Some Aspects of the Chemistry of Alkynylsilanes · TMS TMS 1) MeLi (1 equiv) THF, 0 C 2) acrolein,...

A

G. L. Larson ReviewSyn thesis

SYNTHESIS0 0 3 9 - 7 8 8 1 1 4 3 7 - 2 1 0 XGeorg Thieme Verlag Stuttgart · New York2018, 50, A–ADreviewen

Some Aspects of the Chemistry of AlkynylsilanesGerald L. Larson*

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

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

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Abstract In amongst the considerable chemistry of acetylenes therelies some unique chemistry of alkynylsilanes (silylacetylenes) some ofwhich is reviewed herein. This unique character is exemplified not onlyin the silyl protection of the terminal C–H of acetylenes, but also in theability of the silyl group to be converted into other functionalities afterreaction of the alkynylsilane and to its ability to dictate and improve theregioselectivity of reactions at the triple bond. This, when combinedwith the possible subsequent transformations of the silyl group, makestheir chemistry highly versatile and useful.1 Introduction2 Safety3 Synthesis4 Protiodesilylation5 Sonogashira Reactions6 Cross-Coupling with the C–Si Bond7 Stille Cross-Coupling8 Reactions at the Terminal Carbon9 Cross-Coupling with Silylethynylmagnesium Bromides10 Reactions of Haloethynylsilanes11 Cycloaddition Reactions11.1 Formation of Aromatic Rings11.2 Diels–Alder Cyclizations11.3 Formation of Heterocycles11.4 Formation of 1,2,3-Triazines11.5 [2+3] Cycloadditions11.6 Other Cycloadditions12 Additions to the C≡C Bond13 Reactions at the C–Si Bond14 Miscellaneous Reactions

Key words alkynes, azides, cross-coupling, enynes, protectinggroups, silicon, Stille reaction

1 Introduction

Alkynylsilanes (silylacetylenes) as referred to in this re-view are those wherein the silyl moiety is directly bonded

to the sp-carbon of the C≡C bond. Alkynylsilanes such aspropargylsilanes are, therefore, not included. Acetylenechemistry has been extensively reviewed over the years.Several of the more recent additions are noted here.1

A significant portion of the applications of silylacety-lenes occurs where the silyl group, typically trimethylsilyl,serves as a group for the protection of the reactive terminalC≡C–H bond. Supporting this silyl-protection strategy isthat both the introduction and removal of the silyl groupcan be accomplished in high yield under a variety of mild

Gerald (Jerry) Larson led Vice-President of R&D for Gelest Inc. for nearly 20 years before his retirement where he retains the position of Senior Research Fellow and Corporate Consultant. He received his B.Sc. degree in chemistry from Pacific Lutheran University in 1964 and his Ph.D. in chemistry (organic/inorganic) from the University of California-Davis in 1968. He served an NIH-postdoctoral year with Donald Mat-teson at Washington State University and a postdoctoral year with Diet-mar Seyferth at MIT, after which he joined the faculty of the University of Puerto Rico-Río Piedras as an assistant professor in 1970 reaching full professor in 1979. He has been a visiting professor at various universi-ties including Oregon State, Louisiana State, Universitá di Bari, Universi-tät Würzburg, and Instituto Politécnico de Investigaciones de Mexico. On the industrial side, he rose to Vice-President of Research for Sivento, a Hüls group company, an antecedent of Evonik, after serving as Direc-tor of Applications, in Troisdorf, Germany. He is the author of over 130 publications and 30 patents. His hobbies include tennis, traveling and reading. He was born in 1942, as the first of three sons and a daughter, in Tacoma, Washington where he was raised on a small farm.

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

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conditions. The desilylation protocols are, in general, highlytolerant of other functional groups with the notable excep-tion of silyl-protected alcohols. The reader will note severalexamples in this review where the silyl group basically pro-vides a protective function, but has further synthetic po-tential. A further advantage of the terminal silylacetylenesis that the presence of the silyl group, for both steric andelectronic reasons, can often influence the regio- andstereochemistry of reactions at the C≡C bond. This is mostoften reflected in cyclization reactions and it bears remem-bering that the regioselectively placed silyl group has thepotential to be another group including hydrogen. Finally,the trimethylsilyl group has its own reactivity in the finalproduct of a reaction at the C≡C bond. These often result inthe generation of a vinylsilane unit, which can be furtherreacted under a number of conditions including protiodesi-lylation to the parent alkene.2 Examples of these aspects ofthe chemistry are to be found throughout the review.

2 Safety

A report of an explosion using (trimethylsilyl)acetylenein an oxidative coupling under Glaser–Hay conditions waspublished.3 After a thorough investigation the cause of theexplosion was attributed to static electricity between thesyringe needle used to introduce the copper catalyst and adigital thermometer inside the flask and not the thermalinstability of the silane. It is interesting to note that thetrimethylsilyl group can impart stability to alkynyl systems.A good example of this is 1,4-bis(trimethylsilyl)buta-1,3-diyne, which shows excellent thermal stability compared tothat of the parent buta-1,3-diyne.

3 Synthesis

A well-known and often used approach to silylacety-lenes is via the straightforward acid-base metalation, typi-cally with RMgX or n-BuLi (the base), of a terminal acety-lene (the acid) followed by reaction with an appropriatechlorosilane or related reactive organosilane. As a specificexample, 1-(triisopropylsilyl)prop-1-yne was prepared bylithiation of propyne followed by reaction with triisopro-pylsilyl triflate (Scheme 1).4

The direct trimethylsilylation of a terminal alkyne canbe carried out in a single step with the combination of LDAand TMSCl at low temperature. This was applied to the syn-thesis of 1, which was used in a synthesis of complanadineA (Scheme 2).5

Marciniec and co-workers have demonstrated the directsilylation of terminal acetylenes using an iridium carbonylcatalyst and iodotrimethylsilane in the presence of Hünig’sbase.6 The yields are excellent and the process works wellfor diynes and is tolerant of OH and NH2 groups, albeitthese end up as their trimethylsilylated derivatives in thefinal product (Scheme 3).

Scheme 3 Ir-catalyzed direct trimethylsilylation of terminal alkynes

A direct dehydrogenative cross-coupling of a terminalalkyne and a hydrosilane provided a convenient and simpleroute to silylacetylenes. Thus, reaction of a terminal acety-lene and a silane with a catalytic amount of NaOH or KOHgave the desired silylacetylene in high yield with expulsionof hydrogen. The reaction of a variety of acetylenes with di-methyl(phenyl)silane showed excellent general reactivityfor 25 examples (Scheme 4).7

Scheme 1 Example of a typical synthesis of a silylacetylene

Me LiTIPSOTf

Et2O, –40 to 0 °C

87%

Me TIPS

Scheme 2 Preparation of a silylacetylene employed in a synthesis of complanadine A

NBn

H

N

LDA, TMSCl

THF, –78 °C

80%NBn

H

N

TMS1

R + TMSI[{Ir(μ-Cl)(CO)2}2] (1 mol%)

i-Pr2NEt, toluene, 80 °C, 48 hR TMS

13 examples: 93–99%

Si

Ph

Ph

+ TMSI[{Ir(μ-Cl)(CO)2}2] (1 mol%)

i-Pr2NEt, toluene, 80 °C, 48 hSi

Ph

Ph

TMS TMS

5 diyne examples: 6–97%

[{Ir(μ-Cl)(CO)2}2] (1 mol%)

i-Pr2NEt, toluene, 80 °C, 24 h+ TMSI

HO TMSO

TMS

91%

H2N N

TMS[{Ir(μ-Cl)(CO)2}2] (1 mol%)

i-Pr2NEt, toluene, 80 °C, 48 h+ Me3SiI

TMS

TMS

90%


C


Scheme 4 Base-catalyzed direct dehydrogenative silylation of a terminal alkyne

4 Protiodesilylation

Because trialkylsilyl groups are very commonly used toprotect the terminal C–H of an acetylene, protiodesilylationback to the parent acetylene is an important transforma-tion. This can be accomplished under a number of mild re-action conditions. Among these is the simple reaction of(trimethylsilyl)acetylene derivatives with K2CO3/MeOH or,for more hindered silanes, TBAF/THF. Examples of these areto be found throughout this review. The selective protiode-silylation of (trimethylsilyl)acetylene group in the presenceof an (triisopropylsilyl)acetylene group with K2CO3/THF/MeOH illustrates the potential for selective protec-tion/deprotection (Scheme 5).8

Scheme 5 Selective deprotection of a (trimethylsilyl)acetylene group

1,4-Bis(trimethylsilyl)buta-1,3-diyne was metalatedwith one equivalent of MeLi and reacted with acrolein andsubsequently protiodesilylated to yield vinyl diynyl carbinol2. Transmetalation of 1,4-bis(trimethylsilyl)buta-1,3-diynewith five equivalents of MeLi and reaction with acroleingave the diol 3 in excellent yield.9 These key intermediateswere carried forth in syntheses of (+)- and (–)-falcarinoland (+)- and (–)-3-acetoxyfalcarinol (Scheme 6).9

5 Sonogashira Reactions

Of the many reactions at the terminal C–H of simple si-lylacetylenes, the Sonogashira reaction stands among themost important, where it has proved to be a very importantsynthetic entry into arylacetylenes and conjugated

enynes.10 These approaches typically make use of the Pd-catalyzed protocols employed in most cross-coupling reac-tions. The Au-catalyzed use of silylacetylenes in Sonogashi-ra cross-coupling reactions has been reviewed.11

Under the standard Sonogashira reaction conditions theC–Si bond does not react thus providing excellent protec-tion of this position along with adding more desirable phys-ical properties. Moreover, it provides an excellent entry intoa variety of substituted silylacetylenes. Though the silylgroup nicely provides protection of a terminal position inthe Sonogashira cross-coupling, under modified conditionswherein the silyl group is activated, a Sonogashira-typeconversion at the C–Si bond is possible, thus providing analternative to a two-step protiodesilylation/Sonogashira se-quence.

In an example of the use of the TMS group as a protect-ing group eventually leading to an unsymmetrically arylat-ed system, 1-(trimethylsilyl)buta-1,3-diyne, prepared from1,4-bis(trimethylsilyl)buta-1,3-diyne, was coupled witharyl iodide 4 to give the diyne 5, which was protiodesilylat-ed and further cross-coupled to give 6, a potential hepatitisC NS5A inhibitor (Scheme 7).12

R3SiH (3 equiv)

MOH (10 mol%)

DME, 24–48 h

M = Na, 6 examples: 68–95%; K, 6 examples: 69–95%; R3Si = 12 examples

SiR3

+ H2

+ H2

PhMe2SiH (3 equiv)

NaOH (10 mol%)

DME, 23–65 °C, 24–48 hR SiMe2PhR

25 examples: 52 to >99%

TIPS

TMS

K2CO3

THF, MeOHTIPS

95%

Scheme 6 Selective metalation and protiodesilylation of 1,4-bis(trimethylsilyl)buta-1,3-diyne

TMS

TMS

1) MeLi (1 equiv)

THF, 0 °C

2) acrolein, –78 °C

3) NaOHaq, THF, r.t.

OH

2 73%

TMS

TMS

1) MeLi (5 equiv)

THF, 0 °C

2) acrolein, –78 °C

OH

3 99%

OH

Scheme 7 Sonogashira cross-coupling sequence employing desilyla-tion

TMS

TMS

MeLi, LiBr

Et2O, 15 h

TMS

H

Pd(PPh3)4, CuITHF, Et3N, 40 °C, 15 h

N

NH

HN

I

4

N

NH

HN

TMS

N

NH

HN

HK2CO3

THF, MeOH

Pd(PPh3)4, CuITHF, Et3N, 40 °C, 15 h

IN

NH

HN

5

N

NH

HN N

HN N

H

6


D


Modest yields of symmetrical 1,4-diarylbuta-1,3-diynesresulted from the Sonogashira reaction of an aryl bromideand (trimethylsilyl)acetylene followed by treatment withNaOH/MeCN. The reaction sequence was the combinationof the Sonogashira cross-coupling and a Glaser coupling in atwo-step, single-flask operation. The second step did notrequire the further addition of catalyst. The reaction wastolerant of HO, CO2H, and CHO functional groups (Scheme8).13

Scheme 8 Sonogashira arylation and homocoupling without prior desilylation

The Beller group developed a copper-free protocol forthe Sonogashira reaction with the more available and lesscostly aryl chlorides. Both (trimethylsilyl)acetylene and(triethylsilyl)acetylene reacted without loss of the silylgroup. The key to the success of the reaction proved to bethe sterically hindered ligand 7 (Scheme 9).14

Scheme 9 Copper-free Sonogashira cross-coupling

[3-Cyanopropyl(dimethyl)silyl]acetylene (CPDMSA, 8)was prepared and utilized in the synthesis of arene-spaceddiacetylenes. The purpose of this particular silylacetylenewas twofold, firstly it could be selectively deprotected inthe presence of the (triisopropylsilyl)acetylene group and,secondly, it provided polarity allowing for a facile chro-matographic separation of the key intermediates in the syn-theses of the diethynylarenes (Scheme 10). The arenegroups were introduced via Sonogashira cross-coupling.15

In a good example of the use of (trimethylsilyl)acetyleneas a precursor to 1,2,4,5-tetraethynylbenzene, 1,2,4,5-tetraiodobenzene was reacted with (trimethylsilyl)acety-lene under Sonogashira conditions to give 1,2,4,5-tetrakis[(trimethylsilyl)ethynyl]benzene. The trimethylsilylgroups were then converted into bromides with NBS ingreater than 90% over the two steps. 1,2,4,5-Tetrakis(bromo-

ethynyl)benzene was subsequently reacted with cyclohexa-1,4-diene to give 2,3,6,7-tetrabromoanthracene (Scheme11).16

Scheme 11 Formation of 1,2,4,5-tetrakis(bromoethynyl)benzene

In related chemistry the direct ethynylation of tautom-erizable heterocyclics under Sonogashira conditions with-out the need for conversion of the heterocyclic into an arylhalide was reported. These worked well for both (trimethyl-silyl)acetylene and (triethylsilyl)acetylene (Scheme 12).17

In an interesting and useful approach, (trimethylsi-lyl)acetylene was cross-coupled with aryl iodides, bro-mides, and triflates in the presence of an amidine base andwater. If water was omitted until the second stage of the re-action, i.e. reaction at the C–Si terminus, the result was thesynthesis of unsymmetrical diarylacetylenes (Scheme 13).18

The Sonogashira reaction of (trimethylsilyl)acetylenewith 2,6-dibromo-3,7-bis(triflyloxy)anthracene was inves-

TMS+

PdCl2(PPh3)2, CuI, PPh3

Et3N, 80 °C, 1–3 hArBr

ArAr

Ar

TMS

NaOH (2 equiv)

MeCN, 60 °C, 2–8 h


+ Ar-Cl[PdCl2(MeCN)2] (1 mol%)

7 (3 mol%), Na2CO3 (4 equiv)

toluene, 90 °C, 16 h

total of 13 examples: 31–97%

R = TMS, 75%; R = TES, 77%

N

NPh

Ph

i-Pr i-Pr

P(t-Bu)2

7

R R

Ar

Scheme 10 Sonogashira cross-coupling and selective protiodesilyla-tion

MgBr

H

+Cl

Me2Si CN THF

–20 °C to r.t., 16 h

Me2Si CN

+SiMe2

CN

I

I

1. Pd(PPh3)2Cl2

PPh3, CuI, piperidine

2. TIPS

Me2Si

TIPS

CN

39%8

Me2Si

TIPS

CN

K2CO3

MeOH, THF

TIPS

89%

I

I

I

I

+TMS Pd(PPh3)4, CuI

Et3N, piperidine

TMS

TMS

TMS

TMS92%

NBS, AgNO3

acetone

Br

Br

Br

Br

quant.


E


tigated as an intermediate in a route to anthra[2,3-b:6,7-b′]difuran (anti-ADT). In this reaction the Sonogashiracross-coupling occurred selectively at the triflate leavingthe bromine groups available. This route did not, however,result in a synthetic approach to the desired anthracene di-furan. Success was realized via the Sonogashira cross-cou-pling of (trimethylsilyl)acetylene with 2,6-diacetoxy-3,7-dibromoanthracene followed by desilylative cyclization.The thiofuran analogue, anti-ADT, was prepared via cross-coupling of 9 with (trimethylsilyl)acetylene, iodine cycliza-tion, and reduction. A Suzuki–Miyaura cross-coupling andprotiodesilylation gave the phenyl-substituted anti-ADT 10.In an analogous manner the anti-diselenophene 12 wasprepared from 11 in 62% yield over three steps (Scheme14).19

The relatively simple and economical catalyst system ofFeCl3/N,N′-dimethylethylenediamine was used in the syn-thesis of 1-aryl-2-(triethylsilyl)acetylenes (6 examples, 40–

90% yields). The reaction conditions were not mild, requir-ing 135 °C and 72 hours for completion (Scheme 15).20

The Sonogashira reaction of several terminal alkyneswith 1-fluoro-2-nitrobenzene gave 1-(2-nitrophenyl)-2-(triethylsilyl)acetylene. The use of (triethylsilyl)acetylenegave a considerably higher yield than other terminalalkynes. The TES group was not reacted further in thisstudy (Scheme 16).21

Scheme 16 Sonogashira cross-coupling with 1-fluoro-2-nitrobenzene

Scheme 12 Direct Sonogashira-type ethynylation of tautomerizable heterocycles

N

HN O

TMS

1) PyBrOP (1.2 equiv)

Et3N, dioxane, r.t., 2 h

2) PdCl2(PPh3)2 (5 mol%)

CuI (5 mol%)N

N

TMS

83%

N PBr+

PyBrOP3

PF6–

O

AcO

O O

Ph

N

N

N

NH

O

TES

1) PyBrOP (1.2 equiv)

Et3N, dioxane, r.t., 2 h

2) PdCl2(PPh3)2 (5 mol%)

CuI (5 mol%)

O

AcO

O O

Ph

N

N

N

N

TES

61%

Scheme 13 Symmetrical and unsymmetrical diarylation of (trimethyl-silyl)acetylene

PdCl2(PPh3)2 (6 mol%)

CuI (10 mol%), DBU (6 equiv)

benzene, H2O (0.4 equiv)

r.t. or 60 °C

TMS (0.5 equiv)

Ar

X = I, 17 examples

X = Br, 2 examples 48–84%

X = OTf, 3 examples 67–88%

Ar-X

Ar


CuI (10 mol%), Et3N (6 equiv)

benzene, r.t., 18 h

TMS (1.05 equiv)Ar1

TMSAr2-I

DBU, H2O

r.t., 18 h

Ar1-I

8 examples:61–90%

Ar1

Ar2

Scheme 14 Sonogashira cross-coupling in the synthesis of thiophenes and selenophenes

Br

TfO

OTf

Br+

TMS

Br

TMS

Pd(PPh3)2Cl2

56%

Br

TMS

Br

AcO

OAc

Br+

TMSOAc

TMS

Pd(PPh3)2Cl2

84%

Cs2CO3•H2O

63% O

O

AcO

TMS

MeS

TfO

OTf

SMe

+TMS

TMS

MeS

TMS

SMe

Pd(PPh3)2Cl2quant.

I2

88% S

STMS

I

TMS

I

NaBH4

88% S

S

S

SPh

Ph

PhB(OH)2K3PO4•nH2OPd(PPh3)4

9

68%

10

MeSe

TfO

OTf

SeMe

+TMS

Se

Se

11 12

1) Pd(PPh3)2Cl2 (81%)

2) I2 (89%)

3) LiAlH4 (86%)

Scheme 15 Representative Sonogashira cross-coupling with iodopyri-dine

N

I

+TES

FeCl3 (15 mol%)

dmeda (30 mol%)

CsCO3, toluene

135 °C, 72 hN

TES

58%

NO2

+TES

F

NO2

TES

NaHMDS

THF, 60 °C, 5 h95%


F


6 Cross-Coupling with the C–Si Bond

Hatanaka and Hiyama were the first to report the cross-coupling of (trimethylsilyl)acetylenes.22 This they accom-plished with cross-coupling with β-bromostyrene to formconjugated enynes with TASF promotion. It bears mention-ing that under the same conditions (trimethylsilyl)etheneswere cross-coupled in high yield with aryl and vinyl iodides(Scheme 17).

Scheme 17 Conjugated enynes from (trimethylsilyl)acetylenes

Tertiary 3-arylpropargyl alcohols reacted withbis(trimethylsilyl)acetylene under Rh catalysis to give thehydroxymethyl-enyne regio- and stereoselectively with lossof benzophenone and one equivalent of the starting aryl-ethynyl group as its TMS-substituted derivative. Under Pdcatalysis this silylated enyne could be cross-coupled withan aryl iodide, which was converted into the alkylidene-di-hydrofuran. The alkylidene-dihydrofurans thus preparedexhibited fluorescent properties (Scheme 18).23

Scheme 18 Silyl Sonogashira cross-coupling of propargyl alcohols

Seeking a practical entry into 1,4-skipped diynes as po-tential precursors to polyunsaturated fatty acids, the Syn-genta group investigated the cross-coupling of 1-aryl- or 1-alkyl-2-(trimethylsilyl)acetylene derivatives with propar-gyl chlorides. Under the best conditions the reaction of a(trimethylsilyl)acetylene with a propargyl chloride gave the1,4-skipped diyne under promotion with fluoride ion andCuI catalysis. The method avoids the need for protiodesil-ylation to the parent acetylene, a requirement in other cop-per-catalyzed coupling protocols. The reaction failed withnitrogen-containing groups on the silylacetylene. The reac-tion proceeded well with 1-phenyl-2-(tributylstannyl)acet-ylene (70%) and 4-phenyl-1-(trimethylgermyl)but-1-yne(90%) (Scheme 19).24

Denmark and Tymonko demonstrated the cross-cou-pling of alkynyldimethylsilanols with aryl iodides underpromotion with potassium trimethylsilanolate (Scheme20).25 This protocol avoids the typical necessity of fluorideion promotion and the associated disadvantages of cost andlow tolerance for silicon-based protecting groups. The alky-nylsilanols were prepared in a two-step reaction sequence.Interestingly, a direct comparison of the reaction rates ofhept-1-yne, hept-1-ynyldimethylsilanol, and 1-(trimethyl-silyl)hept-1-yne under the potassium trimethylsilanolatepromotion conditions showed the hept-1-ynyldimethylsila-nol to be considerably faster than hept-1-yne and the 1-(trimethylsilyl)hept-1-yne to be unreactive. This stronglysuggests a role of the silanol group in the cross-coupling. Asimilar experiment with TBAF promotion showed all threeto react with the silanol derivative being the fastest. Underthe same conditions 4-bromotoluene gave a 25% conversionshowing the advantages of using iodoarenes.25 The TBAF-promoted cross-coupling of alkynylsilanols with aryl io-dides had previously been shown.26

Scheme 20 Formation of ethynylsilanols and their cross-coupling with aryl iodides

The bis(trimethylsilyl)enyne 13 was nicely prepared viaa Suzuki cross-coupling with 1-bromo-2-(trimethylsi-lyl)acetylene. The bis(trimethylsilyl)enyne 13 cross-cou-pled with aryl iodides in a sila-Sonogashira reaction to pro-vide the silylated conjugated enyne 14. Similar cross-cou-pling reactions of bis(trimethylsilyl)enyne 13 with vinyliodides led to 1,5-dien-3-ynes 15. Cyclic vinyl triflates alsoreacted well with bis(trimethylsilyl)enyne 13 to form 1,5-dien-3-ynes 16 (Scheme 21).27

R

[PdCl(allyl)]2 (2.5 mol%)

TASF (1.3 equiv)

THF, r.t.

TMS

+ BrPh

Ph

R

3 examples:83–85%

X

Ph

Ph OHTMS

TMS+[(cod)Rh(OH)]2 (4 mol%)

dppb, toluene, 4 h

Ph Ph

O

TMSX

+

+

TMS

Ph Ph

OH

X


TMS

Ph Ph

OH

X

1) Pd(PPh3)2Cl2 (6 mol%)

CuI (10 mol%), YC6H4I

DBU (6 equiv), H2O

toluene, 100 °C

2) KOt-Bu, DMSO X

OPh Ph

Y6 examples: 38–77%

Scheme 19 Cross-coupling approach to 1,4-skipped diynes

TMS

R1+

R2

Cl

CuI (1 equiv)

CsF (1 equiv)

DMI, 80 °C, 2 h R1 R2

7 examples: complex mixture – 72%

n-C5H11

1. n-BuLi, Me2ClSiH

2. [RuCl2(p-cymene)]2, H2O

82%n-C5H11

SiMe2OH

n-C5H11

SiMe2OH

+ Ar-I

TMSOK (2 equiv)

PdCl2(PPh3)2 (2.5 mol%)

CuI (5 mol%), DME, r.t., 3 hn-C5H11

Ar

10 examples:75–95%


G


7 Stille Cross-Coupling

(Trimethylsilyl)acetylene was deprotonated and reactedwith tributyltin chloride to give 1-(tributylstannyl)-2-(trimethylsilyl)acetylene (17) in good yield (Scheme 22).28

Scheme 22 Synthesis of 1-(tributylstannyl)-2-(trimethylsilyl)acetylene

1-(Tributylstannyl)-2-(trimethylsilyl)acetylene (17) wasprepared directly from (trimethylsilyl)acetylene and tribut-yltin methoxide in 49% isolated yield (Scheme 23).29

Scheme 23 Alternative synthesis of 1-(tributylstannyl)-2-(trimethylsi-lyl)acetylene

The bis(silyl)enyne 19 was prepared by cross-coupling1-(tributylstannyl)-2-(trimethylsilyl)acetylene (17) withvinyl iodide 18 in 75% yield. In another approach to this endin the same paper, vinylstannane 20 reacted with 1-bromo-2-(trimethylsilyl)acetylene and 1-bromo-2-(triisopropylsi-lyl)acetylene to give the bis-silylated conjugated enynes 21in good yield (Scheme 24).30

Scheme 24 Stille cross-coupling reactions

The alkynylation of the anomeric position of the benzyl-protected glucose derivatives 22 was accomplished with 1-(tributylstannyl)-2-(trimethylsilyl)acetylene (17) (Scheme25).31

Scheme 25 sp3-sp Cross-coupling of 1-(tributylstannyl)-2-(trimethylsi-lyl)acetylene with a sugar derivative

1-(Tributylstannyl)-2-(trimethylsilyl)acetylene (17) wascross-coupled with 23 and found to be tolerant of a ketaland a cyclopropene. The TMS group was removed alongwith deacetoxylation of the ester upon treatment withK2CO3/MeOH (Scheme 26).32

Scheme 26 Sonogashira cross-coupling showing functional group tol-erance

1-(Tributylstannyl)-2-(trimethylsilyl)acetylene (17) wascross-coupled with the highly substituted aryl bromide 24in a synthesis of (+)-kibdelone A. The TMS group was re-

Scheme 21 Suzuki cross-coupling with 1-bromo-2-(trimethylsi-lyl)acetylene and cross-coupling of the 1-(trimethylsilyl)alk-1-yne

Cy2BR

TMS

+

TMS

Br

CuI (10 mol%)

LiOH•H2O (0.75 equiv)

–15 °C to r.t., overnight

R

TMS

TMS


DBU, r.t., overnight

R

TMS

Ar

ArI


13

14

R1

TMS

TMS


DBU, r.t., overnight

R1

TMS

15R2R2

I+


R

TMS

TMS


DBU, r.t., overnight8 examples: 40–75%

+

R

TMS

16

OTf

13

13

TMS 1) n-BuLi, Et2O

–40 °C, 45 min

2) n-Bu3SnCl, r.t., 24 h

84%

TMS

n-Bu3Sn17

TMS+n-Bu3SnOMe

ZnBr2 (5 mol%)

THF, r.t., 3 h17

49%

+ 17FI

F

TES

Pd(PPh3)4 (10 mol%)

CuI (10 mol%)

THF, reflux, 2 h

75%

F

F

TES

TMS

1918

FSn(n-Bu)3

F

TES

SiR3

Br

+

Pd(PPh3)4 (10 mol%)

CuI (10 mol%)

THF, reflux, 5 hF

F

TES

SiR3

R3Si = TMS 70%

R3Si = TIPS 73%20 21

O

BnO

BnO

X

OBn

BnO

+ 17

1) TMSOTf

CH2Cl2

2) K2CO3, MeOH

X = OMe 37%X = OAc (α and β) 87%X = OAc (β) 54%

O

BnO

BnO

OBn

BnO

TMS

22

Br

OAc

OO

3

+ 17Pd(PPh3)4


76%

OAc

OO

3

TMS

K2CO3, MeOH2 h

88%

OH

OO

3

23


H


moved in 93% yield with AgNO3·pyridine in aqueous ace-tone (Scheme 27).33

Scheme 27 Stille cross-coupling of 1-(tributylstannyl)-2-(trimethylsi-lyl)acetylene with a highly substituted aryl bromide

Similarly to the Sonogashira reaction of (trimethylsi-lyl)acetylene, where the cross-coupling occurs at the C–Hbond, the cross-coupling of 1-(tributylstannyl)-2-(trimeth-ylsilyl)acetylene (17) occurs at the C–Sn bond rather thanthe C–Si bond. This was employed in the synthesis of the in-dole piece of sespendole (Scheme 28).34

Scheme 28 Stille cross-coupling of 1-(tributylstannyl)-2-(trimethylsi-lyl)acetylene with a highly substituted aryl triflate

In an approach to the synthesis of lactonamycins, amodel glycine was prepared wherein a critical step was theaddition of an ethynyl group onto a highly substitutedarene. Thus, bromoarene 25 was subjected to a Stille cross-coupling with 1-(tributylstannyl)-2-(trimethylsilyl)acety-lene (17) to give the ethynylarene 26 in 91% yield. This com-pared favorably with a three-step sequence (Scheme 29).35

Scheme 29 Selective Stille cross-coupling

8 Reactions at the Terminal Carbon

Under a co-catalysis approach, (triisopropylsilyl)acety-lene reacted with enones to form β-ethynyl ketones in highyields (Scheme 30). The reaction worked well with (tert-bu-tyldimethylsilyl)acetylene and (tert-butyldiphenylsi-lyl)acetylene as well, although (triethylsilyl)acetylene gaveonly 40% yield. Under the same reaction conditions thenon-silylated terminal acetylenes phenylacetylene and oct-1-yne gave alkyne oligomerization. An asymmetric versionof the reaction, which gave good yields (5 examples, 53–93%) and acceptable ee (81–90%), was also presented.36

Scheme 30 β-Ethynylation of α,β-unsaturated ketones

Carreira and co-workers reacted terminal acetylenes in-cluding (trimethylsilyl)acetylene with aldehydes in thepresence of (+)-N-methylephedrine to give the propargylalcohol in high yield and high ee (Scheme 31).37

Scheme 31 Asymmetric ethynylation of an aldehyde

The aldehyde 27 was reacted with (trimethylsilyl)acety-lene under Carreira conditions to give a single diastereomerof 28, which was O-silylated followed by protiodesilylationof the TMS group. This material was carried forth in a syn-thesis of hyptolide and 6-epi-hyptolide (Scheme 32).38

Scheme 32 Diastereoselective ethynylation of an aldehyde in a synthe-sis of hyptolide

In keeping with the common use of silylacetylenes assurrogates for the simple ethynyl organometallics, an ‘in si-tu’ process for the ethynylation of aldehydes was developed.In this chemistry a combination of ZnBr2, TMSOTf, andHünig’s base was used to generate the ethynylzinc reagentin situ and, along with a silylating agent, it was reacted withthe aldehyde to generate the doubly silylated propargyl al-cohol, which was O-deprotected with dilute hydrochloricacid (Scheme 33).39

Br

OMe

Pd(PPh3)4


82%

+ 17

OMe

HO

OTBDPS

HO

OTBDPS

TMS

24

OTBS

O

OTf

NO2

Pd(PPh3)4, LiCl

toluene, 100 °C, 2 h+

OTBS

O

NO2

TMS

87%

17

BrCl

OMe

OMe

OMOM+ 17

Cl

OMe

OMe

OMOM

TMS

91%

Pd(PPh3)4 (10 mol%)


25 26

R1 R3

O

R2

+TIPS

Co(OAc)2•4H2O (5 mol%)

dppe (5 mol%), Zn (50 mol%)

DMSO, 80 °C, 20 hR1

O

R2

R3

TIPS


Ph

O

+TIPS

Co(OAc)2•4H2O (10 mol%)

(10 mol%)Ph

O

TIPS

Ph2P PPh2

93%, 87% ee

Zn (50 mol%), DMSO, 80 °C, 20 h

TMS+

Zn(OTf)2, Et3N

(+)-N-methylephedrine


CHO

TMS

OH

93%; 98% ee

CHO

OTBS

TESOTMS

+Zn(OTf)2, Et3N

(–)-N-methylephedrine

toluene, r.t.OTBS

TESO

TMS

OH

77%

1) TBSOTf, 2,6-lutidine

CH2Cl2, 0 °C (87%)

2) K2CO3aq, MeOH, r.t.

(86%)OTBS

TESO

H

OTBS OOAcAcO

OAc

O

hyptolide

2728


I


Scheme 33 ‘In situ’ ethynylation of aldehydes

The aminomethylation of terminal alkynes was appliedto a variety of acetylene derivatives including a single ex-ample with (triethylsilyl)acetylene, which provided the tri-ethylsilylated propargyl amine in good yield. This was sub-sequently protiodesilylated and the resulting propargylamine converted into a mixed bis(aminomethyl)alkyne in a49% yield over three steps (Scheme 34).40

(Triisopropylsilyl)acetylene was employed in a Ni-cata-lyzed, three-component reaction of the ethynylsilane, analkyne, and norbornene. A variety of norbornene deriva-tives were reacted with good success. When (triisopropylsi-lyl)acetylene was used as the sole acetylene reactant, the

bis(triisopropylsilyl)-1,5-enyne was produced. One exam-ple with a bicyclo[2.2.2]octene gave the correspondingproduct in only 12% yield when reacted with (triisopropyl-silyl)acetylene (Scheme 35).41

(Trimethylsilyl)acetylene could be directly alkylated togive 1-(trimethylsilyl)dodec-1-yne in modest yield. Theyield of this sole silicon example was comparable to the di-rect alkylation of other terminal alkynes (Scheme 36).42

Scheme 36 Copper-catalyzed alkylation of (trimethylsilyl)acetylene

9 Cross-Coupling with Silylethynylmagne-sium Bromides

In a useful synthetic approach to alkynylsilanes (triiso-propylsilyl)ethynylmagnesium bromide was cross-coupledwith anisoles (23 examples 42–94% yield). In the cross-cou-pling of either 4-fluoroanisole or 4-cyanoanisole, the cou-pling of the F or CN substituent was favored over that of themethoxy group. The trimethylsilyl enol ether of cyclohexa-none cross-coupled, as did 4,5-dihydrofuran. In one exam-

R H

O

+TES

1) ZnBr2 (20 mol%)

i-Pr2NEt, TMSOTf, Et2O

2) HCl (1 M), THFR

OH

TESR = Ph, 90%; R = i-Bu, 59%

Scheme 34 Aminomethylation of terminal alkynes

N

TES+

FeCl2 (10 mol%)

(t-BuO)2 (2 equiv)

100 °C, 30 h, air

N

TES

82%TBAF (1.2 equiv)

THF89%

N

HN

Nn-C8H17

n-C8H17NMe2

FeCl2 (10 mol%)

(t-BuO)2 (2 equiv)

100 °C, air, 18 h

67%

Scheme 35 Three-component reaction of norbornene with and (triiso-propylsilyl)acetylene and an alkyne

+

TIPS

H

Ar

H+

Ni(cod)2 (10 mol%)

Ph2MeP (20 mol%)


TIPS

Ar

MeO

TIPS

Ar

OMe+

29

30

11 examples52–94%, 29:30 83:17 to 99:<1

TIPS

H+

Ni(cod)2 (10 mol%)

Ph2MeP (20 mol%)


TIPS

TIPS


R

R

R

R

TMS+ n-C10H21-I

31 (3.5 mol%)

CuI (9 mol%)

LiOt-Bu (1.4 equiv)

DMF, r.t., 16 h

TMS

n-C10H21

58%

NMe2

N Ni

NMe2

Cl

31

Scheme 37 Cross-coupling of silylethynylmagnesium bromide with anisoles

OMe TIPS

BrMg

+

Ni(cod)2 (10 mol%)ICy•HCl (20 mol%)

TIPS

32 (2 equiv) 75%

32 (2 equiv)Ni(cod)2 (10 mol%)OTMS

TIPS

O

88%

OH

TIPS

32 (2 equiv)Ni(cod)2 (10 mol%)

OMe32 (2 equiv)

Ni(cod)2 (10 mol%)OMe

XTIPS

32 (2 equiv)Ni(cod)2 (10 mol%)

TIPS

1) TBAF, H2O (73%)OMe

n-Bu

dioxane, 120 °C, 18 h

ICy•HCl (20 mol%)dioxane, 120 °C, 18 h

82%



X = F 73%; X = CN 80%


2) Pd(PPh3)4 4-I-C6H4-Bu (73%)


J


ple the TIPS group was removed with TBAF/H2O and the re-sulting acetylene cross-coupled in a Sonogashira reaction tothe diarylacetylene (Scheme 37).43

The bromomagnesium reagents of (triisopropylsi-lyl)acetylene (32) and (tert-dimethylsilyl)acetylene werecross-coupled with primary and secondary alkyl iodidesand bromides in a Sonogashira-type reaction employing theiron complex 33. The reaction was tolerant of ester, amide,and aryl bromide groups (6 examples, 69–92% yield, 2 ex-amples with TBS, both 83% yield). The free radical nature ofthe reaction was shown by the cross-coupling/cyclization of34 (Scheme 38).44

The synthesis of 2-alkylated ethynylsilanes was accom-plished via a FeBr2-catalyzed coupling reaction between asilylethynylmagnesium bromide reagent and a primary orsecondary alkyl halide. This nicely broadens the scope ofentries into 2-alkylated ethynylsilanes (Scheme 38).45

10 Reactions of Haloethynylsilanes

A combination of the synthesis of TMS-, TIPS-, andCPDMS-substituted acetylenes and their cross-couplingwith vinyl bromides and selective deprotection was effec-tively employed in the syntheses of callyberyne A (38) andcallyberyne B (39). Thus, 1-iodo-2-(triisopropylsilyl)acety-lene was converted into the skipped tetrayne 35, (trimeth-

ylsilyl)acetylene was converted into enediyne 36, and [(3-cyanopropyl)dimethylsilyl]acetylene was converted into di-enyne 37 (Scheme 39).8

Scheme 39 Ethynylsilanes in the syntheses of callyberynes A and B

The Pd-catalyzed phenylation of 1-iodo-2-(trimethylsi-lyl)acetylene in a Kumada-type coupling reaction illustrat-ed the potential of this route to 1-aryl-2-silylacetylenes.Numerous non-silicon terminated iodoalkynes were simi-larly arylated (Scheme 40).46

Scheme 40 Arylation of 1-iodo-2-(trimethylsilyl)acetylene

1-Iodo-3-(trimethylsilyl)acetylene was converted into(trimethylsilyl)ynamide 40, which was subsequently pro-tiodesilylated and the parent ynamide then converted intothe iodoethynamide. In a more practical approach,(trimethylsilyl)acetylene and (triisopropylsilyl)acetylenewere reacted in a two-step, single-flask protocol with NBS

Scheme 38 sp3-sp Cross-coupling with silylethynylmagnesium bro-mide

+ 32Br

Br 33 (5 mol%)

THF, 60 °C, 2 hBr

TIPS

82%

+ 3233 (5 mol%)

THF, 60 °C, 2 h92%

N

Br

Ts NTs

TIPS

34

P PFetBu

tBu

tBu

tBu tBu

tButBu

tBu

Cl Cl

33

TMS

BrMg+

X FeBr2 (10 mol%) TMS

X = I, 51%; X = Br, 48%

O

I SiR3

BrMg+

FeBr2 (10 mol%)

THF, NMP, r.t., 18 h

SiR3

O

SiR3 = TES, TIPS6 examples: 78–96%

THF, NMP, r.t., 18 h

R

R

TIPSIH

HO

3

+Pd2dba3, CuI

Li, Et3N, DMSO85%

HO

3

TIPS

HO

3

TIPS

3

TIPSH

73%35

TMS

H

I OH3

+

OH3

TMS

OH3

TMSCuCl, piperidine

87%

3

TMS

I

55% 36

Br Br4

H

CPDMS

+Pd(PPh3)2Cl2, CuI

n-BuNH2, benzene

77%

Br4

CPDMS 37

35 + 37Pd(PPh3)2Cl2, CuI

pyrrolidine

CPDMS

TIPS

3

4

TBAF, THF

93%

3

4

38 callyberyne A

TIPS

3

1. 34, Pd(PPh3)2Cl2

CuI, pyrrolidine

2. TBAF, THF61%

3

4

39 callyberyne B

TMS

I

+ PhMgBrPd(PPh3)4

THF, 70 °C, 12 h

TMS

Ph 58%


K


and a secondary amine to prepare the corresponding si-lylated ynamide.47,48 The silylated ynamides were subse-quently reported to be excellent precursors to highly substi-tuted indolines (Scheme 41).49

Danheiser and Dunetz were able to prepare ynamidesfrom bromo- and iodoacetylenes, including 1-bromo-2-(trimethylsilyl)acetylene and 1-bromo-2-(triisopropylsi-lyl)acetylene. This work complements other approaches tosubstituted acetylenes. The protocol was extended to in-clude cyclic carbamates, ureas, and sulfonamides, but notwith silyl-substituted acetylenes. The key to the success ofthe reaction was the pre-formation of the amidocopper in-termediate.50 The resulting functionalized silylacetylenescould be readily protiodesilylated to the parent alkyne(Scheme 41).48

The zinc reagent from 41 was reacted with either 1-iodo-2-(trimethylsilyl)acetylene or better with 1-bromo-2-

(trimethylsilyl)acetylene to form 2-amino-5-(trimethylsi-lyl)pent-4-ynoate 42, which was subsequently protiodesil-ylated and the parent acetylene cross-coupled to the 4-po-sition of 43 in a total synthesis of the COPD (chronic ob-structive pulmonary disease) biomarker, (+)-desmosine(44) (Scheme 42).51

Scheme 42 Zinc-catalyzed sp3-sp cross-coupling of 1-halo-2-(trimeth-ylsilyl)acetylenes

Under indium catalysis 1-iodo-2-(trimethylsilyl)acety-lene was reacted onto the anomeric carbon of glycals to fur-nish the α-ethynyl-2,3-unsaturated-C-glycoside. Only a sin-gle example employing 1-iodo-2-(trimethylsilyl)acetylenewas reported. The trimethylsilyl group was converted intothe iodide in 90% yield; this was in turn used in the prepa-ration of a C-disaccharide bridged by an ethynyl group(Scheme 43).52

Scheme 43 Ethynylation of glycals

The advantages of the selective chemistry of differentsilyl groups was applied to the synthesis of tris(biphenyl-4-yl)silyl (TBPS) terminated polyynes. Based on the findingsthat bulky groups on the termini of polyynes provide stabil-ity and calculations showing the TBPS group to have overtwice the radius of the TIPS group, this group was investi-gated in the synthesis and stability of TBPS-terminatedpolyynes. The synthesis of the polyynes started with the re-action of lithium (trimethylsilyl)acetylide with tris(biphe-nyl-4-yl)chlorosilane. Selective protiodesilylation gave theScheme 41 Ethynylation of carbamates

TMS I

1) KHMDS (1 equiv) CuI (1 equiv)

58%

MeO NHBn

O

N

TMS

Bn

CO2Me 40

1) NBS, AgNO3 (5 mol%) acetone, r.t. , 2 h

H

SiR3

N

SiR3

Bn

Ts

R3Si = TMS 40%: R3Si = TIPS 91%

TMS Br

TMS

NH

CO2Me

KHMDS, CuI, pyr

N

CO2Me

TMS

BHT (1 equiv)N

MeO2C TMS

N

Z

R

BHT (1 equiv)

N

Z R

Z

Ts

Tf

CO2Me

CO2Me

R

TMS

TMS

TMS

Yield

56%

68%

74%

69%

KHMDS (1 equiv)CuI (1 equiv), pyrr.t., 2 h then

TMS Br (2 equiv)PhN

CO2Me

H

N TMSPh

MeO2C

56%

N TMSPh

MeO2C

40%

N TIPSPh

MeO2C

74%

2) r.t., 16 h

2) BnNHTs, CuSO4•5H2O 1,10-phenanthroline (0.2 equiv) K2CO3, toluene, 65 °C, 21 h

toluene180 °C, 16 h

toluene180–210 °C, 1.25–16 h

r.t., 20 h

INHBoc

CO2Bn

Zn, TMSCl, DMF r.t., then

TMS X

X = I 35%; X = Br 72%

CO2MeTMS

NHBoc

41 42

N

X

O

NBoc

OBocN

43 X = I, Br

N

CO2HH2N

NH2

CO2H

NH2CO2H

H2N

CO2H +

(+)-desmosine 44

–20 °C to r.t.

I

TMSAcO

AcO

O

AcO

In (2.4 equiv)

CH2Cl2+

AcO

AcO

O

AcO

TMS

82%, α/β = 85:15

AcO

AcO

O

TMS

AgNO3 (10%)

NIS, acetone, 1 h

AcO

AcO

O

I

90%


L


TBPS-substituted acetylene, and NBS bromination gave 1-bromo-2-[tris(biphenyl-4-yl)silyl]acetylene. This bromoderivative was cross-coupled with (trimethylsilyl)acetyleneto give the mixed silylbuta-1,3-diyne, which was subjectedto selective protiodesilylation and homocoupling to give1,8-bis[tris(biphenyl-4-yl)silyl]octa-1,3,5,7-tetrayne in 77%over two steps. Iterations of these reactions were used toprepare the triyne 45 and hexayne 46 (Scheme 44).53

Scheme 44 Synthesis of polyynes

11 Cycloaddition Reactions

Silylacetylenes, like many alkynes, undergo an extensivevariety of cycloaddition reactions. In many cases based onelectronic and steric factors the silyl group can impart use-ful regio- and stereoselectivities in addition to the ability tochemically transform the silyl group to other useful func-tionalities.

11.1 Formation of Aromatic Rings

The tricyclization of alkynes to aromatic rings has longbeen recognized, as has the use of silylacetylenes in thispractice. Silyl-protected arylacetylenes reacted with 2-(phenylethynyl)benzaldehyde under acid catalysis to pro-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 thereaction conditions. However, the more hindered TES-, TBS-, and TIPS-protected derivatives gave the corresponding 3-silylnaphthalenes allowing for the ICl ipso iodination of thesilyl group to provide the iodonaphthalene for further elab-oration via cross-coupling chemistry. The chemistry wasapplied to the synthesis of several highly encumbered pol-yaromatic systems (Scheme 45).54

Scheme 45 Cyclization to aromatic rings from arylacetylenes

The Rh-catalyzed reaction of (trimethylsilyl)acetyleneswith cyclobutenols gave 1,2,3,5-tetrasubstituted benzeneswith the trimethylsilyl group regioselectively positioned inthe 2-position. No conversions of the trimethylsilyl groupwere carried out in this work (Scheme 46).55

Scheme 46 Cyclobutenol to a TMS-substituted arene

Methyl 3-(trimethylsilyl)propynoate was successfullyemployed in the synthesis of 2H-quinolizin-2-ones. In thisapproach the trimethylsilyl group conveniently served thepurpose of protecting the acidic hydrogen of the parent ter-minal acetylene (Scheme 47).56

Scheme 47 Quinolizin-2-ones from methyl 3-(trimethylsilyl)propy-noate

The cationic rhodium catalyst [Rh(cod)2]BF4/BIPHEPbrought about the cyclotrimerization of (trimethylsi-lyl)acetylene and unsymmetrical electron-deficient acety-lenes. Unfortunately, neither the stoichiometry nor the re-gioselectivity of the cyclization was optimal. Larger silylgroups tended to favor the addition of one of the silylacety-lene moieties and two of the electron-deficient alkynes,whereas increasing the steric bulk of the electron-deficient

TMS

Li

Si ClPh

TBPS-Cl

+

3

Et2O

0 °CTBPS

TMS

76%

TBPS

TMSK2CO3

THF, MeOH, 0 °C

TBPS

H85%

TBPS

TMSAgNO3, NBS

TBPS

Br

87%

TMS

HTBPS

Br

+[PdCl2(PPh3)2]/CuCl

i-Pr2NH, THFTBPS TMS

54%

TBPS TMS

1. NaHCO3

THF, MeOH, 0 °C (93%)TBPS TBPS

TBPS TBPSTBPS TBPS

45 46

2. CuCl, TMEDACH2Cl2, O2 (83%)

Ph

O

H+

SiR3

Ph

Cu(OTf)2 (10 mol%)

CF3CO2H (1 equiv)

DCE, 100 °C, 30 min

Ph

SiR3

R3Si = TMS (40%, desilylated); TES (67%); TBS (85%); TIPS (89%); PhMe2Si (78%)

Ph

O

H+

TIPS

Ar

Cu(OTf)2 (10 mol%)

CF3CO2H (1 equiv)

DCE, 100 °C, 30 min

Ar

TIPS

5 examples: 0–78%

Ph

SiR3

ICl, CH2Cl2

r.t., 5 min

Ph

I

R3Si = TES (90%); TBS (93%); TIPS (92%)

n-Bu OH

Ph

+

TMSn-Bu

TMS

Ph

[Rh(OH)(cod)]2 (2.5 mol%)

rac-BINAP (6 mol%)

toluene, 110 °C, 3–3.5 h

50%; rr = >99:1; w/o rac-BINAP 93%; rr = 93:7

TMS

OMe

N

1) LDA, THF, –78 °CO

2)

3) TBAF, THF, r.t., 0.5 h

4) MeCN, 50 °C

N

O



M


alkyne resulted in the reaction of two equivalents of the si-lylacetylene. (Triisopropylsilyl)acetylene failed to react.Protiodesilylation of a mixture of regioisomers was able tosimplify the reaction mixture, but reaction with ICl gave asynthetically challenging mixture of isomers in modestyield (Scheme 48).57

Scheme 48 Mixed substituted arenes from cross-cyclization of (trimethylsilyl)- and (triethylsilyl)acetylene with ethyl but-2-ynoate

The cyclotrimerization of ethyl 3-(trimethylsilyl)propy-noate gave 47 as a single regioisomer in 92% yield (Scheme49).58

Scheme 49 Homocyclization of ethyl 3-(trimethylsilyl)propynoate

Complete regioselection in the formation of 2-aryl-1,3,5-tris(silyl)benzene was realized in the Pd-catalyzed re-action of two equivalents of a terminal alkyne, including(trimethylsilyl)acetylene, and an equivalent of a β-iodo-β-silylstyrene. The nature of the silylstyrene proved crucial astrialkylsilyl (TMS, TES, TBS, Me2BnSi) groups gave pooryields and the phenylated silyl groups gave better yields,with the β-Ph2MeSi-substituted styrene proving optimal.Selective electrophilic substitution of the 5-(trimethylsilyl)group, para relative to the aromatic substituent, provedpossible. In a demonstration of the potential synthetic utili-ty of the highly silylated systems, a number of conversions

of the silyl groups were carried out including protiodesil-ylation, acylation, iodination, and Denmark cross-coupling.It is noteworthy that the iododesilylation of 48 was selec-tive for the formation of 49 and that iododesilylation of aphenyl group from the Ph2MeSi group did not occur. Com-parable selectivity was noted in the acetylation of 48 to 4-phenylacetophenone (Scheme 50).59

Scheme 50 Cyclotrimerization with a vinyl iodide and subsequent conversions

11.2 Diels–Alder Cyclizations

Silylacetylenes were shown to provide excellent re-giochemical control in the cobalt-catalyzed Diels–Alder re-action with 1,3-dienes. In the unsubstituted case various(trialkylsilyl)- and (triphenylsilyl)acetylenes were reactedwith 2-methylbuta-1,3-diene under cobalt catalysis. Theregioselectivity was highly dependent on the accompany-ing ligand employed with CoBr2(py-imin) [py-imin = N-me-sityl-1-(pyridin-2-yl)methanimine, 56] favoring the metaregioisomer 50 after DDQ oxidation to the aromatic deriva-tive. On the other hand, the use of CoBr2(dppe) [dppe = 1,2-bis(diphenylphosphino)ethane] favored the para isomer 51.In addition a number of 1-(trimethylsilyl)alk-1-ynes werereacted with 2-methylbuta-1,3-diene. Here the yields were

TMS

CO2Et

CO2EtTMS

+

CO2Et

[Rh(cod)2]BF4 (10 mol%)

BIPHEP (10 mol%)

CH2Cl2, r.t., 16 h

TMS

CO2Et

EtO2C

TMS

CO2EtEtO2C

TMS

TMS

CO2Et

+

+ +

19%

58%

10% 3%

TES

CO2Et

CO2EtTES

+

CO2Et

[Rh(cod)2]BF4 (10 mol%)

BIPHEP (10 mol%)

CH2Cl2, r.t., 16 h

TES

CO2Et

EtO2C

TES

CO2EtEtO2C

TES

TES

CO2Et

+

+ +

4%38%

6% 1%

EtO2C

TMS Ni(cod)2 (1 mol%)

SIPr (1 mol%)

THF, 23 °C, 24 h3

TMS

EtO2C

EtO2C

TMS

CO2Et

TMS

92%47

SiMePh2

I

Ph

+SiR3 Pd(OAc)2 (5 mol%)

i-Pr2NEt, 30 °C, 24 h

SiMePh2

Ph

R3Si

SiR3

R3Si = PhMe2Si (93%); Ph2MeSi (89%); (i-PrO)2MeSi (80%); TES (34%)

SiMePh2

Ph

TMS

TMS

ICl (1.2 equiv)

CH2Cl2, 0 °C to r.t., 16 h

SiMePh2

Ph

TMS

I64%

48 49

ICl (3.4 equiv)

CH2Cl2, 0 °C to r.t., 16 h

I

Ph

I

I48%

48

AcCl (3.4 equiv)

AlCl3 (3.4 equiv)

CH2Cl2, rt, 3 h

SiMePh2

Ph

TMS

O64%

TBAF (8 equiv)

THF, rt, 15 h

Ph

O

81%

48

SiMePh2

Ph

(i-PrO)Me2Si

(i-PrO)Me2Si

LiAlH4

dioxane, 80 °C, 18 h

SiMePh2

Ph

HMe2Si

HMe2Si

Pd/C, H2O

hexane, r.t., 6 h

SiMePh2

Ph

HOMe2Si

HOMe2Si

Pd(PPh3)4 (10 mol%)

Ag2O (3 equiv)

PhI (6 equiv)

TBAF (0.2 equiv)

THF, 65 °C, 16 h

SiMePh2

Ph

Ph

Ph 32%


N


very high, but the regioselectivity was less than that ob-served with the simple silylacetylenes. Of particular inter-est was the result from the reaction of 3-(trimethylsi-lyl)propargyl acetate with Danishefsky’s diene, 2-(trimeth-ylsiloxy)buta-1,3-diene (Scheme 51).60

Scheme 51 Diels–Alder cyclization of silylacetylenes with 1,3-dienes

The synthesis of aryl and vinyl iodides has taken on in-creased importance due to their facility as electrophilicpartners in various cross-coupling reactions. Building onthe Diels–Alder chemistry of butadienes with (trimethylsi-lyl)acetylenes, the Hilt group devised an efficient route tohighly substituted aryl iodides wherein the TMS groupserved nicely to define the regiochemistry and provide theiodide functionality. The complete reaction sequence couldbe carried out in a single flask although considerable effortwas placed on the oxidation/iodination step. For example,

ICl/CH2Cl2 gave only 5% of the iodide 54, NIS/MeCN gavemodest yields of the iodide in 5 cases, but the reaction wasvery slow and product decomposition led to purificationdifficulties. The combination of H2O2/ZnI2 gave modestyields, but again in a slow reaction that required further ox-idation with DDQ for completion. Finally, the use of tert-butyl hydroperoxide with ZnI2 and K2CO3 was found to givehigh yields of the desired iodides (Scheme 52).61

Scheme 52 Diels–Alder cyclization to cyclic 1,4-dienes

11.3 Formation of Heterocycles

The diynes 57 were subjected to cyclotrimerizationwith hex-1-yne; the TMS-substituted derivative (R = TMS)gave considerably better yields and regioselectivities thanthe protonated analogues (R = H). Interestingly, the applica-tion of this cyclotrimerization towards the synthesis can-nabinols employed the use of 3-(trimethylsilyl)prop-1-yne(instead of hex-1-yne), which showed clean regioselectivityto give 61 from 60. The bis(trimethylsilyl)arene 61 was pro-tiodesilylated to 62, which was carried through to cannabi-nol (63) (Scheme 53).62

Scheme 53 Cyclizations leading to cannabinols

+SiR3

1) CoBr2(py-imin) (10 mol%)

Fe powder (20 mol%)

Zn dust (20 mol%)

ZnI2 (20 mol%)

2) DDQSiR3

SiR3

+

50 51

R3Si = TMS, TES, TIPS, TBS, Ph3Si 80–92%; 50:51 = 92:8–96:4

+

SiR3

1) CoBr2(dppe) (10 mol%)

Zn dust (20 mol%)

ZnI2 (20 mol%)

2) DDQSiR3

SiR3

+

50 51R3Si = TMS, TES, TIPS, TBS, Ph3Si

72–93%; 50:51 = 4:93–8:92

+

TMS

TMS

TMS

+

52 53R

R

R

9 examples: 72–96%; 52:53 = 98:2–18:82


Fe powder (20 mol%)

Zn dust (20 mol%)

ZnI2 (20 mol%)

2) DDQ

+

TMS1) CoBr2(dppe) (10 mol%)

Zn dust (20 mol%)

ZnI2 (20 mol%)

2) DDQR

9 examples: 76–97%; 52:53 = 21:79– 5:95

52 + 53

TMSO+

TMS


Fe powder (20 mol%)

Zn dust (20 mol%)

ZnI2 (20 mol%)

2) DDQOAc

O TMS

81%

TMSO+

TMS 1) CoBr2(py-imin) (10 mol%)

Zn dust (20 mol%)

ZnI2 (20 mol%)

2) SiO2, airOAc

HO

TMS

OAc

80%

1) CoBr2 (55 or 56) (10 mol%)

Zn (20 mol%), ZnI2 (20 mol%)

CH2Cl2, r.t., 24 h

2) SiO2 filtration

R1 +

TMS

R2

R1

TMS

R2

TBHP (4.0 equiv)

ZnI2 (2.0 equiv)

K2CO3 (4.0 equiv)

CH2Cl2, r.t., 15 min

R1

I

R2

11 examples47–89%

Ph2P PPh2

55N N Mes

56

54

O

X

R

n-Bu+

Cp*Ru(cod)Cl (10 mol%)

toluene, MW 300 W, 10 min

O X

n-Bu

H

R

R

H

TMS

H

TMS

X

H2

O

H2

O

Yield

61%

97%

31%

81%

58:5970:30

>95:5

76:24

>95:5

O X

R

H

n-Bu+

57 58

59

OMe

n-C5H11 O

TMS

+ TMSCp*Ru(cod)Cl (10 mol%)

toluene, MW 300 W, 10 min

O

H

TMS

TMS

OMe

n-C5H1160 61

TBAF, THF, DMF

MW, 300 W, 2 min96%

On-C5H11

OMe

On-C5H11

OMe

cannabinol 6362

61


O


Under strong base catalysis, 1-aryl-2-silylacetyleneswere converted into oxasilacyclopentenes upon reactionwith aldehydes or ketones. The reaction required that thesilyl moiety contain a Si–H bond [SiHMe2, SiH(i-Pr)2,SiHPh2]. Among the catalysts investigated KOt-Bu was clear-ly superior, with fluoride ion sources tending to give moreof the product of direct alkynylation of the carbonyl. Silylal-kynylation of the carbonyl followed by base-catalyzed in-tramolecular hydrosilylation of the C≡C bond is proposed.4-Methoxyphenyl- and 2-tolyl-substituted (dimethylsi-lyl)acetylenes on reaction with cyclohexanone gave onlyalkynylation of the ketone, but 4-fluorophenyl- and 4-(tri-fluoromethyl)phenyl-substituted (dimethylsilyl)acetylenesgave good yields of their respective oxasilacyclopentenes (8examples, 48–87% yields). The oxasilacyclopentene 64 wasshown to have synthetic utility as it could be oxidized, ep-oxidized, and cross-coupled all in good yield (Scheme 54).63

Scheme 54 Oxasilacyclopentenes via cyclization with ketones

Cyclotrimerization of 65 (R = TMS) with 4-hydroxypen-tanenitrile gave the desired product regioselectivity, albeitin only 42% yield, this compared to 83% yield from the par-ent diyne 66 (R = H) (Scheme 55).64

Scheme 55 Cyclization of a silylated skipped diyne with a nitrile

Whereas the Ru-catalyzed reaction of an internalalkyne, carbon monoxide, and an enone produced hydro-quinones in a [2+2+1+1]-cycloaddition reaction, (trimethyl-silyl)acetylenes reacted in a [3+2+1] fashion to form an α-pyrone, wherein the carbonyl and α-carbon of the enoneprovided three atoms. The resulting 3-(trimethylsilyl)-2H-pyran-2-ones were not elaborated further (Scheme 56).65,66

The reaction of 1-(methoxydimethylsilyl)-2-phenyl-acetylene with propanenitrile oxide, generated in situ from1-nitropropane and phenyl isocyanate, gave a mixture of 4-and 5-silylated isoxazoles favoring formation of the 4-silylisomer. Acid hydrolysis of this mixture allowed isolation ofthe pure 4-dimethylsilanol derivative in 49% overall yield.In a similar manner the ‘in situ’ generated benzonitrile ox-ide reacted to give, after hydrolysis, the corresponding 4-si-lanol products. These silanols were subjected to Denmarkcross-coupling protocols to take advantage of the positionof the silyl group to introduce aryl substituents at the 4-po-sition of the isoxazole. Unfortunately, in addition to the

O+

SiMe2H

Ph

KOt-Bu (10 mol%)

THF, r.t., 15 min

SiMe2O

+

OH

Ph

86% 10%64

Ph

O+

SiMe2H

Ph

CsF (10 mol%)

THF, r.t., 1 h

SiMe2O

+

OH

Ph11% 58%

Ph

SiMe2O

64

H2O2, LiOH, KF

THF, MeOH

77%

DMDO

70%

TBAF, CuI, THF

allyl chloride

72%

OOH

Ph

SiMe2O

O

OH

Ph

Ph Ph

N R

OMeO

NCOH

CpCo(CO)2

MW, xylenes

N

OMeO

N

OH

65 42%66 83%

65 R = TMS66 R = H

Scheme 56 Carbonylative cyclization with an enone

TMS

R1

+R2

O Ru3(CO)12 (6 mol%)

Et2MeN•HI (20 mol%)

toluene, 160 °C

CO (20 atm)

O

O

TMS

R1 R2R3

R3


Scheme 57 Cyclization to isoxazoles

NO2

Ph SiMe2OMe

+

PhNCO (5 equiv)

Et3N (40 mol%)

toluene, 100 °

ON

PhMeOMe2Si

Et+

ON

SiMe2OMePh

Et

HOAcMeCN, r.t.

ON

PhHOMe2Si

Et

89% conversion67:68 3.4:1

67 68

R

SiMe2OMe+

Ph Cl

NOH

1) KHCO3 (3 equiv)

dioxane, reflux

2) AcOH, MeCN

ON

RHOMe2Si

Ph

R = Ph (52%); Me (33%)

ON

R1HOMe2Si

Ph Pd2dba3•CHCl3 (5 mol%)

NaOt-Bu (2.5 equiv)

dioxane 80 °C

I

R2

+

ON

R1

Ph

R2

R1, R2 = Ph, Me (69%); Ph, OMe (68%); Ph, NO2 (55%); Me, Me (60%); Me, OMe (63%)


P


cross-coupling reaction product, a considerable amount ofprotiodesilylated isoxazole was also generated (Scheme57).67

In a study involving the addition of 2-substituted pyri-dines with 3-substituted propargyl alcohols to give indol-izines, 1-phenyl-3-(trimethylsilyl)prop-2-yn-1-ol was re-acted with ethyl 2-pyridylacetate to give the TMS-substi-tuted indolizine 69 (Scheme 58). The TMS group was notreacted further in this work.68

The acid-catalyzed reaction of 1-phenyl-3-(trimethyl-silyl)prop-2-yn-1-ol with a series of primary amides gave2,4-disubstituted 5-[(trimethylsilyl)methyl]oxazoles in ex-cellent yields. The preferred Brønsted acid for this usefulconversion was PTSA (Scheme 58).69

Scheme 58 Cyclization with 3-(trimethylsilyl)propargyl alcohols

1-Alkyl- or 1-aryl-substituted 2-(trimethylsilyl)acety-lenes were used as alternatives to terminal acetylenes inthe synthesis of tetrahydropyridines (18 examples, 54–96%yield; dr 20:1). In this approach the presence of thetrimethylsilyl group also facilitated the generation of anazomethine ylide, which could be further converted. Thus,reaction of an α,β-unsaturated imine with the 1-alkyl- or 1-aryl-substituted 2-(trimethylsilyl)acetylenes gave the die-nyl imine, which underwent an intramolecular aza-cycliza-tion reaction. The resulting 2-silyl-1,2-dihydropyridine wasreductively desilylated to the tetrahydropyridine, reactedwith an alkyne to give a tropane derivative (7 examples,48–83% yield, dr 15:1 to 20:1, or reacted via a desilylativeelectrocyclization to give a 2-azabicyclo[3.1.0] system(Scheme 59).70

The reaction of thioisotin with 1-(trimethylsilyl)prop-1-yne gave a single regioisomeric -3-(trimethylsilyl)-4H-benzothiopyran-4-one in a decarbonylative cyclization pro-cess. The reaction with (trimethylsilyl)acetylene, however,provided a 6:1 mixture of regioisomers (Scheme 60).71

In an interesting cyclization N-(2-cyanophenyl)-N-phenylbenzamides were reacted with internal acetylenes togive quinolones. When 1-(trimethylsilyl)prop-1-yne wasemployed the trimethylsilyl group was placed on the 4-po-sition with high regioselectivity as compared to that of thetert-butyl analogue (Scheme 61).72

The Ni-catalyzed [4+2] cycloaddition of an internalalkyne with an azetidin-3-one resulted in the formation ofvarious piperidines. Interestingly, the (trimethylsilyl)acety-lene derivatives employed showed reversed regioselectivityto those of the tert-butyl and trimethylstannyl analogues.Although the carbonyl and Boc groups were reduced withLiAlH4, reactions of the trimethylsilyl group were not at-

Ph

TMS

OH

+

NCO2Et

Sm(OTf)3 (10 mol%)

120 °C, neat, 6 hN

TMS

CO2Et

Ph81%

69

Ph

OH

TMSR NH2

O+

PTSA

toluene, refluxO

NPh

TMSR


Scheme 59 Cyclization of 1-alkyl- or 1-aryl-substituted 2-(trimethylsi-lyl)acetylenes with α,β-unsaturated imines and subsequent reactions

TMS

Ph

NBn

+NBn

Ph

TMS

70not isolated

[RhCl(coe)2]2 (2.5 mol%)

4-Me2NC6H4-PEt2 (5 mol%)

toluene, 65–100 °C

Me4NBH(OAc)3

(PhO)2PO2H

CH2Cl2, r.t.

70NBn

Ph

85%, dr = >20:1

70 (PhO)2PO2H

CH2Cl2, 0 °C–r.t.

CO2Me

MeO2C

+Ph Bn

N

70%, dr 15:1

CO2Me

CO2Me

70

1) PhSO3H, CH2Cl2

–78 °C, 2 h

2) Me4NBH(OAc)3

–78 °C to r.t.

NBn

H

Ph

75%; dr 7:1

Scheme 60 Cyclization of 1-(trimethylsilyl)prop-1-yne with thioisotin

S

O

O

TMS

+Ni(cod)2 (10 mol%)

PPh3 (20 mol%)

toluene, 50 °C, 6 hS

TMS

O

58%; single isomer

S

O

O

TMS

+Ni(cod)2 (10 mol%)

PPh3 (20 mol%)

toluene, 50 °C, 6 hS

TMS(H)

O

90%; rr = 6:1

H(TMS)

Scheme 61 Decyanative cyclization of 1-(trimethylsilyl)prop-1-yne with N-(2-cyanophenyl)-N-phenylbenzamides

CN

N

O

Ph

Ph

+R

Ni(cod)2 (5 mol%)

Me2PhP (20 mol%)

MAD (10 mol%)


N

Ph

O

R(Me)

Me(R)

R = TMS; 71%, rr = >20:1R = t-Bu; 71%; rr = 2:1


Q


tempted on these systems. When phenylacetylene deriva-tives were reacted, 1-phenyl-2-(trimethylsilyl)acetylenegave the same regioselectivity as 1-(trimethylsilyl)prop-1-yne, but 1-phenyl-2-(trimethylstannyl)acetylene and 1-(trimethylstannyl)prop-1-yne reversed their regioselectivi-ty. A total of four different (trimethylsilyl)acetylene deriva-tives was investigated (Scheme 62).73

Scheme 62 Cyclization of (trimethylsilyl)acetylene derivatives with azetidinones

In an approach to complanadine A and various lycodinederivatives the Siegel group, 1,4-bis(trialkylsilyl)buta-1,3-diynes were used in a [2+2+2] cycloaddition strategy. Thus,the key intermediate cyanoalkyne 75 was prepared on agram scale and reacted with three different 1,4-bis(trialkyl-silyl)buta-1,3-diynes; 1,4-bis(trimethylsilyl)buta-1,3-diynegave the best yield of the 2-alkynylated pyridine 76 whenthe reaction was carried out with CpCo(CO)2 as catalyst. Asmall amount of the (trimethylsilyl)ethynyl group was pro-tiodesilylated upon silica gel chromatography and 76 wascleanly protiodesilylated upon treatment with TBAF/THF to77. Trimethylsilylation of the terminal alkyne 77 then pro-vided alkynylsilane 78, which was subjected to theCpCo(CO)2-catalyzed [2+2+2] cycloaddition with 75. Thisprovided the undesired 2,2′-bipyridine derivative in a mod-est 43% yield. After considerable study and effort it wasfound that modification of the cyanoalkyne 75 to the N-formyl-cyanoalkyne 79 and reaction with 78 with addedtriphenylphosphine and under very dilute 5 mM conditionsgave an acceptable yield of the desired 2,3-bipyridyl struc-ture 80, which was protiodesilylated and deprotected tocomplanadine A (Scheme 63). In model studies several 1-aryl-2-(trimethylsilyl)acetylenes were reacted with 75 togive the 2-aryl-3-(trimethylsilyl) cycloaddition products inlow to modest yields. In none of these cases was thetrimethylsilyl group reacted further. A facile conversion of75 into lycodine was presented wherein the cycloadditionswas carried out with bis(trimethylsilyl)acetylene followedby protiodesilylation and deprotection in a 24% overall yield(Scheme 63).5,74

1,4-Bis(trimethylsilyl)buta-1,3-diyne is thermally stableand, therefore, serves as an excellent substitute for the ther-mally sensitive buta-1,3-diyne. It was employed in a[2+2+2] cyclization with the alkynyl nitrile 75. The reactionwas extended to 1-aryl-2-(trimethylsilyl)acetylenes,wherein the trimethylsilyl group dictated the regioselectiv-ity to place the trimethylsilyl group on the 3-position of the

NBoc

O

+

R Ni(cod)2 (10 mol%)

PPh3 (10 mol%)

toluene, 60 °C N

O

Boc

R

R

t-Bu

TMS

Bu3Sn

Yield

93%

92%

89%

N

O

Boc R

+

71 7271:72<5:95

>90:10

<5:95

NBoc

O

+

R

Ph

Ni(cod)2 (10 mol%)

PPh3 (10 mol%)

toluene, 60 °C N

O

Boc

R

PhR

TMS

Bu3Sn

Yield

82%

83%

N

O

Boc

Ph

R

+

73 7473:74>95:5

>95:5

Scheme 63 Cyclizations of alkynylsilanes with alkyne functional nitriles

N

H

N

TMS

+ 75CpCo(CO)2

THF, 140 °C

N

Bn

N

N

R

N

H

Bn

R = TMS

R = H

TBAFdioxane, 101 °C

82%

79

80HO

40% + 8% undesired isomer

NBn

H

CN+

R2

R1

CpCo(CO)2

THF, 140 °C, hνNBn

H

N

R1R2

70%

+

NBn

H

N

R282 83

75 R1

TMSTBSTMS

R2

TMSTBSTIPS

82:83

25:11:01:0

Yield

81%63%52%

+

TMS

CpCo(CO)2

THF, 140 °C, hν51%

75

S

NBn

H

N

TMS S

+

TMS

CpCo(CO)2

THF, 140 °C, hν51%

75

TMS

NBn

H

N

TMS

NH

H

N

1. TBAF, dioxane

101 °C (97%)

2. Pd/C, H2

THF, 23 °C (95%)lycodine

NCN

Bn

CpCo(CO)2

THF, 140 °CN

Bn

N

R1 R2

R1

R2

+

R1

TMS

TBS

TMS

R2

TMS

TBS

TIPS

Yield

81%

63%

52%

75

1) 76, TBAF, THF 0 °C2) LHMDS, TMSCl THF, 0 °C, 77% over 2 steps

76 R1,R2 = TMS

77 R1,R2 = H

78 R1= H; R2 = TMS


R


pyridine ring formed. The yields were modest, ranging from<5% to 62% over 9 examples (Scheme 63).5

11.4 Formation of 1,2,3-Triazines

A series of 1,4-disubstituted 1,2,3-triazines 84 was pre-pared in a one-pot, three-step sequence involving first a So-nogashira preparation of a 1-aryl-2-(trimethylsilyl)acety-lene from (trimethylsilyl)acetylene, reaction with an alkylazide and, finally, deprotection of the 5-trimethylsilylgroup (Scheme 64).75

1-Aryl-2-(trimethylsilyl)acetylenes, readily formed via aSonogashira reaction from (trimethylsilyl)acetylene, react-ed with sodium azide and an alkyl bromide in a three-step,one-pot sequence to yield a desilylated 1-alkyl-4-aryl-1,2,3-triazole 85 or 86. The reaction took place via initialdeprotection of the trimethylsilyl group followed by the[3+2] click cycloaddition. This represents a safe and scalableprocess for the formation of 1,4-disubstituted 1,2,3-tri-azoles (Scheme 64).76

The reaction of 1-(trimethylsilyl)alk-1-ynes with CuBr/Et3Nserved to directly prepare the alkynylcopper reagent with-out prior desilylation. The resulting copper reagent under-went reaction with various azides to form the 1,2,3-tria-zenes 87 in excellent yields. When the reaction was carriedout with (trimethylsilyl)acetylene or (triisopropylsilyl)acet-ylene, the reaction occurred at the C–H terminus. TIPS- andTBS-terminated acetylenes failed to react (Scheme 64).77

The dichloropyridazine 88 was converted into the[1,2,3]triazole-fused pyrazinopyridazinedione 89 in athree-step sequence with ethyl 3-(trimethylsilyl)propy-noate. The TMS group was lost in the last step of the se-quence, but provides the desired regioselectivity in theazide click step of the sequence (Scheme 64).78

11.5 [2+3] Cycloadditions

The reaction of ethyl and methyl 3-(trimethylsilyl)pro-pynoate with 2-formylphenylboronic acid under[Rh(OH)(cod)]2 catalysis gave 3-(trimethylsilyl)-1H-inden-1-ols 90 in high yield and with high regioselectivity. Similarresults were realized with 2-acetylphenylboronic acid. 1,4-Bis(trimethylsilyl)buta-1,3-diyne reacted with 2-formyl-phenylboronic acid to give the enyne 92 in high yield(Scheme 65).79

In a related approach 2-bromo- and 2-chlorophenylbo-ronic acids underwent a carbonylative cycloaddition withvarious alkynes including (trimethylsilyl)acetylenes to give1H-inden-1-ones; the reaction was catalyzed by RhCl(cod)2.With the exception of ethyl 3-(trimethylsilyl)propynoate,the regioselectivity was very high. 1H-Inden-1-ones werealso formed via the reaction of 2-bromophenylboronic acid,

a (trimethylsilyl)acetylene, and paraformaldehyde, al-though the reaction took longer and required a higher tem-perature (Scheme 65).80

Benzoyltrimethylsilanes reacted with (trimethylsi-lyl)acetylenes under Au catalysis to form indan-1-ones.Mechanistic studies showed that a migration of the acylsilylgroup to the C≡C bond occurred to form the 2-(trimethylsi-lyl)indan-1-one; the trimethylsilyl group was lost uponworkup. On the other hand the more sterically hinderedand stable benzoyl(tert-butyl)dimethylsilane gave the 2-(tert-butyldimethylsilyl)-substituted indanone. The reac-tion proceeds through the formation of the interesting 2-(trimethylsilyl)-substituted silyl enol ether (Scheme 66).81

Scheme 64 Formation of 1,2,3-triazoles via click chemistry on alkynyl-silanes

TMS

R1

I+

Pd(PPh3)2Cl2 (1 mol%)

CuI (5 mol%)R1

TMS

1) R2N3, 5 min

2) TBAF•H2O

25 °C, 12 h

NN

N

R1R2


84

TMS

Ar

BnBr, NaN3

K2CO3, CuSO4 NN

NBn

Ar

NN

N

Ar

Bn

+

19 examples: 57–96%traces85

TMS

Ar

RX (X = Br, I), NaN3

K2CO3, CuSO4 NN

NR

Ar

NN

N

Ar

R

+

6 examples: 38–68%traces86

TMS

R

+ BnN3

CuBr (15 mol%)

Et3N (1 equiv) NN

N

BnR

DMF, 8 examples: 57–94%DMF-H2O, 8 examples: 43–97%

SiR3+ BnN3

CuBr (15 mol%) NN

N

BnR3Si

R3Si = TMS (77%), TIPS (91%)

87

N

N

Cl

Cl

O

N

N

Cl

N3

O

CO2EtTMS

100 °C, 4 h

N

N

Cl

N

O

N N

CO2Et

TMS

MeO

NH2 1) r.t., 3 h2) 70 °C, 2 h

NN

NN N

O

O HN

OMe

88

89

NaN3

DMF, r.t., 2 h,50 °C, 2 h

Et3N (1 equiv)DMF, 100 °C

DMF, 100 °Cor DMF-H2O

pyridine, ascorbic acidMeOH, H2O, 19–24 h

pyridine, ascorbic acidMeOH, H2O, 18–24 h

DIPA (2 equiv), EtOHargon, 25 °C, 2–3 h


S


Scheme 66 [2+3] Cycloadditions of silylacetylenes with benzoylsilanes

11.6 Other Cycloadditions

A three-component co-cyclization involving ethyl cyclo-propylideneacetate, a 1,3-diyne, and a heteroatom-substi-tuted acetylene gave highly functionalized cyclohepta-1,3-dienes. The 1,3-diynes reacted at only one of the C≡C bonds.When 1-(trimethylsilyl)deca-1,3-diyne was reacted, thehexyl-substituted C≡C bond was the one that reacted togive the cycloheptadiene ring. Protiodesilylation provided

the terminal acetylene with concomitant formation of theenone moiety. A competition experiment using equimolaramounts of ethyl cyclopropylidene acetate, 1-ethynyl-2-(trimethylsilyl)-1H-pyrrole, and 1,4-bis(trimethylsilyl)bu-ta-1,3-diyne and hexadeca-7,9-diyne resulted in the reac-tion of the hexadecadiyne to the exclusion of thebis(trimethylsilyl)butadiyne (Scheme 67).82

Scheme 67 Mixed diyne cyclization with ethyl cyclopropylideneace-tate

A Rh-catalyzed [2+2+1] cross-cyclotrimerization of (tri-isopropylsilyl)acetylene with propynoate esters gave the si-lyl-substituted fulvene in modest to excellent yield. The useof (triethylsilyl)-, (tert-butyldimethylsilyl)-, and (tert-bu-tyldiphenylsilyl)acetylenes gave poor yields of the cyclic tri-mer. N,N-Dimethylbut-2-ynamide and (triisopropylsi-lyl)acetylene gave a very poor yield of fulvene product, with

Scheme 65 [2+3] Cycloadditions of silylacetylenes with 2-functional-ized phenylboronic acids

TMS

+[Rh(OH)(cod)2] (2 mol%)

dioxane, r.t., 3 hRO2C

CHO

B(OH)2

OH

TMS

CO2R

OH

CO2R

TMS+

R

Me

Et

Yield

99%

95%

90:9196:4

96:4

90 91

TMS

TMS

+ [Rh(OH)(cod)2] (2 mol%)

dioxane, r.t., 3 h

CHO

B(OH)2

OH

TMS92

TMS

90%

R1

TMS Br

B(OH)2

+[RhCl(cod)]2 (5 mol%)

O

TMS

R1

R2R2

10 examples: 51–95%; isomeric ratio 1:0 except where R1 = CO2Et; 1.5:1

Ph

TMSCl

B(OH)2

+[RhCl(cod)]2 (5 mol%)

O

TMS

Ph77%

R1

TMSBr

B(OH)2

+

[RhCl(cod)]2 (5 mol%)

BINAP (1 mol%)

O

TMS

R1

R2 R2

6 examples: 36– 69%isomeric ratio 1:0

Na2CO3, CO (1 atm)dioxane,/H2O, 80 °C, 20 h

Na2CO3, CO (1 atm)dioxane,/H2O, 80 °C, 20 h

(CH2O)n (5 equiv)Na2CO3, CO (1 atm)

dioxane/H2O, 100 °C, 30 h

TMS

O

+

TMS

p-Tol

1) (ArO)3PAuNTf2 (5 mol%) DCE, 70 °C

OTMS

p-Tol

TMS

93%

TMS

O

+

TMS

R1

R2

R3

R4


OR2

R3

R4 R1


TBS

O

+

TMS

p-Tol


O

p-Tol

TBS

69%

2) MeOH3) PPh3

2) MeOH3) PPh3

2) MeOH3) PPh3

CO2EtTMS

R

O+ +

Ni(cod)2 (10 mol%)

PPh3 (20 mol%)


O R

CO2Et

TMSR = TMS (63%), n-Hex (32%)

O R

CO2Et

TMS

TBAF (1.2 equiv)

HOAc (1.2 equiv)

THF, 0 °C, 30 min

O R

CO2Et

HR = TMS 91%; R = n-Hex 87%

CO2EtR

R

+ +

Ni(cod)2 (10 mol%)

PPh3 (20 mol%)

toluene, r.t., 24 hN R

CO2Et

R

R = TMS (0%), n-Hex (59%)

N

TMS

Scheme 68 Formation of silylated fulvenes

TIPSCO2Et

+ 2[Rh(cod)2]BF4 (5 mol%)

1,4-dioxane, 80 °C, 16–24 hEtO2C

CO2Et

TIPS

13 examples: 47–89%, E/Z 94:6–31:69 80%

TIPSCONMe2

+ 2[Rh(cod)2]BF4 (5 mol%)

1,4-dioxane, 80 °C, 24 h

NMe2OTIPS

78%

EtO2C

CO2Et

TIPS

2 RhCl3•H2O (1 equiv)

EtOH, 80 °C, 16 h Rh

CO2Et

EtO2C

Cl

Cl88%

93 2


T


ethynylation of the C≡C bond as the predominant pathway.The silylfulvene was reductively complexed with Rh(III) togive the rhodium dimer 93 (Scheme 68).83

12 Additions to the C≡C Bond

The Ru-catalyzed hydroacylation of 4-methoxybenzal-dehyde with 1-(trimethylsilyl)prop-1-yne gave a mixture ofisomeric trimethylsilyl dienol ethers 94 and 95.84 The reac-tion of a tertiary amine with methyl 3-(trimethylsilyl)pro-pynoate gave addition of the amine to the C≡C bond and theformation of an allenoate ion. This, in the presence of anarylaldehyde, gave predominantly bis-addition of the alde-hyde resulting in two products 96 and 97; aliphatic alde-hydes gave addition at the C–H terminus of the C≡C bond togive 98. No reaction occurred with ethyl but-2-ynoate indi-cating that the trimethylsilyl group was essential (Scheme69).85

Scheme 69 Aldehyde addition to an alkynylsilane

(Trimethylsilyl)acetylenes were reacted under Ni cataly-sis with phthalimides to give decarbonylation and alkylide-nation of one of the carbonyl groups. Although the reactionappears to be potentially general, all but two of 11 exam-ples were with N-(pyrrolidino)phthalimide. The use of acatalytic amount of the strong and sterically demandingmethylaluminum bis-(2,6-di-tert-butyl-4-methylphenox-ide) (MAD) was crucial in the success of the reaction. In theabsence of MAD the major products were isoquinolones.Various 1-alkyl and 1-aryl-substituted (trimethylsilyl)acet-ylenes were utilized and gave the E-isomer as the product,but only 1-phenyl-2-(trimethylsilyl)acetylene and 1-(4-me-thoxyphenyl)-2-(trimethylsilyl)acetylene gave mixtures ofZ- and E-isomers. Two additional examples of reactionswhere the silyl groups were PhMe2Si and TBS were success-ful, albeit in lower yield. Two internal alkynes failed to reactindicating that the presence of the TMS group is necessaryfor the reaction (Scheme 70).86,87

Scheme 70 Decarbonylative addition to a silylacetylene

The olefination of ynolates was accomplished with 3-si-lylpropynoates giving excellent selectivity for the E-enyne.Ag-catalyzed cyclization of the resulting enynes was carriedout to give either the 5-exo-tetronic acid derivatives or the6-endo-pyrones. The triethylsilyl-tetronic acid 99 was ste-reoselectively converted into the corresponding iodide 100,which was in turn subjected to phenylation via a Suzukicross-coupling and to ethynylation via Sonogashira cross-coupling (Scheme 71).88

Scheme 71 Addition to silylpropynoates and reaction of the resulting vinylsilanes

A series of silylated propargylic alcohols was preparedvia the straightforward reaction of a lithiated silylacetyleneand a variety of aromatic and aliphatic aldehydes and ke-tones. These silylated propargylic alcohols were then sub-jected to the Meyer–Schuster rearrangement to give acyl-silanes; propargyl alcohols derived from aromatic alde-hydes underwent the rearrangement in good yield undercatalysis with either PTSA·H2O/n-Bu4N·ReO4 or Ph3SiOReO3.The PTSA·H2O/n-Bu4N·ReO4 system did not work for elec-tron-donating aryl systems, though the Ph3SiOReO3 catalystworked well for these. Propargyl alcohols derived from ali-

MeO

O

HRuHCl(CO)(PPh3)3 (2 mol%)


76% (NMR); 94:95 = 16:1

TMS

+

TMSO

OMe

94

95

TMSO

OMe

+

MeO2C

TMS

RCHO, DABCO

benzene, reflux RR

O CO2Me

OTMS

RR

O CO2Me

O

+ +

CO2Me

R OTMS

96 97 9817 examples: 0–100%

N

O

O

N

Ni(cod)2 (10 mol%)

Me3P (20 mol%)

MAD (20 mol%)


TMS

R

+ N

O

N

RTMS11 examples: 64–90%

R3Si

O

OROLi

+

RO

CO2H

SiR3

THF

–78 to–20 °C, 1 h

R3SiTMSTESTBS

Yield51%41%63%

E/Z>99:1>99:1

98.5:1.5

Ri-Bui-BuEt

Ag2CO3 (10 mol%)

DMF, r.t., 1 hRO

CO2H

SiR3

O

SiR3

O

ROR = i-Bu, R3Si = TBS 93%

R = Et, R3Si = TES 78%

O

SiEt3

O

EtO

I2, AgOTf, THF

–78 °C, 1 hO

I

O

EtO

99 100PhB(OH)2

Pd(PPh3)4 (10 mol%)

K2CO3, dioxane/H2O

80 °C, 1 h

O

Ph

O

EtO

63%

O

O

EtOOMPM


CuI (5 mol%), Et3N

THF, r.t., 2.5 h

60%

OMPM


U


phatic aldehydes failed to give acylsilanes with the excep-tion of pivaldehyde. Propargylic alcohols derived from dia-ryl ketones gave either indanones or acylsilanes (Scheme72).89

Scheme 72 Rearrangement and oxidation of silylpropargyl alcohols

A one-step hydroiodination of 1-aryl-2-silylacetylenesto the vinyl iodide, highly useful substrates for cross-cou-pling applications, was found to occur upon treatment ofthe 1-aryl-2-silylacetylenes with iodotrimethylsilane. Thereaction sequence of a Sonogashira cross-coupling of(trimethylsilyl)acetylene and an aryl halide followed by thehydroiodination resulted in a facile synthesis of α-iodosty-rene derivatives; the reaction resulted in the Markovnikovaddition of HI to the C≡C bond. It was further found that theterminal acetylene itself would undergo the reaction aswell. More hindered silyl groups gave a lower yield of thevinyl iodide (Scheme 73).90

A three-component with methyl 3-(trimethylsilyl)pro-pynoate, an amine, and an imine is directed by both the es-ter and the trimethylsilyl moieties. The reaction involves a1,4-silyl shift. When salicyl imines were used as substratesthe products were chromenes. This reaction was shown toproceed through the aminal 101, which could be trappedwith allyltrimethylsilane or the TMS enol ether of aceto-phenone (Scheme 74).91

Scheme 74 Reaction of 3-silylpropynoates with imines

A variety of 3-silylpropynals and silylethynyl ketones,prepared via a silylation, deprotection, oxidation sequence,were converted into 2-silyl-1,3-dithianes, which are usefulsynthons via their potential for anion relay chemistry(ARC).92 Although 8 different silyl groups showed good re-sults, the dithiation did not occur when the silyl was steri-cally hindered, as with TBDPS, TIPS, t-Bu2HSi, or i-Pr2HSi(Scheme 75).93

R3Si

H

1) n-BuLi

2) R1R2COR3Si

HO

R3Si = TMS, TES, TBS, TIPS

41 examples, 40–81%

R1

R2

TES

HO

Ar

H

TES Ar

OPTSA•H2O (5 mol%)

n-Bu4N•ReO4 (5 mol%)

CH2Cl2, r.t.


TES

HO

Ar

H

TES Ar

OPh3SiOReO3 (5 mol%)

Et2O, r.t.

Ar = 3-MeOC6H4 30%

Ar = 4-MeOC6H4 52%

TES

HO

Ph

Ph PTSA•H2O (5 mol%)


CH2Cl2, r.t.

55%

O

TESPh

TES

HO

Ar

Ar PTSA•H2O (5 mol%)


CH2Cl2, r.t.

76%

TES Ar

O Ar

Ar = 3-ClC6H4

Scheme 73 Hydroiodination of alkynylsilanes

Ar

SiR31) TMSI, CH2Cl2

–78 °C, 15 min

2) H2O, 0 °C, 50 minAr

I

6 examples, 57– 93%

t-Bu

SiR3

1) TMSI, CH2Cl2

–78 °C, 15 min

2) H2O, 0 °C, 50 mint-Bu

I

R3Si = TMS (88%), TES (80%), TIPS (54%)

R

NTs+

CO2Me

TMS

+ TsNH2DABCO

THF, reflux, 20 h

TsNH

TsNH

R

CO2Me


OH

NTs

+

CO2Me

TMS

1) DABCO

THF, reflux, 1.5 h

2) HCl, MeOHO

CO2Me

OMeR R

6 examples, 0–81%

O

CO2Me

NHTs

101

TMS

TiCl4, THF, r.t.

100%

O

CO2Me

O

CO2Me

O

PhPh

OTMS

74%

TiCl4, THF, r.t.

Scheme 75 Dithiation of silylpropynals

R3Si

H

O

+HS SH

Al2O3 (10 equiv)

THF, r.t., 3–10 h R3Si H

SSO


R3Si

O

+HS SH R3Si

SSOt-BuOK, t-BuOH

0 °C to r.t., 3 h



V


The lithium aluminum hydride reduction of 4-silylbut-3-yn-2-ones provided the 4-silylbut-3-en-2-ol in goodyields and high E/Z ratios (Scheme 76).94

The β-silyl effect to stabilize β-cationic intermediateswas employed in the regioselective addition of ICl to sily-lacetylenes. The diastereoselectivity of the addition is theopposite of that found for the reaction of ICl with the sim-ple terminal alkyne. The Z/E selectivity is higher with aryl-substituted silylacetylenes, though the Z selectivity of alkyl-substituted silylacetylenes increases with an increase in thesize of the silyl group (Scheme 77).95

Scheme 77 Iodochlorination of silylacetylenes

The addition of the halogens to (trimethylsilyl)acetylenein the absence of light produced the E isomer, which couldbe equilibrated to a mixture of both stereoisomers. In the

cases of the E-dichloride or E-dibromide the equilibrationwas brought about by exposure to light in the presence of atrace of bromine. In the case of the E-diiodide, prolongedrefluxing in cyclooctane produced an E/Z mixture of 9:1(Scheme 78).96

Scheme 78 Halogenation of (trimethylsilyl)acetylene

The reaction of Weinreb amides with internal acety-lenes promoted by a Kulinkovich-type titanium intermedi-ate gave α,β-unsaturated ketones in modest yield. The reac-tion conditions were mild with activation of the titaniumpromoter as the last step at room temperature. With TMS-terminated acetylenes, the yields were comparable to thoseof other alkynes investigated, though with slightly lowerregioselectivity (Scheme 79).97

Scheme 79 Reaction of Weinreb amide with silylacetylenes

The syn addition of two aryl groups from an arylboronicacid to an internal alkyne resulted in the formation of 1,2-disubstituted 1,2-diarylethenes. In the single example usinga silylacetylene, the reaction of ethyl 3-(trimethylsilyl)pro-pynoate with p-tolylboronic acid under Pd catalysis gavethe highly substituted ethyl 2,3-di(p-tolyl)-3-(trimethylsi-lyl)propenoate via the addition of two equivalents of the p-tolyl group (Scheme 80).98,99

The highly regio- and stereoselective addition of aboronic acid to silylacetylenes occurred under mild condi-tions and in high yields. Interesting points were that 1-(tri-ethylsilyl)hex-1-yne was more regioselective than(trimethylsilyl)hex-1-yne, which gave a mixture of isomericvinylsilanes indicating that the steric effect of the silylgroup plays a role, and extended reaction times gave re-duced stereoselectivity. The resulting arylated vinylsilanescould be converted into their corresponding iodide or bro-mide. In the case of the iodide this was performed in a two-step, one-pot reaction sequence, whereas the bromide re-quired two independent steps. In a further extrapolation of

Scheme 76 Lithium aluminum hydride reduction of silylpropargyl alcohols

RMe2Si

HO

LiAlH4, THF

0–25 °CRMe2Si

OH

R = Me (73%; E/Z 9:1), Ph (87%, E/Z 6:1), allyl (61%)

TMS

TMS

ICl, CH2Cl2

–78 °C

Cl

TMS

I

TMS

I

Cl82%

H

H

ICl, CH2Cl2

–78 °C

Cl

I

H

I

H

Cl65%

R

TMS ICl, CH2Cl2

–78 °C68%, E/Z 3:1

RI

TMS

Cl

10 examples 54–93%R = CO2Et 0%

n-Bu

TMSICl, CH2Cl2

–78 °C

68%, E/Z 3:1

n-BuI

TMS

Cl

n-Bu

TESICl, CH2Cl2

–78 °C54%, E/Z 9:1

n-BuI

TES

Cl

TMS

H

+ X2X

X

TMS

H

TMSX

X

HX2 = Cl2, Br2, I2

TMS

Ph

+ Ph NMe

O

OMe

Ti(Oi-Pr)4 (1.5 equiv)

TMS Ph

O

Ph

Ph Ph

O

TMS

+

53%, β-TMS:α-TMS 86:14

t-Bu

Ph

+ Ph NMe

O

OMe

Ti(Oi-Pr)4 (1.5 equiv)t-Bu Ph

O

Ph

35%, β-t-Bu:α-t-Bu 97:3

i-PrMgCl (3 equiv)Et2O, r.t., 4 h

i-PrMgCl (3 equiv)Et2O, r.t., 4 h


W


the chemistry the regio- and stereoselective synthesis of(Z)-α-(4-tolyl)-β-(4-methoxyphenyl)styrene (102) was ac-complished in three steps from 1-phenyl-2-(trimethylsi-lyl)acetylene. The E-isomer was prepared starting from 1-(4-tolyl)-2-(trimethylsilyl)acetylene (Scheme 80). The reac-tion was also possible with the addition of a vinylboronicacid giving a dienylsilane.100

Scheme 80 Addition of boronic acids to alkynylsilanes

The Oshima group reported the syn-hydrophosphina-tion of terminal and internal alkynes. With arylacetylenesthe regioselectivity was approximately 9:1 and with (tri-ethylsilyl)acetylene, the sole silicon example, it was 94:6,slightly less than that with alkylacetylene substrates, whichshowed a 100:0 regioselectivity all placing the phosphineon the terminal position. The products were isolated astheir phosphine sulfides (Scheme 81).101

A chiral NHC catalyst was employed in the enantioselec-tive conjugate addition of 1-(trimethylsilyl)alk-1-ynes to 3-substituted cyclopentenones and 3-substituted cyclohexen-

ones. Thus, the 1-(trimethylsilyl)alk-1-yne was reactedwith diisobutylaluminum hydride to form the 1-(trimethyl-silyl)vinylaluminum reagent, which was then reacted withthe enone, catalyzed by the chiral NHC complex 103. In re-actions with the cyclopentenones, up to 10% of addition ofthe isobutyl group from aluminum was observed; this in-creased to up to 33% for cyclohexenones. The er values wereexcellent, ranging from 92.5:7.5 to 98.5:1.5. Of considerable

TMS

O

OEt

B(OH)2

2 +Pd(OAc)2 (1 mol%)

TMS

EtO2C

72%

Ar2

TES

+Ar1B(OH)2

Pd(OAc)2 (5 mol%)PCy3 (10 mol%)

Ar2H

Ar1

TES18 examples75–96%

H

TES

+PhB(OH)2 HH

Ph

TES


84%

n-Bu

TES

+PhB(OH)2 n-BuH

Ph

TES


45%

n-Bu

TMS

+PhB(OH)2n-Bu

H

Ph

TMS


82%

+n-Bu

Ph

H

TMS

Ph

TMS

+

1. Pd(OAc)2 (5 mol%) PCy3 (10 mol%), 11 hB(OH)2

PhH

I

PhH

I

+

MeO

B(OH)2Pd(OAc)2

PPh3, CsCO3

PhH

OMe102

dioxane, 60 °C

2. NIS, MeCN, r.t., 10 h

THF, 27 °C, 22 h

THF, 27 °C, 22 h

THF, 27 °C, 22 h

THF, 27 °C, 11 h

DMSO, O2, 4 A MS50 °C, 24 h

Scheme 81 Hydrophosphination of (triethylsilyl)acetylene

TES

Ph2PH +

1) n-BuLi (2 equiv) Co(acac)2 (10 mol%) dioxane, reflux, 2 h

69%

HH

Ph2P

TES

S2) S8

Scheme 82 Hydroalumination of 1-silylalk-1-ynes and asymmetric vinylation of enones

N N

Ag

S

Ag

O

NN

SO O

O OPh

Ph

Ar

Ar

O

103 Ar = 2,6-Et2C6H3

OH

MeO

104

n-Pr

TMS

+ (i-Bu)2AlH n-PrAl(i-Bu)2

TMS

O

R2

R1Al(i-Bu)2

TMS+

103 (2.5 mol%)CuCl2•2H2O (5 mol%)

O

R2 TMS

R1

76%, er = 93:7

16 examples50–95%, er 89:11 to 9.5:1.5

TMS

n-Hex

O

MCPBA

CH2Cl2, 0 °C, 3 h

TMS

n-Hex

O

96%

O

n-Hex

O

O

TMS

n-Hex

O

O HCO2H

100 °C, 1 h

70%

O

TMS

n-Hex

NCI (2.6 equiv)

MeCN, 0–22 °C, 12 h

O

I

n-Hex

91%

TMS

n-Hex

O

CF3CO2H

CHCl3, 22 °C, 6 h76%

n-Hex

O

THF, 22 °C, 15 min


X


importance, the resulting vinylsilanes were further reacted.Oxidation with m-chloroperbenzoic acid gave the ketone.NCI converted it into the vinyl iodide and protiodesilylationto the parent alkene. This chemistry was applied to a shortsynthesis of riccardiphenol B (104) (Scheme 82).102

The reaction of indoles with 1-(halophenyl)-2-(trimeth-ylsilyl)acetylenes under Cu(I) catalysis gave addition of theindole to the C≡C bond and, under the basic conditions, pro-tiodesilylation to form the corresponding alkene as a mix-ture of stereoisomers. Very little amination of the aryl halo-gen bond occurred. In fact, a control experiment whereinindole was reacted with a mixture of 1-(4-bromophenyl)-2-(trimethylsilyl)acetylene and 4-iodoanisole a 50% yield ofaddition to the C≡C bond and only 6% reaction of theiodophenyl bond was observed (Scheme 83).103

Scheme 83 Hydroamination of 1-(halophenyl)-2-(trimethylsilyl)acety-lenes with indoles

The hydrosilylation of various propynoate esters wascarried out and served to prepare α-silyl-α,β-unsaturatedesters in good yields. When this reaction was performedwith 3-(trimethylsilyl)propynoate esters, the productformed was the (E)-2,3-bis(silyl)propenoate. Other similarsystems such as the ynone 105 and sulfone 106 gave goodyields of addition products (Scheme 84).104

1,4-Bis(trimethylsilyl)buta-1,3-diyne underwent carbo-magnesiation of one of the C≡C bonds with arylmagnesiumbromide reagents. The resulting vinylmagnesium bromideintermediate could be further reacted, including cross-cou-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 (Scheme85).105

Kimura and co-workers reported on the Ni-catalyzed,four-component coupling of internal alkynes, buta-1,3-di-ene, dimethylzinc, and carbon dioxide. The reactions of 1-substituted 2-(trimethylsilyl)acetylenes gave lower yieldsand poorer regioselectivity than those of alkyl- or aryl-sub-stituted alkynes (Scheme 86).106

The three-component coupling of acetylenes, vinylox-iranes, and dimethylzinc was reported to give alka-2,5-dien-1-ols. Bis(trimethylsilyl)acetylene and (trimethylsi-lyl)acetylene gave lower yields than 1-(trimethylsilyl)prop-1-yne and alkyl- or arylalkynes. In a similar manner vinyl-cyclopropanes gave 1-silyl-1,4-dienes (Scheme 87).107

NH

R

TMS

X

+

DMSO, BtH (20 mol%)

CuI (10 mol%)

KOt-Bu (2 equiv)

120 °C, 20–30 min

or KOH (0.2 equiv), 10–12 h

NX

R

11 examples; 58–90%; E/Z 34:66–0:100

TMS

NH

+

Br

+

I

OMe

CuI, K3PO4

NBr

N

OMe

+

52% 6%

BtH, DMSO

Scheme 84 Hydrosilylation of functionalized silylacetylenes

OEt

TMS

O

+ PhMe2SiHPd(dba)2 (5 mol%)

PhMe2SiTMS

EtO O

99%

TMS

O


PhMe2SiTMS

O

94%105

p-Tol

S

TMS


PhMe2SiTMS

Sp-Tol

92% by NMRO

O

O

O

106

PCy3 (10 mol%)toluene, r.t., 16 h



Scheme 85 Addition of Grignard reagents to 1,4-bis(trimethylsilyl)-buta-1,3-diyne

TMS

TMS

+ ArMgBr1) FeCl2 (10 mol%)

Et2O, r.t., 3 h

2) H3O+

Ar

TMSTMS

H


TMS

+ PhMgBr

1) FeCl2 (10 mol%)

Et2O, r.t., 3 h

2)

NiCl2(dppe) (10 mol%)

r.t., 12 hTMS

BrPh

Ph

TMSTMS

Ph

43%

TMS

+ PhMgBr

1) FeCl2 (10 mol%)

Et2O, r.t., 3 h

2) ZnCl2

3) I2, r.t., 12 hTMS

Ph

TMSTMS

I

49%

Scheme 86 Four-component coupling involving 1-substituted 2-(trimethylsilyl)acetylenes

R

TMS

+

Ni(cod)2 (10 mol%)

PPh3 (20 mol%)

Me2Zn, CO2 (1 atm)TMS

CO2H

RR = Me (35%); Ph (31%)


Y


Scheme 87 Alkylative three-component coupling of silylacetylenes with vinyloxiranes and a vinylcyclopropane

The reaction of silylacetylene 107 by Ru-catalyzed addi-tion of acetic acid gave a mixture of the desired enol acetate108 along with 109; a longer reaction time gave 109 ingood yield. Although 108 was the initial desired intermedi-ate it was 109 that was in fact carried forward in a synthesisof clavosolide A (Scheme 88).108

Scheme 88 Hydroacetation of a silylacetylene

An iron-catalyzed imine-directed 2-vinylation of indolewith internal alkynes produced the 2-vinylated derivativein good yield and regioselectivity. Terminal acetylenes didnot react under the conditions employed. This deficiencywas circumvented by the use of a (trimethylsilyl)acetylene,which reacted with high regioselectivity forming the C2–Cvinyl bond β to the TMS group. These conditions also proveduseful for the formation of C2–Csp3 bonds when the reac-tion was carried out with alkenes (Scheme 89); again thereaction did not occur with terminal alkenes.109

Scheme 89 Coupling of a (trimethylsilyl)acetylene with an α,β-unsatu-rated imine

The addition of DIBAL-H to 1-(trimethylsilyl)prop-1-yne followed by conversion into the lithium aluminate andreaction with formaldehyde resulted in vinylsilane 110.This was in turn used to generated vinylsilane 111 and,from that, vinyl iodide 112, which was then converted intwo steps into norfluorocurarine (113) (Scheme 90).110

Scheme 90 DIBAL-H addition to 1-(trimethylsilyl)prop-1-yne

13 Reactions at the C–Si Bond

A study on the iododesilylation of a series of vinylsilaneswherein the silyl group included TIPS, TBS, and TBDPS wascarried out.111 This was the first report of the iododesilyla-tion of a vinylsilane with sterically hindered silyl moieties.Interestingly, it was found that the rate of the reaction withTIPS or TBS groups was about the same, but that of TIPS wasfaster than that of TBDPS. Four different sources of I+, N-iodosuccinimide (NIS), N-iodosaccharin (NISac), 1,3-diodo-5,5-dimethylhydantoin (DIH), and bis(pyridine)iodoniumtetrafluoroborate (Ipy2BF4) were investigated with compa-rable results for each. The success of the reaction dependedon the solvent system with 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP) showing good results. The reaction was tolerantof epoxides, alkenes, esters, TIPS ethers, and a TIPS acety-lene (12 examples, 86–96% yield) (Scheme 91).111

Scheme 91 Iodination of vinylsilanes, readily available from silylacetyl-enes

1,4-Bis(trimethylsilyl)buta-1,3-diyne was treated withMeLi·LiBr to prepare the monolithiated diyne, which was

TMS

TMS

+Ni(acac)2 (10 mol%)

Me2Zn, hexane, r.t., 24 hTMS

OH

TMSR = H 35% E/Z 2:1R = Me 31% E/Z 1:!

OR

R

TMS

+Ni(acac)2 (10 mol%)


OH

97%, E/Z 2:1

OH

H

TMS

+ Ni(acac)2 (10 mol%)


OH

97%, E/Z 2:1

OH27%, E/Z 2:1

+TMSOH

R

TMS

+ Ni(acac)2 (10 mol%)

Me2Zn, hexane, THF, r.t., 24 hR = TMS 59%, E onlyR = Me 91%, E only

CO2Me

CO2MeR

TMS CO2Me

CO2Me

OTIPS

OH

TMS

[RuCl2(p-cymene)]2

OTIPS

OH

OAc

OTIPS

OH

OAc

+

107 1086 h 108; 55%12 h 109; 69%

109AcOH, Na2CO3toluene, 80 °C

NMe

NPMP

1. Fe(acac)3 (10 mol%)

SIXyl•HCl (20 mol%)

PhMgBr (110 mol%)

THF, 60 °C, 18 h

2. H3O+

TMS

+NMe

CHO

TMS

59%, Z/E >99:1

N N

Cl–

+

SIXyl•HCl

TMS1. DIBAL-H, Et2O

2. MeLi, (CH2O)nHO

TMS

110N

NTMS

OF3C

NIS (2 equiv)

AcOH (1.8 equiv)

HFIP, CH2Cl2, –15 °C

N

NI

CHOH

OF3C

111

112113

N

NH

CHO

HH

TIPS

O

OTBS

iodination agent (120 mol%)

AgCO3 (30 mol%)

HFTP, 0 °CI

O

OTBS

Iodination agentNISNISacDIHIpy2BF4

Yield90%86%88%91%


Z


reacted in a Sonogashira cross-coupling with 2-iodoaniline.The coupling product was reacted with trichloroacetyl iso-cyanate and this converted into desilylated urea 115 in asingle step. The resulting diyne was subjected to a doublecyclization to give the pyrimido[1,6-a]indol-1(2H)-one 116(Scheme 92).112

Pan and co-workers reported the conjugate addition ofalkynyl groups to acrylate derivatives via the reaction of a(trimethylsilyl)acetylene derivative under InCl3 catalysis.Silyl moieties other than that of the TMS group were not in-vestigated. The reaction worked best for 1-phenyl-2-(trimethylsilyl)acetylene wherein the phenyl group is astrongly electron-donating aryl group. Thus, 4-CN-, 4-CO2Me-, and 4-CF3-substituted 1-phenyl-2-(trimethylsi-

lyl)acetylenes failed to react. A direct comparison of 1-bu-tyl- and 1-phenyl-2-(trimethylsilyl)acetylene with hex-1-yne and phenylacetylene, that is, the H-terminated acety-lenes, showed that TMS-terminated acetylenes gave betteryields. Chlorobenzene was found to be the best solvent andEt3N the best base. 1,4-Bis[(trimethylsilyl)ethynyl]benzene(117) reacted with ethyl acrylate to give the mono- ordisubstituted γ,δ-ethynyl esters. The reaction was also oc-curred with methyl vinyl ketone as the acceptor (Scheme93).113

This protocol compares well with the conjugate additionof terminal alkynes to acrylates catalyzed byRu3(CO)12/bis(triphenylphosphine)iminium chloride andwith Pd(OAc)2.114,115

14 Miscellaneous Reactions

β-Amino enone 118 was converted in a two-step, sin-gle-pot sequence into enol ether 119 via reaction with 3-(trimethylsilyl)propargyllithium in 51% overall yield; usingpropargylmagnesium bromide gave the corresponding H-terminated product in 40% yield. Enol ether 119 was uti-lized in a synthesis of 7-hydroxycopodine (Scheme 94).116

1-[(Trialkylsilyl)ethynyl]cyclopropan-1-ols were ringexpanded to 2-alkylidenecyclobutanones in a reaction cata-lyzed by the Ru catalyst 120. Interestingly, the favoredstereoisomer was the Z-isomer. Similar results were ob-

Scheme 92 Lithiation of 1,4-bis(trimethylsilyl)buta-1,3-diyne

TMS

TMS

MeLi•LiBr

TMS

Li

+ Me4Si

TMS

TMS

TMS

Li

I

NH2

Pd(PPh3)4, CuI

NH2

TMS

81%

NH2

TMS

Cl3CCONCO

NH

TMS

96%NH

O

CCl3

O NaHCO3

MeOH, H2ONH

NH2

O

114 (5 mol%)THF, 100 °CMW, 1 h

N

NHO

78%P Au NCMet-Bu

t-Bu

114

76% 115

116

Et3N, Et3N•HCl60 °C, 24 h

MeLi•LiBr

THF, Et2O0 °C, 2 h

+ SbF6–

Scheme 93 Ethynylation of α,β-unsaturated esters with (trimethylsi-lyl)acetylenes

+ OMe

O InCl3 (10 mol%)

Et3N (5 mol%)

TMSOMe

O

R R

15 examples; 68–96%

R1

+ OMe

O InCl3 (10 mol%)

Et3N (5 mol%)R2

R1OMe

O

R1

PhPhn-Bun-Bu

R2

TMSHTMSH

Yield

92%

56%

86%

55%

TMS

TMS117

+ OEt

O

(3 equiv)

InCl3 (20 mol%)

Et3N (10 mol%)6 h

24 h

TMSOEt

O

OEt

O

EtO

O

85%

72%

PhCl, 100 °C, 24 h

PhCl, 100 °C, 24 h

PhCl, 110 °C

Scheme 94 Reaction of 3-(trimethylsilyl)propargyllithium with an iminium salt

N

OTBS

O

i-PrI (as solvent)

55 °C, 42 h N

OTBS

OiPr

LiTMS

THF, –78 °C, 2 hthen to 25 °C

N

OiPr

+

I–

OTBS

TMS51%

118 119

Scheme 95 Rearrangement of 1-(silylethynyl)cyclopropan-1-ols

HO

SiR3

RuCl PPh3

PPh3

120O

R3Si

O SiR3

+

R3Si

TMS

BuMe2Si

PhMe2Si

TES

TBS

TIPS

Yield

98%

94%

96%

97%

98%

87%

Z/E

5.7:1

6.0:1

6.0:1

10.0:1

11.4:1

>20:1

HO

n-C6H13

120

O

n-C6H13

78%


AA


tained with electron-deficient alkynyl cyclopropanols. Onthe other hand, under the same conditions 1-alk-1-ynyl-cyclopropan-1-ols underwent ring expansion to cyclopen-tenones. Stabilization of a β-carbocation in the silyl-substi-tuted examples and a favored Michael addition in the elec-tron-deficient examples helps to explain the formation ofthe four-membered ring (Scheme 95).117

3-(Trimethylsilyl)propynal was nicely used in a conve-nient synthesis of ethynyl-β-lactone 121; propynal did notundergo a corresponding reaction to give 122. The silylatedenantiomerically enriched β-lactone 121 was utilized insynthetic approaches to leustroducsin B and the protiodesi-lylated ethynyl lactone 122 was converted to derivatives ofsimilar structure to the natural products (–)-muricaticin,(–)-japonilure, and (+)-eldanolide.118–120

Scheme 96 Synthesis of silylethynyl-β-lactone

Corey and Kirst were the first to report the synthesisand utility of 3-(trimethylsilyl)propargyllithium (123). Thedirect lithiation of 1-(trimethylsilyl)prop-1-yne occurredusing BuLi/TMEDA in 15 minutes. The reagent 123 reactedwith primary alkyl halides in diethyl ether to form the de-sired alkynes with only small amounts of the isomeric al-lene, a common side product found with propargylmagne-sium chloride reagent.121

Corey and Rucker then utilized 1-(triisopropylsi-lyl)prop-1-yne (124), which was readily lithiated to give themore sterically encumbered 3-(triisopropylsilyl)propargyl-lithium (125). Lithium reagent 125 was reacted with cyclo-hexenones in a 1,2- and 1,4-manner. In addition it was con-verted into the 1,3-bis(triisopropylsilyl)prop-1-yne (126) inquantitative yield on treatment with triisopropylsilyl tri-flate. Reaction of 125 with cyclohexenone gave 1,4-additionin THF/HMPA and 1,2-addition in THF. Bis-TIPS reagent 126reacted with BuLi/THF to give lithiated 126, which reactedwith aldehydes in a Peterson reaction to form an enynes(Scheme 97).4

3-(Trimethylsilyl)propargyllithium (123) was used tointroduce the propargyl group into epoxygeranyl chloridein 85% yield over three steps from geraniol. The TMS groupwas removed with TBAF and the resulting enyne was usedin a synthesis of the triterpene limonin (Scheme 97).122

3-(Trimethylsilyl)propargyllithium (123) reacted withlactone 127 and this was followed by mesylation/elimina-tion to give enynes 128 and 129 in good yield. The TMS

group was removed with AgNO3/aq EtOH en route to ste-reoisomers of bis(acetylenic) enol ether spiroacetals of ar-temisia and chrysanthemum (Scheme 97).123

Fu and Smith demonstrated the enantioselective Ni-cat-alyzed, Negishi cross-coupling arylation of racemic 3-(trimethylsilyl)propargyl bromides; the yields and the eevalues were excellent. The protocol was applied to the syn-thesis of 131, a precursor to pyrimidine 132, an inhibitor ofdihydrofolate reductase (Scheme 98).124

TMS

O

H

EtCOCl, TMS-quinidine

MgCl2, i-Pr2NEt

Et2O, CH2Cl2, –80 °C

TMS

O

O

94%

TBAF

THF, –78 °CO

O

121 122

Scheme 97 Formation and reactions of silylpropargyllithium reagents

TMSn-BuLi, TMEDA

Et2O, –5 °C, 15 minTMS

Li

123

Br

123, Et2O

0 °C, 12 h

TMS50%

Me

Li

TIPSOTf

Et2O, –40 to °C

87% Me

TIPS

124

124nBuLi, THF

–20 °C, 15 min125

TIPS

Li

125 +

OTHF

OH

93%

TIPS

THF–HMPA (3:1)125 +

O O

TIPS

81%

126

TIPS

TIPSTIPSOTf

–78 to –40 °C, 1 h125

126

1) n-BuLi, THF –20 °C, 15 min

TIPSR

3 examples: 57–79%; Z/E >20:1

OCl

+ 123THF

–40 to 0 °CO

TMS

O

O

TESO

TESO

O

1) 123, THF

O

O

TESO

TESO

TMS

O

O

TESO

TESO

TMS

+

127

128 12980%; 128:129 = 1:4

2) RCHO, –78°C to r.t., 6 h

2) MsCl, Et3N CH2Cl2


AB


Scheme 98 Asymmetric arylation of 3-(trimethylsilyl)propargyl bro-mides

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Br NiCl2•glyme (3 mol%)(–)-130 (3.9 mol%)+ ArZnEt

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7 examples, 39–92%, ee 92–94%

NO

N N

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Some Aspects of the Chemistry of Alkynylsilanes · TMS TMS 1) MeLi (1 equiv) THF, 0 C 2) acrolein,...

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