Baran GM Kharasch Reaction and its Related Transformations Klement Foo

Background Asymmetric Development (only in 1990s) - 1895–1957 - Main players: Andrus, Pfaltz, Katsuki - defined the "peroxide effect" - earliest asymmetric development was diastereoselective using chiral anti-Markovnikov via radical additions auxiliaries. - Born Russian but migrated to the USA at age of 13. - best result 30% ee. - Obtained PhD from University of Chicago - Trained Nobel Laureate H. C. Brown Potential for asymmetric Kharasch oxidation depends on the ability of L on - In 1942 (WWII), joined the American Synthetic Cu(III) to induce asymmetric formation of benzoate. Rubber Research Program - polymerization of Bisisoxazoline as ligand: styrene 5 mol % What is the Kharasch Reaction? Y O O Y 1) Allyic oxidation with radicals 2) The Kharasch modified Grignard rxn Y N N Y Cu X=tBu/Ph 3) Addition of poly-halogenated alkanes across olefin O X OTf X Y=H/Me OBz O o Kharasch Allylic Oxidation and its Development Ph O CH3CN, -20 C 2 days - First reported in 1959 by Kharasch ~81% ee O OBz 5 equiv OBz 50% Cu(I) cat. no way to predict which ligand is best O o R Ph O PhH, 80 C R require screening of X/Y Andrus, TL 1995, 36, 2945 Mechanism: cyclooctene slow conversion/ low ee O O acyclic olefins like allylbenzene and 1-octene has been done Cu(I) O O Cu(II) O O Ph O Ph O N N O2CPh diffusion O2CPh controlled O OH (6mol%) O CPh R R CuOTf (5mol%) 2 o 90% ee 63% ee 13% ee geometry retained Acetone, 0 C 9% barrier of rotation 50% 41% 2o radical O (~20 kcal/mol) Ph favored OBz Cu(II) R Pfaltz, TL 1995, 36, 1831 Ph O O -Cu(I) attack at least O Cu(III) hindered C. R Andrus went on to show that weakening perester bond would increase 9:1 regio R (can be 1:1 using AcOH, homolysis and thus increase formation of Cu(II) complex. However Beckwith, JACS 1986, 108, 8230. CuCl, tBuOOH) different peresters require different Cu catalyst: CuBr to CuPF6(CH3CN)4. Walling, JACS 1961, 83, 3877. Kochi, JACS 1965, 87, 4866. T 1997, 53, 6229

Page 1 Baran GM Kharasch Reaction and its Related Transformations Klement Foo

O O O Also studied are proline derived ligands. Best results yet: Observed correlation between coordinating ability of ligand to % ee N N O O stereocontrol increases with the use of more rigid alkenes (cyclic alkenes) tBu Ph Ph Muzart, T:A 1995, 6, 147; Andrus, T 2002, 58, 845 O CuPF6 2 NO2 o CH3CN, -20 C Recent Development: O2N 17 days 96% ee O OCOPh 44% R1 L, Cu(OTf) , R O 2 2 t N PhCO Bu, Shorter reaction time generally give lower ee (>84% ee) R 3 R 90% ee n=1 Able to achieve 99% ee with cyclopentene. N PhNHNH2 O R=H n 97% ee n=2 Andrus, JACS 2002, 124, 8806 R1 n acetone R1=R2=Me/Et/Cp n=1, 2 R2 O or R =Me R =tBu 1 2 Boyd, CC 2008, 5535 Biaryl atropisomeric oxazolines as ligand: Ligand can perform asymmetric cyclopropanation of styrene (88–95% ee) -wider bite angle between 2 nitrogens, forcing allyl radical and X Cu(I/II) X benzoate closer together. Y Y Y X tBuOOCOAr OCOAr Y Y Y O -(S,S,S) ligand shown here. Also available (S,R,S) O3 then NaBH4 N Ph -recoverable by 80% N Ph -73–78% ee for oxidation of cyclopentene and meso X=CH2/CR2/O/NR symmetrising O cyclohexene Y=H/OR NaIO4 Y Y Andrus, JOC 1997, 62, 9365 ArOCO then OH Andrus, T 2000, 56, 5775 NaBH4 X Pyridine based igands: H H H H HO OH HO OCOAr only successful for Y=H and X=CH2 and CR2 O O R up to 70% ee Clark, TL 2004, 45, 9447 R N N N (62–75% ee R N N R for cycloheptene) Kharasch Variant (Schiff base as ligand) PINDY t PhCO3 Bu, OCOAr OMOM Singh, TL 1996, 37, 2633 Kocovsky, OL 2000, 2, 3047 CuPF6(CH3CN)4 (3 mol %) AcO OH O H H O OCOPh C3 Symmetric oxazole as ligand: N N N 81% ee N 3 3 H Ar=Ph 84% ee precursor O H H H OCOPh (3 mol %) N O 88% ee for cyclopentene 38% overall Ar=4-NO2Ph > 99% ee to 2-deoxy- O 58% ee N 15 gram scale streptamine 3 H Ar 85% ee Transforming to 4-NO2Ph then recrystallizing enhances ee.

Katsuki, SL 1995, 1245 SL 1999, 8, 1231 OCOPh Hayashi, OL 2009, 11, 3314

Page 2 Baran GM Kharasch Reaction and its Related Transformations Klement Foo

3. Synthesis of Polyether Toxin Frameworks - Brevetoxin B Summary: tBuOOH (0.2 eq) -Asymmetric Kharasch allylic oxidation has reached >90% ee AcOH (0.8 eq) -But is greatly hampered by the long reaction times (days) and only applicable mostly on simple cyclic substrates. Cu2Cl2 cat. -More complicated or acyclic olefins tend to give mixtures of regioisomers. 80 oC, 52 h OR 82% For detailed reviews on stereocontrol/regiocontrol/mechanistric studies R = OAc then OH see: Andrus, T 2002, 58, 845; C.Eur.J 2008, 14, 9274.

Applications of Kharasch Allylic Oxidation

OAc 1. Synthesis of Leukotriene B4 Alvarez, JOC 1994, 59, 2848 Selective OBz O 4. Synthesis of Chrysanthemic acid ozonolysis H LB4 t OBz OMe PhCO3 Bu, LDA OCOPh 74% CuCl, PhH 75% O CO2Et CO2Et common intermediate 60% H CO2Et to 12 routes to LB4 reported -previously made from OBz 6 steps from 2-deoxy-D-ribose -or 12 steps from D-xylose CO2Et actual 2. Synthesis of Oleanolic Acid -Reported regioisomer does not obey Kharasch reaction mechanism -Found by Andrus that the other regioisomer was actually formed, but

t gives same products. Angelo, TL 1976, 28, 2441 1. PhCO3 Bu H CuBr, PhCl 118 oC, 4 h, 81% 5. CH2OH O 2. NaOH, H O H MeOH-THF H CuCl, O t H TBSO 98% TBSO PhCO3 Bu, O H H H PhH, 4 d H <10% Corey, JACS 1993, 115, 8873 H H

OH BzO OH Guerriero, C&B 2005, 2, 657

Page 3 Baran GM Kharasch Reaction and its Related Transformations Klement Foo

2. Total synthesis of Branimycin 6. Oxidation of oxazolines/thiazolines t O R PhCO3 Bu, OTBS 1 X R1 CuBr, heat X OH R 1. CrO3, 2 R2 Stoichiometric Cu needed TBS OMe O N N ester group crucial for reactivity 3,5-dimethyl- OTBS protection pyrazole OTBS CO2R CO2R OMe 2. CeCl3, X=O or S MOMO NaBH4 OTBS R2=H or Me 65% 2 steps - stereochemistry is due to rigid structure R1=no limit for Cu-mediated OTBS alkyl/aryl. Allow 2o or 3o H of subtrate OMe - 3 steps. Machart, ACIE 2010, 49, 2050 to remain intact if R1= another recent and notable synthesis which employ same strategy: Stock, JACS, 2009, 131, 11402 (Codeine and Morphine) H or iPr or Cy Meyers, JOC 1996, 61, 8207 NHR SePh 3. NCS, py, PhSeNa cat. Ph2Se2 Cl EtOH 70% OH Other applications of Kharasch allylic oxidation: Arcadi, TL 1997, 38, 2329; Bateson, JCS PT1 1991, 2399; Welzel, 63% 87% 1. BH3.SMe2 T 1998, 54, 10753. 2. NaOH, H2O2 Not many applications of Kharasch reaction in synthesis. Scianowski, T 2009, 65, 10162 4. Total Synthesis of ß-Erythroidine Asymmetric Allylic Oxidation in Synthesis - A field that still requires a lot of development. Many synthetic targets OH O O O N N HO contain allylic alcohols, with stereocenters at the alcohol FG. 1 KHMDS O2, rose bengal N - Most commonly seen (in fact >80% of Scifinder hits on this topic) used O O DME hv, then NH2CSNH2 1,2-reduction of enone, where desired stereochem of OH is due to rigid HMPA 73% O structure of substrate - eg. steroids... O O 91% O O O O 1. Routes to AB system of Taxoids (see last week's GM) Alcohol stereochem. defined by cycloaddition KOH, of singlet oxygen. MeI, Et4NBr OBn cat. OBn H H H Ti(OiPr) H SnCl 4 O 2 OBn mCPBA OBn 84% O O 97% O OH OH HO N O O

- 3 steps to allylic alcohol SL 1998, 897 Funk, OL 2006, 8, 3689 O O

Page 4 Baran GM Kharasch Reaction and its Related Transformations Klement Foo

2. Enantioselective borane reduction (of enones) 5. Total synthesis of Frondosin B Ph H Ph O catecholborane (1.5 eq) HO R R Ph R O R H Ph O N R R B cat. OH O (–) (0.15 eq) 97% ee o BH3 (0.6-2 eq) n N B -78 C, 40 h n Ph Ph n=2, 98% ee 1 min Me R R O OH

89% ee Ovaska, OL 2009, 11, 2715 H Corey, JACS 1987, 109, 5551 For allylic C-H oxidation see White, Nature 2009, 547 O R 3. Chiral LA for enantioselective allylic oxidation

A good way to stereoselectively form allylic alcohols (late stage) in total O O synthesis is needed. What other methods are there anyway? Ph S S Ph OAc Pd(OAc)2 (10 mol %) Methods to obtain chiral allylic alcohols R salenCr(III)X (10 mol %) R 1. Enzymatic DKR Resolution R=alkyl, ester, amide, AcOH (1.1 eq), BQ (2 eq) 69-92% alcohol EtOAc, RT, 48 h ~50-60% ee Ph CALB Ph Subtilisin Ph rac. cat. surfactants -for reactions that do not tolerate strongly coordinating ligands OCOR ROCOR OH ROCOR OCOR -weakly coordinating bissulfoxide catalyze C-H cleavage rac. cat. -BQ catalyze C-O formation 89% 97% ee -sequential activity >99% ee -proposed 3 pathways for enantioselectivity: Fastest DKR of alcohols using a metal + enzyme catalysis. Previous rac. cat. either take too long to racemize or need high temp. (think enzyme). Note that small amount of base needed to activate the rac. cat. White, ACIE 2008, 47, 6448 Subsequent copper-cat. allylic substitution inverts stereochemistry with small loss of 4. Rearrangement of epoxide optical activity (~ 75-91% ee if R2 is aryl).

Ph R2MgX Ph First development used chiral lithium base (first eg of enantioselective deprot.) CuBr.DMS R1 R R2 OCOR 2 N Li xs chiral base OLi max. 31% ee works with other enantiomer H O 10% of other regioisomer observed. regioselectivity depends on base/solvent/substrate Backvall, JACS 2005, 127, 8817 removal of H syn to O Whitesell, JOC 1980, 45, 755 Backvall, JOC 2010, 75, 6842 Reviews: O'Brien, JCS PT1 1998, 1439

Page 5 Baran GM Kharasch Reaction and its Related Transformations Klement Foo

excess RMgX Catalytic system DBU ensures monomeric aggregate Br X cat. amine forms aggregate with base O NH HO X = Cl or Br CoBr2 cat. N cat. 2 instances where ee is poor can be improved by using stoichiometric chiral LDA (2 eq) amine. Same system can perform RO Cl DBU (5 eq) resolution on rac-epoxide (2 examples) 5-7 membered R= Me or Et 49-97 %ee PhO Br O same system O OH trace Ph Ph Me Ph Me 94% ee 84% ee -also in this study, he found that the length of the haloalkyl chain affects the product distribution. Andersson, JACS 2000, 122, 6610 if n = 2, major product is PhOMgX + ethylene Not covered in this GM includes: if n = 3, major product is cyclopropane, General allylic oxidation methods if n > 3, major product is PhO(CH2)nH Kharasch, JOC 1953, 18, 575 Ru catalyzed oxidation to enone: see Miller, TL 1996, 37, 3429; Meyer, JACS 2000, 122, 5984 "Reinterpretation of Several Kharasch Reactions" Co catalyzed allylic oxidation: see Iqbal, TL 1995, 36, 159 SO2 induced + O2 oxidation: see Tempesti, JOC 1980, 45, 4278 -argues that interchange reaction occurs between alkyl halide and Grignard Pd catalyzed allylic oxidation: see Yu, Corey, JACS 2003, 125, 3232; reagent (catalyzed by TM). Yu, Corey, OL 2002, 4, 2727 - it is a competing reaction pathway which is more likely to explain the Mercuric acetate allylic oxidation: see Rappoport, JACS 1972, 94, 2320 observation of products (cyclopropane formation) SeO2 catalyzed allylic oxidation: see Gray, JACS 1977, 99, 5526 -products of the modified Grignard reaction is due to hydrolysis of interchanged Mechanism for SeO2 oxidation: see Singleton, JOC 2000, 65, 7554 Grignard reagent.

Kharasch Reactions : The Modified Grignard Reaction CoBr2 PhO Br EtMgBr PhO MgBr EtBr

Kharasch discovered that many transition metal salts, eg. CoCl2, catalyzes a reaction between Grignard reagent and alkyl halide (allylic halide). -PhOMgBr, reflux RR TM 1 Evidence: RX + R MgX R Tried to regenerate Kharasch's radical: 1 RR O R(-H) -CO PhO PhO Kharasch, JOC 1943, 65, 493 For Co catalyzed: H Slaugh, JOC 1961, 83, 2734 Mechanism: 1) RMgX + CoX2 -----> RCoX + MgX2 2) RCoX -----> R + CoX Kharasch's response with a JACS paper: 3) R'X + CoX -----> R' + CoX 2 "Functional exchange does not play an important role, if at all, in these Kharasch suggested that alkyl radicals were formed in the reaction, which reactions" can undergo homocoupling, cross coupling or reduction to the olefin.

Page 6 Baran GM Kharasch Reaction and its Related Transformations Klement Foo

His explanation: For a more recent mechanistic argument supporting the formation of alkyl 3-alkoxy-1-propylmagnesium bromide cannot be a key intermediate, as it radicals, see Henderson, JCS DT 1992, 1259. does not explain formation of propylene. It is also known to be stable under the reaction condition. Neither is it plausible for cyclopropane to A similar recent example of Ni-catalyzed cross coupling: isomerize into propylene FeCl3 R R'MgX cat. NiCl2 R PhO Br X R' R'=alkyl/phenyl 1,3-butadiene R=alkyl/aryl 0C or RT, h 56-100% 33% 25% X=halogen/OTs GC yield Proposed: RMgX RMgX Kambe, JACS 2002, 124, 4222 Y X Y FeCl3 FeCl3 Allyl halide + Grignard Reagent (cat. TM salt) TM salt also observe homocoupling 1,2-H shift X R RMgBr of allyl halide, or H-xfer RMgX Y Interesting development: FeCl3 Kharasch, JACS 1961, 83, 3232 R CuCN.2LiCl conventional PO R Yet another mechanistic input: R'MgX SN2' pathway R' Cu(I) R=alkyl R'=alkyl, EtMgBr + EtBr Et-Et + MgBr2 P=diphenyl- alkenyl, Fe(acac) phosphonate phenyl 3 -addition of radical trap such as styrene, does not affect the rate of ethane R' R formation -----> reduction of styrene should be observed. SN2 pathway -proposed formation of alkylcuprate intermediate. 54-95% Kochi, JACS 1971, 93, 1485 99:1 selectivity Kochi went on to do a detailed study on the interaction of transition Yamamoto, SL 1991, 513 for most cases metal salts with Grignard reagents (without alkyl halides, with or without Application: styrene) and the same on the interaction of mixture of 2 Grignard reagent with TM salts. 1. Regioselective Generation of Dienol Ethers from Enones: Findings: O OTMS OTMS OTMS 1. Radical mechanism can be neglected for homocoupling R-R (one type 1. cat. FeCl3 MeMgBr (1 eq) of GR) since styrene has no effect on rate. Instead it might proceed under 2. TMSCl, Et N bimolecular mechanism: RMXn-x + RMXn-x --> R-R + 2MYn-x 3 2. Disproportionation of GR to give alkene and alkane DMPU 2 plausible mechansims: 9 other examples 99% (2 : 96 : 2) a) "Hydride" RCH CH M --> RCH=CH + HM all with comparable kinetic enol through-conjugated 2 2 2 selectivity ether from enol ether is major RCH2CH2M + HM --> RCH2CH3 + 2M LDA b) "Direct Hydride Migration" RCH2CH2M + RCH2CH2M --> RCH=CH2 + using excess reagents will switch selectivity of endo for exo-enol ether to be RCH2CH3 + 2M major product Kochi, BCSJ 1971, 44, 3063 Holton, JACS 1984, 106, 7619

Page 7 Baran GM Kharasch Reaction and its Related Transformations Klement Foo

2. "Super-Ate" complex of iron: He decided to try his "super-ate" complex on a similar Holton problem: only applicable to GR FeCl cat. RCH CH MgX 2 RCH=CH + RCH CH with 2 or more carbons Expt 1: HC(OMe) 2 2 2 2 3 as reduction process O 3 involves ß-H elimination Holton's recipe TMSO BF3.Et2O O [Fe(MgX )] CO Me 2 n CO Me 2 2 Expt 2: OMe MeMgBr, R Cl SA (0.1 eq); OMe In line with this is the fact that MeMgBr fails to react with the substrate in the dihydro- TMSCl, Et3N, DMPU major 45% presence of any iron catalyst, whereas higher alkyl GR do so much easily. carvone overall Why? Side Products: precursor to HO TMSO sarcodictyin family TMSO Successfully made a iron "super-ate" complex for Me substitution OTMS

MeLi(xs) + FeCl3 ---> [(Me4Fe)(MeLi)][Li(OEt2)]2 + 3LiCl

This "super-ate" (SA) complex does not react with pX-C6H4COOMe or normal Crude product spectrum after quench is virtually identical in both cases. alkenyl halides. It only reacts with activated enol triflates, acid chlorides or The dimer side prdt suggests a SET event. electron deficient heteroarene. do we have an actual "Kharasch reagent"? O O Furstner, ACIE 2006, 45, 450 SA (0.25 eq) SA (1.1 eq) OH Cl HO OH 60% Ar Ar Ar Addition of Per-haloalkanes to olefins Cl Cl 72% (2:1) Overview excess SA complex gives carbonyl addition product and pinacol product. pinacol product suggests some form of SET mechanism on the ketone. R' TM R' Cl CXCl3 anti-Markovnikov CXCl2 Another example of the SET: R R -Discovered by Kharasch, Science 1945, 102, 128 Br -A radical mechanism is proposed, see JOC 1938, 2, 288. SA, THF -Drawbacks include 1. limited scope of polyhalogenated substrates -40 oC 2. harsh reaction conditions (high T and time) N N 83% -Ways to improve: 1. New transition metal complexes (Ru found to be most Br Me Br Me efficient (>40 oC) "Ulmann coupling" (ish) 2. adding Lewis acids as cocatalysts to activate C-X bond -It is noted that different mechanisms exist for each TM catalyst

Page 8 Baran GM Kharasch Reaction and its Related Transformations Klement Foo

General Mechanism for TM-catalyzed Kharasch addition: Ni -Cu cat. Kharasch addition shows a low redox potential is needed. M+ + CXCl + 3 MCl + CXCl2 -"redox-chain" process -Ni(NCN) has a super low potential of +0.14 to +0.57 V (Ni(II)/Ni(III)) (cf. X -MCl+ has a larger normal +0.7 to +1.2 V) Cl -addition of carbon tetrachloride to methyl methacrylate is complete in 15 min CXCl + R chain xfer constant 2 R Cl at RT over 90% conversion ---> mildest and fastest condition yet. NR2 X Cl X 5 mol % cat. Cl + + Cl + MCl Cl + M M R R MeO2C Cl Cl MeO2C Minisci, ACR 1975, 8, 165 NR2 CCl3 NCN ligand ("pincer") Koten, ACR, 1998, 31, 423 Ru -the same Grubb's ruthenium benzylidene complex used for olefin meta- Applications of the Kharasch addition thesis is employed here. 1. Synthesis of Permethrin (NRDC143) moiety -ligands on ruthenium can also be changed to minimize olefin metathesis NaOH, EtO2C or other side reactions that might occur. CCl4, Bz2O2, Cl CCl4, o 15 - 20 h Bu4NHSO4 -reaction can be done at temperatures as low as 40 C in a few hours. Cl3C Cl3C 70% -a different mechanism from the "redox-chain" has been proposed to OH O OH rationalize the markedly different reactivity and selectivity 86 grams Cl -"radical reaction in cooridination sphere" - radicals generated remain under Cl the influence of the metal center Svendsen, JOC 1979, 44, 416 2. Synthesis of 2-pyrones with CF3 groups RuCl (PPh ) + CCl 2 3 2 4 [ RuCl3(PPh3)2][ CCl3] Cl double CO2Me -Ru catalysis also extended to olefin polymerization CO2Me CuCl cat. CO2Me dechlorination F3CCl2C CF3CCl3 o Matsumoto, J. Organomet. C 1979, 174, 157 140 C, 8 h ring CO2Me 57% CO2Me closure Rh 50% O O CF3 -2-pyrones undergo inverse e- demand DA -chiral Rh catalyst allows enantioselective addition to olefin. with acetylenes, spontaneously losing CO Me NEt2 -CO2 -White tried to rationalize Rh stereoselectivity (over Cu(I)/Fe(II)/Ru(II) 2. less e- rich acetylenes require higher temp. 0 oC, 68% by proposing that an oxidative addition first step occurs (analogous to -also undergo DA with olefins, but no loss CO2. hydrogenation of alkene CO2Me -isolated oxidative addition adduct Olefins: OCOMe

Rh(P)3ClCO + CBrCl3 P3Rh(CO)ClBr(CCl3) N O -However, his proposed mechanism is not well received, and others argue Me CF3 that an oxidative addition does not rule out radicals, because there is prec- MeO OMe edence that oxidative addition of Ir and Pt complexes undergo radical NEt2 mechanisms. MeO OMe White, JCS CC 1991, 165; Koten, ACR, 1998, 31, 423 Martin, TL 1985, 26, 3947

Page 9 Baran GM Kharasch Reaction and its Related Transformations Klement Foo

5. Halogen atom transfer cyclization (Mesembrine skeleton) MeO OMe 3. Ring-closed Kharasch addition product NO 2 Cl Cl CCl Cl Ar Ru(II) 3 CCl3 Cl Ar Cl3C CuCl (0.3 eq) 1. Bu3SnH H H H H Ar N Cl CCl4 O 120 oC, 2 h X Cl Ru O N 2. LiAlH4 X X CHPh PCy O N X=O or C(CO2Et)2 major 3 Me Me N no 6-endo trig closure observed. >54% yield in all cases. Me Verpoort, CatL 2002, 83, 9 Itoh, JCS CC 1985, 518 4. More Intramolecular Kharasch Cyclization 6. Chlorinated pyridines 8 mol % Cl HCl, 180 oC R Cl o Dihaloesters: Cu powder or PCl5, HCl, 100 C Cl Cl 105 oC ,12h H CN H R Cl Cl Cl O CN CO2R Cl Cl R O CO2R CO2R CO2R Ru/Fe/Mo O N Cl Cl O complexes R=Cl or CF3 CuCl (6 mol %), 190 oC, 30 min H H H Cl Cl Cl H thermodynamic kinetic Bellus, Pure Appl. Chem. 1985, 57, 1827 7. Another Halogen Atom Transfer Cyclization Haloesters:

Me O Cl H O Cl Cl CCl3CO2Me, H O CuCl, MeCN (CuCl) H H CO2Me O o Cl C 165 C Cl 80 oC MeO2CCl2C H Me MeO C l CO2Me Cl 2 MeO2C FeCl2[3P(OEt)3] + Cl Cl O (9.7 mol %, 29 h) H Me unisolable. Cl more reactive O 9 : 1 87% 56% 32% H Bellus, Pure Appl. Chem. 1985, 57, 1827 H H Ru(II) 8. Ru cat. Intramolecular Addition to 1,3-diene Cl Cl Cl 165 oC CO Et I Me 2 CO2Et CO2Me H Ru(II) CO2Me H O Cl Me O 38% Cl CO2Et 50% Cl H H Halogen atom Cl Cl transfer to olefin major Weinreb, T 1988, 44, 4671 solely 1,4-addition product. E-selective Chem. Rev. 1994, 94, 559

Page 10 Baran GM Kharasch Reaction and its Related Transformations Klement Foo

11. (Extension) Synthesis of (γ,γ−difluoroallyl)carbonyl compounds Cl Cl Cl CO Et Cl CO Et CO Et 2 CClF CCl 2 2 OTMS 2 2 O Cl O CO Et Ru(II) Cl Ru(II) ZnCl cat. 2 2 F 150-55 oC Ph DMF, 100 oC Ph CClF )))) Ph R R R R 2 13 h 80% 67% F -good way to make fluorine containing olefins. 9. Synthesis of bicyclic γ-lactams -modified addition product due to loss of TMS group and subsequent loss of HCl (g). Okano, JOC 1993, 58, 5164 Cl3CCN Pd(II) Grubb's DBU (0.1eq) (0.1eq) o 12. (Extension) Radical Trichloromethylation HN O HN O 60 C HN O OH

CCl3 CCl3 CCl3 155 oC -3-step tandem process Cl -Overman arrangement of allylic trichloroacetimidates, Grubb's ring closing metathesis and lastly Kharasch Cl cyclization (atom transfer). Cl HN Zakarian, JACS 2010, 132, 1482 O 87% Sutherland, OBC 2010, 8, 3418 10. Formation of Spiroindoles O Not covered in this meeting: Cl O 1) Kharasch addition extension to controlled polymerization Cl C Cl Cl 3 PMDETA, Cl Cl 2) Any other "Kharasch reaction" missing N R O N R CuCl, 24 h or N N Conclusion N R N Cl R' R' R' - The mechanisms of all 3 Kharasch reactions are not fully elucidated. 5-exo-trig 6-endo-trig - Synthetic applications of each of the 3 reactions covered here are unfortunately limited. -spiroindole formation verified by HMBC analysis - Good asymmetric allylic oxidations have to be developed. Stevens, E. JOC 2010, 5444

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