00 equiv ) . The reresulting solution was allowed to stir for 4 hours at 22° C . ( E ) - 3 - ( 2 - Fluorovinyl) benzo [ b ] thiophene (E8 ) The reaction was quenched by addition of wet CDC1z and 55 analysis of the unpurified mixture revealed > 98 % consump Following the general procedure, a solution of Mo- E2 in tion of 4 - trifluoromethylstyrene . The resulting orange oil benzene ( 0 . 1 M , 31 uL , 3 . 1 umol, 5 mol % ) was transferred was purified by silica gel chromatography (100 % hexanes ) by syringe to an oven -dried vial containing a solution of to afford E4 ( 7 . 3 mg, 0 . 0353 mmol, 59 % yield ) in > 98 : 2 E : Z E - 1 -chloro - 2 - fluoroethene in toluene ( 2 . 36 M , 264 L , 0 .624 ratio as colorless oil. 'H NMR (400 MHz, CDC1z ): 8 7 .30 60 mmol, 10 .0 equiv ) and 3 -vinylbenzo [b ]thiophene (10 . 0 mg, ( 2H , d , J = 8 . 5 Hz) , 7 . 23 ( 2H , d , J = 8 . 8 Hz) , 6 . 79 ( 1H , d , 0 . 0624 mmol, 1 . 00 equiv ) . The resulting solution was J = 13 .6 Hz ), 6 .63 ( 1H , d , J = 13 . 7 Hz ). allowed to stir for 2 hours at 22° C . The reaction was quenched by addition of wet CDC12 and analysis of the ( E ) - 3 - ( 2 -Chlorovinyl ) - 1H -indole ( E5 ) unpurified mixture revealed 95 % consumption of 3 - vinyl 65 benzo [ b ] thiophene that resulted in the formation of a mix Following the general procedure , a solution of Mo - El in ture of F - and Cl- alkenes (88 : 12 F :Cl ) . The resulting red oil benzene (0 . 1 M , 30 UL , 3 .0 mol, 5 mol % ) was transferred was purified by silica gel chromatography (2 % Et O / US 9 , 850 , 268 B2 147 148 hexanes) to afford E8 ( 7 . 3 mg, 0 . 0410 mmol, 66 % yield ) in afford E11 ( 7 . 9 mg, 0 .0318 mmol, 73 % yield ) in > 98 : < 2 E : Z > 98 : < 2 E : Z ratio as colorless oil. ' H NMR ( 400 MHz, ratio as colorless oil. ' H NMR ( 400 MHz, CDC13 ): 8 7 . 74 CDC1z ) : 8 7 .89 - 7 .85 ( 1H , m ) , 7 .80 - 7 .76 ( 1H , m ) , 7 .45 - 7 . 36 ( 2H , d , J = 8 . 0 Hz) , 7 .25 ( 2H , d , J = 8 . 3 Hz) , 7 .22 ( 1H , dd , ( 2H , m ), 7 . 30 ( 1H , s ) . 7 . 23 ( 1H , dd , J = 83 .5 . 11. 3 Hz) , 6 .63 J = 83 . 0 , 11 . 4 Hz) , 6 . 39 ( 1H , dd , J = 19 . 3 , 11 . 3 Hz) , 1 . 34 ( 12H , ( 1H , ddd , J = 18 . 1 , 11 . 3 , 1 . 0 Hz ) . 5 s ) . As demonstrated above , provided technologies can use ( E )- tert - Butyl( 8 - fluoro - 2 , 6 - dimethyl- 7 - octen - 2 complex compounds with various functional groups as sub yloxy )dimethylsilane ( E9 ) strates , and provide high yield and selectivity , e . g ., regiose lectivity , Z / E - selectivity , etc. In some embodiments , the Following the general procedure , a solution of Mo -E2 in 10 present disclosure provides a method for preparing a fluo benzene ( 0 . 1 M , 18 UL , 1 . 8 umol, 5 mol % )) was transferred rinated derivative of a bioactive molecule . In some embodi by syringe to an oven -dried vial containing a solution of ments , a bioactive molecule is the second species in a E - 1 - chloro - 2 - fluoroethene in toluene ( 2 . 36 M , 78 L , 0 . 185 provided method . In some embodiments , a second species is mmol, 5 . 00 equiv ) and tert- butyl ( 2 , 6 - dimethyl- 7 - octen - 2 a bioactive molecule . In some embodiments , a bioactive yloxyldimethylsilane ( 10 . 0 mg , 0 .0370 mmol, 1 . 00 equiv ) . 15 molecule comprises an olefin . In some embodiments , a The resulting solution was allowed to stir for 2 hours at 22° bioactive molecule comprises a terminal olefin . In some C . The reaction was quenched by addition of wet CDC1, and embodiments , a bioactive molecule comprises a terminal analysis of the unpurified mixture revealed 95 % consump olefin , and the derivatization step converts the = CH , moi tion of tert -butyl (2 , 6 - dimethyl -7 -octen - 2 -yloxy )dimethylsi ety of the terminalolefin into = CHF. In some embodiments , lane that resulted in the formation of a mixture of F - and 20 the present disclosure provides a method for preparing a Cl- alkenes ( 90 : 10 F : C1) . The resulting red oil was purified fluorinated derivative of a bioactive molecule , wherein the by silica gel chromatography ( 100 % pentane ) to afford E9 bioactive molecule comprises a terminal olefin , and the ( 8 .2 mg, 0 .0284 mmol, 77 % yield ) in > 98: < 2 E : Z ratio as derivatization step converts the = CH2moiety of the termi colorless oil . IH NMR ( 400 MHz. CDC1 . ) : 8 6 .48 ( 1H , ddd . nal olefin into = CHF with Z - selectivity . In some embodi J = 86 . 3 , 11 . 1 , 0 . 8 Hz) , 5 .22 ( 1H , ddd , J = 20 . 0 , 11 . 1 , 9 . 0 Hz) , 25 ments , the present disclosure provides a method for prepar 2 . 05 (1H , qt , J = 10 . 9 , 7 . 3 Hz) , 2 . 01 - 1 . 99 ( 1H , m ) , 1 .37 - 1 . 23 ing a fluorinated derivative of a bioactive molecule , wherein (6H , m ), 1. 17 (6H , s) , 1. 00 (3H , s ), 0 .85 (9H , s) , 0 .05 (6H , the bioactive molecule comprises a terminal olefin , and the s ) . derivatization step converts the = CH , moiety of the termi nal olefin into = CHF with E - selectivity . In some embodi Methyl ( 1R ,4aR ,468 ,75 , 10aR ) - 7 - ( ( E ) - 2 - fluorovi 30 ments , a bioactive molecule is an approved drug . In some nyl) - 1 ,4a , 7 - trimethyl- 1, 2 ,3 , 4 ,4a ,4b ,5 ,6 ,7 , 8, 10 ,10a embodiments , a bioactive molecule is a compound in clini dodecahydrophenanthrene- 1 - carboxylate (E10 ) cal trial. In some embodiments , a bioactive molecule is a natural product. As understood by a person having ordinary Following the general procedure, a solution of Mo - E2 in skill in the art, fluorinated derivatives can have one or more benzene (0 . 1 M , 14 uL , 1 .4 umol, 10 mol % ) was transferred 35 improved properties. In some embodiments , the present by syringe to an oven -dried vial containing a solution of disclosure provides a fluorinated derivative of a bioactive E - 1 - chloro - 2 - fluoroethene in toluene ( 2 . 36 M , 30 uL , 0 .0711 molecule comprising a terminal olefin , wherein the fluori mmol, 5 .00 equiv ) and isopimaric acid methyl ester ( 4 . 5 mg, nated derivative comprises a - CH = CHF moiety . In some 0 .0142 mmol, 1 .00 equiv ) . The resulting solution was embodiments , the double bond in — CH = CHF has a Z allowed to stir for 2 hours at 22° C . The reaction was 40 configuration . In some embodiments , the double bond in quenched by addition of wet CDC1, and analysis of the CH = CHF has a E configuration . In some embodiments , unpurified mixture revealed 94 % consumption of isopimaric the present disclosure provides pharmaceutical composi acid methyl ester that resulted in the exclusive formation of tions comprising a fluorinated derivative of a bioactive F -alkene ( > 98 : < 2 F :C1 ) . The resulting red oil was purified by molecule and a pharmaceutically acceptable carrier. silica gel chromatography ( 1 : 1 benzene /hexanes then 10 : 1 45 While several embodiments of the present disclosure have hexanes / Et , 0 ) to afford E10 ( 3 . 5 mg , 0 .0105 mmol, 74 % been described and illustrated herein , those of ordinary skill yield ) in > 98 : 2 E : Z ratio as colorless oil. 'H NMR ( 400 in the art will readily envision a variety of other means MHz. CDC1. ): 8 6 .47 ( 1H , dd , J = 86 . 1 , 11 . 2 Hz) , 5 . 37 ( 1H , and /or structures for performing the functions and / or obtain dd , J = 22 . 8 , 11 . 2 Hz) , 5 . 32 - 5 . 28 ( 1H , m ), 3 .64 ( 3H , s ) , ing the results and /or one or more of the advantages 2 . 14 -0 .63 (25H , m ). 50 described herein , and each of such variations and / or modi fications is deemed to be within the scope of the present ( E ) - 2 - ( 4 - ( 2 - Fluorovinyl) phenyl - 4 , 4 , 5 , 5 - tetramethyl disclosure . More generally , those skilled in the art will 1 , 3 , 2 - dioxaborolane ( E11 ) readily appreciate that all parameters , dimensions, materials , and configurations described herein are meant to be exem Following the general procedure, a solution of Mo - E2 in 55 plary and that the actual parameters , dimensions, materials , benzene ( 0 . 1 M , 22 uL , 2 . 2 umol, 5 mol % ) was transferred and / or configurations will depend upon the specific appli by syringe to an oven - dried vial containing a solution of cation or applications for which the teachings of the present E - 1 - chloro - 2 - fluoroethene in toluene ( 2 . 36 M , 184 uL , 0 . 435 disclosure is /are used . Those skilled in the art will recognize , mmol, 10 . 0 equiv ) and 4 , 4 , 5 , 5 - tetramethyl- 2 - ( 4 - vinylphe - or be able to ascertain using no more than routine experi nyl) - 1 , 3 , 2 - dioxaborolane ( 10 . 0 mg, 0 .0435 mmol, 1 .00 60 mentation , many equivalents to the specific embodiments of equiv ) . The resulting solution was allowed to stir for 2 hours the disclosure described herein . It is , therefore , to be under at 22° C . The reaction was quenched by addition of wet stood that the foregoing embodiments are presented by way CDC1, and analysis of the unpurified mixture revealed > 98 % of example only and that , within the scope of the appended consumption of tert- butyl ( 2, 6 -dimethyl - 7 -octen - 2 - yloxy )di - claims and equivalents thereto , the disclosure may be prac methylsilane that resulted in the formation of a mixture of F - 65 ticed otherwise than as specifically described and claimed . and Cl- alkenes (88 : 12 F : Cl) . The resulting red oil was The present disclosure is directed to each individual feature , purified by silica gel chromatography ( 2 % Et O / hexanes) to system , article , material , kit , and / or method described US 9 ,850 ,268 B2 149 150 herein . In addition , any combination of two or more such gen , oxygen , or sulfur, a 4 - 7 membered saturated or features , systems , articles , materials, kits , and/ or methods , if partially unsaturated heterocyclic ring having 1 - 3 het such features , systems, articles , materials, kits , and / or meth eroatoms independently selected from nitrogen , oxy ods are not mutually inconsistent, is included within the gen , or sulfur, a 7 - 10 membered bicyclic saturated or scope of the present disclosure . 5 The invention claimed is : partially unsaturated heterocyclic ring having 1- 5 het 1 . A method , comprising : eroatoms independently selected from nitrogen , oxy reacting a first species comprising an olefin with a second gen , or sulfur , or an 8 - 14 membered bicyclic or tricyclic species comprising an olefin in the presence of a heteroaryl ring having 1 - 5 heteroatoms independently catalyst or metal complex to provide at least one 10 selected from nitrogen , oxygen , or sulfur ; product comprising an olefin , wherein : Ar is of the following formula : each carbon atom of the olefin in the first species is substituted with at least one halogen ; and the olefin in at least one product comprises a carbon atom mm from the first species and a carbon atom from the 15 (R™ ) C ( D + (R ) second species, and wherein the catalyst or metal complex is of formula II - a : (R *) m II-a 20 wherein : 2 m is 0 - 3 ; RS IR Ring B is an optionally substituted group selected from R phenyl or a 5 -6 membered monocyclic heteroaryl Ro ? 25 ring having 1- 4 heteroatoms independently selected from nitrogen , oxygen , or sulfur ; p and q are independently 0 - 6 ; wherein : each of Ring C and Ring D is independently optionally M is molybdenum or tungsten ; substituted groups selected from phenyl, a 3 - 7 mem R ' is an optionally substituted group selected from C1- 20 30 bered saturated or partially unsaturated carbocyclic aliphatic , C1- 20 heteroaliphatic having 1 - 3 heteroatoms ring , an 8 - 10 membered bicyclic saturated , partially independently selected from nitrogen , oxygen , or sul unsaturated or aryl ring , a 5 -6 membered monocyclic fur, phenyl, a 3 - 7 membered saturated or partially heteroaryl ring having 1 - 4 heteroatoms indepen unsaturated carbocyclic ring , an 8 - 10 membered bicy dently selected from nitrogen , oxygen , or sulfur , a clic saturated , partially unsaturated or aryl ring , a 5 - 6 35 4 - 7 membered saturated or partially unsaturated het membered monocyclic heteroaryl ring having 1 - 4 het erocyclic ring having 1 - 3 heteroatoms independently eroatoms independently selected from nitrogen , oxy selected from nitrogen , oxygen , or sulfur, a 7 - 10 gen , or sulfur, a 4 - 7 membered saturated or partially membered bicyclic saturated or partially unsaturated unsaturated heterocyclic ring having 1 - 3 heteroatoms heterocyclic ring having 1 - 5 heteroatoms indepen independently selected from nitrogen , oxygen , or sul - 40 dently selected from nitrogen , oxygen , or sulfur, or fur, a 7 - 10 membered bicyclic saturated or partially an 8 - 10 membered bicyclic heteroaryl ring having unsaturated heterocyclic ring having 1 - 5 heteroatoms 1 -5 heteroatoms independently selected from nitro independently selected from nitrogen , oxygen , or sul gen , oxygen , or sulfur ; fur, or an 8 - 10 membered bicyclic heteroaryl ring each of R *, R ', and R is independently R '; having 1 - 5 heteroatoms independently selected from 45 R is halogen , OR " , - OR ', - N ( R ') 2 , NR' C ( O ) R ', nitrogen , oxygen , or sulfur, or R ' is optionally substi - NR ' C ( O )OR ' , NR ' C ( O ) N ( R ' ) 2 , NR ' SO , R ', tuted - NR 'SO , N ( R ') , , or — NR 'OR ', or an optionally sub stituted group selected from a 5 - 6 membered monocy clic heteroaryl ring having at least one nitrogen and 0 - 3 50 heteroatoms independently selected from nitrogen , oxygen , or sulfur, a 4 - 7 membered saturated or partially unsaturated heterocyclic ring having at least one nitro man gen and 0 - 2 heteroatoms independently selected from nitrogen , oxygen , or sulfur, a 7 - 10 membered bicyclic each of R² and R3 is independently R ', — OR ', — SR ', 55 saturated or partially unsaturated heterocyclic ring hav - N (R ') 2 , OC (O )R ', SOR ', — SO R ', — SO , ing at least one nitrogen and 0 - 4 heteroatoms indepen N (R ') 2, C (O ) N (R ') 2 , - NR 'C (O )R ', or — NR 'SO R ', dently selected from nitrogen , oxygen , or sulfur, or an provided that R² and R3 are not simultaneously hydro 8 - 10 membered bicyclic heteroaryl ring having at least gen ; one nitrogen and 0 - 4 heteroatoms independently R4 is R ?, or an optionally substituted group selected from 60 selected from nitrogen , oxygen , or sulfur; - Ar, C1- 20 aliphatic , C1- 20 heteroaliphatic having 1 - 3 R is an optionally substituted group selected from C1- 20 heteroatoms independently selected from nitrogen , aliphatic , C1- 20 heteroaliphatic having 1 - 3 heteroatoms oxygen , or sulfur, phenyl, a 3 -7 membered saturated or independently selected from nitrogen , oxygen , or sul partially unsaturated carbocyclic ring , an 8 - 10 mem fur, phenyl, a 3 - 7 membered saturated or partially bered bicyclic saturated , partially unsaturated or aryl 65 unsaturated carbocyclic ring, an 8 - 10 membered bicy ring , a 5 - 6 membered monocyclic heteroaryl ring hav clic saturated , partially unsaturated or aryl ring , a 5 -6 ing 1 - 4 heteroatoms independently selected from nitro membered monocyclic heteroaryl ring having 1 - 4 het US 9 ,850 ,268 B2 151 152 eroatoms independently selected from nitrogen , oxy bered saturated or partially unsaturated carbocyclic gen , or sulfur, a 4 - 7 membered saturated or partially ring, an 8 - 10 membered bicyclic saturated , partially unsaturated heterocyclic ring having 1 - 3 heteroatoms unsaturated or aryl ring, a 5 - 6 membered monocyclic independently selected from nitrogen , oxygen , or sul heteroaryl ring having 1 - 4 heteroatoms indepen fur , a 7 -10 membered bicyclic saturated or partially 5 dently selected from nitrogen , oxygen , or sulfur, a unsaturated heterocyclic ring having 1 -5 heteroatoms 4 -7 membered saturated or partially unsaturated het independently selected from nitrogen , oxygen , or sul erocyclic ring having 1- 3 heteroatoms independently fur, or an 8 - 14 membered bicyclic or tricyclic het selected from nitrogen , oxygen , or sulfur, a 7 - 10 eroaryl ring having 1 - 5 heteroatoms independently membered bicyclic saturated or partially unsaturated selected from nitrogen , oxygen , or sulfur, and 10 heterocyclic ring having 1 - 5 heteroatoms indepen each R ' is independently hydrogen or an optionally sub dently selected from nitrogen , oxygen , or sulfur, or stituted group selected from C1- 20 aliphatic , phenyl, a an 8 - 10 membered bicyclic heteroaryl ring having 3 - 7 membered saturated or partially unsaturated carbo 1 - 5 heteroatoms independently selected from nitro cyclic ring , an 8 - 10 membered bicyclic saturated , par gen , oxygen , or sulfur; and tially unsaturated or aryl ring , a 5 -6 membered mono - 15 each R is independently halogen , R ', OR , SR ', cyclic heteroaryl ring having 1 - 4 heteroatoms - S (O )R ', - S ( O )2R ', OSi( R ') 3, — N (R ') 2 , independently selected from nitrogen , oxygen , or sul — NR ' C ( O ) R ', — NR 'C ( O )OR ', — NR ' C ( O ) N ( R ') , fur , a 4 - 7 membered saturated or partially unsaturated - NR 'SO , R ', - NR ' SO , N ( R ') 2 , or — NR 'OR ' . heterocyclic ring having 1 - 3 heteroatoms indepen 2 . A method , comprising : dently selected from nitrogen , oxygen , or sulfur, a 7 - 10 20 reacting a first species comprising an olefin with a second membered bicyclic saturated or partially unsaturated species comprising an alkyne in the presence of a heterocyclic ring having 1 - 5 heteroatoms indepen catalyst or metal complex to provide at least one dently selected from nitrogen , oxygen , or sulfur , or an product comprising an olefin , wherein : 8 - 10 membered bicyclic heteroaryl ring having 1 - 5 each carbon atom of the olefin in the first species is heteroatoms independently selected from nitrogen , 25 substituted with at least one halogen ; and oxygen , or sulfur, wherein : the olefin in at least one product comprises a carbon atom two R ' groups on the same nitrogen atom are optionally from the first species and a carbon atom from the taken together with the nitrogen atom to form an second species ; and optionally substituted 3 - 8 membered , saturated , par wherein the catalyst or metal complex is of formula II -a : tially unsaturated , or aryl ring having 1 - 4 heteroa - 30 toms independently selected from nitrogen , oxygen , or sulfur ; II - a each R ' is independently an optionally substituted group selected from — Ar' , C1- 20 aliphatic , C1- 20 heteroali — phatic having 1 - 3 heteroatoms independently selected 35 from nitrogen , oxygen , or sulfur, phenyl, a 3 - 7 mem RS M bered saturated or partially unsaturated carbocyclic R40 ring , an 8 - 10 membered bicyclic saturated , partially unsaturated or aryl ring, a 5 - 6 membered monocyclic heteroaryl ring having 1 - 4 heteroatoms independently 40 wherein : selected from nitrogen , oxygen , or sulfur, a 4 - 7 mem M is molybdenum or tungsten ; bered saturated or partially unsaturated heterocyclic R ' is an optionally substituted group selected from C1- 20 ring having 1 - 3 heteroatoms independently selected aliphatic , C1- 20 heteroaliphatic having 1 - 3 heteroatoms from nitrogen , oxygen , or sulfur, a 7 - 10 membered independently selected from nitrogen , oxygen , or sul bicyclic saturated or partially unsaturated heterocyclic 45 fur, phenyl, a 3 - 7 membered saturated or partially ring having 1 - 5 heteroatoms independently selected unsaturated carbocyclic ring, an 8 - 10 membered bicy from nitrogen , oxygen , or sulfur, or an 8 - 14 membered clic saturated , partially unsaturated or aryl ring, a 5 -6 bicyclic or tricyclic heteroaryl ring having 1 - 5 heteroa membered monocyclic heteroaryl ring having 1 - 4 het toms independently selected from nitrogen , oxygen , or eroatoms independently selected from nitrogen , oxy sulfur; and two RP are optionally taken together with 50 gen , or sulfur, a 4 - 7 membered saturated or partially the oxygen atoms they are bound to form a bidentate unsaturated heterocyclic ring having 1 - 3 heteroatoms ligand ; and independently selected from nitrogen , oxygen , or sul Ar' is of the following formula : fur , a 7 - 10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1 - 5 heteroatoms 55 independently selected from nitrogen , oxygen , or sul mm fur , or an 8 - 10 membered bicyclic heteroaryl ring ((R ' ) p, to having 1 -5 heteroatoms independently selected from nitrogen , oxygen , or sulfur ; or R ' is optionally substi 60 tuted wherein : t is 0 - 4 ; www p is 0 - 6 ; 65 each Ring B ' and Ring C ' is independently an optionally substituted group selected from phenyl, a 3 - 7 mem US 9 , 850 , 268 B2 153 154 each of R² and R3 is independently R ', - OR ', SR ', ing at least one nitrogen and 0 - 4 heteroatoms indepen - N ( R ' ) 2 , OC (O ) R ', - SOR ', SO N ( R ') 2 , - C ( O ) dently selected from nitrogen , oxygen , or sulfur, or an N (R ') 2, - NR 'C ( O ) R ', or — NR 'SO , R ', provided that 8 - 10 membered bicyclic heteroaryl ring having at least R2 and R3 are not simultaneously hydrogen ; one nitrogen and 0 -4 heteroatoms independently R4 is R², or an optionally substituted group selected from 5 selected from nitrogen , oxygen , or sulfur ; - Ar, C1- 20 aliphatic , C1- 20 heteroaliphatic having 1 -3 R? is an optionally substituted group selected from C1- 20 heteroatoms independently selected from nitrogen , aliphatic , C1- 20 heteroaliphatic having 1- 3 heteroatoms oxygen , or sulfur, phenyl , a 3 - 7 membered saturated or independently selected from nitrogen , oxygen , or sul partially unsaturated carbocyclic ring, an 8 - 10 mem fur, phenyl, a 3 - 7 membered saturated or partially bered bicyclic saturated , partially unsaturated or aryl 10 unsaturated carbocyclic ring, an 8 - 10 membered bicy ring , a 5 - 6 membered monocyclic heteroaryl ring hav clic saturated , partially unsaturated or aryl ring, a 5 - 6 ing 1 - 4 heteroatoms independently selected from nitro membered monocyclic heteroaryl ring having 1- 4 het gen , oxygen , or sulfur, a 4 - 7 membered saturated or eroatoms independently selected from nitrogen , oxy partially unsaturated heterocyclic ring having 1 - 3 het - 16 gen , or sulfur, a 4 - 7 membered saturated or partially eroatoms independently selected from nitrogen , oxy unsaturated heterocyclic ring having 1 - 3 heteroatoms gen , or sulfur, a 7 - 10 membered bicyclic saturated or independently selected from nitrogen , oxygen , or sul partially unsaturated heterocyclic ring having 1 - 5 het fur, a 7 - 10 membered bicyclic saturated or partially eroatoms independently selected from nitrogen , oxy unsaturated heterocyclic ring having 1 -5 heteroatoms gen , or sulfur, or an 8 - 14 membered bicyclic or tricyclic 20 independently selected from nitrogen , oxygen , or sul heteroaryl ring having 1 - 5 heteroatoms independently fur, or an 8 - 14 membered bicyclic or tricyclic het selected from nitrogen , oxygen , or sulfur; eroaryl ring having 1 - 5 heteroatoms independently Ar is of the following formula : selected from nitrogen , oxygen , or sulfur; and each R ' is independently hydrogen or an optionally sub 25 mm stituted group selected from C1- 20 aliphatic , phenyl, a 3 - 7 membered saturated or partially unsaturated carbo ( R ) - C D (R cyclic ring , an 8 - 10 membered bicyclic saturated , par tially unsaturated or aryl ring, a 5 - 6 membered mono cyclic heteroaryl ring having 1 - 4 heteroatoms (R *) m 30 independently selected from nitrogen , oxygen , or sul fur , a 4 - 7 membered saturated or partially unsaturated wherein : heterocyclic ring having 1 - 3 heteroatoms indepen m is 0 - 3 ; dently selected from nitrogen , oxygen , or sulfur, a 7 - 10 Ring B is an optionally substituted group selected from 35 membered bicyclic saturated or partially unsaturated phenyl or a 5 - 6 membered monocyclic heteroaryl heterocyclic ring having 1 - 5 heteroatoms indepen ring having 1 - 4 heteroatoms independently selected dently selected from nitrogen , oxygen , or sulfur, or an from nitrogen , oxygen , or sulfur; 8 - 10 membered bicyclic heteroaryl ring having 1 - 5 p and q are independently 0 - 6 ; heteroatoms independently selected from nitrogen , each of Ring C and Ring D is independently optionally 40 oxygen , or sulfur, wherein : substituted groups selected from phenyl, a 3 - 7 mem two R ' groups on the same nitrogen atom are optionally bered saturated or partially unsaturated carbocyclic taken together with the nitrogen atom to form an ring , an 8 - 10 membered bicyclic saturated , partially optionally substituted 3 - 8 membered , saturated , par unsaturated or aryl ring , a 5 - 6 membered monocyclic tially unsaturated , or aryl ring having 1 - 4 heteroa heteroaryl ring having 1 - 4 heteroatoms indepen - 45 toms independently selected from nitrogen , oxygen , dently selected from nitrogen , oxygen , or sulfur, a or sulfur ; 4 - 7 membered saturated or partially unsaturated het each R7 is independently an optionally substituted group erocyclic ring having 1 - 3 heteroatoms independently selected from - Ar' , C1- 20 aliphatic , C1- 20 heteroali selected from nitrogen , oxygen , or sulfur , a 7 - 10 phatic having 1 - 3 heteroatoms independently selected membered bicyclic saturated or partially unsaturated 50 from nitrogen , oxygen , or sulfur , phenyl, a 3 - 7 mem heterocyclic ring having 1 - 5 heteroatoms indepen bered saturated or partially unsaturated carbocyclic dently selected from nitrogen , oxygen , or sulfur, or ring, an 8 - 10 membered bicyclic saturated , partially an 8 - 10 membered bicyclic heteroaryl ring having unsaturated or aryl ring , a 5 - 6 membered monocyclic 1 - 5 heteroatoms independently selected from nitro heteroaryl ring having 1 - 4 heteroatoms independently gen , oxygen , or sulfur; 5355 each of R * , R " , and R is independently R ; selected from nitrogen , oxygen , or sulfur , a 4 - 7 mem R is halogen , - OR " , - OR " , - N ( R ') 2 , - NR ' C ( O ) R ', bered saturated or partially unsaturated heterocyclic - NR' C ( O )OR ', NR ' C ( O ) N ( R ') 2 , NR ' SO , R ', ring having 1 - 3 heteroatoms independently selected - NR 'SO N (R ') 2 , or — NR 'OR ', or an optionally sub from nitrogen , oxygen , or sulfur, a 7 - 10 membered stituted group selected from a 5 -6 membered monocy - 60 bicyclic saturated or partially unsaturated heterocyclic clic heteroaryl ring having at least one nitrogen and 0 - 3 ring having 1 - 5 heteroatoms independently selected heteroatoms independently selected from nitrogen , from nitrogen , oxygen , or sulfur, or an 8 - 14 membered oxygen , or sulfur , a 4 - 7 membered saturated or partially bicyclic or tricyclic heteroaryl ring having 1 - 5 heteroa unsaturated heterocyclic ring having at least one nitro toms independently selected from nitrogen , oxygen , or gen and 0 - 2 heteroatoms independently selected from 65 sulfur; and two R ’ are optionally taken together with nitrogen , oxygen , or sulfur, a 7 - 10 membered bicyclic the oxygen atoms they are bound to form a bidentate saturated or partially unsaturated heterocyclic ring hav ligand ; and US 9, 850 ,268 B2 155 156 Ar ' is of the following formula :

(RPR ) p, ACto I 5 B ' wherein each of X and Y is independently halogen ; and ( R ) wherein the product is produced in a E : Z ratio greater than 80 : 20 . 10 7 . The method of claim 4 , comprising reacting the first wherein : species with the second species via a metathesis reaction t is 0 - 4 ; between the olefin of the first species and the olefin of the p is 0 -6 ; second species with regioselectivity to provide as products : each Ring B ' and Ring C ' is independently an optionally CH2= CHY; and substituted group selected from phenyl, a 3 -7 mem - 15 at least one product comprising an olefin wherein the bered saturated or partially unsaturated carbocyclic olefin comprising = CHX , over CH2 = CHX and a ring , an 8 - 10 membered bicyclic saturated , partially product comprising an olefin wherein the olefin com unsaturated or aryl ring , a 5 - 6 membered monocyclic prising = CHY, wherein X is smaller than Y. 8 . The method of claim 7 , wherein X is – F . heteroaryl ring having 1 - 4 heteroatoms indepen 9 . The method of claim 8 , wherein the regioselectivity is dently selected from nitrogen , oxygen , or sulfur, a 20 greater than 80 : 20 . 4 - 7 membered saturated or partially unsaturated het 10 . The method of claim 6 , comprising reacting the first erocyclic ring having 1 - 3 heteroatoms independently species with the second species via a metathesis reaction selected from nitrogen , oxygen , or sulfur, a 7 - 10 between the olefin of the first species and the olefin of the membered bicyclic saturated or partially unsaturated second species with regioselectivity to provide as products : heterocyclic ring having 1- 5 heteroatoms indepen - 2525 CH2 = CHY ; and dently selected from nitrogen , oxygen , or sulfur , or at least one product comprising an olefin wherein the an 8 - 10 membered bicyclic heteroaryl ring having olefin comprising = CHX , over CH = CHX and a 1 - 5 heteroatoms independently selected from nitro product comprising an olefin wherein the olefin com gen , oxygen , or sulfur ; and prising = CHY , wherein X is smaller than Y . each RS is independently halogen , R ', — OR ', — SR ', 30 . 11 . The method of claim 10 , wherein X is – F . - S ( O ) R ' , - S ( O ) , R ', OSi( R ' ) 3 , N ( R ' ) 2, 12 . The method of claim 11 , wherein the regioselectivity - NR ' C ( O ) R ', — NR 'C (O ) OR ', NR ' C ( O ) N (R ') 2 is greater than 80 :20 . — NR 'SO , R ', — NR 'SO N ( R ') 2 , or — NR 'OR '. 13 . Themethod of claim 9 , wherein the second species is 3 . Themethod of claim 1 , wherein the olefin in at least one R - CH = CH ,, and at least one product is (ZR product is formed via a metathesis reaction between the 35 CH = CHF . olefin in the first species and the olefin in the second species ; 14 . The method of claim 12 , wherein the second species and is R - CH = CH2, and at least one product is (ZR — the halogen substituent of the first carbon atom of the CH = CHF. double bond in the first species and the halogen sub 15 . The method of claim 1 , wherein R ' is optionally stituent of the second carbon atom of the double bond 10 substituted adamantyl, or R ' is substituted phenyl compris in the first species is cis, and the olefin in the at least 40 ing one or more electron -withdrawing substituents , wherein one product comprises a carbon atom from the first each electron -withdrawing substituent is independently species and a carbon atom from the second species is halogen or substituted C1- 6 alkyl comprising one or more produced with Z - selectivity . halogen . 4 . The method of claim 3 , wherein the first species has the 45 16 . The method of claim 15 , wherein Rl is structure of: F

50 wherein each of X and Y is independently halogen ; and YF: wherein the product is produced in a Z : E ratio greater than II mm 80 : 20 . 5 . Themethod of claim 1 , wherein the olefin in at least one 55 product is formed via a metathesis reaction between the olefin in the first species and the olefin in the second species ; R4 is optionally substituted and the halogen substituent of the first carbon atom of the double bond in the first species and the halogen sub - 60 stituent of the second carbon atom of the double bond mu in the first species is trans, and the olefin in the at least one product comprises a carbon atom from the first species and a carbon atom from the second species is produced with E -selectivity . 65 6 . The method of claim 5 , wherein the first species has the structure of : US 9, 850 ,268 B2 157 158 and RS is optionally substituted mi

10

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