Some Aspects of the Chemistry of Alkynylsilanes

Home , Acetylene, Glaser coupling, Hydrosilane, Silane, Trimethylsilyl

SYNTHESIS0039-78811437-210X Georg Thieme Verlag Stuttgart · New York 2018, 50, A–AD review A en

Syn thesis G. L. Larson Review

Gerald L. Larson*

Gelest Inc., 11 East Steel Road, Morrisville, PA 18940, USA [email protected]

Received: 26.01.2018 Accepted after revision: 13.03.2018 Published online: 18.05.2018 DOI: 10.1055/s-0036-1591979; Art ID: ss-2018-e0053-sr License terms:

Abstract In amongst the considerable chemistry of acetylenes there lies some unique chemistry of alkynylsilanes (silylacetylenes) some of which is reviewed herein. This unique character is exemplified not only in the silyl protection of the terminal C–H of acetylenes, but also in the ability of the silyl group to be converted into other functionalities after reaction of the alkynylsilane and to its ability to dictate and improve the regioselectivity of reactions at the triple bond. This, when combined Gerald (Jerry) Larson led Vice-President of R&D for Gelest Inc. for with the possible subsequent transformations of the silyl group, makes nearly 20 years before his retirement where he retains the position of their chemistry highly versatile and useful. Senior Research Fellow and Corporate Consultant. He received his B.Sc. 1 Introduction degree in chemistry from Pacific Lutheran University in 1964 and his 2 Safety Ph.D. in chemistry (organic/inorganic) from the University of California- 3 Synthesis Davis in 1968. He served an NIH-postdoctoral year with Donald Mat- 4 Protiodesilylation teson at Washington State University and a postdoctoral year with Diet- 5 Sonogashira Reactions mar Seyferth at MIT, after which he joined the faculty of the University 6 Cross-Coupling with the C–Si Bond of Puerto Rico-Río Piedras as an assistant professor in 1970 reaching full 7 Stille Cross-Coupling professor in 1979. He has been a visiting professor at various universi- 8 Reactions at the Terminal Carbon ties including Oregon State, Louisiana State, Universitá di Bari, Universi- 9 Cross-Coupling with Silylethynylmagnesium Bromides tät Würzburg, and Instituto Politécnico de Investigaciones de Mexico. 10 Reactions of Haloethynylsilanes On the industrial side, he rose to Vice-President of Research for Sivento, 11 Cycloaddition Reactions a Hüls group company, an antecedent of Evonik, after serving as Direc- 11.1 Formation of Aromatic Rings tor of Applications, in Troisdorf, Germany. He is the author of over 130 11.2 Diels–Alder Cyclizations publications and 30 patents. His hobbies include tennis, traveling and 11.3 Formation of Heterocycles reading. He was born in 1942, as the first of three sons and a daughter, 11.4 Formation of 1,2,3-Triazines in Tacoma, Washington where he was raised on a small farm. 11.5 [2+3] Cycloadditions 11.6 Other Cycloadditions 12 Additions to the C≡C Bond to the sp-carbon of the C≡C bond. Alkynylsilanes such as 13 Reactions at the C–Si Bond 14 Miscellaneous Reactions propargylsilanes are, therefore, not included. Acetylene chemistry has been extensively reviewed over the years. Key words alkynes, azides, cross-coupling, enynes, protecting Several of the more recent additions are noted here.1 groups, silicon, Stille reaction A significant portion of the applications of silylacetylenes occurs where the silyl group, typically trimethylsilyl, 1 Introduction serves as a group for the protection of the reactive terminal C≡C–H bond. Supporting this silyl-protection strategy is Alkynylsilanes (silylacetylenes) as referred to in this re- that both the introduction and removal of the silyl group view are those wherein the silyl moiety is directly bonded can be accomplished in high yield under a variety of mild

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Syn thesis G. L. Larson Review conditions. The desilylation protocols are, in general, highly tolerant of other functional groups with the notable excep- H H tion of silyl-protected alcohols. The reader will note several LDA, TMSCl examples in this review where the silyl group basically pro- N N THF, –78 °C N N Bn Bn vides a protective function, but has further synthetic po- 80% tential. A further advantage of the terminal silylacetylenes is that the presence of the silyl group, for both steric and electronic reasons, can often influence the regio- and 1 TMS stereochemistry of reactions at the C≡C bond. This is most often reflected in cyclization reactions and it bears remem- Scheme 2 Preparation of a silylacetylene employed in a synthesis of complanadine A bering that the regioselectively placed silyl group has the potential to be another group including hydrogen. Finally, the trimethylsilyl group has its own reactivity in the final product of a reaction at the C≡C bond. These often result in The direct trimethylsilylation of a terminal alkyne can the generation of a vinylsilane unit, which can be further be carried out in a single step with the combination of LDA reacted under a number of conditions including protiodesi- and TMSCl at low temperature. This was applied to the syn- lylation to the parent alkene.2 Examples of these aspects of thesis of 1, which was used in a synthesis of complanadine the chemistry are to be found throughout the review. A (Scheme 2).5 Marciniec and co-workers have demonstrated the direct silylation of terminal acetylenes using an iridium carbonyl 2 Safety catalyst and iodotrimethylsilane in the presence of Hünig’s base.6 The yields are excellent and the process works well

A report of an explosion using (trimethylsilyl)acetylene for diynes and is tolerant of OH and NH2 groups, albeit in an oxidative coupling under Glaser–Hay conditions was these end up as their trimethylsilylated derivatives in the published.3 After a thorough investigation the cause of the final product (Scheme 3). explosion was attributed to static electricity between the syringe needle used to introduce the copper catalyst and a [{Ir(μ-Cl)(CO)2}2] (1 mol%) R + TMSI R TMS digital thermometer inside the flask and not the thermal i-Pr2NEt, toluene, 80 °C, 48 h instability of the silane. It is interesting to note that the 13 examples: 93–99% trimethylsilyl group can impart stability to alkynyl systems. A good example of this is 1,4-bis(trimethylsilyl)buta-1,3- Ph Ph [{Ir(μ-Cl)(CO)2}2] (1 mol%) diyne, which shows excellent thermal stability compared to Si + TMSI TMS Si TMS i-Pr NEt, toluene, 80 °C, 48 h Ph 2 Ph that of the parent buta-1,3-diyne. 5 diyne examples: 6–97%

TMS 3 Synthesis HO TMSO

[{Ir(μ-Cl)(CO)2}2] (1 mol%) + TMSI A well-known and often used approach to silylacety- i-Pr2NEt, toluene, 80 °C, 24 h lenes is via the straightforward acid-base metalation, typi- 91% cally with RMgX or n-BuLi (the base), of a terminal acety- TMS lene (the acid) followed by reaction with an appropriate H2N TMS N chlorosilane or related reactive organosilane. As a specific [{Ir(μ-Cl)(CO)2}2] (1 mol%) + Me3SiI TMS example, 1-(triisopropylsilyl)prop-1-yne was prepared by i-Pr2NEt, toluene, 80 °C, 48 h lithiation of propyne followed by reaction with triisopro- 90% pylsilyl triflate (Scheme 1).4 Scheme 3 Ir-catalyzed direct trimethylsilylation of terminal alkynes

A direct dehydrogenative cross-coupling of a terminal

TIPSOTf alkyne and a hydrosilane provided a convenient and simple Me Li Me TIPS Et2O, –40 to 0 °C route to silylacetylenes. Thus, reaction of a terminal acety- 87% lene and a silane with a catalytic amount of NaOH or KOH gave the desired silylacetylene in high yield with expulsion Scheme 1 Example of a typical synthesis of a silylacetylene of hydrogen. The reaction of a variety of acetylenes with dimethyl(phenyl)silane showed excellent general reactivity for 25 examples (Scheme 4).7

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TMS R3SiH (3 equiv) 1) MeLi (1 equiv) OH MOH (10 mol%) + H2 THF, 0 °C DME, 24–48 h SiR3 2) acrolein, –78 °C TMS 2 73% M = Na, 6 examples: 68–95%; K, 6 examples: 69–95%; R3Si = 12 examples 3) NaOHaq, THF, r.t.

PhMe2SiH (3 equiv) TMS OH NaOH (10 mol%) 1) MeLi (5 equiv) R R SiMe2Ph + H2 DME, 23–65 °C, 24–48 h THF, 0 °C 25 examples: 52 to >99% 2) acrolein, –78 °C TMS 3 99% Scheme 4 Base-catalyzed direct dehydrogenative silylation of a terminal alkyne OH Scheme 6 Selective metalation and protiodesilylation of 1,4- bis(trimethylsilyl)buta-1,3-diyne 4 Protiodesilylation

Because trialkylsilyl groups are very commonly used to enynes.10 These approaches typically make use of the Pd- protect the terminal C–H of an acetylene, protiodesilylation catalyzed protocols employed in most cross-coupling reac- back to the parent acetylene is an important transformations. The Au-catalyzed use of silylacetylenes in Sonogashi- tion. This can be accomplished under a number of mild re- ra cross-coupling reactions has been reviewed.11 action conditions. Among these is the simple reaction of Under the standard Sonogashira reaction conditions the

(trimethylsilyl)acetylene derivatives with K2CO3/MeOH or, C–Si bond does not react thus providing excellent protec- for more hindered silanes, TBAF/THF. Examples of these are tion of this position along with adding more desirable phys- to be found throughout this review. The selective protiode- ical properties. Moreover, it provides an excellent entry into silylation of (trimethylsilyl)acetylene group in the presence a variety of substituted silylacetylenes. Though the silyl of an (triisopropylsilyl)acetylene group with K2CO3/ group nicely provides protection of a terminal position in THF/MeOH illustrates the potential for selective protec- the Sonogashira cross-coupling, under modified conditions tion/deprotection (Scheme 5).8 wherein the silyl group is activated, a Sonogashira-type conversion at the C–Si bond is possible, thus providing an

K2CO3 TIPS alternative to a two-step protiodesilylation/Sonogashira se- TIPS THF, MeOH quence. 95% In an example of the use of the TMS group as a protecting group eventually leading to an unsymmetrically arylat- TMS ed system, 1-(trimethylsilyl)buta-1,3-diyne, prepared from Scheme 5 Selective deprotection of a (trimethylsilyl)acetylene group 1,4-bis(trimethylsilyl)buta-1,3-diyne, was coupled with aryl iodide 4 to give the diyne 5, which was protiodesilylated and further cross-coupled to give 6, a potential hepatitis 1,4-Bis(trimethylsilyl)buta-1,3-diyne was metalated C NS5A inhibitor (Scheme 7).12 with one equivalent of MeLi and reacted with acrolein and subsequently protiodesilylated to yield vinyl diynyl carbinol TMS TMS Pd(PPh3)4, CuI MeLi, LiBr THF, Et N, 40 °C, 15 h N 2. Transmetalation of 1,4-bis(trimethylsilyl)buta-1,3-diyne 3 H TMS Et O, 15 h N N with five equivalents of MeLi and reaction with acrolein 2 N H H I 5 9 N N gave the diol 3 in excellent yield. These key intermediates TMS H H were carried forth in syntheses of (+)- and (–)-falcarinol 4 and (+)- and (–)-3-acetoxyfalcarinol (Scheme 6).9 Pd(PPh3)4, CuI K CO THF, Et3N, 40 °C, 15 h 2 3 N H THF, MeOH H N N N I H H N N 5 Sonogashira Reactions H

H N N N H Of the many reactions at the terminal C–H of simple si- H N N N lylacetylenes, the Sonogashira reaction stands among the H 6 most important, where it has proved to be a very important synthetic entry into arylacetylenes and conjugated Scheme 7 Sonogashira cross-coupling sequence employing desilylation

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Modest yields of symmetrical 1,4-diarylbuta-1,3-diynes MgBr Me Me2 2 THF resulted from the Sonogashira reaction of an aryl bromide + Si CN Si CN Cl –20 °C to r.t., 16 h and (trimethylsilyl)acetylene followed by treatment with H NaOH/MeCN. The reaction sequence was the combination of the Sonogashira cross-coupling and a Glaser coupling in a Me2Si CN two-step, single-flask operation. The second step did not I require the further addition of catalyst. The reaction was 1. Pd(PPh3)2Cl2 tolerant of HO, CO2H, and CHO functional groups (Scheme PPh3, CuI, piperidine 13 Si CN + 8). Me2 2. TIPS 8 39% I TMS TMS PdCl2(PPh3)2, CuI, PPh3 ArBr + Et3N, 80 °C, 1–3 h TIPS Ar

NaOH (2 equiv) Me2Si CN MeCN, 60 °C, 2–8 h

Ar Ar K2CO3 17 examples: 0–60% MeOH, THF Scheme 8 Sonogashira arylation and homocoupling without prior 89% desilylation

TIPS The Beller group developed a copper-free protocol for TIPS the Sonogashira reaction with the more available and less Scheme 10 Sonogashira cross-coupling and selective protiodesilylation costly aryl chlorides. Both (trimethylsilyl)acetylene and (triethylsilyl)acetylene reacted without loss of the silyl group. The key to the success of the reaction proved to be ethynyl)benzene was subsequently reacted with cyclohexa- the sterically hindered ligand 7 (Scheme 9).14 1,4-diene to give 2,3,6,7-tetrabromoanthracene (Scheme 11).16 Ph N TMS TMS I I R R Ph P(t-Bu)2 [PdCl2(MeCN)2] (1 mol%) N TMS Pd(PPh3)4, CuI + Ar-Cl + 7 (3 mol%), Na2CO3 (4 equiv) i-Pr i-Pr Et3N, piperidine Ar I I toluene, 90 °C, 16 h 92% TMS TMS total of 13 examples: 31–97% 7 R = TMS, 75%; R = TES, 77% NBS, AgNO3 quant. acetone Scheme 9 Copper-free Sonogashira cross-coupling Br Br

[3-Cyanopropyl(dimethyl)silyl]acetylene (CPDMSA, 8) was prepared and utilized in the synthesis of arene-spaced diacetylenes. The purpose of this particular silylacetylene Br Br was twofold, firstly it could be selectively deprotected in Scheme 11 Formation of 1,2,4,5-tetrakis(bromoethynyl)benzene the presence of the (triisopropylsilyl)acetylene group and, secondly, it provided polarity allowing for a facile chro- In related chemistry the direct ethynylation of tautom- matographic separation of the key intermediates in the syn- erizable heterocyclics under Sonogashira conditions with- theses of the diethynylarenes (Scheme 10). The arene out the need for conversion of the heterocyclic into an aryl groups were introduced via Sonogashira cross-coupling.15 halide was reported. These worked well for both (trimethyl- In a good example of the use of (trimethylsilyl)acetylene silyl)acetylene and (triethylsilyl)acetylene (Scheme 12).17 as a precursor to 1,2,4,5-tetraethynylbenzene, 1,2,4,5- In an interesting and useful approach, (trimethylsi- tetraiodobenzene was reacted with (trimethylsilyl)acety- lyl)acetylene was cross-coupled with aryl iodides, bro- lene under Sonogashira conditions to give 1,2,4,5- mides, and triflates in the presence of an amidine base and tetrakis[(trimethylsilyl)ethynyl]benzene. The trimethylsilyl water. If water was omitted until the second stage of the re- groups were then converted into bromides with NBS in action, i.e. reaction at the C–Si terminus, the result was the greater than 90% over the two steps. 1,2,4,5-Tetrakis(bromo- synthesis of unsymmetrical diarylacetylenes (Scheme 13).18 The Sonogashira reaction of (trimethylsilyl)acetylene with 2,6-dibromo-3,7-bis(triflyloxy)anthracene was inves-

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TMS TMS 1) PyBrOP (1.2 equiv) H Br OTf Br N O N TMS + Et3N, dioxane, r.t., 2 h + Pd(PPh3)2Cl2 N PBr PF – 6 TfO Br Br 2) PdCl2(PPh3)2 (5 mol%) 3 56% N N TMS CuI (5 mol%) PyBrOP TMS Br OAc TMS 83% TMS + Pd(PPh3)2Cl2 OAc TES AcO Br 84% AcO O TMS Cs CO •H O O N N 2 3 2 NH N 63% O AcO 1) PyBrOP (1.2 equiv) AcO N N N N O Et3N, dioxane, r.t., 2 h O TMS 2) PdCl (PPh ) (5 mol%) MeS OTf MeS 2 3 2 TMS Pd(PPh3)2Cl2 OO OO + CuI (5 mol%) quant. TfO SMe SMe TES Ph Ph 9 TMS 61% I S S Scheme 12 Direct Sonogashira-type ethynylation of tautomerizable I2 NaBH4 TMS TMS heterocycles 88% S 88% S I PhB(OH)2 68% K3PO4•nH2O Pd(PPh3)4 PdCl2(PPh3)2 (6 mol%) Ar Ph CuI (10 mol%), DBU (6 equiv) S Ar-X benzene, H O (0.4 equiv) 2 Ar S r.t. or 60 °C 10 Ph X = I, 17 examples (0.5 equiv) TMS X = Br, 2 examples 48–84% MeSe OTf TMS 1) Pd(PPh ) Cl (81%) Se X = OTf, 3 examples 67–88% + 3 2 2 2) I (89%) TfO SeMe 2 Se 11 3) LiAlH (86%) 12 PdCl2(PPh3)2 (6 mol%) 4 TMS Ar2 CuI (10 mol%), Et3N (6 equiv) Ar2-I Ar1-I Scheme 14 Sonogashira cross-coupling in the synthesis of thiophenes benzene, r.t., 18 h DBU, H O and selenophenes Ar1 2 Ar1 TMS (1.05 equiv) r.t., 18 h 8 examples: 61–90% TES Scheme 13 Symmetrical and unsymmetrical diarylation of (trimethyl- FeCl3 (15 mol%) I silyl)acetylene TES dmeda (30 mol%) + CsCO , toluene N 3 N tigated as an intermediate in a route to anthra[2,3-b:6,7- 135 °C, 72 h 58% b′]difuran (anti-ADT). In this reaction the Sonogashira cross-coupling occurred selectively at the triflate leaving Scheme 15 Representative Sonogashira cross-coupling with iodopyri- dine the bromine groups available. This route did not, however, result in a synthetic approach to the desired anthracene difuran. Success was realized via the Sonogashira cross-coupling of (trimethylsilyl)acetylene with 2,6-diacetoxy-3,7- 90% yields). The reaction conditions were not mild, requir- dibromoanthracene followed by desilylative cyclization. ing 135 °C and 72 hours for completion (Scheme 15).20 The thiofuran analogue, anti-ADT, was prepared via cross- The Sonogashira reaction of several terminal alkynes coupling of 9 with (trimethylsilyl)acetylene, iodine cycliza- with 1-fluoro-2-nitrobenzene gave 1-(2-nitrophenyl)-2- tion, and reduction. A Suzuki–Miyaura cross-coupling and (triethylsilyl)acetylene. The use of (triethylsilyl)acetylene protiodesilylation gave the phenyl-substituted anti-ADT 10. gave a considerably higher yield than other terminal In an analogous manner the anti-diselenophene 12 was alkynes. The TES group was not reacted further in this prepared from 11 in 62% yield over three steps (Scheme study (Scheme 16).21 14).19 NO2 NO2 The relatively simple and economical catalyst system of TES NaHMDS + FeCl /N,N′-dimethylethylenediamine was used in the syn- THF, 60 °C, 5 h 3 F 95% thesis of 1-aryl-2-(triethylsilyl)acetylenes (6 examples, 40– TES Scheme 16 Sonogashira cross-coupling with 1-fluoro-2-nitrobenzene

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6 Cross-Coupling with the C–Si Bond CuI (1 equiv) TMS R2 CsF (1 equiv) Hatanaka and Hiyama were the first to report the cross- + R1 DMI, 80 °C, 2 h R1 R2 coupling of (trimethylsilyl)acetylenes.22 This they accom- Cl plished with cross-coupling with β-bromostyrene to form 7 examples: complex mixture – 72% conjugated enynes with TASF promotion. It bears mention- Scheme 19 Cross-coupling approach to 1,4-skipped diynes ing that under the same conditions (trimethylsilyl)ethenes were cross-coupled in high yield with aryl and vinyl iodides (Scheme 17). Denmark and Tymonko demonstrated the cross-coupling of alkynyldimethylsilanols with aryl iodides under TMS Ph Ph [PdCl(allyl)]2 (2.5 mol%) promotion with potassium trimethylsilanolate (Scheme + Br 25 TASF (1.3 equiv) R 20). This protocol avoids the typical necessity of fluoride R THF, r.t. 3 examples: ion promotion and the associated disadvantages of cost and 83–85% low tolerance for silicon-based protecting groups. The alky- Scheme 17 Conjugated enynes from (trimethylsilyl)acetylenes nylsilanols were prepared in a two-step reaction sequence. Interestingly, a direct comparison of the reaction rates of Tertiary 3-arylpropargyl alcohols reacted with hept-1-yne, hept-1-ynyldimethylsilanol, and 1-(trimethyl- bis(trimethylsilyl)acetylene under Rh catalysis to give the silyl)hept-1-yne under the potassium trimethylsilanolate hydroxymethyl-enyne regio- and stereoselectively with loss promotion conditions showed the hept-1-ynyldimethylsila- of benzophenone and one equivalent of the starting aryl- nol to be considerably faster than hept-1-yne and the 1- ethynyl group as its TMS-substituted derivative. Under Pd (trimethylsilyl)hept-1-yne to be unreactive. This strongly catalysis this silylated enyne could be cross-coupled with suggests a role of the silanol group in the cross-coupling. A an aryl iodide, which was converted into the alkylidene-di- similar experiment with TBAF promotion showed all three hydrofuran. The alkylidene-dihydrofurans thus prepared to react with the silanol derivative being the fastest. Under exhibited fluorescent properties (Scheme 18).23 the same conditions 4-bromotoluene gave a 25% conversion showing the advantages of using iodoarenes.25 The TBAF- O Ph OH promoted cross-coupling of alkynylsilanols with aryl io- TMS X TMS + Ph Ph Ph dides had previously been shown.26 [(cod)Rh(OH)]2 (4 mol%) Ph Ph + TMS dppb, toluene, 4 h OH SiMe2OH 5 examples: 57–87% + X 1. n-BuLi, Me2ClSiH TMS n-C5H11 2. [RuCl2(p-cymene)]2, H2O X n-C5H11 82% 1) Pd(PPh3)2Cl2 (6 mol%) Ph Ph Ph Ph CuI (10 mol%), YC6H4I O OH DBU (6 equiv), H2O TMSOK (2 equiv) SiMe2OH toluene, 100 °C Ar PdCl2(PPh3)2 (2.5 mol%) TMS X Y + Ar-I X 2) KOt-Bu, DMSO CuI (5 mol%), DME, r.t., 3 h 6 examples: 38–77% n-C5H11 n-C5H11 Scheme 18 Silyl Sonogashira cross-coupling of propargyl alcohols 10 examples: 75–95% Seeking a practical entry into 1,4-skipped diynes as po- Scheme 20 Formation of ethynylsilanols and their cross-coupling with tential precursors to polyunsaturated fatty acids, the Syn- aryl iodides genta group investigated the cross-coupling of 1-aryl- or 1- alkyl-2-(trimethylsilyl)acetylene derivatives with propar- The bis(trimethylsilyl)enyne 13 was nicely prepared via gyl chlorides. Under the best conditions the reaction of a a Suzuki cross-coupling with 1-bromo-2-(trimethylsi- (trimethylsilyl)acetylene with a propargyl chloride gave the lyl)acetylene. The bis(trimethylsilyl)enyne 13 cross-cou- 1,4-skipped diyne under promotion with fluoride ion and pled with aryl iodides in a sila-Sonogashira reaction to pro- CuI catalysis. The method avoids the need for protiodesil- vide the silylated conjugated enyne 14. Similar cross-cou- ylation to the parent acetylene, a requirement in other cop- pling reactions of bis(trimethylsilyl)enyne 13 with vinyl per-catalyzed coupling protocols. The reaction failed with iodides led to 1,5-dien-3-ynes 15. Cyclic vinyl triflates also nitrogen-containing groups on the silylacetylene. The reac- reacted well with bis(trimethylsilyl)enyne 13 to form 1,5- tion proceeded well with 1-phenyl-2-(tributylstannyl)acet- dien-3-ynes 16 (Scheme 21).27 ylene (70%) and 4-phenyl-1-(trimethylgermyl)but-1-yne (90%) (Scheme 19).24

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CuI (10 mol%) TMS F Pd(PPh3)4 (10 mol%) TMS TMS F TMS LiOH•H2O (0.75 equiv) R I CuI (10 mol%) R + F + 17 Cy2B –15 °C to r.t., overnight THF, reflux, 2 h F Br TMS 13 TES 75% TES 18 19

PdCl2(PPh3)2 (20 mol%) ArI DBU, r.t., overnight

F Pd(PPh3)4 (10 mol%) F SiR3 SiR3 11 examples: 54–86% TMS Sn(n-Bu)3 CuI (10 mol%) F + F R THF, reflux, 5 h TES Br TES R Si = TMS 70% 203 21 Ar 14 R3Si = TIPS 73% Scheme 24 Stille cross-coupling reactions TMS TMS 1 PdCl2(PPh3)2 (4 mol%) R R1 I + R2 DBU, r.t., overnight 2 The alkynylation of the anomeric position of the benzyl- R 15 TMS 13 7 examples: 38–74% protected glucose derivatives 22 was accomplished with 1- (tributylstannyl)-2-(trimethylsilyl)acetylene (17) (Scheme TMS 25).31 TMS OTf R PdCl2(PPh3)2 (20 mol%) R + OBn DBU, r.t., overnight BnO OBn 1) TMSOTf BnO TMS 13 8 examples: 40–75% CH Cl O 16 O 2 2 + 17 BnO BnO 2) K2CO3, MeOH Scheme 21 Suzuki cross-coupling with 1-bromo-2-(trimethylsi- BnO BnO X X = OMe 37% lyl)acetylene and cross-coupling of the 1-(trimethylsilyl)alk-1-yne 22 X = OAc (α and β) 87% X = OAc (β) 54% TMS Scheme 25 sp3-sp Cross-coupling of 1-(tributylstannyl)-2-(trimethylsi- 7 Stille Cross-Coupling lyl)acetylene with a sugar derivative

(Trimethylsilyl)acetylene was deprotonated and reacted 1-(Tributylstannyl)-2-(trimethylsilyl)acetylene (17) was with tributyltin chloride to give 1-(tributylstannyl)-2- cross-coupled with 23 and found to be tolerant of a ketal (trimethylsilyl)acetylene (17) in good yield (Scheme 22).28 and a cyclopropene. The TMS group was removed along with deacetoxylation of the ester upon treatment with 1) n-BuLi, Et O 32 TMS 2 TMS K2CO3/MeOH (Scheme 26). –40 °C, 45 min

2) n-Bu3SnCl, r.t., 24 h n-Bu3Sn 84% 17 O O O O Scheme 22 Synthesis of 1-(tributylstannyl)-2-(trimethylsilyl)acetylene Pd(PPh3)4 OAc + 17 OAc toluene, 90 °C, 2 h 3 3 1-(Tributylstannyl)-2-(trimethylsilyl)acetylene (17) was 76% Br prepared directly from (trimethylsilyl)acetylene and tribut- 23 TMS yltin methoxide in 49% isolated yield (Scheme 23).29 K2CO3, MeOH 2 h TMS 88% ZnBr2 (5 mol%) n-Bu3SnOMe + 17 THF, r.t., 3 h 49% Scheme 23 Alternative synthesis of 1-(tributylstannyl)-2-(trimethylsi- O O lyl)acetylene OH 3 The bis(silyl)enyne 19 was prepared by cross-coupling 1-(tributylstannyl)-2-(trimethylsilyl)acetylene (17) with Scheme 26 Sonogashira cross-coupling showing functional group tol- vinyl iodide 18 in 75% yield. In another approach to this end erance in the same paper, vinylstannane 20 reacted with 1-bromo- 2-(trimethylsilyl)acetylene and 1-bromo-2-(triisopropylsilyl)acetylene to give the bis-silylated conjugated enynes 21 1-(Tributylstannyl)-2-(trimethylsilyl)acetylene (17) was in good yield (Scheme 24).30 cross-coupled with the highly substituted aryl bromide 24 in a synthesis of (+)-kibdelone A. The TMS group was re-

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moved in 93% yield with AgNO3·pyridine in aqueous ace- O Co(OAc)2•4H2O (5 mol%) 3 33 O R tone (Scheme 27). TIPS + dppe (5 mol%), Zn (50 mol%) R1 R3 R1 DMSO, 80 °C, 20 h TMS R2 R2 TIPS HO Br HO Pd(PPh3)4 15 examples: + 17 toluene, 110 °C, 21 h 40–97% OMe OMe 82% OTBDPS OTBDPS Co(OAc)2•4H2O (10 mol%) 24 O O TIPS + Ph 2 P PPh 2 (10 mol%) Scheme 27 Stille cross-coupling of 1-(tributylstannyl)-2-(trimethylsi- Ph Ph lyl)acetylene with a highly substituted aryl bromide Zn (50 mol%), DMSO, 80 °C, 20 h TIPS 93%, 87% ee

Scheme 30 β-Ethynylation of α,β-unsaturated ketones Similarly to the Sonogashira reaction of (trimethylsilyl)acetylene, where the cross-coupling occurs at the C–H bond, the cross-coupling of 1-(tributylstannyl)-2-(trimeth- Carreira and co-workers reacted terminal acetylenes in- ylsilyl)acetylene (17) occurs at the C–Sn bond rather than cluding (trimethylsilyl)acetylene with aldehydes in the the C–Si bond. This was employed in the synthesis of the in- presence of (+)-N-methylephedrine to give the propargyl dole piece of sespendole (Scheme 28).34 alcohol in high yield and high ee (Scheme 31).37

OH CHO TMS Zn(OTf) , Et N OTBS OTBS TMS + 2 3 OTf (+)-N-methylephedrine TMS Pd(PPh3)4, LiCl O + 17 O toluene, 23 °C, 2 h toluene, 100 °C, 2 h NO NO 93%; 98% ee 2 87% 2 Scheme 31 Asymmetric ethynylation of an aldehyde Scheme 28 Stille cross-coupling of 1-(tributylstannyl)-2-(trimethylsilyl)acetylene with a highly substituted aryl triflate The aldehyde 27 was reacted with (trimethylsilyl)acetylene under Carreira conditions to give a single diastereomer In an approach to the synthesis of lactonamycins, a of 28, which was O-silylated followed by protiodesilylation model glycine was prepared wherein a critical step was the of the TMS group. This material was carried forth in a syn- addition of an ethynyl group onto a highly substituted thesis of hyptolide and 6-epi-hyptolide (Scheme 32).38 arene. Thus, bromoarene 25 was subjected to a Stille cross- TESO TESO OH coupling with 1-(tributylstannyl)-2-(trimethylsilyl)acety- TMS CHO Zn(OTf)2, Et3N lene (17) to give the ethynylarene 26 in 91% yield. This com- + (–)-N-methylephedrine pared favorably with a three-step sequence (Scheme 29).35 OTBS OTBS TMS toluene, r.t. 28 27 77% O OMe OMe TMS Cl Br Cl 1) TBSOTf, 2,6-lutidine TESO OTBS Pd(PPh3)4 (10 mol%) AcO OAc O + 17 CH2Cl2, 0 °C (87%) OMOM toluene, 115 °C, 8 h OMOM 2) K CO , MeOH, r.t. 91% 2 3aq OTBS H OMe 26 OAc hyptolide OMe 25 (86%)

Scheme 29 Selective Stille cross-coupling Scheme 32 Diastereoselective ethynylation of an aldehyde in a synthesis of hyptolide 8 Reactions at the Terminal Carbon In keeping with the common use of silylacetylenes as Under a co-catalysis approach, (triisopropylsilyl)acety- surrogates for the simple ethynyl organometallics, an ‘in si- lene reacted with enones to form β-ethynyl ketones in high tu’ process for the ethynylation of aldehydes was developed. yields (Scheme 30). The reaction worked well with (tert-bu- In this chemistry a combination of ZnBr2, TMSOTf, and tyldimethylsilyl)acetylene and (tert-butyldiphenylsi- Hünig’s base was used to generate the ethynylzinc reagent lyl)acetylene as well, although (triethylsilyl)acetylene gave in situ and, along with a silylating agent, it was reacted with only 40% yield. Under the same reaction conditions the the aldehyde to generate the doubly silylated propargyl al- non-silylated terminal acetylenes phenylacetylene and oct- cohol, which was O-deprotected with dilute hydrochloric 1-yne gave alkyne oligomerization. An asymmetric version acid (Scheme 33).39 of the reaction, which gave good yields (5 examples, 53– 93%) and acceptable ee (81–90%), was also presented.36

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bis(triisopropylsilyl)-1,5-enyne was produced. One exam- 1) ZnBr2 (20 mol%) OH O TES ple with a bicyclo[2.2.2]octene gave the corresponding i-Pr2NEt, TMSOTf, Et2O + R R H 2) HCl (1 M), THF product in only 12% yield when reacted with (triisopropyl- TES 41 R = Ph, 90%; R = i-Bu, 59% silyl)acetylene (Scheme 35). (Trimethylsilyl)acetylene could be directly alkylated to Scheme 33 ‘In situ’ ethynylation of aldehydes give 1-(trimethylsilyl)dodec-1-yne in modest yield. The yield of this sole silicon example was comparable to the di- The aminomethylation of terminal alkynes was applied rect alkylation of other terminal alkynes (Scheme 36).42 to a variety of acetylene derivatives including a single example with (triethylsilyl)acetylene, which provided the tri- 31 (3.5 mol%) TMS NMe2 ethylsilylated propargyl amine in good yield. This was sub- TMS CuI (9 mol%) + n-C10H21-I sequently protiodesilylated and the resulting propargyl LiOt-Bu (1.4 equiv) N Ni Cl n-C10H21 amine converted into a mixed bis(aminomethyl)alkyne in a DMF, r.t., 16 h 58% NMe2 49% yield over three steps (Scheme 34).40 31 Scheme 36 Copper-catalyzed alkylation of (trimethylsilyl)acetylene N N TES TES FeCl2 (10 mol%) + 9 Cross-Coupling with Silylethynylmagne- (t-BuO)2 (2 equiv) sium Bromides 100 °C, 30 h, air 82% TBAF (1.2 equiv) 89% In a useful synthetic approach to alkynylsilanes (triiso- THF propylsilyl)ethynylmagnesium bromide was cross-coupled with anisoles (23 examples 42–94% yield). In the cross-cou- N N n-C H NMe pling of either 4-fluoroanisole or 4-cyanoanisole, the cou- N 8 17 2 H n-C8H17 FeCl2 (10 mol%) pling of the F or CN substituent was favored over that of the

(t-BuO)2 (2 equiv) methoxy group. The trimethylsilyl enol ether of cyclohexa- 100 °C, air, 18 h none cross-coupled, as did 4,5-dihydrofuran. In one exam- 67% Scheme 34 Aminomethylation of terminal alkynes TIPS Ni(cod) (10 mol%) TIPS 2 OMe ICy•HCl (20 mol%) + (Triisopropylsilyl)acetylene was employed in a Ni-cata- BrMg dioxane, 120 °C, 18 h lyzed, three-component reaction of the ethynylsilane, an 32 (2 equiv) 75% alkyne, and norbornene. A variety of norbornene deriva- 32 (2 equiv) TIPS tives were reacted with good success. When (triisopropylsi- OTMS Ni(cod)2 (10 mol%) lyl)acetylene was used as the sole acetylene reactant, the ICy•HCl (20 mol%) dioxane, 120 °C, 18 h 82% TIPS 32 (2 equiv) Ni(cod)2 (10 mol%) Ni(cod)2 (10 mol%) OH TIPS Ar Ar O ICy•HCl (20 mol%) Ph MeP (20 mol%) dioxane, 120 °C, 18 h 2 TIPS + + 88% H H toluene, 80 °C, 6 h 29 OMe 11 examples + 32 (2 equiv) OMe OMe 52–94%, 29:30 83:17 to 99:<1 TIPS Ni(cod)2 (10 mol%)

X ICy•HCl (20 mol%) dioxane, 120 °C, 18 h TIPS MeO X = F 73%; X = CN 80%

Ar 30 TIPS n-Bu OMe 32 (2 equiv) TIPS Ni(cod)2 (10 mol%) TIPS 1) TBAF, H2O (73%) R Ni(cod) (10 mol%) 2 R 2) Pd(PPh ) + ICy•HCl (20 mol%) 3 4 Ph MeP (20 mol%) dioxane, 120 °C, 18 h 4-I-C6H4-Bu (73%) H 2 R toluene, 80 °C, 6 h TIPS R 5 examples: 63–99%

Scheme 35 Three-component reaction of norbornene with and (triiso- Scheme 37 Cross-coupling of silylethynylmagnesium bromide with propylsilyl)acetylene and an alkyne anisoles

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ple the TIPS group was removed with TBAF/H2O and the re- ylsilyl)acetylene was converted into enediyne 36, and [(3- sulting acetylene cross-coupled in a Sonogashira reaction to cyanopropyl)dimethylsilyl]acetylene was converted into di- the diarylacetylene (Scheme 37).43 enyne 37 (Scheme 39).8 The bromomagnesium reagents of (triisopropylsi- TIPS lyl)acetylene (32) and (tert-dimethylsilyl)acetylene were H HO Pd2dba3, CuI + I TIPS HO cross-coupled with primary and secondary alkyl iodides Li, Et3N, DMSO 3 and bromides in a Sonogashira-type reaction employing the 85% 3 iron complex 33. The reaction was tolerant of ester, amide, TIPS H TIPS and aryl bromide groups (6 examples, 69–92% yield, 2 ex- HO amples with TBS, both 83% yield). The free radical nature of 3 73% 3 the reaction was shown by the cross-coupling/cyclization of 35 TMS 44 CuCl, piperidine 34 (Scheme 38). I OH + TMS OH 3 87% The synthesis of 2-alkylated ethynylsilanes was accom- H 3 plished via a FeBr2-catalyzed coupling reaction between a I TMS OH TMS silylethynylmagnesium bromide reagent and a primary or 3 55% 36 3 secondary alkyl halide. This nicely broadens the scope of entries into 2-alkylated ethynylsilanes (Scheme 38).45 H 4 Pd(PPh3)2Cl2, CuI Br + 4 n-BuNH , benzene Br Br CPDMS 2 77% CPDMS 37 tBu tBu

TIPS t t Bu P P Bu Pd(PPh3)2Cl2, CuI tBu Fe tBu 35 + 37 4 pyrrolidine Cl Cl 3

tBu 33 tBu TIPS CPDMS Br 33 (5 mol%) + 32 TBAF, THF THF, 60 °C, 2 h Br Br 93% 82%

Ts 4 Ts N 33 (5 mol%) TIPS 3 N + 32 Br THF, 60 °C, 2 h 38 callyberyne A 92% 34

1. 34, Pd(PPh3)2Cl2 TMS TMS CuI, pyrrolidine X FeBr2 (10 mol%) 3 4 + 2. TBAF, THF 3 THF, NMP, r.t., 18 h BrMg 61% 39 callyberyne B X = I, 51%; X = Br, 48% TIPS Scheme 39 Ethynylsilanes in the syntheses of callyberynes A and B

R I SiR3 SiR3 FeBr2 (10 mol%) + O THF, NMP, r.t., 18 h BrMg R The Pd-catalyzed phenylation of 1-iodo-2-(trimethylsi- O lyl)acetylene in a Kumada-type coupling reaction illustrat- SiR3 = TES, TIPS 6 examples: 78–96% ed the potential of this route to 1-aryl-2-silylacetylenes. Numerous non-silicon terminated iodoalkynes were simi- Scheme 38 sp3-sp Cross-coupling with silylethynylmagnesium bro- 46 mide larly arylated (Scheme 40).

TMS TMS Pd(PPh3)4 + PhMgBr 10 Reactions of Haloethynylsilanes THF, 70 °C, 12 h I Ph 58% Scheme 40 Arylation of 1-iodo-2-(trimethylsilyl)acetylene A combination of the synthesis of TMS-, TIPS-, and CPDMS-substituted acetylenes and their cross-coupling with vinyl bromides and selective deprotection was effec- 1-Iodo-3-(trimethylsilyl)acetylene was converted into tively employed in the syntheses of callyberyne A (38) and (trimethylsilyl)ynamide 40, which was subsequently pro- callyberyne B (39). Thus, 1-iodo-2-(triisopropylsilyl)acety- tiodesilylated and the parent ynamide then converted into lene was converted into the skipped tetrayne 35, (trimeth- the iodoethynamide. In a more practical approach, (trimethylsilyl)acetylene and (triisopropylsilyl)acetylene were reacted in a two-step, single-flask protocol with NBS

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Syn thesis G. L. Larson Review and a secondary amine to prepare the corresponding si- (trimethylsilyl)acetylene to form 2-amino-5-(trimethylsilylated ynamide.47,48 The silylated ynamides were subse- lyl)pent-4-ynoate 42, which was subsequently protiodesil- quently reported to be excellent precursors to highly substi- ylated and the parent acetylene cross-coupled to the 4-po- tuted indolines (Scheme 41).49 sition of 43 in a total synthesis of the COPD (chronic ob- Danheiser and Dunetz were able to prepare ynamides structive pulmonary disease) biomarker, (+)-desmosine from bromo- and iodoacetylenes, including 1-bromo-2- (44) (Scheme 42).51 (trimethylsilyl)acetylene and 1-bromo-2-(triisopropylsilyl)acetylene. This work complements other approaches to Zn, TMSCl, DMF NHBoc r.t., then substituted acetylenes. The protocol was extended to in- I NHBoc TMS X CO2Bn clude cyclic carbamates, ureas, and sulfonamides, but not TMS CO2Me –20 °C to r.t. 41 with silyl-substituted acetylenes. The key to the success of 42 X = I 35%; X = Br 72% the reaction was the pre-formation of the amidocopper intermediate.50 The resulting functionalized silylacetylenes NH2 could be readily protiodesilylated to the parent alkyne 48 CO2H O (Scheme 41). BocN O CO H NH The zinc reagent from 41 was reacted with either 1- X 2 2 N Boc iodo-2-(trimethylsilyl)acetylene or better with 1-bromo-2- H2N CO2H

CO H N N 2 + O 1) KHMDS (1 equiv) TMS 43 X = I, Br H N CuI (1 equiv) 2 MeO NHBn Bn (+)-desmosine 44 2) TMS I N 3 r.t., 16 h CO2Me 40 Scheme 42 Zinc-catalyzed sp -sp cross-coupling of 1-halo-2-(trimeth- 58% ylsilyl)acetylenes

1) NBS, AgNO3 (5 mol%) Under indium catalysis 1-iodo-2-(trimethylsilyl)acety- SiR3 acetone, r.t. , 2 h SiR3 lene was reacted onto the anomeric carbon of glycals to fur- 2) BnNHTs, CuSO4•5H2O Bn nish the α-ethynyl-2,3-unsaturated-C-glycoside. Only a sin- H 1,10-phenanthroline (0.2 equiv) N K2CO3, toluene, 65 °C, 21 h Ts gle example employing 1-iodo-2-(trimethylsilyl)acetylene was reported. The trimethylsilyl group was converted into R Si = TMS 40%: R Si = TIPS 91% 3 3 the iodide in 90% yield; this was in turn used in the preparation of a C-disaccharide bridged by an ethynyl group (Scheme 43).52 KHMDS, CuI, pyr BHT (1 equiv) N AcO TMS Br toluene AcO O NH N TMS MeO2C TMS 180 °C, 16 h TMS O In (2.4 equiv) CO2Me CO2Me + AcO AcO CH2Cl2 AcO I AcO 82%, α/β = 85:15 TMS BHT (1 equiv) AcO AcO N toluene O O N R AgNO (10%) 180–210 °C, 1.25–16 h Z R 3 AcO AcO Z NIS, acetone, 1 h Z R Yield 90% Ts TMS 56% Tf TMS 68% TMS I

CO2Me TMS 74% Scheme 43 Ethynylation of glycals

CO2Me TMS 69%

The advantages of the selective chemistry of different KHMDS (1 equiv) CuI (1 equiv), pyr silyl groups was applied to the synthesis of tris(biphenyl-4- H r.t., 2 h then Ph yl)silyl (TBPS) terminated polyynes. Based on the findings N N TMS Ph CO2Me TMS Br (2 equiv) that bulky groups on the termini of polyynes provide stabil- MeO2C r.t., 20 h ity and calculations showing the TBPS group to have over 56% Ph Ph twice the radius of the TIPS group, this group was investi- N TIPS N TMS gated in the synthesis and stability of TBPS-terminated MeO2C MeO2C 74% 40% polyynes. The synthesis of the polyynes started with the reaction of lithium (trimethylsilyl)acetylide with tris(biphe- Scheme 41 Ethynylation of carbamates nyl-4-yl)chlorosilane. Selective protiodesilylation gave the

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TBPS-substituted acetylene, and NBS bromination gave 1- O SiR Cu(OTf)2 (10 mol%) bromo-2-[tris(biphenyl-4-yl)silyl]acetylene. This bromo 3 Ph H CF3CO2H (1 equiv) + derivative was cross-coupled with (trimethylsilyl)acetylene DCE, 100 °C, 30 min to give the mixed silylbuta-1,3-diyne, which was subjected Ph SiR3 to selective protiodesilylation and homocoupling to give Ph R Si = TMS (40%, desilylated); TES (67%); TBS (85%); TIPS (89%); PhMe Si (78%) 1,8-bis[tris(biphenyl-4-yl)silyl]octa-1,3,5,7-tetrayne in 77% 3 2 over two steps. Iterations of these reactions were used to O TIPS Cu(OTf)2 (10 mol%) prepare the triyne 45 and hexayne 46 (Scheme 44).53 Ar H CF3CO2H (1 equiv) + DCE, 100 °C, 30 min TMS TMS Ar TIPS Et2O Ph Si Cl + Ph 0 °C 5 examples: 0–78% 3 Li 76% TBPS TBPS-Cl Ph Ph TMS TBPS ICl, CH2Cl2 K2CO3 r.t., 5 min TBPS THF, MeOH, 0 °C SiR3 I 85% H R3Si = TES (90%); TBS (93%); TIPS (92%) TMS Br AgNO3, NBS Scheme 45 Cyclization to aromatic rings from arylacetylenes 87% TBPS TBPS

Br TMS [PdCl2(PPh3)2]/CuCl The Rh-catalyzed reaction of (trimethylsilyl)acetylenes + TBPS TMS i-Pr NH, THF TBPS H 2 with cyclobutenols gave 1,2,3,5-tetrasubstituted benzenes 54% with the trimethylsilyl group regioselectively positioned in 1. NaHCO3 the 2-position. No conversions of the trimethylsilyl group THF, MeOH, 0 °C (93%) 55 TBPS TMS TBPS TBPS were carried out in this work (Scheme 46). 2. CuCl, TMEDA CH2Cl2, O2 (83%) n-Bu n-Bu OH TMS TMS TBPS TBPS TBPS TBPS [Rh(OH)(cod)]2 (2.5 mol%) 45 46 + rac-BINAP (6 mol%) Ph Scheme 44 Synthesis of polyynes Ph toluene, 110 °C, 3–3.5 h 50%; rr = >99:1; w/o rac-BINAP 93%; rr = 93:7 11 Cycloaddition Reactions Scheme 46 Cyclobutenol to a TMS-substituted arene

Silylacetylenes, like many alkynes, undergo an extensive Methyl 3-(trimethylsilyl)propynoate was successfully variety of cycloaddition reactions. In many cases based on employed in the synthesis of 2H-quinolizin-2-ones. In this electronic and steric factors the silyl group can impart use- approach the trimethylsilyl group conveniently served the ful regio- and stereoselectivities in addition to the ability to purpose of protecting the acidic hydrogen of the parent ter- chemically transform the silyl group to other useful func- minal acetylene (Scheme 47).56 tionalities. 1) LDA, THF, –78 °C O 11.1 Formation of Aromatic Rings 2) TMS O OMe N The tricyclization of alkynes to aromatic rings has long N 3) TBAF, THF, r.t., 0.5 h been recognized, as has the use of silylacetylenes in this 4) MeCN, 50 °C 6 examples: 43–60% practice. Silyl-protected arylacetylenes reacted with 2- Scheme 47 Quinolizin-2-ones from methyl 3-(trimethylsilyl)propy- (phenylethynyl)benzaldehyde under acid catalysis to pro- noate duce the 2-aryl-3-silylnaphthalene in good yield. The TMS- protected arylalkynes resulted in the formation of 2-aryl- naphthalene with protiodesilylation taking place under the The cationic rhodium catalyst [Rh(cod)2]BF4/BIPHEP reaction conditions. However, the more hindered TES-, TBS- brought about the cyclotrimerization of (trimethylsi- , and TIPS-protected derivatives gave the corresponding 3- lyl)acetylene and unsymmetrical electron-deficient acety- silylnaphthalenes allowing for the ICl ipso iodination of the lenes. Unfortunately, neither the stoichiometry nor the re- silyl group to provide the iodonaphthalene for further elab- gioselectivity of the cyclization was optimal. Larger silyl oration via cross-coupling chemistry. The chemistry was groups tended to favor the addition of one of the silylacety- applied to the synthesis of several highly encumbered pol- lene moieties and two of the electron-deficient alkynes, yaromatic systems (Scheme 45).54 whereas increasing the steric bulk of the electron-deficient

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Syn thesis G. L. Larson Review alkyne resulted in the reaction of two equivalents of the si- of the silyl groups were carried out including protiodesil- lylacetylene. (Triisopropylsilyl)acetylene failed to react. ylation, acylation, iodination, and Denmark cross-coupling. Protiodesilylation of a mixture of regioisomers was able to It is noteworthy that the iododesilylation of 48 was selec- simplify the reaction mixture, but reaction with ICl gave a tive for the formation of 49 and that iododesilylation of a synthetically challenging mixture of isomers in modest phenyl group from the Ph2MeSi group did not occur. Com- yield (Scheme 48).57 parable selectivity was noted in the acetylation of 48 to 4- phenylacetophenone (Scheme 50).59 TMS CO Et TMS TMS 2 CO2Et CO2Et Ph + [Rh(cod) ]BF (10 mol%) Ph 2 4 + R3Si SiMePh2 SiR3 BIPHEP (10 mol%) TMS SiMePh2 Pd(OAc)2 (5 mol%) + 19% CO Et i-Pr NEt, 30 °C, 24 h CH2Cl2, r.t., 16 h 2 I 2 58% SiR3 TMS TMS R3Si = PhMe2Si (93%); Ph2MeSi (89%); (i-PrO)2MeSi (80%); TES (34%) CO2Et Ph Ph + + TMS SiMePh2 TMS SiMePh2 EtO2C EtO2C CO2Et ICl (1.2 equiv)

CH2Cl2, 0 °C to r.t., 16 h 10% 3% 64% TMS 48 I 49 Ph TES I I TES CO2Et TES CO2Et CO2Et ICl (3.4 equiv) 48 + [Rh(cod)2]BF4 (10 mol%) + CH2Cl2, 0 °C to r.t., 16 h 48% BIPHEP (10 mol%) TES I 4% CO2Et CH2Cl2, r.t., 16 h Ph Ph 38% TMS SiMePh2 AcCl (3.4 equiv) TBAF (8 equiv) TES TES 48 AlCl (3.4 equiv) THF, rt, 15 h CO2Et 3 81% + + CH2Cl2, rt, 3 h 64% O O EtO2C EtO2C CO2Et Ph Ph 6% 1% (i-PrO)Me2Si SiMePh2 HMe2Si SiMePh2 Scheme 48 Mixed substituted arenes from cross-cyclization of LiAlH4 (trimethylsilyl)- and (triethylsilyl)acetylene with ethyl but-2-ynoate dioxane, 80 °C, 18 h

(i-PrO)Me2Si HMe2Si

Ph Ph The cyclotrimerization of ethyl 3-(trimethylsilyl)propy- Pd(PPh3)4 (10 mol%) HOMe Si SiMePh noate gave 47 as a single regioisomer in 92% yield (Scheme 2 2 Ph SiMePh2 Pd/C, H2O Ag2O (3 equiv) 58 49). hexane, r.t., 6 h PhI (6 equiv) TBAF (0.2 equiv) TMS HOMe2Si Ph 32% TMS Ni(cod)2 (1 mol%) THF, 65 °C, 16 h EtO2C TMS SIPr (1 mol%) 3 Scheme 50 Cyclotrimerization with a vinyl iodide and subsequent THF, 23 °C, 24 h EtO C CO Et conversions EtO2C 92% 2 2 TMS 47 11.2 Diels–Alder Cyclizations Scheme 49 Homocyclization of ethyl 3-(trimethylsilyl)propynoate Silylacetylenes were shown to provide excellent re- Complete regioselection in the formation of 2-aryl- giochemical control in the cobalt-catalyzed Diels–Alder re- 1,3,5-tris(silyl)benzene was realized in the Pd-catalyzed reaction with 1,3-dienes. In the unsubstituted case various action of two equivalents of a terminal alkyne, including (trialkylsilyl)- and (triphenylsilyl)acetylenes were reacted (trimethylsilyl)acetylene, and an equivalent of a β-iodo-β- with 2-methylbuta-1,3-diene under cobalt catalysis. The silylstyrene. The nature of the silylstyrene proved crucial as regioselectivity was highly dependent on the accompany- trialkylsilyl (TMS, TES, TBS, Me2BnSi) groups gave poor ing ligand employed with CoBr2(py-imin) [py-imin = N-me- yields and the phenylated silyl groups gave better yields, sityl-1-(pyridin-2-yl)methanimine, 56] favoring the meta with the β-Ph2MeSi-substituted styrene proving optimal. regioisomer 50 after DDQ oxidation to the aromatic deriva-

Selective electrophilic substitution of the 5-(trimethylsilyl) tive. On the other hand, the use of CoBr2(dppe) [dppe = 1,2- group, para relative to the aromatic substituent, proved bis(diphenylphosphino)ethane] favored the para isomer 51. possible. In a demonstration of the potential synthetic utili- In addition a number of 1-(trimethylsilyl)alk-1-ynes were ty of the highly silylated systems, a number of conversions reacted with 2-methylbuta-1,3-diene. Here the yields were

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very high, but the regioselectivity was less than that ob- ICl/CH2Cl2 gave only 5% of the iodide 54, NIS/MeCN gave served with the simple silylacetylenes. Of particular inter- modest yields of the iodide in 5 cases, but the reaction was est was the result from the reaction of 3-(trimethylsi- very slow and product decomposition led to purification lyl)propargyl acetate with Danishefsky’s diene, 2-(trimeth- difficulties. The combination of H2O2/ZnI2 gave modest ylsiloxy)buta-1,3-diene (Scheme 51).60 yields, but again in a slow reaction that required further oxidation with DDQ for completion. Finally, the use of tert-

1) CoBr2(py-imin) (10 mol%) butyl hydroperoxide with ZnI2 and K2CO3 was found to give 61 Fe powder (20 mol%) high yields of the desired iodides (Scheme 52). SiR SiR3 3 Zn dust (20 mol%) + + ZnI (20 mol%) 1) CoBr (55 or 56) (10 mol%) 2 TMS 2 SiR3 TMS 2) DDQ 50 51 Zn (20 mol%), ZnI2 (20 mol%) R1 + R1 R Si = TMS, TES, TIPS, TBS, Ph Si 3 3 CH2Cl2, r.t., 24 h 2 80–92%; 50:51 = 92:8–96:4 R2 R 2) SiO2 filtration TBHP (4.0 equiv)

1) CoBr2(dppe) (10 mol%) ZnI2 (2.0 equiv) SiR3 SiR3 Zn dust (20 mol%) K2CO3 (4.0 equiv) + + CH2Cl2, r.t., 15 min ZnI2 (20 mol%) Ph2P PPh2 SiR3 N N Mes 2) DDQ 50 51 55 56 I R Si = TMS, TES, TIPS, TBS, Ph Si 3 3 R1 72–93%; 50:51 = 4:93–8:92 R2 54 1) CoBr (py-imin) (10 mol%) 2 11 examples Fe powder (20 mol%) 47–89% TMS R TMS Zn dust (20 mol%) + + Scheme 52 Diels–Alder cyclization to cyclic 1,4-dienes ZnI2 (20 mol%) TMS R R 2) DDQ 52 53 9 examples: 72–96%; 52:53 = 98:2–18:82 11.3 Formation of Heterocycles

1) CoBr2(dppe) (10 mol%) TMS The diynes 57 were subjected to cyclotrimerization Zn dust (20 mol%) + 52 + 53 with hex-1-yne; the TMS-substituted derivative (R = TMS) ZnI2 (20 mol%) R 2) DDQ gave considerably better yields and regioselectivities than 9 examples: 76–97%; 52:53 = 21:79– 5:95 the protonated analogues (R = H). Interestingly, the applica- tion of this cyclotrimerization towards the synthesis can- 1) CoBr (py-imin) (10 mol%) 2 nabinols employed the use of 3-(trimethylsilyl)prop-1-yne TMS Fe powder (20 mol%) O TMS (instead of hex-1-yne), which showed clean regioselectivity Zn dust (20 mol%) + to give 61 from 60. The bis(trimethylsilyl)arene 61 was pro- ZnI2 (20 mol%) TMSO tiodesilylated to 62, which was carried through to cannabi- 2) DDQ OAc 81% nol (63) (Scheme 53).62

TMS 1) CoBr2(py-imin) (10 mol%) n-Bu TMS Zn dust (20 mol%) H R + n-Bu Cp*Ru(cod)Cl (10 mol%) ZnI2 (20 mol%) OAc X + H TMSO HO toluene, MW 300 W, 10 min R + 2) SiO2, air O R X Yield 58:59 OAc n-Bu 80% R O X 57 H H2 61% 70:30 58 O X Scheme 51 Diels–Alder cyclization of silylacetylenes with 1,3-dienes TMS O 97% >95:5 H H2 31% 76:24 59 TMS O 81% >95:5 TMS

The synthesis of aryl and vinyl iodides has taken on in- OMe H Cp*Ru(cod)Cl (10 mol%) OMe creased importance due to their facility as electrophilic + TMS toluene, MW 300 W, 10 min TMS partners in various cross-coupling reactions. Building on n-C5H11 O n-C H O 60 TMS 5 11 the Diels–Alder chemistry of butadienes with (trimethylsi- 61 lyl)acetylenes, the Hilt group devised an efficient route to OMe highly substituted aryl iodides wherein the TMS group OMe TBAF, THF, DMF 61 served nicely to define the regiochemistry and provide the MW, 300 W, 2 min 96% n-C5H11 O iodide functionality. The complete reaction sequence could n-C5H11 O cannabinol 63 be carried out in a single flask although considerable effort 62 was placed on the oxidation/iodination step. For example, Scheme 53 Cyclizations leading to cannabinols

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Syn thesis G. L. Larson Review

Under strong base catalysis, 1-aryl-2-silylacetylenes Whereas the Ru-catalyzed reaction of an internal were converted into oxasilacyclopentenes upon reaction alkyne, carbon monoxide, and an enone produced hydro- with aldehydes or ketones. The reaction required that the quinones in a [2+2+1+1]-cycloaddition reaction, (trimethylsilyl moiety contain a Si–H bond [SiHMe2, SiH(i-Pr)2, silyl)acetylenes reacted in a [3+2+1] fashion to form an α-

SiHPh2]. Among the catalysts investigated KOt-Bu was clear- pyrone, wherein the carbonyl and α-carbon of the enone ly superior, with fluoride ion sources tending to give more provided three atoms. The resulting 3-(trimethylsilyl)-2H- of the product of direct alkynylation of the carbonyl. Silylal- pyran-2-ones were not elaborated further (Scheme 56).65,66 kynylation of the carbonyl followed by base-catalyzed intramolecular hydrosilylation of the C≡C bond is proposed. O O TMS Ru3(CO)12 (6 mol%) TMS 4-Methoxyphenyl- and 2-tolyl-substituted (dimethylsi- 2 R Et2MeN•HI (20 mol%) O + lyl)acetylenes on reaction with cyclohexanone gave only toluene, 160 °C 3 1 2 R R1 R R alkynylation of the ketone, but 4-fluorophenyl- and 4-(tri- CO (20 atm) fluoromethyl)phenyl-substituted (dimethylsilyl)acetylenes R3 gave good yields of their respective oxasilacyclopentenes (8 12 examples: examples, 48–87% yields). The oxasilacyclopentene 64 was 15–59% shown to have synthetic utility as it could be oxidized, ep- Scheme 56 Carbonylative cyclization with an enone oxidized, and cross-coupled all in good yield (Scheme 54).63 The reaction of 1-(methoxydimethylsilyl)-2-phenyl- SiMe2 SiMe2H O OH acetylene with propanenitrile oxide, generated in situ from O KOt-Bu (10 mol%) Ph + 1-nitropropane and phenyl isocyanate, gave a mixture of 4- THF, r.t., 15 min + Ph Ph and 5-silylated isoxazoles favoring formation of the 4-silyl 64 86% 10% isomer. Acid hydrolysis of this mixture allowed isolation of the pure 4-dimethylsilanol derivative in 49% overall yield.

SiMe2 In a similar manner the ‘in situ’ generated benzonitrile ox- SiMe2H O OH O CsF (10 mol%) Ph ide reacted to give, after hydrolysis, the corresponding 4-si- + THF, r.t., 1 h + lanol products. These silanols were subjected to Denmark Ph Ph 11% 58% cross-coupling protocols to take advantage of the position of the silyl group to introduce aryl substituents at the 4-po- OH O sition of the isoxazole. Unfortunately, in addition to the H2O2, LiOH, KF THF, MeOH Ph

77% PhNCO (5 equiv) SiMe2 SiMe2 N O O NO Et N Et 2 O O Ph Ph Et3N (40 mol%) DMDO + + O toluene, 100 ° 70% Ph SiMe2OMe MeOMe2Si Ph Ph SiMe2OMe 89% conversion 64 67 68 67:68 3.4:1 OH HOAc TBAF, CuI, THF MeCN, r.t. allyl chloride Ph Et N 72% O

Scheme 54 Oxasilacyclopentenes via cyclization with ketones HOMe2Si Ph

Cyclotrimerization of 65 (R = TMS) with 4-hydroxypen- 1) KHCO3 (3 equiv) N SiMe OMe OH Ph 2 N dioxane, reflux O tanenitrile gave the desired product regioselectivity, albeit + R 2) AcOH, MeCN in only 42% yield, this compared to 83% yield from the par- Ph Cl HOMe2Si R R = Ph (52%); Me (33%) ent diyne 66 (R = H) (Scheme 55).64

OH NC N CpCo(CO)2 OH Ph O Ph N I MW, xylenes O Pd2dba3•CHCl3 (5 mol%) N R N + MeO 65 42% N NaOt-Bu (2.5 equiv) R1 O 2 66 83% 1 R MeO O HOMe2Si R 65 R = TMS dioxane 80 °C 66 R = H R2 1 2 Scheme 55 Cyclization of a silylated skipped diyne with a nitrile R , R = Ph, Me (69%); Ph, OMe (68%); Ph, NO2 (55%); Me, Me (60%); Me, OMe (63%) Scheme 57 Cyclization to isoxazoles

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Syn thesis G. L. Larson Review cross-coupling reaction product, a considerable amount of TMS protiodesilylated isoxazole was also generated (Scheme TMS NBn Ph 67 [RhCl(coe) ] (2.5 mol%) NBn 57). + 2 2 In a study involving the addition of 2-substituted pyri- Ph 4-Me2NC6H4-PEt2 (5 mol%) dines with 3-substituted propargyl alcohols to give indol- toluene, 65–100 °C 70 izines, 1-phenyl-3-(trimethylsilyl)prop-2-yn-1-ol was re- not isolated Ph acted with ethyl 2-pyridylacetate to give the TMS-substi- Me4NBH(OAc)3 NBn 70 tuted indolizine 69 (Scheme 58). The TMS group was not (PhO)2PO2H 68 reacted further in this work. CH2Cl2, r.t. The acid-catalyzed reaction of 1-phenyl-3-(trimethyl- 85%, dr = >20:1 silyl)prop-2-yn-1-ol with a series of primary amides gave CO2Me 2,4-disubstituted 5-[(trimethylsilyl)methyl]oxazoles in ex- CO2Me Ph Bn cellent yields. The preferred Brønsted acid for this useful (PhO)2PO2H N 70 + CO Me 69 2 conversion was PTSA (Scheme 58). CH2Cl2, 0 °C–r.t. MeO2C

70%, dr 15:1 OH Sm(OTf)3 (10 mol%) + N CO2Et Ph CO2Et 120 °C, neat, 6 h 1) PhSO H, CH Cl N 3 2 2 81% Ph TMS TMS Ph –78 °C, 2 h NBn 69 70 2) Me4NBH(OAc)3 –78 °C to r.t. OH H O Ph 75%; dr 7:1 PTSA + N Ph TMS Scheme 59 Cyclization of 1-alkyl- or 1-aryl-substituted 2-(trimethylsi- R NH2 toluene, reflux R TMS O 10 examples: 78–92% lyl)acetylenes with α,β-unsaturated imines and subsequent reactions Scheme 58 Cyclization with 3-(trimethylsilyl)propargyl alcohols

O O 1-Alkyl- or 1-aryl-substituted 2-(trimethylsilyl)acety- TMS TMS Ni(cod)2 (10 mol%) O + lenes were used as alternatives to terminal acetylenes in PPh3 (20 mol%) S S the synthesis of tetrahydropyridines (18 examples, 54–96% toluene, 50 °C, 6 h 58%; single isomer yield; dr 20:1). In this approach the presence of the trimethylsilyl group also facilitated the generation of an O O azomethine ylide, which could be further converted. Thus, TMS TMS(H) Ni(cod)2 (10 mol%) reaction of an α,β-unsaturated imine with the 1-alkyl- or 1- O + PPh3 (20 mol%) aryl-substituted 2-(trimethylsilyl)acetylenes gave the die- S S H(TMS) toluene, 50 °C, 6 h nyl imine, which underwent an intramolecular aza-cycliza- 90%; rr = 6:1 tion reaction. The resulting 2-silyl-1,2-dihydropyridine was Scheme 60 Cyclization of 1-(trimethylsilyl)prop-1-yne with thioisotin reductively desilylated to the tetrahydropyridine, reacted with an alkyne to give a tropane derivative (7 examples, Ph Ph 48–83% yield, dr 15:1 to 20:1, or reacted via a desilylative Ni(cod)2 (5 mol%) N Ph R N O Me PhP (20 mol%) electrocyclization to give a 2-azabicyclo[3.1.0] system + 2 70 O MAD (10 mol%) (Scheme 59). CN Me(R) toluene, 120 °C, 12 h The reaction of thioisotin with 1-(trimethylsilyl)prop- R(Me) 1-yne gave a single regioisomeric -3-(trimethylsilyl)-4H- R = TMS; 71%, rr = >20:1 benzothiopyran-4-one in a decarbonylative cyclization pro- R = t-Bu; 71%; rr = 2:1 cess. The reaction with (trimethylsilyl)acetylene, however, Scheme 61 Decyanative cyclization of 1-(trimethylsilyl)prop-1-yne provided a 6:1 mixture of regioisomers (Scheme 60).71 with N-(2-cyanophenyl)-N-phenylbenzamides In an interesting cyclization N-(2-cyanophenyl)-N- phenylbenzamides were reacted with internal acetylenes to The Ni-catalyzed [4+2] cycloaddition of an internal give quinolones. When 1-(trimethylsilyl)prop-1-yne was alkyne with an azetidin-3-one resulted in the formation of employed the trimethylsilyl group was placed on the 4-po- various piperidines. Interestingly, the (trimethylsilyl)acety- sition with high regioselectivity as compared to that of the lene derivatives employed showed reversed regioselectivity tert-butyl analogue (Scheme 61).72 to those of the tert-butyl and trimethylstannyl analogues. Although the carbonyl and Boc groups were reduced with

LiAlH4, reactions of the trimethylsilyl group were not at-

Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–AD Q

Syn thesis G. L. Larson Review tempted on these systems. When phenylacetylene deriva- 1,4-Bis(trimethylsilyl)buta-1,3-diyne is thermally stable tives were reacted, 1-phenyl-2-(trimethylsilyl)acetylene and, therefore, serves as an excellent substitute for the ther- gave the same regioselectivity as 1-(trimethylsilyl)prop-1- mally sensitive buta-1,3-diyne. It was employed in a yne, but 1-phenyl-2-(trimethylstannyl)acetylene and 1- [2+2+2] cyclization with the alkynyl nitrile 75. The reaction (trimethylstannyl)prop-1-yne reversed their regioselectivi- was extended to 1-aryl-2-(trimethylsilyl)acetylenes, ty. A total of four different (trimethylsilyl)acetylene deriva- wherein the trimethylsilyl group dictated the regioselectiv- tives was investigated (Scheme 62).73 ity to place the trimethylsilyl group on the 3-position of the

O O Ni(cod) (10 mol%) O R 2 R 1 PPh (10 mol%) R + 3 + N N N toluene, 60 °C CpCo(CO) Boc Boc Boc R 2 + R Yield 71:72 CN THF, 140 °C 71 72 N N N t-Bu 93% <5:95 R1 R2 Yield Bn Bn TMS 92% >90:10 R2 TMS TMS 81% 75 Bu Sn 89% <5:95 3 TBS TBS 63% R1 R2 TMS TIPS 52% 76 R1,R2 = TMS O O R Ni(cod)2 (10 mol%) O R Ph 1) 76, TBAF, THF 77 R1,R2 = H PPh (10 mol%) + 3 + 0 °C N toluene, 60 °C N N 2) LHMDS, TMSCl 78 R1= H; R2 = TMS Boc Ph Boc Ph Boc R THF, 0 °C, 77% R Yield 73:74 73 74 over 2 steps TMS 82% >95:5

Bu3Sn 83% >95:5 Scheme 62 Cyclization of (trimethylsilyl)acetylene derivatives with azetidinones N N R H Bn CpCo(CO)2 Bn In an approach to complanadine A and various lycodine + 75 N N derivatives the Siegel group, 1,4-bis(trialkylsilyl)buta-1,3- N N THF, 140 °C 40% + 8% undesired isomer 80 diynes were used in a [2+2+2] cycloaddition strategy. Thus, O H the key intermediate cyanoalkyne 75 was prepared on a R = TMS H 79 TMS TBAF gram scale and reacted with three different 1,4-bis(trialkyl- dioxane, 101 °C 82% R = H silyl)buta-1,3-diynes; 1,4-bis(trimethylsilyl)buta-1,3-diyne gave the best yield of the 2-alkynylated pyridine 76 when R1 H H H the reaction was carried out with CpCo(CO)2 as catalyst. A CpCo(CO)2 small amount of the (trimethylsilyl)ethynyl group was pro- + + CN THF, 140 °C, hν N N N N N tiodesilylated upon silica gel chromatography and 76 was Bn R2 70% Bn Bn cleanly protiodesilylated upon treatment with TBAF/THF to 75 R1 R2 Yield 82:83 77. Trimethylsilylation of the terminal alkyne 77 then pro- TMS TMS 81% 25:1 R2 R1 vided alkynylsilane 78, which was subjected to the TBS TBS 63% 1:0 52% 82 83 TMS TIPS 1:0 R2 CpCo(CO)2-catalyzed [2+2+2] cycloaddition with 75. This provided the undesired 2,2′-bipyridine derivative in a modest 43% yield. After considerable study and effort it was H found that modification of the cyanoalkyne 75 to the N- S CpCo(CO)2 formyl-cyanoalkyne 79 and reaction with 78 with added 75 + THF, 140 °C, hν N N Bn triphenylphosphine and under very dilute 5 mM conditions 51% gave an acceptable yield of the desired 2,3-bipyridyl struc- TMS ture 80, which was protiodesilylated and deprotected to TMS S complanadine A (Scheme 63). In model studies several 1- H H aryl-2-(trimethylsilyl)acetylenes were reacted with 75 to TMS 1. TBAF, dioxane CpCo(CO)2 101 °C (97%) give the 2-aryl-3-(trimethylsilyl) cycloaddition products in 75 + ν THF, 140 °C, h N N 2. Pd/C, H2 N N low to modest yields. In none of these cases was the Bn H TMS 51% trimethylsilyl group reacted further. A facile conversion of THF, 23 °C (95%) lycodine 75 into lycodine was presented wherein the cycloadditions TMS was carried out with bis(trimethylsilyl)acetylene followed Scheme 63 Cyclizations of alkynylsilanes with alkyne functional nitriles by protiodesilylation and deprotection in a 24% overall yield (Scheme 63).5,74

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Syn thesis G. L. Larson Review pyridine ring formed. The yields were modest, ranging from TMS 5 Pd(PPh3)2Cl2 (1 mol%) <5% to 62% over 9 examples (Scheme 63). I TMS CuI (5 mol%) 1 R1 + R DIPA (2 equiv), EtOH argon, 25 °C, 2–3 h 11.4 Formation of 1,2,3-Triazines 2 1) R N3, 5 min 20 examples: 24–77% 2) TBAF•H2O A series of 1,4-disubstituted 1,2,3-triazines 84 was pre- 25 °C, 12 h pared in a one-pot, three-step sequence involving first a So- N N N R2 nogashira preparation of a 1-aryl-2-(trimethylsilyl)acety- 84 R1 lene from (trimethylsilyl)acetylene, reaction with an alkyl BnBr, NaN3 TMS Bn K2CO3, CuSO4 N N N N azide and, finally, deprotection of the 5-trimethylsilyl N Bn + N pyridine, ascorbic acid group (Scheme 64).75 Ar Ar Ar MeOH, H2O, 18–24 h 85 traces 1-Aryl-2-(trimethylsilyl)acetylenes, readily formed via a 19 examples: 57–96%

Sonogashira reaction from (trimethylsilyl)acetylene, react- RX (X = Br, I), NaN3 TMS R K2CO3, CuSO4 N N N N ed with sodium azide and an alkyl bromide in a three-step, N R + N one-pot sequence to yield a desilylated 1-alkyl-4-aryl- Ar pyridine, ascorbic acid Ar Ar MeOH, H O, 19–24 h 2 86 traces 1,2,3-triazole 85 or 86. The reaction took place via initial 6 examples: 38–68% deprotection of the trimethylsilyl group followed by the CuBr (15 mol%) TMS Et3N (1 equiv) N N [3+2] click cycloaddition. This represents a safe and scalable + BnN 3 N Bn process for the formation of 1,4-disubstituted 1,2,3-tri- DMF, 100 °C R R or DMF-H2O 87 76 azoles (Scheme 64). DMF, 8 examples: 57–94% DMF-H2O, 8 examples: 43–97% The reaction of 1-(trimethylsilyl)alk-1-ynes with CuBr/Et3N SiR3 CuBr (15 mol%) N N served to directly prepare the alkynylcopper reagent with- + BnN 3 N Bn Et3N (1 equiv) R3Si out prior desilylation. The resulting copper reagent under- DMF, 100 °C went reaction with various azides to form the 1,2,3-tria- R3Si = TMS (77%), TIPS (91%) zenes 87 in excellent yields. When the reaction was carried O O O Cl Cl Cl out with (trimethylsilyl)acetylene or (triisopropylsilyl)acet- N NaN N TMS CO2Et 3 N CO2Et N N N ylene, the reaction occurred at the C–H terminus. TIPS- and Cl DMF, r.t., 2 h, N 100 °C, 4 h 3 N TMS 77 88 50 °C, 2 h TBS-terminated acetylenes failed to react (Scheme 64). N N NH The dichloropyridazine 88 was converted into the 2 1) r.t., 3 h [1,2,3]triazole-fused pyrazinopyridazinedione 89 in a 2) 70 °C, 2 h MeO three-step sequence with ethyl 3-(trimethylsilyl)propy- OMe noate. The TMS group was lost in the last step of the se- O HN O quence, but provides the desired regioselectivity in the N 78 N azide click step of the sequence (Scheme 64). N 89 N N 11.5 [2+3] Cycloadditions Scheme 64 Formation of 1,2,3-triazoles via click chemistry on alkynylsilanes The reaction of ethyl and methyl 3-(trimethylsilyl)propynoate with 2-formylphenylboronic acid under

[Rh(OH)(cod)]2 catalysis gave 3-(trimethylsilyl)-1H-inden- a (trimethylsilyl)acetylene, and paraformaldehyde, al- 1-ols 90 in high yield and with high regioselectivity. Similar though the reaction took longer and required a higher tem- results were realized with 2-acetylphenylboronic acid. 1,4- perature (Scheme 65).80 Bis(trimethylsilyl)buta-1,3-diyne reacted with 2-formyl- Benzoyltrimethylsilanes reacted with (trimethylsi- phenylboronic acid to give the enyne 92 in high yield lyl)acetylenes under Au catalysis to form indan-1-ones. (Scheme 65).79 Mechanistic studies showed that a migration of the acylsilyl In a related approach 2-bromo- and 2-chlorophenylbo- group to the C≡C bond occurred to form the 2-(trimethylsi- ronic acids underwent a carbonylative cycloaddition with lyl)indan-1-one; the trimethylsilyl group was lost upon various alkynes including (trimethylsilyl)acetylenes to give workup. On the other hand the more sterically hindered

1H-inden-1-ones; the reaction was catalyzed by RhCl(cod)2. and stable benzoyl(tert-butyl)dimethylsilane gave the 2- With the exception of ethyl 3-(trimethylsilyl)propynoate, (tert-butyldimethylsilyl)-substituted indanone. The reac- the regioselectivity was very high. 1H-Inden-1-ones were tion proceeds through the formation of the interesting 2- also formed via the reaction of 2-bromophenylboronic acid, (trimethylsilyl)-substituted silyl enol ether (Scheme 66).81

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Syn thesis G. L. Larson Review

TMS OH OH the terminal acetylene with concomitant formation of the CHO [Rh(OH)(cod)2] (2 mol%) + CO R + TMS enone moiety. A competition experiment using equimolar dioxane, r.t., 3 h 2 RO2C B(OH)2 amounts of ethyl cyclopropylidene acetate, 1-ethynyl-2- R Yield 90:91 TMS CO2R Me 99% 96:4 90 91 (trimethylsilyl)-1H-pyrrole, and 1,4-bis(trimethylsilyl)bu- Et 95% 96:4 ta-1,3-diyne and hexadeca-7,9-diyne resulted in the reac- TMS OH tion of the hexadecadiyne to the exclusion of the CHO [Rh(OH)(cod)2] (2 mol%) 82 + TMS bis(trimethylsilyl)butadiyne (Scheme 67). dioxane, r.t., 3 h TMS B(OH)2 90% TMS 92 TMS CO Et 2 Ni(cod) (10 mol%) TMS O 2 Br CO Et [RhCl(cod)] (5 mol%) 2 2 2 + O + PPh3 (20 mol%) + R R2 TMS Na CO , CO (1 atm) R1 B(OH)2 2 3 toluene, 50 °C, 24 h dioxane,/H2O, 80 °C, 20 h 1 R R = TMS (63%), n-Hex (32%) 1 R 10 examples: 51–95%; isomeric ratio 1:0 except where R = CO2Et; 1.5:1 TMS O R TMS O Cl [RhCl(cod)]2 (5 mol%) CO2Et + TMS Na2CO3, CO (1 atm) CO2Et B(OH)2 Ph dioxane,/H2O, 80 °C, 20 h TBAF (1.2 equiv) Ph 77% HOAc (1.2 equiv) TMS THF, 0 °C, 30 min TMS [RhCl(cod)]2 (5 mol%) O O R H Br R = TMS 91%; R = n-Hex 87% BINAP (1 mol%) O R + R2 R2 TMS 1 (CH2O)n (5 equiv) R B(OH)2 Na2CO3, CO (1 atm) R1 CO2Et dioxane/H2O, 100 °C, 30 h 6 examples: 36– 69% R Ni(cod) (10 mol%) isomeric ratio 1:0 CO2Et TMS 2

PPh3 (20 mol%) Scheme 65 [2+3] Cycloadditions of silylacetylenes with 2-functional- + N + R ized phenylboronic acids toluene, r.t., 24 h N R R = TMS (0%), n-Hex (59%) R

Scheme 67 Mixed diyne cyclization with ethyl cyclopropylideneace- OTMS tate O TMS 1) (ArO)3PAuNTf2 (5 mol%) DCE, 70 °C TMS + TMS 2) MeOH A Rh-catalyzed [2+2+1] cross-cyclotrimerization of (tri- p-Tol 3) PPh3 p-Tol isopropylsilyl)acetylene with propynoate esters gave the si- 93% lyl-substituted fulvene in modest to excellent yield. The use O O of (triethylsilyl)-, (tert-butyldimethylsilyl)-, and (tert-bu- TMS 1) (ArO) PAuNTf (5 mol%) R2 3 2 R2 TMS DCE, 70 °C tyldiphenylsilyl)acetylenes gave poor yields of the cyclic tri- + mer. N,N-Dimethylbut-2-ynamide and (triisopropylsi- 3 2) MeOH 3 R R1 R 3) PPh3 1 lyl)acetylene gave a very poor yield of fulvene product, with R4 R4 R 19 examples: 45–93%

TMS O TIPS O 1) (ArO)3PAuNTf2 (5 mol%) DCE, 70 °C CO Et TBS + TBS 2 TIPS CO2Et 2) MeOH [Rh(cod)2]BF4 (5 mol%) p-Tol 3) PPh + 2 3 p-Tol 1,4-dioxane, 80 °C, 16–24 h 69% EtO2C 80% 13 examples: 47–89%, E/Z 94:6–31:69 Scheme 66 [2+3] Cycloadditions of silylacetylenes with benzoylsilanes

CONMe O NMe2 TIPS 2 TIPS [Rh(cod)2]BF4 (5 mol%) + 2 11.6 Other Cycloadditions 1,4-dioxane, 80 °C, 24 h 78% A three-component co-cyclization involving ethyl cyclo- TIPS propylideneacetate, a 1,3-diyne, and a heteroatom-substi- CO2Et 2 CO2Et RhCl3•H2O (1 equiv) tuted acetylene gave highly functionalized cyclohepta-1,3- Cl EtOH, 80 °C, 16 h Rh dienes. The 1,3-diynes reacted at only one of the C≡C bonds. 88% EtO2C EtO2C Cl When 1-(trimethylsilyl)deca-1,3-diyne was reacted, the 93 2 hexyl-substituted C≡C bond was the one that reacted to give the cycloheptadiene ring. Protiodesilylation provided Scheme 68 Formation of silylated fulvenes

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ethynylation of the C≡C bond as the predominant pathway. O O TMS Ni(cod)2 (10 mol%) The silylfulvene was reductively complexed with Rh(III) to Me3P (20 mol%) 83 N N + N N give the rhodium dimer 93 (Scheme 68). MAD (20 mol%) R toluene, 110 °C, 2 h O R TMS 12 Additions to the C≡C Bond 11 examples: 64–90% Scheme 70 Decarbonylative addition to a silylacetylene

The Ru-catalyzed hydroacylation of 4-methoxybenzal- dehyde with 1-(trimethylsilyl)prop-1-yne gave a mixture of The olefination of ynolates was accomplished with 3-si- isomeric trimethylsilyl dienol ethers 94 and 95.84 The reac- lylpropynoates giving excellent selectivity for the E-enyne. tion of a tertiary amine with methyl 3-(trimethylsilyl)pro- Ag-catalyzed cyclization of the resulting enynes was carried pynoate gave addition of the amine to the C≡C bond and the out to give either the 5-exo-tetronic acid derivatives or the formation of an allenoate ion. This, in the presence of an 6-endo-pyrones. The triethylsilyl-tetronic acid 99 was ste- arylaldehyde, gave predominantly bis-addition of the alde- reoselectively converted into the corresponding iodide 100, hyde resulting in two products 96 and 97; aliphatic alde- which was in turn subjected to phenylation via a Suzuki hydes gave addition at the C–H terminus of the C≡C bond to cross-coupling and to ethynylation via Sonogashira cross- give 98. No reaction occurred with ethyl but-2-ynoate indi- coupling (Scheme 71).88 cating that the trimethylsilyl group was essential (Scheme 85 O 69). OLi OR CO2H THF + O –78 to–20 °C, 1 h RO TMS OMe R Si R Si Yield E/Z H 3 R 3 SiR RuHCl(CO)(PPh ) (2 mol%) 3 + 3 3 OMe i-Bu TMS 51% >99:1 MeO toluene, 100 °C, 18 h i-Bu TES 41% >99:1 + Et TBS 63% 98.5:1.5 76% (NMR); 94:95 = 16:1 O TMSO CO2H Ag2CO3 (10 mol%) 94 TMSO O RO DMF, r.t., 1 h 95 RO SiR 3 R = i-Bu, R3Si = TBS 93% SiR3 R = Et, R3Si = TES 78% TMS R OTMS O O RCHO, DABCO O CO2Me O CO2Me R ++R benzene, reflux I2, AgOTf, THF R R O O MeO2C OTMS O –78 °C, 1 h 17 examples: 0–100% CO2Me EtO EtO

96 97 98 SiEt I PhB(OH)2 99 3 100 Pd(PPh ) (10 mol%) Scheme 69 Aldehyde addition to an alkynylsilane OMPM 3 4 K CO , dioxane/H O PdCl2(PPh3)2 (5 mol%) 2 3 2 60% 63% 80 °C, 1 h CuI (5 mol%), Et3N THF, r.t., 2.5 h O (Trimethylsilyl)acetylenes were reacted under Ni cataly- O sis with phthalimides to give decarbonylation and alkylide- O nation of one of the carbonyl groups. Although the reaction O EtO EtO appears to be potentially general, all but two of 11 exam- OMPM Ph ples were with N-(pyrrolidino)phthalimide. The use of a catalytic amount of the strong and sterically demanding Scheme 71 Addition to silylpropynoates and reaction of the resulting methylaluminum bis-(2,6-di-tert-butyl-4-methylphenox- vinylsilanes ide) (MAD) was crucial in the success of the reaction. In the absence of MAD the major products were isoquinolones. A series of silylated propargylic alcohols was prepared Various 1-alkyl and 1-aryl-substituted (trimethylsilyl)acet- via the straightforward reaction of a lithiated silylacetylene ylenes were utilized and gave the E-isomer as the product, and a variety of aromatic and aliphatic aldehydes and ke- but only 1-phenyl-2-(trimethylsilyl)acetylene and 1-(4-me- tones. These silylated propargylic alcohols were then sub- thoxyphenyl)-2-(trimethylsilyl)acetylene gave mixtures of jected to the Meyer–Schuster rearrangement to give acyl- Z- and E-isomers. Two additional examples of reactions silanes; propargyl alcohols derived from aromatic alde- where the silyl groups were PhMe2Si and TBS were success- hydes underwent the rearrangement in good yield under ful, albeit in lower yield. Two internal alkynes failed to react catalysis with either PTSA·H2O/n-Bu4N·ReO4 or Ph3SiOReO3. indicating that the presence of the TMS group is necessary The PTSA·H2O/n-Bu4N·ReO4 system did not work for elec- 86,87 for the reaction (Scheme 70). tron-donating aryl systems, though the Ph3SiOReO3 catalyst worked well for these. Propargyl alcohols derived from ali-

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Syn thesis G. L. Larson Review phatic aldehydes failed to give acylsilanes with the excep- 1) TMSI, CH2Cl2 SiR3 tion of pivaldehyde. Propargylic alcohols derived from dia- I –78 °C, 15 min ryl ketones gave either indanones or acylsilanes (Scheme Ar 2) H2O, 0 °C, 50 min 89 Ar 72). 6 examples, 57– 93%

HO R2 H SiR3 1 R 1) TMSI, CH2Cl2 1) n-BuLi I –78 °C, 15 min 2) R1R2CO t-Bu R3Si R3Si 2) H2O, 0 °C, 50 min R3Si = TMS, TES, TBS, TIPS R Si = TMS (88%), TES (80%), TIPS (54%) 41 examples, 40–81% 3 t-Bu HO H PTSA•H O (5 mol%) 2 O Scheme 73 Hydroiodination of alkynylsilanes Ar n-Bu4N•ReO4 (5 mol%) TES Ar CH2Cl2, r.t. TES 8 examples, 58–80% R CO2Me HO H NTs CO2Me O DABCO TsNH + + TsNH Ar Ph SiOReO (5 mol%) 2 3 3 R THF, reflux, 20 h TES Ar TMS TsNH Et2O, r.t. 10 examples, 34–49%

TES Ar = 3-MeOC6H4 30% NTs Ar = 4-MeOC6H4 52% CO2Me 1) DABCO CO2Me THF, reflux, 1.5 h + HO Ph PTSA•H O (5 mol%) O R R 2 2) HCl, MeOH OH TMS O OMe Ph n-Bu4N•ReO4 (5 mol%) 6 examples, 0–81%

CH2Cl2, r.t. TES CO Me TES 55% Ph TMS 2

TiCl , THF, r.t. 4 O HO Ar PTSA•H O (5 mol%) CO2Me 2 O Ar 100% Ar n-Bu4N•ReO4 (5 mol%) TES Ar O NHTs TiCl4, THF, r.t. CH2Cl2, r.t. 101 CO2Me TES Ar = 3-ClC6H4 76% OTMS 74% O Scheme 72 Rearrangement and oxidation of silylpropargyl alcohols Ph O Ph

A one-step hydroiodination of 1-aryl-2-silylacetylenes Scheme 74 Reaction of 3-silylpropynoates with imines to the vinyl iodide, highly useful substrates for cross-coupling applications, was found to occur upon treatment of A variety of 3-silylpropynals and silylethynyl ketones, the 1-aryl-2-silylacetylenes with iodotrimethylsilane. The prepared via a silylation, deprotection, oxidation sequence, reaction sequence of a Sonogashira cross-coupling of were converted into 2-silyl-1,3-dithianes, which are useful (trimethylsilyl)acetylene and an aryl halide followed by the synthons via their potential for anion relay chemistry hydroiodination resulted in a facile synthesis of α-iodosty- (ARC).92 Although 8 different silyl groups showed good re- rene derivatives; the reaction resulted in the Markovnikov sults, the dithiation did not occur when the silyl was steri- addition of HI to the C≡C bond. It was further found that the cally hindered, as with TBDPS, TIPS, t-Bu2HSi, or i-Pr2HSi terminal acetylene itself would undergo the reaction as (Scheme 75).93 well. More hindered silyl groups gave a lower yield of the vinyl iodide (Scheme 73).90 O H A three-component with methyl 3-(trimethylsilyl)pro- O Al2O3 (10 equiv) S S + pynoate, an amine, and an imine is directed by both the es- HS SH THF, r.t., 3–10 h R3Si H ter and the trimethylsilyl moieties. The reaction involves a R3Si 8 examples, 48–93% 1,4-silyl shift. When salicyl imines were used as substrates the products were chromenes. This reaction was shown to O proceed through the aminal 101, which could be trapped t-BuOK, t-BuOH O S S with allyltrimethylsilane or the TMS enol ether of aceto- + HS SH 0 °C to r.t., 3 h R Si 91 R Si 3 phenone (Scheme 74). 3 8 examples, 35–100% Scheme 75 Dithiation of silylpropynals

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HO cases of the E-dichloride or E-dibromide the equilibration OH was brought about by exposure to light in the presence of a LiAlH4, THF RMe Si trace of bromine. In the case of the E-diiodide, prolonged 0–25 °C 2

RMe2Si refluxing in cyclooctane produced an E/Z mixture of 9:1 R = Me (73%; E/Z 9:1), Ph (87%, E/Z 6:1), allyl (61%) (Scheme 78).96 Scheme 76 Lithium aluminum hydride reduction of silylpropargyl H alcohols TMS X + X2 X X X TMS TMS X2 = Cl2, Br2, I2 H H The lithium aluminum hydride reduction of 4-silylbut- Scheme 78 Halogenation of (trimethylsilyl)acetylene 3-yn-2-ones provided the 4-silylbut-3-en-2-ol in good yields and high E/Z ratios (Scheme 76).94 The β-silyl effect to stabilize β-cationic intermediates The reaction of Weinreb amides with internal acety- was employed in the regioselective addition of ICl to sily- lenes promoted by a Kulinkovich-type titanium intermedi- lacetylenes. The diastereoselectivity of the addition is the ate gave α,β-unsaturated ketones in modest yield. The reac- opposite of that found for the reaction of ICl with the sim- tion conditions were mild with activation of the titanium ple terminal alkyne. The Z/E selectivity is higher with aryl- promoter as the last step at room temperature. With TMS- substituted silylacetylenes, though the Z selectivity of alkyl- terminated acetylenes, the yields were comparable to those substituted silylacetylenes increases with an increase in the of other alkynes investigated, though with slightly lower size of the silyl group (Scheme 77).95 regioselectivity (Scheme 79).97

TMS I O TMS Cl Ph O TMS Ph Ph ICl, CH Cl Me Ti(Oi-Pr)4 (1.5 equiv) 2 2 + Ph N + –78 °C i-PrMgCl (3 equiv) O TMS OMe Et O, r.t., 4 h 82% 2 Cl β α Ph Ph TMS 53%, -TMS: -TMS 86:14 TMS TMS I

H H Ph O O I Me Ti(Oi-Pr)4 (1.5 equiv) Cl + Ph N t-Bu Ph i-PrMgCl (3 equiv) t-Bu OMe Ph ICl, CH2Cl2 Et2O, r.t., 4 h

–78 °C 35%, β-t-Bu:α-t-Bu 97:3 65% Cl Scheme 79 Reaction of Weinreb amide with silylacetylenes I H H Cl The syn addition of two aryl groups from an arylboronic TMS ICl, CH2Cl2 I R acid to an internal alkyne resulted in the formation of 1,2- –78 °C 68%, E/Z 3:1 TMS disubstituted 1,2-diarylethenes. In the single example using R 10 examples 54–93% a silylacetylene, the reaction of ethyl 3-(trimethylsilyl)pro- R = CO2Et 0% pynoate with p-tolylboronic acid under Pd catalysis gave the highly substituted ethyl 2,3-di(p-tolyl)-3-(trimethylsi- TMS Cl lyl)propenoate via the addition of two equivalents of the p- ICl, CH Cl 2 2 I 98,99 n-Bu tolyl group (Scheme 80). –78 °C n-Bu 68%, E/Z 3:1 TMS The highly regio- and stereoselective addition of a boronic acid to silylacetylenes occurred under mild conditions and in high yields. Interesting points were that 1-(tri- TES Cl ethylsilyl)hex-1-yne was more regioselective than ICl, CH2Cl2 I n-Bu (trimethylsilyl)hex-1-yne, which gave a mixture of isomeric –78 °C vinylsilanes indicating that the steric effect of the silyl n-Bu 54%, E/Z 9:1 TES group plays a role, and extended reaction times gave re- Scheme 77 Iodochlorination of silylacetylenes duced stereoselectivity. The resulting arylated vinylsilanes could be converted into their corresponding iodide or bro- The addition of the halogens to (trimethylsilyl)acetylene mide. In the case of the iodide this was performed in a two- in the absence of light produced the E isomer, which could step, one-pot reaction sequence, whereas the bromide re- be equilibrated to a mixture of both stereoisomers. In the quired two independent steps. In a further extrapolation of

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the chemistry the regio- and stereoselective synthesis of 1) n-BuLi (2 equiv) TES (Z)-α-(4-tolyl)-β-(4-methoxyphenyl)styrene (102) was ac- Co(acac)2 (10 mol%) TES dioxane, reflux, 2 h H complished in three steps from 1-phenyl-2-(trimethylsi- Ph2PH + H 2) S8 lyl)acetylene. The E-isomer was prepared starting from 1- Ph2P 69% S (4-tolyl)-2-(trimethylsilyl)acetylene (Scheme 80). The reaction was also possible with the addition of a vinylboronic Scheme 81 Hydrophosphination of (triethylsilyl)acetylene acid giving a dienylsilane.100 ones. Thus, the 1-(trimethylsilyl)alk-1-yne was reacted EtO2C with diisobutylaluminum hydride to form the 1-(trimethyl- TMS TMS B(OH)2 silyl)vinylaluminum reagent, which was then reacted with Pd(OAc)2 (1 mol%) 2 + the enone, catalyzed by the chiral NHC complex 103. In re- DMSO, O2, 4 A MS O 50 °C, 24 h actions with the cyclopentenones, up to 10% of addition of OEt 72% the isobutyl group from aluminum was observed; this in-

1 creased to up to 33% for cyclohexenones. The er values were TES Pd(OAc)2 (5 mol%) Ar PCy (10 mol%) excellent, ranging from 92.5:7.5 to 98.5:1.5. Of considerable 1 3 H Ar B(OH)2 + Ar2 THF, 27 °C, 11 h Ar2 18 examples TES 75–96% Ph O O TES Pd(OAc)2 (5 mol%) Ph S N PCy3 (10 mol%) N Ar H O MeO PhB(OH)2 + H THF, 27 °C, 22 h H TES Ag Ag 84% OH Ar TES Ph Pd(OAc)2 (5 mol%) O N PCy3 (10 mol%) H N PhB(OH)2 + n-Bu THF, 27 °C, 22 h TES n-Bu 45% S Ph 104 O O TMS Pd(OAc) (5 mol%) Ph H 2 103 Ar = 2,6-Et2C6H3 PCy3 (10 mol%) H Ph n-Bu + PhB(OH)2 + n-Bu TMS THF, 27 °C, 22 h Al(i-Bu) n-Bu TMS TMS 2 82% + (i-Bu)2AlH n-Pr TMS n-Pr

TMS 1. Pd(OAc)2 (5 mol%) O O B(OH)2 103 (2.5 mol%) PCy3 (10 mol%), 11 h Al(i-Bu) 1 2 + R CuCl2•2H2O (5 mol%) H + 2. NIS, MeCN, r.t., 10 h 1 Ph Ph TMS THF, 22 °C, 15 min R R2 I 76%, er = 93:7 R2 TMS 16 examples 50–95%, er 89:11 to 9.5:1.5 Pd(OAc)2 O O B(OH)2 PPh3, CsCO3 + MCPBA H MeO dioxane, 60 °C H O Ph Ph CH Cl , 0 °C, 3 h n-Hex 2 2 n-Hex I 96% TMS TMS O O

102 OMe HCO H O 2 Scheme 80 Addition of boronic acids to alkynylsilanes n-Hex 100 °C, 1 h n-Hex 70% TMS O The Oshima group reported the syn-hydrophosphina- O O tion of terminal and internal alkynes. With arylacetylenes NCI (2.6 equiv) the regioselectivity was approximately 9:1 and with (tri- n-Hex MeCN, 0–22 °C, 12 h n-Hex ethylsilyl)acetylene, the sole silicon example, it was 94:6, TMS 91% I slightly less than that with alkylacetylene substrates, which O O showed a 100:0 regioselectivity all placing the phosphine CF CO H on the terminal position. The products were isolated as 3 2 CHCl , 22 °C, 6 h 101 n-Hex 3 n-Hex their phosphine sulfides (Scheme 81). 76% A chiral NHC catalyst was employed in the enantioselec- TMS tive conjugate addition of 1-(trimethylsilyl)alk-1-ynes to 3- Scheme 82 Hydroalumination of 1-silylalk-1-ynes and asymmetric substituted cyclopentenones and 3-substituted cyclohexen- vinylation of enones

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importance, the resulting vinylsilanes were further reacted. TMS EtO O Pd(dba)2 (5 mol%) Oxidation with m-chloroperbenzoic acid gave the ketone. + PhMe SiH 2 TMS PCy3 (10 mol%) NCI converted it into the vinyl iodide and protiodesilylation PhMe2Si O toluene, r.t., 16 h 99% to the parent alkene. This chemistry was applied to a short OEt synthesis of riccardiphenol B (104) (Scheme 82).102 The reaction of indoles with 1-(halophenyl)-2-(trimeth- TMS O Pd(dba)2 (5 mol%) ylsilyl)acetylenes under Cu(I) catalysis gave addition of the + PhMe2SiH PCy3 (10 mol%) TMS PhMe2Si O toluene, r.t., 14 h indole to the C≡C bond and, under the basic conditions, pro- 94% tiodesilylation to form the corresponding alkene as a mix- 105 ture of stereoisomers. Very little amination of the aryl halo- O TMS p-Tol gen bond occurred. In fact, a control experiment wherein Pd(dba)2 (5 mol%) S O + PhMe2SiH O PCy3 (10 mol%) TMS indole was reacted with a mixture of 1-(4-bromophenyl)-2- PhMe Si S toluene, r.t., 16 h 2 92% by NMR (trimethylsilyl)acetylene and 4-iodoanisole a 50% yield of O p-Tol 106 addition to the C≡C bond and only 6% reaction of the Scheme 84 Hydrosilylation of functionalized silylacetylenes iodophenyl bond was observed (Scheme 83).103

X TMS H DMSO, BtH (20 mol%) R 1) FeCl2 (10 mol%) Ar CuI (10 mol%) + ArMgBr R + X Et2O, r.t., 3 h TMS TMS N KOt-Bu (2 equiv) N + 2) H3O H 5 examples: 65–83% 120 °C, 20–30 min TMS TMS or KOH (0.2 equiv), 10–12 h Ph 11 examples; 58–90%; E/Z 34:66–0:100 TMS 1) FeCl2 (10 mol%) Br Et2O, r.t., 3 h Ph + PhMgBr 2) Ph I N Br TMS TMS NiCl2(dppe) (10 mol%) CuI, K3PO4 TMS Br r.t., 12 h + + N + N BtH, DMSO 43% H TMS TMS OMe OMe 1) FeCl (10 mol%) 52% 6% 2 I Et2O, r.t., 3 h Ph Scheme 83 Hydroamination of 1-(halophenyl)-2-(trimethylsilyl)acety- + PhMgBr 2) ZnCl2 lenes with indoles TMS TMS 3) I , r.t., 12 h TMS 2 49% The hydrosilylation of various propynoate esters was Scheme 85 Addition of Grignard reagents to 1,4-bis(trimethylsilyl)- carried out and served to prepare α-silyl-α,β-unsaturated buta-1,3-diyne esters in good yields. When this reaction was performed with 3-(trimethylsilyl)propynoate esters, the product formed was the (E)-2,3-bis(silyl)propenoate. Other similar systems such as the ynone 105 and sulfone 106 gave good TMS Ni(cod)2 (10 mol%) yields of addition products (Scheme 84).104 PPh3 (20 mol%) CO2H + TMS 1,4-Bis(trimethylsilyl)buta-1,3-diyne underwent carbo- Me2Zn, CO2 (1 atm) R R magnesiation of one of the C≡C bonds with arylmagnesium R = Me (35%); Ph (31%) bromide reagents. The resulting vinylmagnesium bromide Scheme 86 Four-component coupling involving 1-substituted 2- intermediate could be further reacted, including cross-cou- (trimethylsilyl)acetylenes pling to form various substituted silylated enynes. 1-Phe- nyl-4-(trimethylsilyl)buta-1,3-diyne underwent carbomag- nesiation at the phenyl-substituted C≡C bond (Scheme The three-component coupling of acetylenes, vinylox- 85).105 iranes, and dimethylzinc was reported to give alka-2,5- Kimura and co-workers reported on the Ni-catalyzed, dien-1-ols. Bis(trimethylsilyl)acetylene and (trimethylsi- four-component coupling of internal alkynes, buta-1,3-di- lyl)acetylene gave lower yields than 1-(trimethylsilyl)prop- ene, dimethylzinc, and carbon dioxide. The reactions of 1- 1-yne and alkyl- or arylalkynes. In a similar manner vinyl- substituted 2-(trimethylsilyl)acetylenes gave lower yields cyclopropanes gave 1-silyl-1,4-dienes (Scheme 87).107 and poorer regioselectivity than those of alkyl- or aryl-substituted alkynes (Scheme 86).106

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TMS R The addition of DIBAL-H to 1-(trimethylsilyl)prop-1- Ni(acac)2 (10 mol%) OH + O TMS yne followed by conversion into the lithium aluminate and R Me Zn, hexane, r.t., 24 h TMS 2 TMS R = H 35% E/Z 2:1 reaction with formaldehyde resulted in vinylsilane 110. R = Me 31% E/Z 1:! This was in turn used to generated vinylsilane 111 and, TMS Ni(acac)2 (10 mol%) OH from that, vinyl iodide 112, which was then converted in + TMS O 110 H Me2Zn, hexane, r.t., 24 h two steps into norfluorocurarine (113) (Scheme 90). 97%, E/Z 2:1 TMS

+ Ni(acac)2 (10 mol%) OH + O TMS OH H TMS TMS N H Me2Zn, hexane, r.t., 24 h 27%, E/Z 2:1 TMS 97%, E/Z 2:1 1. DIBAL-H, Et2O HO TMS CO2Me 2. MeLi, (CH2O)n CO2Me TMS N + Ni(acac)2 (10 mol%) TMS CO2Me CO2Me 110 R Me Zn, hexane, THF, r.t., 24 h R F3C 2 O R = TMS 59%, E only 111 R = Me 91%, E only NIS (2 equiv) Scheme 87 Alkylative three-component coupling of silylacetylenes AcOH (1.8 equiv) with vinyloxiranes and a vinylcyclopropane HFIP, CH2Cl2, –15 °C

N N I The reaction of silylacetylene 107 by Ru-catalyzed addi- H tion of acetic acid gave a mixture of the desired enol acetate H N 108 along with 109; a longer reaction time gave 109 in CHO H N F3C CHO 112 good yield. Although 108 was the initial desired intermedi- H 113 O ate it was 109 that was in fact carried forward in a synthesis Scheme 90 DIBAL-H addition to 1-(trimethylsilyl)prop-1-yne of clavosolide A (Scheme 88).108

OTIPS OTIPS OTIPS 13 Reactions at the C–Si Bond H H H O O O + [RuCl2(p-cymene)]2 A study on the iododesilylation of a series of vinylsilanes AcOH, Na CO TMS 2 3 OAc OAc wherein the silyl group included TIPS, TBS, and TBDPS was 107 toluene, 80 °C 108 109 6 h 108; 55% carried out.111 This was the first report of the iododesilyla- 12 h 109; 69% tion of a vinylsilane with sterically hindered silyl moieties. Scheme 88 Hydroacetation of a silylacetylene Interestingly, it was found that the rate of the reaction with TIPS or TBS groups was about the same, but that of TIPS was An iron-catalyzed imine-directed 2-vinylation of indole faster than that of TBDPS. Four different sources of I+, N- with internal alkynes produced the 2-vinylated derivative iodosuccinimide (NIS), N-iodosaccharin (NISac), 1,3-diodo- in good yield and regioselectivity. Terminal acetylenes did 5,5-dimethylhydantoin (DIH), and bis(pyridine)iodonium not react under the conditions employed. This deficiency tetrafluoroborate (Ipy2BF4) were investigated with compa- was circumvented by the use of a (trimethylsilyl)acetylene, rable results for each. The success of the reaction depended which reacted with high regioselectivity forming the C2– on the solvent system with 1,1,1,3,3,3-hexafluoropropan-

Cvinyl bond β to the TMS group. These conditions also proved 2-ol (HFIP) showing good results. The reaction was tolerant useful for the formation of C2–Csp3 bonds when the reac- of epoxides, alkenes, esters, TIPS ethers, and a TIPS acety- tion was carried out with alkenes (Scheme 89); again the lene (12 examples, 86–96% yield) (Scheme 91).111 reaction did not occur with terminal alkenes.109 O O iodination agent (120 mol%) 1. Fe(acac)3 (10 mol%) AgCO (30 mol%) NPMP CHO 3 TMS SIXyl•HCl (20 mol%) TIPS OTBS I OTBS TMS HFTP, 0 °C PhMgBr (110 mol%) Iodination agent Yield + THF, 60 °C, 18 h NIS 90% N N Me + Me NISac 86% 2. H3O DIH 88% 59%, Z/E >99:1 Ipy2BF4 91% + N N Scheme 91 Iodination of vinylsilanes, readily available from silylacetyl- Cl– enes

SIXyl•HCl Scheme 89 Coupling of a (trimethylsilyl)acetylene with an α,β-unsatu- 1,4-Bis(trimethylsilyl)buta-1,3-diyne was treated with rated imine MeLi·LiBr to prepare the monolithiated diyne, which was

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Syn thesis G. L. Larson Review reacted in a Sonogashira cross-coupling with 2-iodoaniline. lyl)acetylenes failed to react. A direct comparison of 1-bu- The coupling product was reacted with trichloroacetyl iso- tyl- and 1-phenyl-2-(trimethylsilyl)acetylene with hex-1- cyanate and this converted into desilylated urea 115 in a yne and phenylacetylene, that is, the H-terminated acety- single step. The resulting diyne was subjected to a double lenes, showed that TMS-terminated acetylenes gave better cyclization to give the pyrimido[1,6-a]indol-1(2H)-one 116 yields. Chlorobenzene was found to be the best solvent and 112 (Scheme 92). Et3N the best base. 1,4-Bis[(trimethylsilyl)ethynyl]benzene (117) reacted with ethyl acrylate to give the mono- or TMS TMS disubstituted γ,δ-ethynyl esters. The reaction was also oc- MeLi•LiBr + Me4Si curred with methyl vinyl ketone as the acceptor (Scheme 93).113 TMS Li I TMS This protocol compares well with the conjugate addition TMS TMS NH2 of terminal alkynes to acrylates catalyzed by MeLi•LiBr Pd(PPh ) , CuI 3 4 Ru3(CO)12/bis(triphenylphosphine)iminium chloride and THF, Et O Et N, Et N•HCl 114,115 2 3 3 NH with Pd(OAc) . TMS 0 °C, 2 h Li 60 °C, 24 h 2 2 81% TMS TMS 14 Miscellaneous Reactions NaHCO Cl3CCONCO O O 3 O 96% MeOH, H2O NH2 N N CCl3 76% N NH2 β-Amino enone 118 was converted in a two-step, sin- H H 115 H – t-Bu + SbF6 gle-pot sequence into enol ether 119 via reaction with 3- t-Bu 114 (5 mol%) P Au NCMe 78% THF, 100 °C (trimethylsilyl)propargyllithium in 51% overall yield; using MW, 1 h propargylmagnesium bromide gave the corresponding H-

114 N terminated product in 40% yield. Enol ether 119 was uti- NH lized in a synthesis of 7-hydroxycopodine (Scheme 94).116 116 O

Scheme 92 Lithiation of 1,4-bis(trimethylsilyl)buta-1,3-diyne OiPr O OiPr TMS i-PrI (as solvent) Li N + Pan and co-workers reported the conjugate addition of N 55 °C, 42 h N THF, –78 °C, 2 h I– then to 25 °C TMS alkynyl groups to acrylate derivatives via the reaction of a OTBS OTBS 51% 118 OTBS 119 (trimethylsilyl)acetylene derivative under InCl3 catalysis. Silyl moieties other than that of the TMS group were not in- Scheme 94 Reaction of 3-(trimethylsilyl)propargyllithium with an iminium salt vestigated. The reaction worked best for 1-phenyl-2- (trimethylsilyl)acetylene wherein the phenyl group is a strongly electron-donating aryl group. Thus, 4-CN-, 4- 1-[(Trialkylsilyl)ethynyl]cyclopropan-1-ols were ring

CO2Me-, and 4-CF3-substituted 1-phenyl-2-(trimethylsi- expanded to 2-alkylidenecyclobutanones in a reaction catalyzed by the Ru catalyst 120. Interestingly, the favored O stereoisomer was the Z-isomer. Similar results were ob- TMS O InCl3 (10 mol%) OMe Et N (5 mol%) OMe 3 R + R PhCl, 100 °C, 24 h SiR 15 examples; 68–96% 3 PPh3 R3Si O Ru HO Cl PPh O O 2 O InCl3 (10 mol%) 3 SiR3 R OMe 120 Et3N (5 mol%) + + OMe R1 PhCl, 100 °C, 24 h R1 R2 Yield R Si Yield Z/E R1 3 Ph TMS 92% TMS 98% 5.7:1 Ph H 56% BuMe2Si 94% 6.0:1 TMS n-Bu TMS 86% PhMe2Si 96% 6.0:1 n-Bu H 55% TES 97% 10.0:1 OEt O InCl (20 mol%) TMS TBS 98% 11.4:1 3 6 h Et3N (10 mol%) 85% O TIPS 87% >20:1 + OEt PhCl, 110 °C 24 h (3 equiv) 72% EtO OEt n-C6H13 O

O O HO TMS 120 117 78% n-C H Scheme 93 Ethynylation of α,β-unsaturated esters with (trimethylsi- 6 13 lyl)acetylenes Scheme 95 Rearrangement of 1-(silylethynyl)cyclopropan-1-ols

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tained with electron-deficient alkynyl cyclopropanols. On Li n-BuLi, TMEDA the other hand, under the same conditions 1-alk-1-ynyl- TMS TMS Et2O, –5 °C, 15 min cyclopropan-1-ols underwent ring expansion to cyclopen- 123 tenones. Stabilization of a β-carbocation in the silyl-substi- 123, Et2O tuted examples and a favored Michael addition in the elec- Br 0 °C, 12 h 50% tron-deficient examples helps to explain the formation of TMS 117 Li the four-membered ring (Scheme 95). TIPS 3-(Trimethylsilyl)propynal was nicely used in a conve- TIPSOTf Et2O, –40 to °C nient synthesis of ethynyl-β-lactone 121; propynal did not Me 124 undergo a corresponding reaction to give 122. The silylated 87% Me enantiomerically enriched β-lactone 121 was utilized in nBuLi, THF Li 124 TIPS synthetic approaches to leustroducsin B and the protiodesi- –20 °C, 15 min lylated ethynyl lactone 122 was converted to derivatives of 125 TIPS similar structure to the natural products (–)-muricaticin, O OH 118–120 THF (–)-japonilure, and (+)-eldanolide. 125 + 93%

O EtCOCl, TMS-quinidine O O O THF–HMPA (3:1) H MgCl2, i-Pr2NEt TBAF O 125 + 81% TMS Et2O, CH2Cl2, –80 °C O THF, –78 °C O 94% TIPS TMS 121 122 TIPS TIPSOTf Scheme 96 Synthesis of silylethynyl-β-lactone 125 TIPS –78 to –40 °C, 1 h 126 Corey and Kirst were the first to report the synthesis 1) n-BuLi, THF –20 °C, 15 min and utility of 3-(trimethylsilyl)propargyllithium (123). The TIPS 126 R direct lithiation of 1-(trimethylsilyl)prop-1-yne occurred 2) RCHO, –78°C to r.t., 6 h 3 examples: 57–79%; Z/E >20:1 using BuLi/TMEDA in 15 minutes. The reagent 123 reacted TMS with primary alkyl halides in diethyl ether to form the de- THF sired alkynes with only small amounts of the isomeric al- O + 123 O Cl –40 to 0 °C lene, a common side product found with propargylmagnesium chloride reagent.121 TESO TESO TESO Corey and Rucker then utilized 1-(triisopropylsi- O O O lyl)prop-1-yne (124), which was readily lithiated to give the TESO TESO + TESO O 1) 123, THF O O more sterically encumbered 3-(triisopropylsilyl)propargyl- 2) MsCl, Et N O 3 lithium (125). Lithium reagent 125 was reacted with cyclo- CH2Cl2 127 hexenones in a 1,2- and 1,4-manner. In addition it was con- 80%; 128:129 = 1:4 128 TMS 129 TMS verted into the 1,3-bis(triisopropylsilyl)prop-1-yne (126) in quantitative yield on treatment with triisopropylsilyl tri- Scheme 97 Formation and reactions of silylpropargyllithium reagents flate. Reaction of 125 with cyclohexenone gave 1,4-addition in THF/HMPA and 1,2-addition in THF. Bis-TIPS reagent 126 reacted with BuLi/THF to give lithiated 126, which reacted with aldehydes in a Peterson reaction to form an enynes group was removed with AgNO3/aq EtOH en route to ste- (Scheme 97).4 reoisomers of bis(acetylenic) enol ether spiroacetals of ar- 3-(Trimethylsilyl)propargyllithium (123) was used to temisia and chrysanthemum (Scheme 97).123 introduce the propargyl group into epoxygeranyl chloride Fu and Smith demonstrated the enantioselective Ni-cat- in 85% yield over three steps from geraniol. The TMS group alyzed, Negishi cross-coupling arylation of racemic 3- was removed with TBAF and the resulting enyne was used (trimethylsilyl)propargyl bromides; the yields and the ee in a synthesis of the triterpene limonin (Scheme 97).122 values were excellent. The protocol was applied to the syn- 3-(Trimethylsilyl)propargyllithium (123) reacted with thesis of 131, a precursor to pyrimidine 132, an inhibitor of lactone 127 and this was followed by mesylation/elimina- dihydrofolate reductase (Scheme 98).124 tion to give enynes 128 and 129 in good yield. The TMS

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(12) Ivachtchenko, A. V.; Mitkin, O. D.; Yamanushkin, P. M.; Br NiCl2•glyme (3 mol%) Ar + ArZnEt (–)-130 (3.9 mol%) Kuznetsova, I. V.; Bulanova, E. A.; Shevkun, N. A.; Koryakova, A. R R G.; Karapetian, R. N.; Bichko, V. V.; Trifelenkov, A. S.; TMS glyme, –20 °C TMS Kravchenko, D. V.; Vostokova, N. V.; Veselov, M. S.; Chufarova, N. 7 examples, 39–92%, ee 92–94% V.; Ivanenkov, Y. A. J. Med. Chem. 2014, 57, 7716. OMe (13) Gong, Y.; Liu, J. Tetrahedron Lett. 2016, 57, 2143.

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