Gelest,Inc. Silicon-Based Reducing Agents · PDF file6 Silane Reduction of Alkyl Halides As...

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Silicon-Based Reducing Agents

Gerald L. LarsonVice President, Research & Development

Materials for the reduction of:AldehydesKetonesAcetalsKetalsEsters

LactonesThioestersEnamines

IminesAcids

AmidesHalidesOlefi ns

Metal Halides

Supplement to the Gelest Catalog, “Silicon, Germanium & Tin Compounds, Metal Alkoxides and Metal Diketonates” which is available on request.

127

� � � � Gelest, Inc.

AZmax TEL: 035543-1630 • FAX: 03-5543-0312 • www.azmax.co.jp (215) 547-1015 • FAX: (215) 547-2484 • www.gelest.com

Gerald L. LarsonVice President, Research & Development

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SILICON-BASED REDUCING AGENTS

Introduction The widely used organometallic-based reducing agents can be broadly classifi ed as either ionic, such as lithium aluminum hydride and sodium borohydride, or free-radical such as tri-n-butyltin hydride. The mechanistic differences between these two classes of reducing agents very often complement one another in their ability to reduce organic substrates. Organosilanes have been found to possess the ability to serve as both ionic and free-radical reducing agents. These reagents and their reaction by-products are safer and more easily handled and disposed of than other reagents. Their reductive abilitiesare accomplished by changes in the nature of the groups attached to silicon, which can modify the character of the Si-H bond in the silane. For example, the combination of a triethylsilane and an acid has proven to be excellent for the reduction of substrates that can generate a “stable” carbenium ion intermediate. Examples of substrates that fall into this class are olefi ns, alcohols, esters, lactones, aldehydes, ketones, acetals, ketals, and other like materials. On the other hand triphenylsilane andespecially tris(trimethylsilyl)silane have proven to be free-radical reducing agents that can substitute for tri-n-butyltin hydride.The reductions with silanes can take place with acid catalysis in which the silane provides the hydride to a carbenium ion intermediate. This is often the situation in the reduction of carbonyls, ketals, acetals and similar species. Additionally, the silane reductions can also be carried out with fl uoride ion catalysis to generate a silane with more hydridic character.

Some of the key reductions possible with silanes are summarized in Table 1.

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General Considerations Hydridosilanes are readily produced on an industrial scale through the use of Grignard chemistry starting with trichlorosilane, methyldichlorosilane, and dimethylchlorosilane, among others, as key raw materials. Alternatively, the Si-X (X = primarily Cl or OR) bond can be reduced to Si-H.

The organosilanes are basically hydrocarbon-like in that they are stable to water, are, in general, fl ammable and are lipophilic. In contrast to hydrocarbons, the low molecular weight silanes such as monosilane, methylsilane, and dichlorosilaneare pyrophoric. The silanes will react with base or, more slowly, with acid to give the corresponding siloxane with the evolutionof hydrogen gas. They show a strong, characteristic, carbonyl-like absorption in the infrared at about 2200 cm-1.1

The metallic nature of silicon and its low electronegativity relative to hydrogen - 1.8 versus 2.1 on the Pauling scale - lead to polarization of the Si-H bond such that the hydrogen is hydridic in nature. This provides an ionic, hydridic reducingagent that is milder than the usual aluminum-, boron-, and other metal-based hydrides. Thus, triethylsilane, among others, has been used to provide the hydride in Lewis acid-catalyzed reductions of various carbenium ion precursors. In addition, the Si-H bond can be employed in various radical reductions wherein the silane provides the hydrogen radical.

Table 2 shows the Si-H bond strengths for several silanes. From these data the rather wide variation in the Si-H bond strengths from tris(trimethylsilyl)silane on the low-energy end to trifl uorosilane on the high-energy end can be noted. This is yet another example of the extraordinary effect that groups attached to silicon can have on the chemistry of the silane and that these effects can go beyond the simple steric effects that have been so successfully applied with the silicon-based blockingagents.2-4

TABLE 2 BOND STRENGTHS OF VARIOUS HYDRIDOSILANES

Compound Product Code Bond Strength ReferencekJ mol-1 kcal mol-1

F3Si-H SIT8373.0 419 100 5

Et3Si-H SIT8330.0 398 95 6

Me3Si-H SIT8570.0 398 95 7

H3Si-H SIS6950.0 384 92 6

Cl3Si-H SIT8155.0 382 91 5

PhMeHSi-H SIP6742.0 382 91 6

Me3SiSiMe

2-H not offered 378 90 6

PhH2Si-H SIP6750.0 377 90 6

(MeS)3Si-H not offered 366 87 6

H3SiSiH

2-H SID4594.0 361 86 5

(Me3Si)

3Si-H SIT8724.0 351 84 6

Although triethylsilane has been the most popular of the silicon-based reducing agents, in principal any Si-H-containing system can provide the hydride for many or most of these reductions. Considerations would include availability, economics, and silicon-containing by-products. The silicon-containing by-products are usually the silanol or disiloxane in the case of the trisubstituted silanes, or silicones in the case of the di- or monosubstituted silane reducing agents. Such considerations can result in greater ease of handling and purifi cation of the fi nal product.

Silicon-based reductions have been reviewed, though never in a comprehensive manner.6,8-13 A comprehensive review has been accepted for publication.14

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Silicon-Based Radical Reductions Griller and Chatgilialoglu6 realized that the low bond energy of the Si-H bond in tris(trimethylsilyl)silane compared well with that of the Sn-H bond in tri-n-butyltin hydride (322 kJmol-1; 77 kcal mol-1), and that this reagent should, therefore, be a viable alternative for radical reductions and one that would avoid the potential problems of working with toxictin materials and trace tin-containing impurities in the fi nal product. This proved to be the case, and a number of radical reductions with tris(trimethylsilyl)silane have been reported and reviewed.15,16 Included among these are the reductions of organic halides, 17-19 esters,20 xanthates, selenides, sulfi des, thioethers, and isonitriles.21

As an example of a free radical reduction, the diphenylsilane reduction of thioesters to ethers has been recently reported.22 This reaction uses the catalytic triphenyltin hydride as the actual reducing agent.

O

S

O

1) Ph2SiH2

Ph3SnH cat.Et3B/rt/1h

60%2) AIBN/85-100 °C

Ionic Reductions with Silanes – General Considerations As pointed out above the silanes provide a mild form of the hydride and as such can be useful in various hydridic reductions. The general and, admittedly simplifi ed, view of such reductions can be visualized as shown below where a carbenium ion is reduced by a silane. In this scenario, the carbenium ion receives the hydride from the silane, and the silanetakes on the leaving group from the carbon center.

R3C-X + R3Si-H R3C-H + R3Si-X

It has been shown that in the gas phase the reaction shown below is exothermic by approximately 8 kcal/mol indicating that the trimethylsilicenium ion is, at least in the gas phase, more stable than the tert-butyl carbenium ion.23

Although the existence of free silicenium ions do not exist in solution under normal, “unbiased” conditions, it can be assumed that the silicon center is free to take on considerable positive charge in its reactions. Reductions based on this premise includethose of olefi ns, ketones, aldehydes, esters, organic halides, acid chlorides, acetals, ketals, alcohols as well as metal salts.

(CH3)3C + + (CH3)3Si-H (CH3)3C-H + (CH3)3Si +

Silane Reduction of Alcohols to Alkanes The general equation for the silane reduction of alcohols to alkanes is illustrated below. The reaction proceeds best when the alcohol can lead to a stabilized carbenium ion. Thus, secondary and tertiary aliphatic alcohols and benzylic alcohols are readily reduced. Trialkyl substituted silanes are more reactive than dialkylsilanes and di- or triarylsilanes. Typicaland highly effective conditions for these reductions are treatment of the alcohol with the silane and trifl uoroacetic acid in dichloromethane. Triethylsilane is often the silane of choice due to its ease of handling and high reactivity.23,24

R3C-OH + R3Si-H R3C-H + R3Si-OH and/or R3Si-O-SiR3

Acid

catalyst

The reduction of secondary alcohols with a silane and a protic acid does not occur. These reductions require the use of a strong Lewis acid such as boron trifl uoride or aluminum chloride.25,26

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Primary aliphatic alcohols are not reduced with silanes.27 Benzylic alcohols, on the other hand, are reduced under rather mild conditions to the corresponding toluene derivative.28

tBu

tBu

tBu

OH

CH2Cl2/TFA

tBu

tBu

tBu

Me

R3Si-H

The selective reduction of a benzylic alcohol in the presence of benzyl ethers, a tetrahydrofuran and an acetal has been reported.29

OBnO

OBn

OEt

MeO

HO

Et3Si-H/TFA

CH2Cl2/ rt

OBnO

OBn

OEt

MeO76%

Primary alcohols can be reduced to the alkane when the reaction is catalyzed by the very strong Lews acid, tris(pentafl uorophenyl)borane. The reaction requires two equivalents of the silane as the fi rst equivalent serves to silylate the alcohol. It is believed that the silylated alcohol is nucleophilically displaced in these transformations.30 On the other hand, with boron trifl uoride etherate as the catalyst, the benzylic alcohol can be reduced in the presence of a primary or secondary alcohol.31,32

E t3S iH , B (C 6F 5) 3

C H 2C l2, rt, 20 hPh OH Ph

95%

O H

O H

Ph

Ph O HPh

Ph

E t3S iH , C H 2C l2

E t2O• B F 3, 0o, 0.5 h

90%

O

O

N

OM e

M eO

H

H

O H

H O

M e

E t3S iH , C H C l3

E t2O •B F 3

O

O

N

O M e

M eO

H

H

H O

M e92%

The reduction of an allylic alcohol in the presence of a tertiary alcohol is possible.33

H OOH

E t3S iH , L iC lO 4

E t2O, rt, 16 h

O H

52%

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Silane Reduction of Alkyl Halides As with the reduction of alcohols to alkanes, the acid-catalyzed reduction of alkyl halides to alkanes requires the formation of a relatively stable carbenium ion intermediate that can accept the hydride from the silane. Thus, tertiary, secondary, allylic and benzylic halides lend themselves to this type of reduction. Under certain conditions primary halides canbe reduced, but carbenium ion rearrangements are a problem.34,35

Br

Et3SiD

AlCl3

D

+

E t3S iH , A lC l3

H C l

39% 26%

B r

ClEt3SiH

AlCl3

H

57%

Trialkylsilanes, being better hydride donors, provide less rearranged product in these reductions than their dialkyl or monoalkyl counterparts.35

The reduction of organic halides with pentacoordinate hydridosilanes has been reported.36

Tertiary alkyl fl uorides can be reduced to the alkane in excellent yield.37 β-Chloro ethyl ethers are cleanly reduced to the alkane.38 An allyl chloride was reduced in the presence of an allylic tosylate.39

OPh

F

O

OPh

O

E t3S iH , B F 3• OE t2

C H 2C l2, –20o, 8 h

100%

OO

C l OO

E t3S iH , PdC l2

rt, 10 min

95%

S O 2T ol

C l

S O 2T olPh2S iH 2, Z nC l2, Pd(PPh3)4

T H F , rt, 12 h, 50° , 6 h

58%

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The reduction of α-halo ketones and α-halo esters has been reported to occur with the combinations of PhSiH

3/Mo(CO)

6,40 Ph

2SiH

2/ZnCl

2/(PPh

3)

4Pd,40 and Et

3SiH/PdCl

238 with the fi rst of these proving to be the best.

2-Bromopropiophenone was reduced to propiophenone with polymethylhydrogensiloxane, PMHS, without reduction of the carbonyl.41

Br

O O

PMHS, Pd(PPh3)4, Bn3N

MeCN/Me2SO (1:1), 110o, 3 h

80%

The tetramethyldisiloxane reduction of an aryl chloride in the presence of a benzophenone moiety was carried out in high yield.42 The high-yield reduction of an aryl trifl ate has been reported.43

O

C l

H M e2S iOS iM e2H , 10% N i/C

PPh3, dioxane, reflux, 15 h

O

96%

N

N C F 3

C F 3

OT fn-C 10H 21N

N C F 3

C F 3

n-C 10H 21

E t3S iH , Pd(OA c)2

dppp, D M F , 60° , 3 d

95%

Silane Reduction of Alkynes The reduction of p-tolylacetylene with triethylsilane gave p-ethyltoluene although in low yield.44

E t3S iH , T F A

rt, 120 hH

21%

Most of the alkyne reductions have been carried out on suitable enynes, diynes, or bromo acetylene derivatives to produce cyclic products.45-47

T B S OO T M S

PM H S , Pd2(bpa)3• C H C l3, (o-tol)3P

H OA c, C lC H 2C H 2C l, rtT B S O

O T M S

90%

B r

O E t3S iH , Pd(PPh3)4

C s2C O 3, D M F , 80° , 3 h

O

48%

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8

Silane Reduction of Aromatics Furans are reduced to tetrahydrofurans with triethylsilane under suitable catalysis.48 Thiophenes can be similarly reduced.49

O O

E t3S iH , T F A , F 3B •OE t2

20o, 4 min

70%

SO

OE t3S iH , T F A , 55° , 15 h

SOS iE t3

O

45%

Anthracene was reduced to 9,10-dihydroanthracene in good yield with triethylsilane and boron trifl uoride hydrate.50

The partial reduction of other polyaromatics was reported.50

E t3S iH , F 3B • OH 2

C H 2C l2, 25o, 1 h

89%

The pyridine ring of quinoline was reduced in preference to the benzene ring. The isolated product was the N-silylated derivative. Some of the dihydroreduction product was also observed.51,52

N

PhM eS iH 2, C p2T iM e2

80o, 8 hN

S iPhM eH

N

S iPhM eH

56% 18%

+

Silane Reduction of Ethers Trityl ethers are readily removed as triphenylmethane with triethylsilane and triethylsilyltrifl ate as the catalyst.53

B zO O

B zO

OB zO

O T r

E t3S iH , E t3S iOT f

C H 2C l2, rt, 5 min

87%

+ Ph3C HO

H O

H O

O T r

O T rB zO O

B zO

OB zO

O H

O

H O

H O

O H

OH

Under the infl uence of the strong Lewis acid, tris(pentafl uorophenyl)borane, dialkyl ethers were cleaved in high yield.54

A tertiarybutylcyclopropenyl ether was reduced to give the cyclopropene.55

n-C 16H 33O

C 16H 33-nE t3S iH , B (C 6F 5)3

C H 2C l2, rt, 20 hn-C 16H 34 + n-C 16H 33O S iE t3

98% 98%

Ph

Ph

Ph

O B u-t

E t3SiH, TFAPh

Ph

Ph

H45%

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Silane Reduction of Carboxylic Acids Ethyldimethylsilane and a ruthenium catalyst were used to reduce aliphatic carboxylic acids to the corresponding alcohol.56 With tris(pentafl uorophenyl)borane as catalyst, triethylsilane reduces carboxylic acids to the alkane.57,58

O H

O

OHE tM e2S iH , catalyst

1,4-dioxane, 20° , 0.5 h

72%

R uR u(C O)2(O C )2R u

O(C O)2

C O 2HE t3S iH , B (C 6F 5)3

C H 2C l2, rt, 20 h

94%

Silane Reduction of Esters and Lactones The reduction of esters and lactones has proven to be possible with the isolation of the corresponding alcohol, ether, hemiacetal, or monosilyl acetal. Thus, an ester was reduced to the alcohol in good yield in the presence of an epoxide.59 A methyl ester was selectively reduced to the alcohol in the presence of a tert-butyl ester.60 A butyrolactone was reduced to the tetrahydrofuran,56 as well as to a hemiacetal.56,61,62

O

H

O E t

OO

H

O H

PM H S , C p2T iC l2, n-B uL i

T H F , rt, 1 h

91%

M eO OB u-t

O O

H O OB u-t

O

87%

PM H S , C p2T iC l2, n-B uL i

T H F , –78o, 1 h

O

O O

O

B nOO

O O

OH

B nO

PM H S , C p2T i(OC 6H 4-C l-p)2

T B A F /A lumina, M eC 6H 5, rt

91%

Both an intermolecular63 and an intramolecular version of the conversion of an ester to a silyl acetal have been reported.64,65

O M e

O

O M e

OS iE t3

E t3S iH , E tI , E t2N H , [R uC l2(C O) 3]2

M eC 6H 5, 100° , 16 h

92%

S iM es2H

T B A F , 0°

OM es2S i

O E t

dr = 98:2

OO

OO

E t E t E t E t

C O 2E t

91%

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The reduction of α,β-unsaturated esters can occur with 1,4-adddition to provide the silyl ketene acetal or the β-silyl ester.66 The intermediate silyl ketene acetal can be trapped with a suitable electrophile either in an intermolecular or intramolecular fashion.67,68

O E t

O

O E t

OS iE t3E t3S iH , C lR h(PPh3)3

C 6H 6, 80° , 2 h

74%

+ O E t

O S iE t3

6%

OE t

O

O E t

O

O E t

O S iE t3

E t3S i E t3S i+E t3S iH , C lR h(PPh3)3

C 6H 6, 70° , 3 h

52% 28%

O

OO

+ M e3S iH , R hC l3• 3H 2O, 25° O

OM e3S iO

34%

E t3S iH , R hH (PPh3)4

M ePh, 50° , 16 hH

O

C O 2Pr-i

OS iE t3

C O 2Pr-i

O S iE t3

C O 2Pr-i+

20% 40%

Silane Reduction of Aldehydes The acid-catalyzed reduction of aldehydes with silanes works best in the presence of water.69 In addition esters can be formed when an organic acid is the catalyst employed.70

H

O Et3SiH

TFAO OH O2CCF3

+ +

nC7H15CHOEt3SiH

(n-C7H15)2O + n-C7H15-OH

66% 34%F3B•OEt2

PhCHOEt3SiH

TFA

Et3SiH

H2O/H2SO4

PhCH2-O-CH2Ph

PhCH2OH

80%

98%sulfolane

An excellent alternative for the reduction of aldehydes to alcohols is through the use of triethylsilane with uncomplexed boron trifl uoride in dichloromethane.71 This method gives the corresponding alcohol in high yield and very short reaction times. An extremely high-yield reductive conversion of aldehydes to unsymmetrical ethers involves the reaction of the aldehyde with a trimethylsilyl ether in the presence of a silane and a strong Lewis acid, with trimethylsilyl trifl ate being especially effi cient.72 Such silicon-based reductive-condensation chemistry should be applicable to combinatorial chemistry where product isolation is a crucial issue.

n-C4H9CHO + n-C6H13OSiMe3

Et3SiH/Me3SiI

CH2Cl2/0 °C/2hn-C5H11-O-C6H13-n

100%

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Aromatic aldehydes can be fully reduced to the corresponding toluene derivative.71,73

OCH3

CHO

Et3SiH/BF3

CH2Cl2/0 °C/10 min

OCH3

CH3

OCH3

CHO

Et3SiH/TFA

rt/45 min

83%100%

The conversion of aromatic aldehydes to benzylic halides has also been shown.74-76 The best reducing agent for this seems to be tetramethyldisiloxane.

Cl

CHO

Cl

CH2I

(HMe2Si)2O/Me3SiCl

NaI/CH3CN/0 °C/5 min

95%

Under catalysis by fl uoride ion aldehydes are reduced to the corresponding silyl ether of the alcohol. Hydrolysis of the silyl ethers provides the unprotected alcohols. Cesium fl uoride has been shown to be an excellent promoter for these conversions,77,78 as have tetra-n-butyl ammonium fl uoride (TBAF) and tris(diethylamino)sulfonium difl uorotrimethylsilicate (TASF).79 This can also be used as a route to trimethylsilyl-protected alcohols from aldehydes.

2 n-C6H12CHOPh2SiH2

CsF(n-C7H15O)2SiPh2

The reduction of aldehydes to alcohols has also been carried out with polylmethylhydrogensiloxane (PMHS) as the hydride source. In this case, the work-up includes reaction with methanol to release the free alcohol.80

The selective reduction of aldehydes over ketones can be realized with polymethylhydrogensiloxane as the reducing agent with fl uoride ion-catalysis.81

PhH

O

Ph nBu

O

+PMHS

TBAF

Ph

Ph nBu

OH

+

OH 87%

< 8%

The reductive amidation of aldehydes proved possible via the acid-catalyzed triethylsilane reduction in the presence of a nitrile or a primary amide.82,83

PhC H O + C H 3C N PhC H 2N H C O M eaq. H 2S O 4

E t3S iH80%

H O 2C

C H O

H O 2C

NH

Ph

O

E t3S iH , T F A , PhC ON H 2

M eC 6H 5, 120o, 18 h

96%

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12

The reduction of α,β-unsaturated aldehydes can occur in a 1,2- or 1,4-fashion.84

C H O O HPh2S iH 2, (Ph3P)3R hC l

0o, 1 h

97%

C H O C H OE t3S iH , (Ph3P)3R hC l

rt, 1 h

97%

Silane Reduction of Ketones Silanes have been used for the reduction of ketones to alcohols with excellent results.85 The reduction of ketones or aldehydes in the presence of acetonitrile and an acid provides an alkyl acetamide.82 The comparable reduction of aldehydes to alkyl acetamides is also possible.82

O

HO H

H

Et3SiH

TFA

HO H

H

OH

α:β ratio = 1:4

O

Et3SiH/CH3CN

75% aq. H2SO4/rt/65h NHCOMe

In a similar manner, the reduction of ketones and aldehydes to esters has been reported.82 This reaction is always accompanied with the formation of the symmetrical ether.

O

Et3SiH/TFA

rt/1.5h

H O2CCF3

+ O

275% 25%

Et3SiH/HCOOH

rt/8h

CHOO2CH O

+

The reduction of aryl ketones (acetophenone derivatives) to the methylene is readily accomplished.86 Triethylsilane with titanium tetrachloride works best for this transformation, though other systems also work well.

Ar R

O

AcidAr R

R3SiH

138



13

The selective reduction of aryl ketones to alcohols over dialkyl ketones can be carried out with phenyldimethylsilane in the presence of cuprous chloride or cuprous acetate.87

Cyclic ethers can be formed in the reduction of diketones or hydroxyketones.88-90 Epoxy ketones can lead to ethers as well.91

O O

1. M e3S iH , T M S OT f, C H 2C l2

0° , 4 h then rt, 2 h

2. H 2O

O

H O

O

O

M e3S iH , T M S OT f

C H 2C l2, 0° , 4 h, then rt, 2 h

O O+

42% 42%

S

OO HO

: OS

O:E t3S iH , T M S OT f

C H 2C l2, 0° , 15 min

97%

O O

Ph3S iH , catalyst, C H 2C l2

–78° , 6 h; 0° , 12 h OH H

OH81%

The reductive halogenation of ketones has been shown. Thus, acetophenone derivatives are converted to benzylic halides.92,93 An ynone was converted to the propargyl chloride in good yield.92

C l

B r

C l

C l

B r

O

M e2C lS iH , I n(OH )3

C H C l3, rt, 4 h

99%

O I

T M D S , I 2, C H 2C l2

–5o, 5 min

76%

O C l

M e2C lS iH , In(OH )3

C H C l3, 0o, 0.3 h

78%

The reduction of aliphatic ketones to the methylene is best accomplished with the tris(pentafl uorophenyl)borane catalyst.94

O

PM H S , B (C 6F 5)3, C H 2C l2

rt, 5 - 20 min

90%

139



14

Dimethyl(diethylamino)silane served as the reducing agent and the amine source in the reductive amination of acetophenone.95

O N E t2E t2N S iH M e2, T iC l4

C H 2C l2, 0o to rt, 36 h

65%

The reduction of α,β-unsaturated ketones can occur in a 1,2- or 1,4-fashion.84

O O O H

+E t2S iH 2, (Ph3)3R hC l

0° , 30 min

3% 97%

O O OH

+E t3S iH , (Ph3)3R hC l

80° , 25 h

90% 6%

Some selectivity was seen in the reduction of an enone in the presence of a ketal96 and an acid, allyl alcohol, and halide.97

Ph2S iH 2, Z nC l2

Pd(PPh3) 4, rt, 1 hO

O

O

O

O

O95%

O

C l C F 3

H O

H O 2CO

C l C F 3

H O

H O 2CE t3S iH , T F A , 0o, 1 h

rt, 48 h

82%

Silane Reduction of Other Carbonyl Systems The reduction of amides to the amine has been shown to occur in high yields employing triethylsilane or diphenylsilane.98,99

N

O

NE t3S iH , R e(C O) 10, E t2N H

M eC 6H 5, 100°

96%

The one-pot reduction of amides to aldehydes with diphenylsilane has been reported.99 This provides a potentially highly-useful, non-oxidative entry into aldehydes.

N CN Pr-i2

O

10N C

H

O

10

Ph2S iH 2, T i(OPr-i)4, 20°

80%

NMe2

O

TBSOPh2SiH2 (1.1 eq)

Ti(OPr-i)4 (1 eq)

87%

H

O

TBSO

140



15

The reduction of acids and esters to alcohols with polymethylhydrogensiloxane occurs in good yields in the presence of titanium tetraisopropoxide100 or tetrabutylammonium fl uoride.101 The reduction of esters has also been carried out with diphenylsilane and rhodium catalysis.102

OEt

O

OBnPMHS

Ti(OiPr)4/THF OH

OBn

89%

OMe

O

8OH8

PMHS

TBAF95%

The triethoxysilane reduction of esters to alcohols in high yields is possible.103 This transformation also takes place with PMHS as the reducing agent.104,105

COOEt (EtO)3SiH/Ti(OiPr)4

40 - 50 °COH

The conversion of lactones to lactols was accomplished via a titanium-catalyzed reduction with PMHS.106

O

O

Cp2Ti(OC6H4Cl)2

TBAF/Al2O3

PMHS/toluene

O

OH

94%

The reduction of imines to amines with trichlorosilane and dichlorosilane was reported. Dichlorosilane gave the best results.107

S

OMe

N

S

OMeHN

Silane

Cl2SiH2

Cl3SiH

90%

61%

F3B•OEt2

The reduction of oximes to alkoxyamines is accomplished with phenyldimethylsilane and trifl uoroacetic acid.108

NR2

R1 OR3PhMe2SiH

TFANH

R2

R1 OR3

141



16

Silane Reduction of Acetals, Ketals and Aminals The silane reduction of acetals and ketals occurs readily in the presence of a variety of silanes and acid catalysts. Both arylalkyl and dialkyl ketals can be reduced to the methylene group.107

Ph

OO

1. E t3S iH , S nB r2-A cB r,

C H 2C l2, rt, 24 h

2. n-B u3SnH , A I B N ,

C 6H 6, reflux, 0.5 h

Ph

77%

M eO O M e

Ph Ph

1. E t3S iH , S nB r2-A cB r,

C H 2C l2, rt, 24 h

2. n-B u3S nH , A I B N ,

C 6H 6, reflux, 0.5 h

67%

The reduction of the acetal of benzaldehyde was carried out in good yield in the presence of an alkyl azide.109 The reduction of a peroxymethyl ketal occurred to give triethylmethoxysilane and keep the peroxide group as well as a primary alkyliodide.110 In another similar example the peroxide functionality was lost.110

N 3

OO

PhH

PM H S , A lC l3, E t2O, C H 2C l2

rt, 12 h

69%7

N 3

B nOH O

7

OOM eO

OOH

E t3S iH , H OT f

II

H H56%

OO

OE t3S iH , H OT f O

51%

Aminals and hemiaminals are reduced to amines.111 N-Trimethylsilyloxymethylimines can be reduced to the corresponding imine.112 Related reactions are also possible.113,114

NN

H OM e

C O 2M e

E t3S iH , T F A

rt, 4 hN

N

HM e

C O 2M e

79%

M eO

NH

OH

O

E t3S iH , T F A

C H C l3, rt, 1- 4 h

M eO

N H M e

O

91%

O

NM eO 2C

OH

E t3S iH , T F A

C H C l3, rt, 20 h

O

NM eO 2C

M e63%

O

N OF moc NM e

OF moc

OH

E t3S iH , T F A

C H C l3, rt, 22 h

98%

142



17

Silane Reduction of Enamines and Enamides The organosilane reduction of enamines has been reported.116 The reduction of enamides can be carried out selectively in the presence of enones.117,118

NH

M eO

M eO

E t3S iH , T F A

50° , 64 h

N

N Ph

HN

O

NH

M eO

M eO

N

N Ph

HN

O

58%

N

C O 2M e

C l

O

E t3S iH , T F A , C H 2C l2

0° , 6 h then rt, 6 hN

C O 2M e

C l

O

56%

N

O

O

OE t3S iH , T F A , C H C l3

20° , 24 h

N

O

O

O

75%

Silane Reduction of Olefi ns Not surprisingly the ionic reduction of suitable olefi ns, i.e. those which can generate a relatively stable carbenium ion, can be carried out by silanes in the presence of an acid catalyst. The ability to generate the carbenium ion is essential to thesuccess of the reaction. For example, 1-methylcyclohexene is readily reduced to methylcyclohexane whereas cyclohexene itself is not reduced under the same and even more forcing conditions.118 The most common set of conditions for these reductions is an excess of trifl uoroacetic acid, a strong acid with a conjugate base of low nucleophilicity, and triethylsilane.119-123 Likewise, terminal olefi ns that are not styrenic in nature and 1,2-disubstituted olefi ns are not reduced with silanes, again, due to the inability to form a suitable carbenium ion intermediate. On the other hand, the reduction of enol ethers and similar olefi ns which can form good carbenium ions is possible.122,124

+2 Et3SiH/TFA

+

70% 100%

The reduction of α,β-unsaturated carbonyls to their saturated counterparts is conveniently carried out with silanes in the presence of a rhodium or copper catalyst.125,126

OnC12H25

O

PhMe2SiH

CuCl/DMIOnC12H25

O95%

O

conditions

[Ph3PCuH]6 5 mol %

O

Bu3SnH; 40 min 80%

PhSiH3; 8 min 86%

143



18

Ojima and Kogure84 have shown that the reduction of α,β-unsaturated ketones or aldehydes with triethylsilane or ethyldimethylsilane gives 1,4-addition resulting in reduction of the double bond whereas diphenylsilane gives 1,2-addition and straight reduction of the carbonyl.

O

silane

(Ph3P)3RhCl

OH

+

O

EtMe2SiHPh2SiH2

2%99%

98%1%

An example of the reduction of a styrenic double bond in the presence of another double bond and a ketone is shown below.127 The double bond of an α,β-unsaturated ketone was reduced with the triethylsilane/acid combination, though regeneration of the ketones was necessary.128

O

H

Et3SiH

TFA/CH2Cl2

O

H

H

1) Et3SiH

TFA/CH2Cl2

O

O

H

O

O

2) NaOH/H2O

3) [O]

The reduction of a trisubstituted olefi n in the presence of an ester was shown.129

O2CCH3 O2CCH3

Et3SiH/TFA

iPrNO2/LiClO4

90%

The silane reduction of acetylenes to alkanes is not a practical approach to this transformation.130 The reduction of vinylcyclopropane gave ethylcyclopropane in quantitative yield.131 Vinyl ethers are reduced to the corresponding alkyl ether.132

E t3S iH

T F A , 25o

100%

E t3SiH

T F AO O

80%

144



19

Stereoselective Silane-Based Reductions Doyle and West133 demonstrated that the acid-catalyzed reduction of alkyl-substituted cyclohexanones with di-tert-butylsilane, di-tert-butylmethylsilane and tri-tert-butylsilane proceeds with predominant formation of the less stable isomer asthe trifl uoroacetate. For example, 4-tert-butylcyclohexanone gives 67% of the cis-4-tert-butylcyclohexyl trifl uoroacetate.

OtBu2MeSiH/CF3CO2H

O2CCF3

OEt3SiH OSiEt3

CF3CO2H

The reduction of 4-tert-butylcyclohexanone with triethylsilane or dimethylphenylsilane preferentially gives the trans product. Very high trans to cis stereoselectivity of this transformation with triethoxysilane and TBAF was reported as was thereduction of 3-phenyl-2-butanone to anti 3-phenyl-2-butanol.134

The stereoselective silane reduction of β-hydroxy ketones with diisopropylchlorosilane has been demonstrated.135-137

OH OiPr2ClSiH

Et3N

O OSi-H

iPr

iPr

1) SnCl4

2) HF/H2O

OH OH

67% de >98%

The highly diastereoselective reduction of oximes has been reported.108 The diastereoselectivity was much higher than that reported for the corresponding reduction with lithium aluminum hydride in diethyl ether.

PhOAc

NBnO

PhMe2SiH

TFA PhOAc

NHBnO

PhOAc

NHBnO

+

73%99 1

PhOAc

N PhMe2SiH

TFA PhOAc

NHBnO

PhOAc

NHBnO

+77%

% %

OBn

82 18

The Lewis acid-catalyzed triphenylsilane reduction of hemiketals was shown to occur with high stereoselectivity.140

OPh

S

S

PhOH

PhMe2SiH/TiCl4

OPh

S

S

PhH

cis:trans = 82:1

CH2Cl2/5 min

145



20

Asymmetric silane reductions A very effi cient asymmetric reduction of arylalkyl ketones has been shown. The reaction, which does not work well for prochiral dialkyl ketones, is carried out with PMHS in the presence of a chiral titanium catalyst.138

O

"Ti"/C6H6

PMHS

OH

73% yield; 73% ee

A number of asymmetric, silane-based reductions have been reported. In many cases these result in very high enantioselectivity and offer an alternative to the asymmetric hydrogenation protocol. Enones have been reduced in a 1,2-fashion, as well as in a 1,4-manner, with high ee values.141,142

1. PhSiH3, (EBTHI)Ti, MeOH,

60°, pyrrolidine, MeOH, THF

2. PMHS, ketone, MeOH, 15°, 4 h

O OH

90%; 84% ee

O

Ph

O

Ph

PMHS, Ph3PCuH, DTBM-SEGPHOS

MeC6H5, –35°, 16 h

95%; 99.5% ee

The intermediate enol silyl ether from the reduction of an enone can be trapped with benzyl bromide.143

O

O

Bn

Ph2SiH2, CuCl, NaOBu-t

(S)-p-Tol-BINAP, MeC6H5, 0°, 2 - 3 h

Ph

Ph

OSiPh2H

Ph

95% ee

BnBr, TBAT

CH2Cl2/MeC6H5, rt

69%; dr = 94:6

146



21

The DTBM-SEGPHOS-catalyzed PMHS reduction of α,β-unsaturated esters provides the saturated ester in high enantiomeric excess.144

OEt

Ph

O

OEt

Ph

O

HPMHS, (Ph3P)CuH

t-BuOH, MeC6H5, 0°

92%; 98% ee

O

O

Ph

O

O

H

Ph

PMHS, (Ph3P)CuH

t-BuOH, MeC6H5, 0°

96%; 99% ee

Buchwald and coworkers139 have reported the reduction of imines in very high enantiomeric excess through the use of a titanium catalyst activated with phenylsilane and the reduction with polymethylhydrogen siloxane or phenylsilane. The asymmetric reduction of imines has been reported in very high enantiomeric excesses.139,145-147

NActivated Ti cat.

PMHS or PhSiH3

slow addition of 3° amine

HN

95% 98% ee

NPhSiH3, catalyst

i-BuNH2, 65°, 2.5 h

Cl

OMe

HN

Cl

OMe

E : Z = 15:1 92%, 99% ee

Reductions With Other Group 14 Hydrides The tri-n-butyltin hydride reductions are well-known and have been reviewed.148 A recent report shows that tri-n-butyltin hydride can provide the hydrogen for the reductive amination of ketones and aldehydes, thus providing an alternative to sodium cyanoborohydride for this transformation.149 This same transformation was reported using polymethylhydrogen siloxane, PMHS, as the reducing agent.150

R1 R2

O

+ R2NH2+ ClO4

-Bu3SnH

DMF R1 R2

NR2

Triphenylgermane has been shown to reduce acid chlorides to aldehydes with palladium(0) catalysis.151

R Cl

OPh3GeH

Pd(PPh3)4

HMPA/80-100 °C

R H

O

Tri-n-butylgermane has been employed in the reductive alkylation of active olefi ns, in particular acrylonitrile.152

CN+ R-I

Bu3GeH

AIBN/80 °C/8h

RCN + R-H

54 - 79 % 3 - 14 %

147



22

TRI-SUBSTITUTED SILANE REDUCING AGENTSTABLE 3REDUCING AGENT STRUCTURE COMMENTS

SIT8330.0TRIETHYLSILANE[617-86-7]TSCA

SiC2H5 H

C2H5

C2H5

Used to reduce metal salts.153 Enhances deprotection of t-butoxycarbonyl-protected amines and tert-butylesters.154

Used in the reductive amidation of oxazolidinones with amino acids to provide dipeptides.155 Converts aldehydes to symmetrical and unsymmetrical ethers. 156 Used in the ‘in-situ’ preparation of diborane and haloboranes.157

SIT8570.0TRIMETHYLSILANE[993-07-7]TSCA

SiH

CH3

CH3

CH3

Potential reducing agent that will produce low boiling hexamethyldisiloxane by-product.

SIT8385.0TRIISOPROPYLSILANE[6485-79-6]

Si

CH

H3C CH3

HCH3C

H3C CH

H3C CH3

H

Very sterically-hindered silane. Used as a cation scavenger in the deprotection of peptides.158

SIT8665.0TRIPHENYLSILANE[789-25-3]TSCA

Si H

More effective radical-based reagent for reduction of organic halides than the trialkylsilanes.156 Compares well with tri-n-butyltin hydride in reduction of enones to ketones.63 Shows good selectivity in the reduction of cyclic hemiacetals.77 Converts O-acetyl furanoses and pyranoses to deoxy sugars.159

SIT8709.0TRI-n-PROPYLSILANE[998-29-8]TSCA

Si

CH2CH2CH3

CH2CH2CH3

H CH2CH2CH3

Reactivity similar to that of triethylsilane.

SIT8376.0TRI-n-HEXYLSILANE[2929-52-4]TSCA

SiCH3(CH2)5 H

(CH2)5CH3

(CH2)5CH3

Reactivity similar to that of triethylsilane but has higher boiling point and produces a higher boiling by-product.

SIT8185.0TRIETHOXYSILANE[998-30-1] Si

OC2H5

H

OC2H5

OC2H5

Reduces esters in the presence of zinc hydride catalyst.52

Reduces aldehydes and ketones to alcohols via the silyl ethers in presence of fluoride ion.160 Gives 1,2-reduction of enones to allyl alcohols.161

SIT8721.0TRIS(TRIMETHYLSILOXY)SILANE[1873-89-8]

SiH

O

Si(CH3)3

O Si(CH3)3

O

Si(CH3)3

Gives highly stereoselective reduction of substituted cyclohexanones.51

148



23

SIT8724.0TRIS(TRIMETHYLSILYL)SILANE[1873-77-4] Si

Si(CH3)3

Si(CH3)3

Si(CH3)3H

Undergoes exothermic decomposition at >100 °C.Radical-based reducing agent for organic halides, selenides, xanthates and isocyanides and ketones in high yields.20 Can provide complementary stereoselectivity to tri-n-butyltin hydride in the reduction of gem dihalides.162 Mild reducing agent in nucleoside chemistry.163

SID3258.0DI-tert-BUTYLMETHYLSILANE[56310-20-4]

H3CCCH3

H3CSi

CH3C

CH3H3C

H

CH3

Used in reductive trifluoroacetolysis of ketones. Reacts faster than di-tert-butylsilane.72

SID3410.0DIETHYLMETHYLSILANE[760-32-7]TSCA

CH3CH2Si

H

CH3CH3CH2

Similar to triethylsilane with lower boiling point.

SID3535.0DIISOPROPYLCHLOROSILANE[2227-29-4]TSCA

Si

CH

CH

H3C CH3

CH3H3C

ClH

Used in a silylation-reduction-allylation sequence of β-hydroxy esters to homoallylic-substituted 1,3-diols.164

Used in the silylation-hydrosilation-oxidation of allyl alcohols to 1,3-diols.165 Reaction carried out in diastereoselective manner. Reduces β-hydroxy ketones to anti-1,3 diols. 166

SID4070.0DIMETHYLCHLOROSILANE[1066-35-9]TSCA

SiH

CH3

CH3

Cl

Will form high-boiling polymeric by-products with aqueous work-up.

SID4125.0DIMETHYLETHOXYSILANE[14857-34-2]TSCA

SiH

CH3

CH3

OC2H5

Will form high-boiling polymeric by-products with aqueous work-up.

SID4555.0DIPHENYLMETHYLSILANE[776-76-1]TSCA

SiCH3

H

Used to reduce α-alkoxy ketones to diols and α-aminoketones to aminoethanols with high stereoselectivity.167

SIE4894.0ETHYLDIMETHYLSILANE[758-21-4]TSCA

SiCH3CH2 CH3

CH3H Similar to triethylsilane with lower boiling point.

SIE4890.0ETHYLDICHLOROSILANE[1789-58-8]TSCA

SiCH3CH2 Cl

ClH Will form high-boiling polymeric by-products with aqueous work-up.

149



24

SiH3C

H

Cl

Cl

SiH3C

H

OC2H5

OC2H5

CH3(CH2)16CH2 Si

CH3

CH3

H

Si

CH3

CH3

H

α

α

α

SiCH3

H

Cl

SiCH2CH2SiH

CH3 CH3

H

CH3CH3

SiCl

H

Cl

Cl

150



25

DIALKYLSILYL REDUCING AGENTSTABLE 4REDUCING AGENT STRUCTURE COMMENTS

SID4230.0DIMETHYLSILANE[1111-74-6]TSCA

SiH

CH3

CH3

H

Very low boiling point silane that is a gas at atmospheric conditions.

SID3342.0DI-tert-BUTYLSILANE[30736-07-3]

H3CCCH3

H3CSi

CH3C

CH3H3C

H

H

Sterically-hindered silane reducing agent.

SID3368.0DICHLOROSILANE[4109-96-0]TSCA

HSi

H

Cl

Cl

Gives improved yields in reduction of imines over that of trichlorosilane.56

SID3368.2DICHLOROSILANE, 25%in xylene[4109-96-0]TSCA

HSi

H

Cl

Cl

Easier to handle form of dichlorosilane.

SID3415.0DIETHYLSILANE[542-91-6]TSCA

CH3CH2Si

H

HCH3CH2

Used in the ‘in-situ’ preparation of diborane and haloboranes.157

SID4559.0DIPHENYLSILANE[775-12-2]TSCA

SiH

H

Used in the preparation of silyl-substituted alkylidene complexes of tantalum.177 Used in the ionic reduction of enones to saturated ketones.178 Used in the reductivecyclization of unsaturated ketones.179,180 Reduces estersin the presence of zinc hydride catalyst.53 Reduces α-haloketones in presence of Mo(0).181 Reduces thio esters toethers.22 Reduces esters to alcohols with Rh catalysis.49

Employed in the asymmetric reduction of methyl ketones114

and other ketones.182,183 Reductively cleaves allyl acetates.184

SIP6742.0PHENYLMETHYLSILANE[766-08-5]TSCA

SiCH3

H

H

Used in the preparation of silyl-substituted alkylidene complexes of tantalum.177

151



MONO-SUBSTITUTED SILANE REDUCING AGENTSTABLE 5REDUCING AGENT STRUCTURE COMMENTS

SIH6166.2n-HEXYLSILANE[1072-14-6]TSCA

SIO6635.0n-OCTADECYLSILANE[18623-11-5]TSCA

SIO6712.5n-OCTYLSILANE[871-92-1]TSCA

SIP6750.0PHENYLSILANE[694-53-1]TSCA

Employed in the reduction of esters to ethers.185

Reduces α,β-unsaturated ketones to saturated ketones in the presence of tri-n-butyltin hydride.186 Reduces tin amides to tin hydrides.187 Used in the tin-catalyzed reduction of nitroalkanes to alkanes.188 Reduces α-halo ketones in presence of Mo(0).181

SILOXANE-BASED SILANE REDUCING AGENTSTABLE 6REDUCING AGENT STRUCTURE COMMENTS

SIO6696.5OCTAKIS(DIMETHYLSIL-OXY)-T8-SILSESQUIOXANE[125756-69-6]

Solid siloxane reducing agent. Offers 8 Si-H bonds. Potential for easy removal of silicon by-products.

SIH6117.01,1,3,3,5,5-HEXAMETHYL-TRISILOXANE[1189-93-1]TSCA

High molecular weight silane reducing agent.

SIP6718.0PENTAMETHYLCYCLO-PENTASILOXANE, 90%[6166-86-5]TSCA

SIH5844.0HEPTAMETHYLTRISIL-OXANE[2895-07-0]

152



SIP6736.5PHENYLHYDROCYCLOSIL-OXANES, contains linears.

High-boiling siloxane reducing agent.

SIP6826.0PHENYLTRIS(DIMETHYLSILOXY)SILANE, 95%[18027-45-7]TSCA


SIT7274.01,1,3,3-TETRAISOPROPYL-DISILOXANE[18043-71-5]

Sterically-hindered silane reducing agent with potential for diastereoselective reductions.

SIT7278.0TETRAKIS(DIMETHYL-SILOXY)SILANE[17082-47-2]TSCA


SIT7530.01,3,5,7-TETRAMETHYL-CYCLO-TETRASILOXANE[2370-88-9]TSCA


SIT7546.01,1,3,3-TETRAMETHYL-DISILOXANE[30110-74-8]TSCA

Reduces aromatic aldehydes to benzyl halides.38 Used in the reductive halogenation of aldehydes and epoxides.189

SIT8721.0TRIS(TRIMETHYLSILOXY)-SILANE[1873-89-8]


METHYLHYDROSILOXANE-DIMETHYLSILOXANE CO-POLYMERSHMS-013 through HMS-501having various MW’s, vis-cosities, and hydride content.[68037-59-2]TSCA

Potential reducing agents in the mode of HMS-991 or HMS-992.

153



HMS-991 or HMS-992POLYMETHYLHYDROSILOXANE[63148-57-2]TSCA

Reduces lactones to lactols.55 Reduces aldehydes, ketones, esters, lactones, triglycerides and epoxides to alcohols with zinc hydride catalysis.52 With titanium tetraisopropoxide catalysis, carries out reductive amination of ketones and aldehydes82 and the reduction of acids or esters to 1° alcohols.50 With TBAF catalysis, selectively reduces aldehydes over ketones.43 Used to generate tri-n-butyltin hydride ‘in-situ’ and in a one-pot hydrostannylation/Stille coupling sequence.190 Reduces esters to alcohols.54

GERMANIUM AND TIN-BASED REDUCING AGENTSTABLE 7REDUCING AGENT STRUCTURE COMMENTS

SNT8130TRI-n-BUTYLTIN HYDRIDE[688-73-3]TSCA

Has been reviewed.80 Catalyzes the Si-H reduction of α,β-unsaturated ketones.186 Useful in the reductive amination of ketones and aldehydes to form 3° amines.81

GET8100TRI-n-BUTYLGERMANE[998-39-0]

Reduces acid chlorides to aldehydes in presence of Pd(0).83 Effects free-radical reductive addition of alkyl halides to olefins.191 Reduces benzylic chlorides 70x faster than silyl hydrides.192

GET8660TRIPHENYLGERMANE[2816-43-5]

Readily adds to terminal acetylenes and olefins.193 Used in the reductive alkylation of acrylonitrile and enones.84

GET8560TRIMETHYLGERMANE[1449-63-4]

Effects halogen displacement of alkyl halides with hydrogen when exposed to UV.194

154



1

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