Vol. 6 No. 5

Synthetic Methods Organosilicon Chemistry

Alkyne Hydrosilylation

* • [Cp Ru(MeCN)3]PF6 and Other Catalysts

Organosilanes for Cross-coupling • Dimethylsilanols • Triethoxysilanes • Polyvinylsiloxanes

Multicomponent Couplings • 2-Silyl-1,3-dithianes

Boc-protected 2-pyrrolyldimethylsilanol: a potent nucleophile in Pd-catalyzed cross-coupling

sigma-aldrich.com 

Introduction Silicon has long held a privileged status in organic synthesis. Indeed, the use of silicon protecting groups in the majority of lengthy multi-step natural product syntheses illustrates the necessity of organosilicon compounds. Other silicon reagents, such as allyl Vol. 6 No. 5 and crotyl silanes, have also become omnipresent within the field as powerful methods for the construction of new C–C bonds. Organosilicon chemistry has matured substantially over the course of the past decade and new methods have been developed for both the Aldrich Chemical Co., Inc. introduction of silicon groups, as well as new methods for chemical manipulation of those Sigma-Aldrich Corporation groups. Of particular importance are the use of catalytic methods such as hydrosilylation 6000 N. Teutonia Ave. of alkynes and cross-coupling of organosilanes. Milwaukee, WI 53209, USA This edition of ChemFiles describes the applications of new catalysts and reagents within the field of organosilicon chemistry. Sigma-Aldrich is proud to provide cutting- To Place Orders edge catalysts, ligands, organometallic reagents, and other synthetic reagents for the rapid and successful construction of complex chemical architectures. In most cases, the Telephone 800-325-3010 (USA) methodologies illustrated herein exhibit high levels of chemo-, regio-, and stereoselectivity. FAX 800-325-5052 (USA) For a complete listing of products related to chemical synthesis, please visit us at sigmaaldrich.com/chemicalsynthesis. Customer & Technical Services At Sigma-Aldrich, we are committed to be the preferred supplier for all of your research Customer Inquiries 800-325-3010 needs. If you are unable to find a product for your research efforts in organic synthesis Technical Service 800-231-8327 ™

Introduction or drug discovery, we welcome your input. “Please Bother Us” with your suggestions at SAFC 800-244-1173 [email protected] or contact your local Sigma-Aldrich office. Custom Synthesis 800-244-1173 Flavors & Fragrances 800-227-4563 International 414-438-3850 24-Hour Emergency 414-438-3850 Web Site sigma-aldrich.com NEW Product Email [email protected] Directory Available! Subscriptions Boron Reagents for Suzuki Coupling To request your FREE subscription to ChemFiles, please contact us by: Phone: 800-325-3010 (USA) Mail: Attn: Marketing Communications The directory contains Aldrich Chemical Co., Inc. Sigma-Aldrich’s extensive Sigma-Aldrich Corporation portfolio of high-quality P.O. Box 355 Milwaukee, WI 53201-9358 boronic acids, Email: [email protected] boronate esters, and trifluoroborate salts International customers, please contact your for use in Suzuki coupling local Sigma-Aldrich office. For worldwide contact information, please see back cover. and other important reactions. ChemFiles are also available in PDF format on the Internet at sigma-aldrich.com/chemfiles.

Aldrich brand products are sold through Sigma- Aldrich, Inc. Sigma-Aldrich, Inc. warrants that its With a special foreword by products conform to the information contained in Prof. Akira Suzuki. this and other Sigma-Aldrich publications. Purchaser must determine the suitability of the product for its particular use. See reverse side of invoice or packing Available electronically at sigma-aldrich.com/boronpd slip for additional terms and conditions of sale.

About Our Cover The cover graphic depicts the structure of a dimethylsilanol reagent, (N-Boc-2-pyrrolyl)- ChemFiles is a publication of Aldrich Chemical Co., dimethylsilanol, which has been successfully employed in Pd-catalyzed cross-coupling Inc. Aldrich is a member of the Sigma-Aldrich Group. reactions. Dimethylsilanols have recently emerged as attractive reagents for facile © 2006 Sigma-Aldrich Co. construction of new C–C bonds. sigma-aldrich.com 

Alkyne Hydrosilylation SiR3 * R3Si [Cp Ru(MeCN) ]PF and Other Catalysts H SiR3 MLn SiR3 3 6 + R' R' R' R' H Vinyl-metal reagents play a pivotal role in organic synthesis. trans-β-vinylsilane cis-β-vinylsilane α-vinylsilane Among the vinyl-metal reagents available, silicon-based reagents are of increasing importance. This is largely due to their low R'' R'' SiR3 R3Si R3Si Aldrich Chemical Co., Inc. cost, minimal toxicity, ease of handling, and the simplicity of H SiR3 MLn SiR3 R'' R'' + R' R' R' R' Sigma-Aldrich Corporation byproduct removal. Particularly attractive is the ability to carry R' R'' the silyl moiety through a series of synthetic manipulations. 6000 N. Teutonia Ave. Z-vinylsilanes E-vinylsilanes Milwaukee, WI 53209, USA Much of the impetus for the growing relevance of vinylsilanes arises from the successful cross-coupling strategies developed for Scheme 1 these useful organometallic species. Vinylsilanes are also useful To Place Orders as Michael acceptors in conjugate addition reactions and as masked ketones in Tamao–Fleming oxidations. BF4 Telephone 800-325-3010 (USA) O Hydrosilylation Alkyne FAX 800-325-5052 (USA) Of the available methods for preparation of vinylsilanes, the Me2Si SiMe2 Cl H2PtCl6 Rh Rh Rh Cl hydrosilylation of alkynes is the most direct and atom-economical Pt

approach (Scheme 1). A number of transition metal catalysts Speier's catalyst Karstedt's catalyst [Rh(cod)2]BF4 [Rh(nbd)Cl]2 Customer & Technical Services have been devised to execute these reactions in a regio- and Customer Inquiries 800-325-3010 stereocontrolled fashion (Figure 1). Methods for hydrosilylation

Technical Service 800-231-8327 PPh PPh3 of terminal alkynes were developed some time ago, particularly 3 PF6 ™ Ar Cl Cl Cl SAFC 800-244-1173 for the preparation of cis- and trans-β-vinylsilanes. Classical Ph3P Rh Cl Ru Ru Ru Ru Cl Cl Ar Cl Ph MeCN NCMe 1 2 PPh Custom Synthesis 800-244-1173 Pt-catalysis (Speier’s and Karstedt’s catalysts), as well as 3 PPh3 NCMe 4 Flavors & Fragrances 800-227-4563 6 st * Rh-based catalysis ([Rh(cod)2]BF4 and [RhCl(nbd)]2 ), remain Wilkinson's catalyst [Ru(η -arene)Cl2]2 Grubbs' 1 generation [Cp Ru(MeCN)3]PF6 International 414-438-3850 powerful methods for synthesis of trans-β-vinylsilanes. catalyst 24-Hour Emergency 414-438-3850 Wilkinson’s catalyst was also demonstrated to yield the trans Web Site sigma-aldrich.com product in polar solvents, with the cis isomer predominating Figure 1 Email [email protected] 5 in non-polar media. Ru-based catalysts (e.g. [Ru(benzene)Cl2]2 6 or [Ru(p-cymene)Cl2]2) allow for access to cis-β-vinylsilanes. Under certain conditions, Grubbs’ 1st generation catalyst also SiR3 R3SiH R3Si gives cis products, although the stereo- and regioselectivity of R' H + Subscriptions * the hydrosilylation is highly dependent on the alkyne, silane, [Cp Ru(MeCN)3]PF6 R' R' To request your FREE subscription to ChemFiles, rt, 1 h and solvent.7 While there exists a wealth of methods for α β please contact us by: preparation of linear β-vinylsilanes, until recently there were Scheme 2 Phone: 800-325-3010 (USA) no general methods for the preparation of 1,1-disubstituted

α-vinylsilanes.8 Moreover, although selective intramolecular 7 2 3 8 . 1 3 2 . 0 0 8 . 1 : e c i v r e S l a c i n h c e T 0 1 0 3 . 5 2 3 . 0 0 8 . 1 : r e d r O Mail: Attn: Marketing Communications 9 hydrosilylation of internal alkynes can be achieved, a selective Entry Alkyne R3SiH Loading (%) Ratio (a:b) Yield (%) Aldrich Chemical Co., Inc. intermolecular variant was virtually unknown.10 The Trost group Sigma-Aldrich Corporation 1 MeO (EtO)2MeSiH 1 9:1 86 (a) at Stanford University developed a remarkably robust protocol P.O. Box 355 for hydrosilylation of terminal acetylenes to give α-vinylsilanes, Milwaukee, WI 53201-9358 Br * 11,12 2 (EtO)3SiH 1 13:1 92 (a+b) relying on the ruthenium(II) catalyst, [Cp Ru(MeCN)3]PF6. This Email: [email protected] catalyst also provides a competent method for regioselective intra- and intermolecular hydrosilylation of internal alkynes, 3 MeO2C (EtO)3SiH 4 n.d. 61 (a) giving exclusively Z-trisubstituted alkenes. MeO2C International customers, please contact your OTBDPS local Sigma-Aldrich office. For worldwide contact Terminal Alkynes 4 (EtO)3SiH 10 20:1 87 (a+b) information, please see back cover. A diverse set of terminal alkynes underwent rapid and mild H * hydrosilylation in the presence of [Cp Ru(MeCN)3]PF6 to give 5 (EtO) SiH 1 13:1 77 (a) ChemFiles are also available in PDF format on the 1,1-disubstituted a-vinylsilanes in good to excellent yield, often O 3 Internet at sigma-aldrich.com/chemfiles. with low catalyst loadings (Scheme 2, Table 1). The reaction is 6 BnMe2SiH 1 >20:1 99 (a+b) MeO2C ( )6 tolerant to a wide range of functional groups including halogens, (BDMS-H) Aldrich brand products are sold through Sigma- free alcohols, alkenes, internal alkynes, esters, and amines. 7 OH BDMS-H 1 14:1 91 (a+b) Aldrich, Inc. Sigma-Aldrich, Inc. warrants that its Moreover, a breadth of silanes can be used in the reaction with BnO products conform to the information contained in excellent predictability. 8 (EtO)3SiH 1 9:1 71 (a+b) this and other Sigma-Aldrich publications. Purchaser The a-vinylsilanes are useful intermediates that can participate ( ) must determine the suitability of the product for its in a host of synthetically valuable transformations. The simplest OH 5 particular use. See reverse side of invoice or packing manipulation, protodesilylation, is achieved by treatment of Table 1 slip for additional terms and conditions of sale. the vinylsilane with TBAF in the presence of catalytic CuI (Scheme 3).13

Si(OEt)3 TBAF, CuI 78% O THF, rt O ChemFiles is a publication of Aldrich Chemical Co., Inc. Aldrich is a member of the Sigma-Aldrich Group. Scheme 3 © 2006 Sigma-Aldrich Co.

Ready to scale up? For competitive quotes on larger quantities or custom synthesis, contact SAFC™ at 1-800-244-1173 (USA), or visit www.safcglobal.com. Alkyne Hydrosilylation  sigma-aldrich.com to furnish the primary alcohol or the diol respectively.diol the or alcohol primary the furnish to Tamao–Flemingor protodesilylation to treatedconditions be then could adduct The stereocenters. contiguous four with siloxane a yielding reaction, (IMDA) Diels-Alder intramolecular an in resulted triene the Heating linkage. siloxane a give to hexadienol a with predictability. excellent with reaction,hydrosilylation in participate can in shown As reduction. the to complement a is a to reduction alkyne for method useful a provideshydrosilylation-protodesilylationprotocol Therefore, the single a providesmixture product the of protodesilylation 3), (entry hydrosilylationnon-regioselective but stereo- undergo may differentiatedalkynes non-sterically though cross-coupling. Pd-catalyzed and oxidation, Tamao–Flemingcycloaddition, protodesilylation, including: processesreaction numerous in active are addition internal Like 9). (entry substrate alkyne the in residing centers asymmetric of integrity stereochemical the maintaining [Cp using hydrosilylation Significantly,8). and the 5 (entries siloxane cyclic a of formation the in results substituent) ethoxy an (e.g., group leaving a bearing silane a with hydrosilylation alcohols, bishomopropargylic 10–13). (entries the of position distal the occupies selectively again of case the in (iv) 5–9); the of functionality hydroxyl the to distal residesgroup silyl the that such occurs hydrosilylation substrates, alcohol bishomopropargylic and homopropargylic,propargylic, the in position sterically-demanding more the occupy will substituent silyl the 2-position, the in not is alkyne the where substrates for (ii) 2); and 1 (entries position sterically-demanding less the occupying group of formation the in results 2-alkynes of hydrosilylation (i) follows: as summarized be can regioselectivity The well. as regioselective is reactionhydrosilylation the ( alkyne the to silane Z [Cp with alkynes internal of hydrosilylationTrost that The products.demonstrated has group addition isomeric four give potentially would alkynes internal of hydrosilylation non-selective 1, Scheme in illustrated As Alkynes Internal ( cross-coupling Pd-catalyzed promoted, benzyldimethylsilanes and ( elaboration further to amenable are that carbocycles silicon-functionalized yielding catalyst, generation 2nd Grubbs’ with metathesis ring-closing towards active also are vinylsilanes Internal -vinylsilanes exclusively, as a result of exclusively,result -vinylsilanes a as a -vinylsilanes, hydrosilylation products resulting fromresulting products hydrosilylation -vinylsilanes, Me Me O O 2 2 Si(OEt) C C Scheme 4 Scheme 11b The resultant alkenylchlorosilane was trapped was alkenylchlorosilaneresultant The 11,15 3 Si(OEt) OAc For free propargylic, homopropargylic, and homopropargylic,propargylic, free For Scheme 7 Scheme 3 ). a Scheme 8 Scheme 1) TBAF cis 2) 11 * , Ru(MeCN) b 14 MesN For example, both triethoxysilanes both example, For 010 (USA), or visit or (USA), 1-800-32 5-3010 call -selectivity observed in the Lindlar the in observed -selectivity I [( -alkynylcarbonyls, the silyl group silyl the -alkynylcarbonyls, are active participants in fluoride- in participants active are Cl Cl * π (4 mol%) (2 mol%) ORDER: Contact your local Sigma-Aldrich office (see back cover), back (see office Sigma-Aldrich local your Contact TO ORDER: Ru(MeCN) -allyl)PdCl] 12 Ru PCy h , NMes Table 3 OM Ph , even highly reactive silanes reactive highly even , 2 e 3

]PF Z -alkene (entry 4); (iii) for (iii) 4); (entry -alkene trans 3 2 6 ]PF Z can be performed while performed be can Schemes 5 Schemes Me Me ). trans -alkenes with the silyl the with -alkenes Z 11 O O 6 trans -alkene (entries -alkene 14 gives trisubstituted gives Importantly, 2 2 addition of the of addition C C OM For example, For diastereomer. e alkene and alkene OAc Si(OEt) Z and 73% -alkene

3 87% 6 Scheme 5 Scheme 4

). 13 11

sigma-aldrich.com/chemicalsynthesi *Yield of *Yield Entry 13 12 11 10 4 3 2 1 9 8 7 6 5 Et Me MeO MeO O MeO O trans Hex Et ( HO Ph Ph CO EtO CO OH Et 2 2 ) C C O Alkyne 2 H 9 OH C 2 ( 2 C OTBDPS OH OH R' O OH Ph 2 C 2 Me Et ) Me alkene after protodesilylation with TBAF/CuI. with protodesilylation after alkene 6 C 7 O OH H Me Me Me OAc SiM Et C 15 CO Et Et Me 2) HSiM 1) [Cp O 6 i Me -Pr Me H BDM Me Me 13 2 e R'' Me Et 2 Me BnMe (BDMS-H) * S (EtO) (EtO) (EtO) (EtO) (EtO) BDMS-H BDMS-H BDMS-H BDMS-H Ru(MeCN) (TES-H) e R Et TES-H 2 [Cp*Ru(MeCN) (EtO)SiH 2 Et 3 Cl, 15mi 3 SiH SiH 3 + 3 3 3 3 3 N 2 SiH SiH SiH SiH SiH 2) 1) TBAF,0°C SiH rt, 0.5 R Pd I 3 3 SiH ]PF 2 (2.5 mol%) n − (dba) OH Loading (%) Loading 1 6 h (1mol%) 3 ]PF 20 mi 3 •CHCl 0.5 1 1 1 1 1 1 1 3 2 2 1 1 Ac TBAF, DMF, TBAF, DMF, H 6

2 n O 80 °C 69% 2 3 65% , 60°C

, R

3 s Me Si . CO Major Product Major Me MeO MeO O MeO Hex ( R' EtO O 2 HO ( Ph Et Ph Et ) Me OH 2 2 ) (EtO) 6 O 2 R'' 2 C C 9 C 2 OTBDPS C EtO O C OH O O Si(OEt) OH Ph Si(OEt) Me TES EtO 87% Si 3 TES Si OEt BDMS Si(OEt) HO HO C + BDMS BDMS BDMS SiMe BDMS 2 7 3 OH Et H 2 Si Me Et Me Me Me 3 O C C 15 Me OAc O 2 6 Me i Me Me -Pr H 3 Me R' Me 13 OH R'' Et Ac CO Et CO Et >20:1 >20:1 >20:1 Ratio SiR 14:1 13:1 7:1 5:1 6:1 5:1 5:1 6:1 1:1 5:1 2 2 sealed tube PhH, 180°C 89% Et Et 3 IMDA Scheme 8 Scheme 7 Scheme 6 Yield (%) Yield (major) (major) (major) (major) Table 2 96* 88 99 94 98 98 73 91 99 71 92 70 86

Alkyne

 Hydrosilylation

Order: 1.800.325.3010 Technical Service: 1.800.231.8327 O Me Me Me 2 98% 53% H

O O O • Me OH Cl 3 3 O 10 Me Scheme 9 O ) Rh OH OH OH Scheme 11 Scheme 10 ( e PPh Rh 10 PPh Cl Cl ) 4 Ph Ph Ph O 88% from alkyne ( P BF 3 Me Rh Rh , Ph 2 O , OH 2 3 N H 3 2 1 g 5 g Me Si O O F (+)-spectalin 2

Si Me K , CH 2 79% O Me HO O 3 250 mg 100 mg 500 mg 100 mg 500 mg Me 74% 98% 2 3 N H O OH, KHC Me 3 TBAF, DM Me C OH

then KHC CH TBAF, THF, 40 °C TBAF, then 6 F

6 . , Pd/ ]P S 2 F 3 THF H Me ]P m Me ) 3 2) aq. HCl, 1) BDM BDMS O Ph ) m Me OH Me O Ru(MeCN) (2 mol %) OH * alkyne , 0 °C p 10 (5 mol%) 82% fro 2 Ru(MeCN) ) Ph * Ph O p Cl ( -CPBA, 2 1) TMDS (neat 2) [C m

6 3 CH l 1) TMDS (neat F 2) [C 84% ]P 3 Me H •CHC O Me O − 3 OH S PhI 10 OH ) 3 O (dba) ( N 2 BDM Ru(MeCN) * Pd p O Me 2 [C www.safcglobal.co G G G G G (5 mol %), TBAF, 55 °C (2 mol %), acetone, rt (2 mol %), acetone, ] ] ]

Me · H 2 Me Rh G G 3 Rh Rh 4 2 OH -urea 3 2 ClP BF Cl N O 2 OH 45 24 16 925.22 H then TBAF H H H adduct, DMF, Me Ph 54 16 14 14694-95-2 207124-65-0 12257-42-0 Tris(triphenylphosphine)rhodium(I) chloride Tris(triphenylphosphine)rhodium(I) Catalyst Wilkinson’s C FW: [ 199982-250M 199982-1 199982-5 Bis(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate hydrate, 97% C FW: 406.07 [ 334987-100M 334987-500M (Bicyclo[2.2.1]hepta-2,5-diene)rhodium(I) chloride dimer C FW: 460.99 [ 249939-100M 249939-500M

6

8

PF 2

e O 2 H 16b

SiM e •

NCMe ). 6 -diol. Pt O NCM Ru Si PtCl 2 2 syn H ). Subsequent 17 Me -epoxy ). MeCN 1 g 5 g 5 g

25 g 25 g syn at 1-800-244-1173 (USA), or visit 250 mg Scheme 10 , as well as a number ™ 6 Scheme 9 ]PF 3 Scheme 11 Ru(MeCN) * contact SAFC Ready to scale up? For competitive quotes on larger quantities or custom synthesis, ) intramolecular hydrosilylation, gave a cyclic Z G ] ] ] O G G 2 PRu G G G 3 Pt 2 N 6 · H 6 F OSi 24 18 H H PtCl -CPBA in a diastereoselective fashion ( 8 2 16 68478-92-2 26023-84-7 99604-67-8 of other catalysts and silanes for hydrosilylation. cross-coupling cross-coupling provides an excellent method for introducing a new carbon bond at an alkyne carbon that is in a remote position from a free hydroxyl group ( We are pleased to offer [Cp with concomitant cyclization gave (+)-spectaline in respectable yield. The sequence of intramolecular hydrosilylation and subsequent Treatment of the homopropargyl alcohol Treatment with tetramethyldisilazane (TMDS), followed by regio- (distal) and stereoselective ( oxidation followed azidosiloxane. by Tamao–Fleming reduction Intramolecular Hydrosilylation intramolecular hydrosilylation is Finally, possible using hydroxyalkynes, as illustrated in the concise synthesis of the 3-hydroxypiperidine alkaloid (+)-spectaline ( alcohol, while Tamao–Fleming oxidation alcohol, provides a while Tamao–Fleming this Therefore, process can be used as a surrogate to the aldol condensation. is also feasible. For example, vinylsilanes are readily epoxidized by m protodesilylation furnishes the corresponding Manipulation Manipulation of the alkene prior to protodesilylation or oxidation [ 479519-5 479519-25 solution, 0.10 M in xylene Catalyst Karstedt’s C FW: 381.48 398322-25 Platinum(0)-1,3-divinyl-1,1,3,3-tetramethyldisiloxane complex [ 398322-1 398322-5 Chloroplatinic Chloroplatinic acid hydrate, 99.9% Catalyst Speier’s H 409.81 FW: 667412-250M ruthenium(II) hexafluorophosphate C 504.42 FW: [ Pentamethylcyclopentadienyltris(acetonitrile)- Alkyne Hydrosilylation  sigma-aldrich.com Encapsulated OsCatalysts sigma-aldrich.com/osenca EnCat Os on information application comprehensive For Lett. Org. Ley,TetroxideV.Osmium S. of MicroencapsulationPolyurea. al. in et reaction.dihydroxylation useful industrially the in reagent OsO conventional versus advantages EnCat Os create to matrix polyurea a in encapsulation by reagent, volatile and toxic a tetroxide, osmium immobilized has Reaxa transformations. synthetic practical in use for catalysts first-to-market offer to pleased is Ltd., Reaxa with collaboration in Sigma-Aldrich, loss activity no with recycled be can Catalyst • product final in metal Os of levels Low • catalyst of recovery Facile • OsO versus stability storage Greater • Safer,• nonvolatile easier-to-handle,and Os EnCat 230197-100 230197-25 230197-5 [ FW: C TES-H Triethylsilane,99% 579726-5 579726-1 [ FW: C Grubbs’ 1stGenerationCatalyst Benzylidene-bis(tricyclohexylphosphine)dichlororuthenium(II) 343706-5 343706-1 [ FW: C Dichloro( 341568-5 341568-1 [ FW: C dimer Benzenedichlororuthenium(II) 172222-30-9 52462-29-0 37366-09-9 617-86-7 6 43 20 12 H H H H 16 116.28 822.96 612.39 500.18 72 28 12 Si Cl Cl Cl

4 4 2 P Ru Ru G G G G G G G ] ™ 2 p 2003 Ru G 2 2 40. This innovative product offers safety and handling and safety offersproduct innovative This 40. -cymene)ruthenium(II) dimer -cymene)ruthenium(II) G ] ]

] , ™ 5 ™ , 185. , 40 40, please visit us at us visit please 40, 010 (USA), or visit or (USA), 1-800-32 5-3010 call ORDER: Contact your local Sigma-Aldrich office (see back cover), back (see office Sigma-Aldrich local your Contact TO ORDER: t . 4 , while acting as an alternative alternative an as acting while , 4

100 g 25 g 5 g 1 g 5 g 1 g 5 g 5 g 1 g Cl Cl Cl Cl Ru Ru Et Ru PPh PPh Cl Cl Cl Cl Si Et Et Ru Ru 3 3 H

Ph Cl Cl sigma-aldrich.com/chemicalsynthesi FW: C 98% Chlorodimethylsilane, 390143-50M 390143-10M [ FW: C Triethoxysilane,95% 282626-100 282626-25 [ FW: C Trimethoxysilane,95% 483141-10M [ FW: C BDMS-H 99% Benzyldimethylsilane, 139246-10 139246-1 [ FW: C TMDS 1,1,3,-Tetramethyldisilazane,97% 144207-50 [ 998-30-1 2487-90-3 1631-70-5 15933-59-2 1066-35-9 2 6 3 9 4 H H H H H 224286-100 224286-25 4-Methylmorpholine 658685-5 658685-1 658685-500M [ FW: OsO microencapsulatedtetroxide, Osmium EnCat Os 224286-5 [ FW: C 20816-12-0 7529-22-8 7 16 10 14 15 5 94.62 164.27 122.20 150.29 133.34 ClSi H O O Si NSi 11 4 3 3 254.23 117.15 Si Si NO 2 G ] G G G ] ] ] 2 G ] G G G ™ L L L G ] mmol/g Os loading Os mmol/g 0.3 40, G ] G N -oxide, 97% -oxide, s . 500 mg 100 g 50 mL 10 mL 10 mL 25 g 100 g 5 g 5 g 1 g 25 g 10 g 50 g 1 g Me Me MeO EtO Cl Si H N H Si Me Me Si OEt OEt Si OM OM Si Si Me Me H H H H e e Me Me H Organosilanes for

 Cross-coupling

Order: 1.800.325.3010 Technical Service: 1.800.231.8327 2 OH Me Et 3 Table 2 Si Figure Figure R Me CO BDMS Scheme 15 Scheme 16 Scheme 12 Scheme 13 Scheme 14 Scheme 17 76 70 72 81 80 71 82 56 RK-397 74% 63% 81% Yield Yield (%) 80% 68% 11 OH OH O Me H Me CN SH 5 3 Si Si C RK-397

OH OH Me Me Me Me • HCl 77%, dr = 3:1 i Si OTBS Et Et N 2 2 11 OH Me Me HOAc, CH H h X CO 5 CO

OS OH 2 C MeO THPO OH OEt Me 2

. I 3 Si OH , 4 4 4 4 18 12 12 24 2 m R l I Me h I OTBS Time (h) •CHCl OH SiC OH Me 3 78 °C 2 78 °C − Si − -allyl)PdCl] + 78 to 0 °C

π (5 mol %) 78 to 0 °C − 2 79%, dr = 5:1

− 3 OH (dba) 2 3 Me 2 , or Me TMSOK (2.5 mol %) 3 3 O DME, rt, 9 O 2 -Bu) SiO) SiO) t 2 2 OH H 80 °C SiO) TBAF, [( e SiO) e THPO − P( Pd(dba) 2 2 -BuLi, THF, 2 e e -BuLi, THF, NaH, Pd n t

-BuLi, THF, OH I t NO 2) (M THPO n 2) (M 1)

1) 11 (5 mol %) 2) (M 1) RLi 2) (M then 1) H S 2 5 = O C 10 mi 2 Et Et 2 2 2 PdCl BDM Br O Br EtN, NMP, 60 Et R 2 2 Me BPTBP (10 mol %), 4-Ac 4-CN 2-CN BPTBP 4-Me Me O X 4-NO Me 4-OMe -Pr 4-CO 2-CO i O Si CO 2 Me www.safcglobal.co X = NBoc, S, 11 Me NO HO 2 H O 5 Br Me C I Si TBAF, Pd(dba) Me R 85% + Me O HO (EtO)Si) 2 e 1 2 3 4 5 6 7 8 (M Entry

18 25

19 ). The 27 ). Scheme 15 at 1-800-244-1173 (USA), or visit ™ Scheme 17 followed by quenching The utility of performing 23 1,21 ), ). The base use of Hünig’s 3 Alkynylsilanols have also been 24 ). or by metal-halogen exchange of Table Table contact SAFC , 19,20 ) Scheme 13 Specifically, the polyene segment Specifically, of the Ready to scale up? For competitive quotes on larger quantities or custom synthesis, Scheme 16 26 ). 2 Scheme 14 Scheme 12 Figure Figure while the other silyl substituent remains inert. Subsequent fluoride-promoted coupling of the benzyldimethylsilyl group provided the necessary tetraenoate linkage for completion of the target molecule. RK-397 ( natural product was by prepared sequential cross-coupling of a 1,4-bissilylbutadiene differentiable unit ( dimethylsilanol moiety readily couples under basic activation, found to be active coupling partners under similar conditions. Both strategies, fluoride and basic activation, were demonstrated in the total synthesis of the antifungal polyene macrolide generation of a nucleophilic silanolate. the cross-coupling under basic activation lies in the ability to perform the reaction in the presence of fluoride-sensitive silyl protecting groups ( silanols readily react with both aryl and alkenyl halides to give the coupled adducts in very good yield ( the Pd-catalyzed Alternatively, cross-coupling can also be performed under basic activation using TMSOK for in situ and BPTBP as a ligand additive gave the most optimal results in the silylation reaction. In the presence of a fluoride activation source, alkenyldimethyl- Alternatively, aryldimethylsilanols can Alternatively, be synthesized by a sequence of transition metal-catalyzed silylation of aryl bromides with a diethoxydisilane reagent, followed by acid hydrolysis of the silyl ether ( with a silicon-based electrophile. Hexamethylcyclotrisiloxane and dichlorodimethylsilane are particularly attractive silylating reagents, due to their affordability. cross-coupling cross-coupling of dimethylsilanols is the most mature. Dimethylsilanols are readily by prepared directed metallation of heterocycles ( aryl or alkenyl bromides ( Organosilicon compounds are easily from prepared inexpensive starting materials, and have are low active toxicity, nucleophiles in coupling reactions with organohalides and pseudohalides. Among the many available organosilicon compounds, the silicon compounds has rapidly gained acceptance as a suitable alternative to more commonly known methods such as: Stille (Sn), Kumada (Mg), Suzuki (B), and Negishi (Zn) cross-couplings. Organosilanes for Cross-coupling for Organosilanes Dimethylsilanols Over the past several years, Pd-catalyzed cross-coupling of Organosilanes for Cross-coupling  sigma-aldrich.com Bu) P( and dimer chloride (2-methylallyl)palladium(II) preparedfrom readily is It nucleophiles. organosilicon for catalysts coupling cross- used commonly many to superior is that activity high very displays catalyst Pd(I) The observed. are yields in decreases discernible no and iodides, aryl with than shorter generally ( Moore and Weissman by developed catalyst Pd(I) highly-active a to changing by reaction the in used be can bromides aryl expensive Less ( iodides aryl electron-deficient and electron-rich both with couple easily Pd of presence the in iodides aryl with heteroaryldimethylsilanols other of cross-coupling to applicable is methodology This silanolates. situ-formed in of that parallels reactivity whose materials storable and isolable also are additive. an without coupled CuI. of presence the in iodides aryl with cross-coupling Pd-catalyzed NaO from situ in generated Silanolates activation). (basic silanolate sodium a of generation for call protocols Both ( substrates difficult these of coupling for protocols general of set a developed have co-workers coupling (Suzuki yield acceptable in product coupling (Stille conditions Typicalreaction C-2. harsh at for proceduresnucleophilicity called decreased the to owing challenging, particularly were indoles Boc-protected lacking. were nucleophiles 2-heteroaryl of cross-coupling for methods recently,general Until and mild Ph using effective most was iodides of coupling while toluene, in additive ligand a as dppb using coupled be could Bromides Cs using halides aryl of set diverse a with phenyl)dimethylsilanol (4-methoxy- of coupling the in obtained were yields excellent to Good bromides. and iodides aryl of variety a of coupling biaryl for developed been have protocols experimental Robust Entry 2 2 3 9 8 7 6 5 4 3 2 1 CO (dba) dioxane. in As 3 in the presence of base. of presence the in 31 Alternatively, silanolates generated in situ from NaH can be can NaH from situ in Alternatively,generated silanolates 3 to generate the silanolate in situ ( situ in silanolate the generate to 3 Scheme 4-CO ·CHCl 4-OMe 2-NO Me 2-CF 2-Me 4-Me 4-Ac 4-Cy 4-H R O 2 Scheme 3 Et 2 3 . Me 20,32 20 Si Me Br Br Br Br Br X I I I I Thiophene, furan, and pyrrole nucleophiles pyrrole and furan, Thiophene, OH , Table6 21 additive (10mol%),90°C , [( π Table7 29 Time (h) Time -allyl)PdCl 010 (USA), or visit or (USA), 1-800-32 5-3010 call Cs ) or failed to deliver the coupled the deliver to failed or ) 24 24 24 18 18 12 18 24 ORDER: Contact your local Sigma-Aldrich office (see back cover), back (see office Sigma-Aldrich local your Contact TO ORDER: 2 3 20 CO ). Finally, dimethylsilanolates sodium 3 , R ] H 2 ). (5mol%), 2 O X 33 The reactions times are times reactions The Additive Scheme 19 Scheme Ph Ph Ph Ph dppb dppb dppb dppb dppb 3 3 3 3 As As As As Scheme 18 Scheme MeO 30 ). Denmark and Denmark ). Solvent dioxane dioxane dioxane toluene toluene toluene toluene toluene toluene , t Table5 -Bu undergo -Bu , Table4 R Scheme 18 Scheme Yield (%) Yield efficient ). Table4 91 83 82 85 79 92 85 90 90

).

t -

sigma-aldrich.com/chemicalsynthesi Entry Entry Entry 7 6 5 4 3 2 1 8 7 6 5 4 3 2 1 6 5 4 3 2 1 Pd(I) catalyst: 4-CO 4-OMe 4-OMe 2-OMe 4-NO 4-CF 4-CN NBoc NBoc R O O X S S 2 X 3 X =NBoc,S, Et 2 O O O O X S S S S Si X ( Me Boc N t OH -Bu) NaO NaO NaO NaO Me Base NaH NaH NaH Si Si Me 3 Me OH PPd t t t t OH -Bu -Bu -Bu -Bu Me O Me 4-CO 4-CO 4-CO 4-OMe 4-OMe Pd(I)catalyst(2.5mol%), 2-Me Me Cl R 2 2 2 PdP( Additive Et Et Et toluene, 50°C (5 mol%),additive, 4-OMe 4-OMe Pd 4-CF 4-CF 2-Me 2-Me 4-CN 4-CN (5 mol%),toluene, toluene, temp Cul Cul Cul Cul — — — Pd R t NaH 2 -Bu) (dba) base 3 3 2 (dba) R 3 tem Temp(°C) NaH 3 Br R •CHCl 3 p I •CHC R 80 50 rt rt rt rt Temp(°C) I 3

s l 3 . 80 50 50

rt rt rt rt Me Time (h) Time 3 3 3 6 3 3 3 3 P + X Time (h) Time X Boc N ( Pd 24 36 t Time (h) Time -Bu) 3 1 3 3 R 24 24 22 Cl Cl 3 3 3 3 6 R R Pd + NaOH Yield (%) Yield Scheme Scheme 19 Scheme Yield (%) Yield Yield (%) Yield 71 71 73 66 77 86 78 71 Me 61 82 78 72 76 72 Table7 Table6 Table5 68 82 81 72 75 82 84 21 20 Organosilanes for

 Cross-coupling

Order: 1.800.325.3010 Technical Service: 1.800.231.8327 OH 8 8 8 8 8 8 Me OH Me Me OH Me Si Me Si Si Me Me ONa Me Me Me Me OH ONa Me OH Si Me Si Si Si N Boc Me N Boc Me O S Si eO M Me HO 5 g 1 g 1 g 1 g 5 g 1 g 5 g 1 g 5 g 1 g 5 g 5 g

. m

www.safcglobal.co ] ] ] 2 Si Si G G G G G G G G G G G G Si 2-furyldimethylsilanolate 3 3 2 Si Si 2 2 O NO NO OSSi NaOSi O NaO 18 19 21 241.36 291.42 158.29 174.25 164.21 182.29 226.42 10 11 9 14 H H H -Boc-2-indolyl)dimethylsilanol -Boc-2-pyrrolyl)dimethylsilanol H H H H 6 8 6 9 11 15 10 N N 197009-90-8 22868-26-4 2754-32-7 667900-5 Dimethyl(2-thienyl)silanol, 97% FW: FW: 669164-1 ( FW: 667900-1 C FW: [ 667099-1 667099-5 Sodium dimethylphenylsilanolate C FW: 673269-1 673269-5 Sodium C FW: 673250-1 673250-5 (4-Methoxyphenyl)dimethylsilanol, (4-Methoxyphenyl)dimethylsilanol, 96% C FW: [ 667951-1 667951-5 1,4-Bis(hydroxydimethylsilyl)benzene, 95% C FW: [ 497193-5 ( C C Me 8 8 8 8 2 Me OEt OH Me Me -Bu) Cl O t Si Pd Si Me Me Me Si P( O Si Me Me Si Cl Cl Me Me O Me Si Me Si Cl Pd Me Me EtO 1 L 1 g 5 g 1 g 5 g 1 g 1 g 5 g

25 g 25 g 100 g Me 100 mL at 1-800-244-1173 (USA), or visit

250 mg ™

contact SAFC Ready to scale up? For competitive quotes on larger quantities or custom synthesis, -butylphosphine, 97% tert L G ] ] ] G L ] G G 2 ] G G G G G G G 2 3 ] Pd Si Si Si 2 3 2 2 P OSi O O Cl Cl 27 152.27 206.43 129.06 222.46 298.40 393.94 12 22 6 18 14 H H H H H H 8 8 2 6 20 8 5272-18-4 18419-84-6 75-78-5 541-05-9 224311-51-7 12081-18-4 667110-1 667110-5 Dimethylphenylsilanol, 97% C FW: [ 667897-1 667897-5 C FW: [ 440272-100M 440272-1M 1,2-Diethoxy-1,1,2,2-tetramethyldisilane, 97% C FW: [ 235687-100 Dichlorodimethylsilane, 99% FW: FW: [ 235687-25 638439-25 Hexamethylcyclotrisiloxane, 98% C [ 638439-1 638439-5 (2-Biphenyl)di- BPTBP C FW: 673064-250M 673064-1 -Methylallyl)palladium(II) (2-Methylallyl)palladium(II) chloride dimer C FW: [ Organosilanes for 10 Cross-coupling sigma-aldrich.com 592641-5 592641-1 [ FW: C 1-(Triethoxysilyl)-predominantly 2-pentene, 175560-500M 175560-100M [ FW: C Triethoxyvinylsilane,97% 592420-5 592420-1 [ FW: C 98% Cyclohexyltriethoxysilane, 596043-5 [ FW: C 98% Cyclopentyltriethoxysilane, 131903-4 131903-1 131903-500M 131903-25M [ FW: C Tetraethyl98% orthosilicate, complexes ( complexes acceptors Michael both towards nucleophiles as ( reagent Stille or Suzuki analogous the than results better or similar gave arylsiloxane halides. Pd-catalyzed cross-coupling with aryl, with cross-coupling Pd-catalyzed activator,in fluoride participate a siloxanes of presence the In transitionor metal-catalyzed silylation reactions ( triethoxysilanesarereadily prepared Grignard,by varietysyntheticallyof useful C–Cbondforming reactions. Aryl demonstratedtriethoxysilanes activebeto substrates a in TheDeShong group theUniversityat Marylandof has Triethoxysilanes 78-10-4 698999-32-5 78-08-0 18151-84-3 154733-91-2 11 8 12 11 8 H H H H H 18 20 232.39 190.31 246.42 232.39 208.33 24 26 24 O O O O O 3 4 Si 3 3 Si 3 Si Si Si ] ] 39 L L G G G G G R For example, coupling of 5-bromotropolone with an 5-bromotropolonewith of coupling example, For ] L Scheme ] ] L L L X 24 ). Rh orPd,(EtO) Scheme 41 2) Si(OEt) 1) 010 (USA), or visit or (USA), 1-800-32 5-3010 call o X =halide 2) Si(OEt) 1) Mg -metallation X =Br, X = ORDER: Contact your local Sigma-Aldrich office (see back cover), back (see office Sigma-Aldrich local your Contact TO ORDER: H 4 I 4 23 3 SiH ). 35,37 38 Triethoxysilanes act also alkenyl, 500 mL 100 mL 500 mL 25 mL cis R Scheme Me 34 5 g 1 g 5 g 1 g 5 g 40 4 L 1 L

38 and Pd-allyl and o and alkyl and EtO -metallation, Si(OEt) Si(OEt) Si OEt OEt Si(OEt) Si(OEt) Scheme OEt 3 22 Si(OEt) 3 3 ). 3 36 3 22 35 sigma-aldrich.com/chemicalsynthesi 596477-10 596477-1 [ FW: C 4-(Triethoxysilyl)aniline,97% 630438-5 630438-1 [ FW: C Triethoxy[4-(trifluoromethyl)phenyl]silane,97% 591572-5 591572-1 [ FW: C Triethoxy- 175609-1K 175609-250 175609-5 [ FW: C Triethoxyphenylsilane,98% 596353-10 596353-1 [ FW: C Triethoxy(1-phenylethenyl)silane,98% 7003-80-7 188748-63-2 18412-57-2 780-69-8 90260-87-0 12 13 13 12 14 H H H H H 255.39 308.37 254.40 240.37 266.41 21 19 22 20 22 NO F O O O 3 BzO 3 3 3 O Si Si Si 3 3 G G G G G G G ] Si Si G G ] G Br p G ] ] -tolylsilane, 97% -tolylsilane, O ] OMe TBAF, THF,16h,60°C Me Pd(dba) O =SnBu =B(OH) M =Si(OEt) Me Me O O 2 (10mol%) cat. Pd(0) OM 3 Si(OEt 2 , 59% , 87% 3 , 89% e M ) 3 s . MeO Me MeO O 250 g OMe 10 g 10 g 1 kg O 1 g 5 g 1 g 5 g 1 g 1 g 1 g F H Me 3 C

2 N OMe 88% Scheme Scheme Si(OEt) Si(OEt) Si(OEt) Si(OEt) Si(OEt) 3 3 3 3 3 24 23 Organosilanes for

11 Cross-coupling

Order: 1.800.325.3010 Technical Service: 1.800.231.8327 3 25 3 3 Si(OEt) 3 Table 8 Table 3 Si(OEt) Si(OEt) Scheme Si(OEt) 91 83 86 54 86 75 80 O Si(OEt) S Yield Yield (%) 1 g 1 g 1 g 5 g

10 g 10 g 10 g R Si 3

(EtO) , . 3 5 5 10 14 17 20 m Me O Si Time (h) O Me Si (5 mol %) O Me Si 2 O Si PdBr BPTBP (10 mol %) TBAF, THF, 50 °C Me Br Et Et OH 2 2 R 2 R 2-Et 4-Ac 4-OMe 2-OMe 4-CO 2-CO 4-CH www.safcglobal.co ] ] ] ] G G G 2 2 G G G G SSi Si Si Si 3 6 6 4 O O O O 18 34 38 18 246.40 402.63 478.73 230.33 1 2 3 4 5 6 7 H H H H 10 18 24 10 Entry 17984-89-3 16067-99-5 123640-93-7 75905-12-3 C FW: [ 597007-1 597007-10 -Bis(triethoxysilyl)benzene, 1,3-Bis(triethoxysilyl)benzene, 96% C FW: [ 598135-1 598135-10 4,4’-Bis(triethoxysilyl)-1,1’-biphenyl, 95% C FW: [ 638102-1 638102-10 96% 3-(Triethoxysilyl)furan, C FW: [ 592315-5 97% 2-(Triethoxysilyl)thiophene, 3 3 3 3 Si(OEt) Si(OEt) Si(OEt) F Si(OEt) F F Si O 3 F F Cl Me or bromides 5 g 5 g 5 g 1 g (EtO) 42 10 g 20 g 20 g 10 g 50 mL 10 mL at 1-800-244-1173 (USA), or visit ™ contact SAFC Both electron-withdrawing and 43 ). Ready to scale up? For competitive quotes on larger quantities or custom synthesis, Table 8 Table , L L ] ] ] ] ] G G G G 25 Si Si 4 2 3 G G G G 3 Si Si Si O 4 6 4 5 O O F ClO O 24 34 15 19 22 344.66 402.63 330.32 274.82 270.40 H H H H H 12 18 12 12 13 Scheme 2554-06-5 2615-18-1 20083-34-5 21700-74-3 21130-91-6 electron-donating electron-donating groups are well tolerated in the vinylation reaction. 2,4,6,8-Tetramethyl-2,4,6,8-tetravinylcyclotetrasiloxane has 2,4,6,8-Tetramethyl-2,4,6,8-tetravinylcyclotetrasiloxane emerged as an inexpensive but powerful reagent for preparation of styrenes from the corresponding aryl iodides ( Polyvinylsiloxanes 396281-10M 396281-50M 2,4,6,8-tetravinylcyclotetrasiloxane 2,4,6,8-Tetramethyl- C FW: [ [ 598038-5 598038-20 1,4-Bis(triethoxysilyl)benzene, 96% C FW: 592757-5 592757-10 (Pentafluorophenyl)triethoxysilane, (Pentafluorophenyl)triethoxysilane, 97% C FW: [ 597910-1 597910-10 (4-Chlorophenyl)triethoxysilane, (4-Chlorophenyl)triethoxysilane, 97% C FW: [ 597015-5 597015-20 Triethoxy(4-methoxyphenyl)silane, 97% Triethoxy(4-methoxyphenyl)silane, C FW: [ Multicomponent 12 Couplings sigma-aldrich.com methodology. this using yield good preparedin were systems 1,3,5-oxygenated ( units dithiane distinct two between relayed is site nucleophilic a which in (ARC), chemistry relay anion of concept the involve to protocol coupling linchpin multicomponent the broadened has Finally,group Smith the ( aziridines to nucleophiles dithiane silylated of addition controlled the on relied (–)-205B alkaloid and 223AB (–)-indolizidine alkaloids, frog-derivedneotropical the of syntheses total The electrophile. second the for bisepoxide a of use the on relied that used was tactic coupling linchpin ( mycoticins Schreiber’sthe to subtarget trisacetonide C a prepareto methodology modified a used co-workers and Smith terminus. vinyl the at occurring addition nucleophilic with electrophiles, active be to reported been also ( chloride of displacement S by followed carbon epoxide the at attack nucleophilic by epoxide terminal a of formation the in resultselectrophile second the as epichlorohydrin optically-active of use The intermediates. product natural complex several of syntheses the in used been has methodology This additions. epoxide of order the altering by simply orchestrated be can groupprotecting silyl the of Importantly,location electrophile. final epoxide the second a with react to positioned then is species This carbon. dithiane the to back site nucleophilic the of migration simultaneous with rearrangement,Brook solvent-controlled a in resultsreaction the HMPAof to Addition anion. alkoxide intermediate an generates epoxide an with 2-silyl-1,3-dithianes Treatmentmetallated the of ( intermediates synthetic advanced extraordinarily give to electrophiles epoxide unique two by alkylation tandem and 2-TBS-1,3-dithiane of combination the using performed been have couplings three-component one-pot, example, For synthesis. molecule complex in use for couplings linchpin multicomponent 2-silyl-1,3-dithiane of field the in Pennsylvania) of (University III Smith B. Amos of work recent the to attributed be can field this progressin the of Much intermediates. heteroatom-rich and active optically advanced, yielding possible, are couplings multicomponent that extent the to evolved substantially.maturedhave reactions Contemporary Seebach, and Corey of work pioneering ( construction bond C–C in equivalents anion acyl as use their in particularly synthesis, organic in tools valuable are Dithianes 2-Silyl-1,3-dithianes Multicomponent Couplings Scheme Scheme 2 -symmetric masked polyol fragment that could be converted be could that fragment polyol masked -symmetric 30 26 Scheme ). the in ago years forty over introduction their Since ). 51 50

29 ). 49 Scheme In this instance, a five-component a instance, this In 010 (USA), or visit or (USA), 1-800-32 5-3010 call Scheme ORDER: Contact your local Sigma-Aldrich office (see back cover), back (see office Sigma-Aldrich local your Contact TO ORDER: 28 31 ). Vinyl epoxides have epoxides Vinyl ). ). A variety of masked of variety A ). 44 47 48 dithiane chemistry has chemistry dithiane in the syntheses of syntheses the in Scheme n 2 27 ).

45 46

sigma-aldrich.com/chemicalsynthesi S S S S Selected Examples: Me 2.5 equiv TBS S S TBS S R =Me,E TBS S 3) Me ( Me R − )-indolizidine 223AB S 2) O 1) alkaloid Me R S S OTBS

73% − S

H − Cl t 1 78 °Ctort S S -BuLi, Et 2) , − 3) ,HMPA, 78 °Ctort 1) 1) 2) =

TBS t H − t − -BuLi, Et N H -BuLi, Et S Br BnO OTBS O BnO 78 to N H Me 78 to O ( S − 1.0 equiv 2.3 equiv )-205B 1) 2 O Me S O − Me H − OMe t 45 °C -BuLi 25 °C S 3) ,HMPA, 2) , 1) 2 2 Me O, O, t O -BuLi, Et O O BnO O − O 78 to − 78 to Me 78 °Ctort Electrophile (E 73% BnO − S S S 2 45 °C Cl BnO O, Me R − S R = O S 25 °C 1 TBS − TBSO 78 to O O S i TBSO -Pr, E O − 78 to − 30 °C,THF/Et − 2) OTBS S 77% 45 °C ) − HO = S R S 78 °Ctort − 20 mi 2 16 HO S TBS S S 25 °C − 74% O BnO S OBPS X R S Me OH OH TBSO n 16 Me R

Me s OH S R S S Rearrangement 2 OB . Me O OH O 1 S (+)-mycoticin B(R=Me) (+)-mycoticin A(R=H) n OB HMPA BnO S Brook R Me 2 OH OM S OTBS n S S S S TBSO R e TBS TBS OH S OH S [O] S Me S R =Me,E 71% R' OH S S OH O S S 59% BnO Me S Me R S O OH 1 TBSO S OTBS 69% O S = 28 O TBS R OTBS O O O 2 S NTs NTs 28 Scheme Scheme Scheme Scheme Scheme Scheme O S S HMPA OBn Me Me S Cl O R 31 30 29 28 27 26 Multicomponent

13 Couplings

Order: 1.800.325.3010 Technical Service: 1.800.231.8327 3 Ph CH SS SS SS 1 g 5 g 5 g

1 g 25 g 25 g 1 mL 5 mL 10 g 100 g 100 g

. m

30NP wet, nanoparticles, 0.4 mmol/g Pd loading

™ G www.safcglobal.co G G G L L ] ] G G ] G G G 30NP, 30NP, 106.42 2 2 S ™ 2 S , 1843. J.-Q.; (2)(a) Wu, H.-C.; Yu, S 12 120.24 134.26 196.33 8 10 H Pd(0) EnCat Palladium(0), microencapsulated in polyurea matrix Pd FW: 653667-1 653667-10 653667-100 H H 4 5 10 505-23-7 6007-26-7 5425-44-5 1,3-Dithiane, 97% C FW: [ 157872-1 157872-5 157872-25 157872-100 2-Methyl-1,3-dithiane, 99% C FW: [ 359130-1M 359130-5M 2-Phenyl-1,3-dithiane, 97% C FW: [ 279617-5 279617-25 2002

Synlett S , 678. (b) Ley, S. V.; Mitchell, C.; , Pears, S. 678. D.; V.; (b) Ramarao, Ley, C.; TBS TM TIPS SS SS SS

. 2003

p 1 g 5 g 1 g 1 g 25 g at 1-800-244-1173 (USA), or visit ™

, 4665. Chem. Commun. 5 , 99% ; 2003 contact SAFC

0NP sigma-aldrich.com/30n 3

Ready to scale up? For competitive quotes on larger quantities or custom synthesis, ™ Org. Lett. 30NP include aryl ketones, aldehydes, and epoxides 30NP is a new microencapsulated hydrogenation ] ™ ™ ] ] G G G G G Si Si Si 2 2 3-dithiane, -Butyldimethylsilyl)-1, 97% 2 S S S 28 22 192.42 276.58 234.50 16 H H tert H Highly chemoselective under both hydrogenation & transfer hydrogenation conditions activity catalyst of reproducibility batch-to-batch Excellent 7 13 10 13411-42-2 145251-89-4 95452-06-5 220817-25 [ 220817-1 220817-5 3-dithiane, 2-Trimethylsilyl-1, C FW: 409413-1 3-dithiane, 97% 2-(Triisopropylsilyl)-1, C FW: [ 514241-1 2-( C FW: [ Yu, J.-Q.; Zhou, Yu, W. For comprehensive application information on Pd(0) EnCat please visit us at (1) Bremeyer, N.; Ley, S. V.; Ramarao, C.; Shirley, I. Ramarao, M.; C.; Smith, Shirley, S. S. V.; C. N.; Ley, (1) Bremeyer, S. J. Ramarao, V. B.; C.; Ley, Spencer, Pd(0) EnCat to the corresponding alcohols; and nitroarenes aryl nitriles to the corresponding amines; alkenes and alkynes to the corresponding alkanes; and the debenzylation of aryl benzyl ethers. Pd(0) EnCat catalyst offering key advantages over existing heterogeneous hydrogenation catalysts. Reductive transformations catalyzed by • Excellent catalyst recyclability • • Safe and nonpyrophoric removal of • catalyst Trivial from reactor • low Very metal contamination of product Highly Versatile Catalyst for for Catalyst Versatile Highly Hydrogenations Chemoselective Pd(0) EnCat Pd(0) • Encapsulated Pd Catalysts 14

References (1) For a recent example, see: Denmark, S. E.; Wehrli, D. Org. (24) Denmark, S. E.; Sweis, R. F. J. Am. Chem. Soc. 2001, 123, 6439. Lett. 2000, 2, 565. (25) Denmark, S. E.; Tymonko, S. A. J. Org. Chem. 2003, 68, 9151. (2) For recent examples, see: (26) Denmark, S. E.; Fujimori, S. J. Am. Chem. Soc. 2005, 127, 8971. (a) Itami, K. et al. J. Org. Chem. 2002, 67, 2645. (27) Denmark, S. E.; Tymonko, S. A. J. Am. Chem. Soc. 2005, (b) Denmark, S. E.; Wang, Z. Org. Lett. 2001, 3, 1073. 127, 8004. (c) Denmark, S. E.; Wang, Z. Org. Synth. 2005, 81, 54. (28) (a) Denmark, S. E.; Ober, M. H. Org. Lett. 2003, 5, 1357. (3) Takeuchi, R. et al. J. Org. Chem. 1995, 60, 3045. (b) Denmark, S. E.; Ober, M. H. Adv. Synth. Catal. 2004, 346, (4) Sato, A. et al. Org. Lett. 2004, 6, 2217. 1703. (5) Takeuchi, R.; Tanouchi, N. J. Chem. Soc., Perkin Trans. 1 (29) Labadie, S. S.; Teng, E. J. Org. Chem. 1994, 59, 4250. 1994, 2909. (30) (a) Tyrell, E.; Brookes, P. Synthesis 2003, 469. (6) Na, Y.; Chang, S. Org. Lett. 2000, 2, 1887. (b) Johnson, C. N. et al. Synlett 1998, 1025. (7) (a) Maifeld, S. V. et al. Tetrahedron Lett. 2005, 46, 105. (31) Denmark, S. E.; Baird, J. D. Org. Lett. 2004, 6, 3649. (b) Menozzi, C. et al. J. Org. Chem. 2005, 70, 10717. (32) For examples of cross-coupling of dimethyl(4-isoxazolyl)silanols, (c) Aricó, C. S.; Cox, L. R. Org. Biomol. Chem. 2004, 2, 2558. see: Denmark, S. E.; Kallemeyn, J. M. J. Org. Chem. 2005, 70, (8) While references 7a and 7b illustrate access to a-vinylsilanes 2839.

using Ph3SiH, the method does not appear to be general. (33) (a) Weissman, H. et al. Organometallics 2004, 23, 3931. Isomeric mixtures are often formed with other silanes. (b) Werner, H.; Kühn, A. J. Organomet. Chem. 1979, 179, (9) For recent examples, see: 439. (a) Denmark, S. E.; Pan, W. Org. Lett. 2003, 5, 1119. (34) Manoso, A. S. et al. J. Org. Chem. 2004, 69, 8305. References (b) Denmark, S. E.; Pan, W. Org. Lett. 2002, 4, 4163. (35) Seganish, W. M.; DeShong, P. J. Org. Chem. 2004, 69, 6790. (c) Denmark, S. E.; Pan, W. Org. Lett. 2001, 3, 61. (36) (a) Manoso, A. S.; Deshong, P. J. Org. Chem. 2001, 66, 7449. (10) For a recent example, see: Hamze, A. et al. Org. Lett. 2005, (b) Murata, M. et al. Org. Lett. 2002, 4, 1843. 7, 5625. (c) Murata, M. et al. J. Org. Chem. 1997, 62, 8569. (11) (a) Trost, B. M. et al. J. Am. Chem. Soc. 2001, 123, 12726. (37) (a) Mowery, M. E.; DeShong, P. J. Org. Chem. 1999, 64, 1684. (b) Trost, B. M.; Ball, Z. T. J. Am. Chem. Soc. 2005, 127, 17644. (b) McElroy, W. T.; DeShong, P. Org. Lett. 2003, 5, 4779. (12) For a mechanistic rationale of this Ru-catalyzed hydrosi- (c) Tamao, K. et al. Tetrahedron Lett. 1989, lylation, see: Chung, L. W. et al. J. Am. Chem. Soc. 2003, 30, 6051. 125, 11578. (38) Seganish, W. M. et al. J. Org. Chem. 2005, 70, 8948. (13) Trost, B. M. et al. J. Am. Chem. Soc. 2002, 124, 7922. (39) Lee, J.-Y.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 5616. (14) Trost, B. M. et al. Org. Lett. 2003, 5, 1895. (40) Oi, S. et al. Org. Lett. 2002, 4, 667. (15) Trost, B. M.; Ball, Z. T. J. Am. Chem. Soc. 2004, 126, 13942. (41) DeShong, P.; Correia, R. J. Org. Chem. 2001, 66, 7159. (16) (a) Trost, B. M. et al. Angew. Chem. Int. Ed. 2003, 42, 3415. (42) (a) Denmark, S. E.; Wang, Z. Synthesis 2000, 999. (b) Trost, B. M. et al. J. Am. Chem. Soc. 2005, 127, 10028. (b) Denmark, S. E.; Wang, Z. J. Organomet. Chem. 2001, (c) Trost, B. M. et al. Org. Lett. 2005, 7, 4911. 621, 372. (17) Trost, B. M.; Ball, Z. T. J. Am. Chem. Soc. 2003, 125, 30. (43) Denmark, S. E.; Butler, C. R. Org. Lett. 2006, 8, 63. (18) For recent reviews, see: (44) Corey, E. J.; Seebach, D. Angew. Chem. Int. Ed. 1965, 4, 1075. (a) Denmark, S. E.; Sweis, R. F. Acc. Chem. Res. 2002, 35, 835. (45) (a) Smith, A. B., III; Boldi, A. M. J. Am. Chem. Soc. 1997, (b) Denmark, S. E.; Sweis, R. F. Chem. Pharm. Bull. 2002, 50, 119, 6925. 1531. (b) Smith, A. B., III et al. J. Am. Chem. Soc. 2003, 125, 14435. (c) Denmark, S. E.; Ober, M. H. Aldrichimica Acta 2003, 36, 75. (46) For an example, see: Smith, A. B., III et al. Org. Lett. 2002, 4, (19) Denmark, S. E.; Neuville, L. Org. Lett. 2000, 2, 3221. 783. (20) Denmark, S. E.; Baird, J. D. Org. Lett. 2006, 8, 793. (47) Smith, A. B., III et al. Org. Lett. 2003, 5, 2751. (21) Hirabayashi, K. et al. Bull. Chem. Soc. Jpn. 2000, 73, 1409. (48) Poss, C. S. et al. J. Am. Chem. Soc. 1993, 115, 3360. (22) Denmark, S. E.; Kallemeyn, J. M. Org. Lett. 2003, 5, 3483. (49) Smith, A. B., III; Pitram, S. M. Org. Lett. 1999, 1, 2001. (23) For mechanistic implications of fluoride vs. basic activation of (50) (a) Smith, A. B., III; Kim, D.-S. Org. Lett. 2005, 7, 3247. dimethylsilanols in Pd-catalyzed cross-coupling, see: (b) Smith, A. B., III; Kim, D.-S. J. Org. Chem. 2006, 71, 2547. (a) Denmark, S. E. et al. J. Am. Chem. Soc. 2004, 126, 4865. (51) Smith, A. B., III; Xian, M. J. Am. Chem. Soc. 2006, 128, 66. (b) Denmark, S. E.; Sweis, R. F. J. Am. Chem. Soc. 2004, 126, 4876.

TO ORDER: Contact your local Sigma-Aldrich office (see back cover),

sigma-aldrich.com call 1-800-325-3010 (USA), or visit sigma-aldrich.com/chemicalsynthesis. Alkyne Building Blocks from Sigma-Aldrich Sigma-Aldrich is pleased to offer the following versatile synthons for chemical synthesis, expanding your world of research possibilities.

4-(Trimethylsilyl)-3-butyn-2-ol, 97% 8 1-Ethynyl-1-cyclohexanol, 99%

C7H14OSi OH C8H12O FW: 142.27 FW: 124.18 OH CH H C 3 [6999-19-5] 3 Si [78-27-3] H3C CH3

666955-5G 5 g E51406-5ML 5 mL 666955-25G 25 g E51406-100ML 100 mL

4-Hexyn-3-ol, 97% 8 Methyl 2-hexynoate, 98% C6H10O OH C H O FW: 98.14 CH3 7 10 2 O FW: 126.15 [20739-59-7] H C 3 [18937-79-6] OCH3 H3C 669318-1G 1 g 669318-10G 10 g 649090-5G 5 g 649090-25G 25 g 3-Hexyn-2-ol, 97% 8

C6H10O OH FW: 98.14 Ethyl 2-pentynoate, 97% CH H C 3 C7H10O2 [109-50-2] 3 O FW: 126.15 O CH3 669296-5G 5 g [55314-57-3] H3C 669296-25G 25 g 632112-5G 5 g 2-Hexyn-1-ol, 97% 632112-25G 25 g

C6H10O OH FW: 98.14 [764-60-3] N-(2-Butynyl)phthalimide, 97% H3C C12H9NO2 O 630829-5G 5 g FW: 199.21 N [113439-83-1] H C 630829-25G 25 g 3 O

2-Heptyn-1-ol, 97% 663034-5G 5 g C7H12O OH 663034-25G 25 g FW: 112.17

[1002-36-4] H3C 4-Trimethylsilylethynylbenzonitrile, 97% 630810-5G 5 g C12H13NSi CN 630810-25G 25 g FW: 199.32

[75867-40-2] H C 2-Octyn-1-ol, 97% 3 Si H3C CH3 C8H14O OH FW: 126.20 658391-1G 1 g [20739-58-6] H3C 658391-10G 10 g

630837-5G 5 g 630837-25G 25 g 3-Cyclopentyl-1-propyne, 97%

C8H12 1-Pentyn-3-ol, 98% FW: 108.18 C5H8O [116279-08-4] FW: 84.12 OH CH3 [4187-86-4] 632074-1G 1 g 632074-5G 5 g E28404-1G 1 g E28404-10G 10 g 3-Cyclohexyl-1-propyne, 97%

2-(2-Fluorophenyl)-3-butyn-2-ol C9H14 C10H9FO FW: 122.21 HO CH3 FW: 164.18 [17715-00-3]

F 632066-1G 1 g 648949-1G 1 g 632066-5G 5 g

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