Synthesis and Utility of Fluorinated Acylsilanes - ACS Symposium

Chapter 22

Synthesis and Utility of Fluorinated Acylsilanes JohnT.Welch, Woo Jin Chung, Seiichiro Higashiya, SilvanaC.Ngo, and Dong Sung Lim

Downloaded by MONASH UNIV on May 14, 2013 | http://pubs.acs.org Publication Date: July 21, 2005 | doi: 10.1021/bk-2005-0911.ch022

Department of Chemistry, University at Albany, State University of New York, 1400 Washington Avenue, Albany,NY12222

A variety of fluorinated acylsilanes were synthesized. Difluoroacetyltrialkylsilanes (3) were prepared through retroBrook rearrangement from reaction of trifluoroethanol and chlorotrialkylsilanes in the presence ofLDA.Sequential Mg -promoted defluorination in the presence of chlorotrimethylsilane, followed by acidic hydrolysis resulted in the formation of monofluoroacetyltrialkylsilanes (4). Electrophilic fluorination of 1,1-difluoro-2-trialkylsilyl-2-trialkylsilyloxy ethenes (2) with Selectfluor® gave trifluoro-acetyltrialkyl silanes (5). The synthetic utility of fluorinated acylsilanes in olefination and allylation reactions under a variety of reaction conditions is also described.

378

© 2005 American Chemical Society

In Fluorine-Containing Synthons; Soloshonok, V.; ACS Symposium Series; American Chemical Society: Washington, DC, 2005.


379 Since A. G. Brook's first observation at late 50's that a carbonyl group located α to silicon atom displays unusual reactivity (1), acylsilanes have attracted interest. In response to the potential preparative utility of these materials various synthetic methods for the formation of acylsilanes have been developed (2). Brook originally discovered and investigated the intramolecular 1,2-anionic migration of a silyl group from carbon to oxygen in the late 50's and early 60's (3). The migratory aptitude of a silyl group is a general phenomenon, comprising a family of [l,n]-carbon to oxygen silyl migration events commonly referred to as Brook rearrangements (Figure 1) (4). The reverse process dubbed a retro-Brook rearrangement, an intramolecular migration of a silyl group from oxygen to carbon, was also reported and extensively studied (Figure 1) (5). X R* t

?'

Β1 R

0-M+ , SiR M +

f

i R 3

Β1 R

OS'iR

Λ

3

ΛιΛ , *Xa

_ . Brook rearrangement^ Retro-Brook rearrangement Brook rearrangement _ Retro-Brook rearrangement

3

f1,21-SMy» migration R

R

3

R

'

M

V

JkjiA ,

Si(

?

R

[1,n]-SHylmigration

Figure 1. Brook and retro-Brook rearrangement

Thus, Brook and retro-Brook rearrangements of acylsilanes have found increasing use in organic synthesis for the formation of useful building blocks. A variety of applications and utilities as synthetic intermediates in the construction of complex natural products have been described (6). The remarkable impact thatfluorinationhas on agricultural, medicinal and materials chemistry has lead to a rapid growth in the development of methods for the regio- and stereospecific introduction of fluorine into organic molecules. Considerable effort has been devoted to both the preparation of fluorinated building blocks, which can be transformed to the desired target molecules and to the development of new fluorinating reagents for direct fluorination at an appropriate point in a synthesis (7). Combining both fluorine and the unique reactivity of silicon, fluorinated acylsilanes, in particular, could easily be expected to be versatile fluorinated building blocks with diverse synthetic utility. However reports on either the synthetic methods necessary for the formation of fluorinated acylsilanes or the applications of these compounds have been very limited.

Discussion Synthesis offluorinatedacylsilanes Trifluoroacetyltriphenyl-

and

trifluoroacetyldimethylphenylsilane were


380


synthesized by the reaction of the appropriate organosilyllithium reagent and trifluoroacetic anhydride in the presence of cuprous iodide. However, this method is limited to the formation of aryl substituted trifluoroacylsilanes due to the instability of silyllithium reagents (Figure 2a) (8a-b). Recently, a new two step synthetic method employing an electrochemical transformation for the construction of trifluoroacetyltrimethylsilane from ethyl trifluoroacetate was reported. Unfortunately the requirement for special electrochemical apparatus is a significant drawback to general use of this method (Figure 2b) (8c). Clearly, a more effective and general synthetic method for the formation of fluorinated acylsilanes from easily available starting materials under convenient reaction conditions is still highly desired. «

(CF CO) Q

U B * v R

i'

= M

3

eR2!p

c

a

t

Ο

2

C

u

n

l

«

FaC^SiR^R,

2

Ο

2 e /

F C"N)Et

TMSC. H S0

3

2

4

j> F C^SiMe 3

3

Figure 2. Synthesis of trifluoroacylsilanes

Synthesis of difluoroacetyltrialkylsilanes (3) A new strategy was designed based on the reactivity of a difluorovinyl anion generated from protected trifluoroethanol by treatment with strong base (9). Silylation of the protected difluorovinyl anion [I] with a variety of chlorotrialkylsilanes would generate l,l-difluoro-2-trialkylsilylenol ethers (2), which could be further transformed by deprotection to difluoroacetyltrialkylsilanes (3). In addition, reductive defluorination (10) of (3) or electrophilic fluorination (11) of (2) would lead to formation of either monofluoroacetyltrialkylsilanes (4) or trifluoroacetyltrialkylsilanes (5) (Figure 3). F C-CH OPG 3

2

1

Base -HF -H+

F

w

CISiRa

0PG

F

•vr F

2

SIR,

electrophilic fluorination Ο

defluorlnation H F C " ^SIR 4 2

3

χ

HF C^SiR 3 2

3

F C^SiR 3

3

Figure 3. Newly designed synthetic method for the formation offluorinat acylsilanes

In a model reaction, the triethylsilyl ether of trifluoroethanol (la) (see Table I) was prepared and treated with lithium diisopropylamide (LDA).


381

Unexpectedly, the penultimate target difluoroacetyltriethylsilane (3a) was obtained directly instead of the anticipated l,l-difluoro-2-trimethylsilyl-2triethylsilyloxyethene (2a). It was postulated that difluoroacetyltriethylsilane (3a) was formed by retro-Brook rearrangement (Figure 4).

F C-CH OSIEt 1a


3

2

3

Figure 4. Unexpected silyl group migration During the course of exploring the generality of the formation of difluoroacetyltrialkylsilanes (3), it was found that trialkylsilyl trifluoroethyl ethers (1), prepared in situ, could be used without purification prior to subsequent transformations. It was necessary for the addition of LDA to a mixture of trifluoroethanol and appropriate chlorotrialkylsilanes in tetrahydrofuran (THF) to be carried out carefully so that the reaction temperature was not allowed to exceed than -30 °C. The difluorovinyl anion [I] was apparently unstable at temperatures greater than -30 °C. The formation of difluoroacetyltrialkylsilanes (3) can be rationalized as occurring via two consecutive reactions; initial defluorination followed by a second deprotonation of trialkylsilyl trifluoroethyl ethers (1) to generate the difluorovinyl anion [I], which upon retro-Brook rearrangement generated intermediate [II], and secondly hydrolysis [Π] to form the difluoroacetyltrialkylsilanes (3) (Figure 5). OH + CISiR

3 3

F3C

retro-Brook rearrangement

9SiR

LDA (3.5-4 eg.) THF

!

0SiR

3

3

F

^

F C^ 3

1)H 0 2

1

2)HF

HF C 2

S1R3

Figure 5. Plausible mechanism for the formation of (3) As summarized in Table I, a variety of difluoroacetyltrialkylsilanes (3) were synthesized in moderate yield. Difluoroacetyltriethylsilane (3a) and difluoroacetyl-feri-butyldiphenylsilane (3c) were obtained in 60% and 74%, respectively. On the other hand, difluoroacetyltrialkylsilanes with more hindered silyl groups, such as triisopropylsilyl (3b) and feri-butyldimethylsilyl (3d), required the addition of hexamethylphosphoramide (HMPA). The much less


382 hindered trimethylsilyl derivative (3e) and relatively labile triphenylsilyl derivative (3f) were formed in only low yields in the crude mixture and were not isolable by the same method employed in the preparation of (3a-d).


Table I. Synthesis of difluoroacetyltrialkylsilanes (3) 3 3a 3b

SiR SiEt Si'Pr-)

3c 3d 3e 3f 3f

Si'BuPh Si'BuMe SiMe SiPh SiPh

Condition Yield (%) 60 0°C,3hrs 0 °C, 36 hours, and then room temp, for 24 63 hours with HMPA 74 Room temp. 24 hours 13 -20 °C for overnight with HMPA 0 -15 °C for overnight -15 °C for overnight 0 Acidic work-up / controlled hydrolysis 18

3

3

2

2

3

3

3

Synthesis of l,l-difluoro-2-triaIkylsilyl-2-trialkylsilyIoxyethenes (2) During the study of the formation of difluoroacetyltrialkylsilanes (3), it was possible to trap enolate intermediate [II] on introduction of another equivalent chlorotrialkylsilane to form the difluoroenoxysilanes (2) (Figure 6). In all cases (Table II), the 14-difluoro-24rialkylsilyl-2-trialkylsilyloxyethe (2) were obtained in good yields, even with the 2-feri-butyldimethylsilyl (2d). The 2trimethylsilyl (2e-l), and 2-triphenylsilyI (2g-h) derivatives that had not previously given satisfactory results did form the corresponding acylsilanes (Figure 5, Table I). Interestingly, the initial aliquot of chlorotrialkylsilane leads to C-silylation through retro-Brook rearrangement from intermediate [I] and an additional equivalent of a second silylating reagent results in 0-silylation. This process generally occurs without interchange of the silyl groups to predictably form the desired products (2). These observations clearly establish that the intermediate exists as an enolate [II], generated from retro-Brook rearrangement of silyl group from [I], rather than as difluorovinyl anion [I].

CISiR

LDA (3.5-4 eq.)

3

THF

retro-Brook isomerization

CISiR' (1.5eq.)

?

3

S I R

~ ΥΝ^ Ρ

F

3

.

Figure 6. Formation oflJ-difluoro-2-trialkylsilyl-2~trialkylsfy


*

(2)

383


Table Π. Synthesis of l,l-dinuoro-2-trialkylsilyl-2-trialkylsilyloxyethenes (2) Entry 1 2 3 4 5 6 7 8

Sfl^ SiEt Si'Prj Si'BuPh Si'BuMe SiMe SiMe SiPh SiPh

2 2a 2b 2c 2d 2e 2f 2g 2h

SiR^ SiMe SiMe SiMe SiMe SiMe SiPh SiMe SiPh

3

Yield (Ψο) 80 69 71 65 62 68 67 43

3 3

2

3

3

2

3

3

3

3

3

3

3

3

Synthesis of monofluoroacetyltrialkylsilanes (4) and corresponding monofluoroenoxysilanes (6) The reductive defluorination by magnesium metal in the presence chlorotrimethylsilane, a method reported by Uneyama (10), was employed for the formation of monofluoroacetyltrialkylsilanes (4). The addition of HMPA prevented passivation of the magnesium surface. The monofluoroenoxysilanes (6) and the corresponding hydrolysis products, monofluoroacetyltrialkylsilanes (4), were prepared in good yields (Figure 7, Table III). Mg(4eq.) TMSCI (3 eq.) \

0

V

QTMS

f

u

HF C^SIR 2

THF-HMPA 0°Ctort

3

3

acidic hydrolysis ^

SIR

H

Q

V H FC"%iR

3

2

3

3 6

4

Figure 7. Synthesis of monofluoroenoxysilanes (6) and monofluoroacetyltriakylsilanes (4)

Table III. Synthesis of (4) and (6) 3 3a 3b 3c 3d 3f

SiR SiEt Si'Pr Si'BuPh Si'BuMe SiPh 3

3

3

2

2

3

6 6a 6b 6c 6d 6f

Yield (%) 74 76 69

4 4a 4b 4c 4d 4f

Yield (Ψο) 75 82 69 85 68


384


Electrophilic halogenation of (2) Enoxysilanes are well known precursors to α-functionalized ketones (12). Of the α-functionalized ketones, α-haloketones are important synthetic building blocks for the introduction of the ketone moiety into molecules by Reformatsky reactions (13). Electrophilic halogenation reactions of difluoroenoxysilanes bearing either the triisopropylsilyl (2b) or the triphenylsilyl group (2g) on vinyl carbon were utilized for the synthesis of α,α-difluoro-a-haloacetyltrialkylsilanes (7) (Figure 8). Reaction of (2b) and (2g) with electrophilic halogenating reagents (2 equivalents), such as iV-chlorosuccinimide (NCS), iV-bromosucdnimide (NCS), and iodine (I ), in THF at 0 °C for 30 minutes gave the corresponding α,αdifluoro-a-halo-acetyltrialkylsilanes (7), in good to moderate yields. Chlorination with NCS did require longer reaction times and higher reaction temperatures (room temperature) compared to bromination and iodination. Using 10 equivalents of NCS to affect chlorination of 2b gave a satisfactory yield in shorter reaction times (2 days). However, when the excess of chlorinating reagent was decreased to 5 equivalents, not only did reaction times (4 days) increase, byproduct formation also increased lowering the yield of 7. 2

Figure 8. Electrophilic halogenation reactions of (2)

Synthesis of trifluoroacetyltrialkylsilanes (5) Electrophilicfluorinationof (2) with appropriate fluorinating reagents can lead to the formation of trifluoroacetyltrialkylsilanes (5), synthetic equivalents of trifluoroacetaldehyde. Highly volatile and reactive trifluoroacetaldehyde is commonly generated in situfromprecursors such as hemiacetals, hemiaminals, or aminals under acidic conditions (14). With synthetic methods for the formation of trifluoroacetyltrialkylsilanes very limited (8), a general method for the facile formation of trifluoroacetyltrialkylsilanes was highly desirable. Reaction of (2) with 1.5 equivalents of Selectfluor® in a mixture of dichloromethane and acetonitrile (1:4) at room temperature for 1 day resulted in the formation of trifluoroacetyltriakylsilanes (5) (Figure 9). In general, 1,1difluoro-2-trialkylsilyl-2-trimethylsilyloxyethenes (2) bearing bulky silyl groups gave higher yields of 5 as consequence of reduced volatility. On work-up and evaporation of solvents, (5) was spectroscopically (*H and F NMR) pure and 19


385 can be used in subsequent reactions without additional purification. Formation of trifluoroacetyltrimethylsilane (5e) was also observed by F NMR with a resonance at δ -80.6 ppm corresponding CF group. Unfortunately isolation was unsuccessful, presumably as a consequence of the volatile nature of (5e) (Table IV) (8c). 19

3

OTMS Τ F> ^f^SIRa F

_ , , Selectfluor

Ο ji

M

CH CN : CH CI = 4 :1 F C 3

2

2

SiR

3

2

3

5


Figure 9. Electrophilicfluorinationof (2) with Selectfluor®

Table IV. Synthesis of trifluoroacetyltrialkylsilanes (5) Entry 1 2 3 4 5 6 7

5 5a 5a 5a 5b 5c 5d 5e

Temperature -78 °C 0°C Room Temp. Room Temp. Room Temp. Room Temp. Room Temp.

Source: Reproduced with permission from J. 2004.

SiK, Si'BuPhz Si'BuPh Si'BuPh SiPh Si'Pr SiEt SiMe 2

2

3

3

3

3

Yield (%) 0 0 87 73 48 35 0

Fluorine Chem. 2004,125, 543.

Copyright

Synthetic utility of fluorinated acylsilanes Olefination reactions of fluorinated acylsilanes The reactions of acylsilanes with phosphorus and sulfur ylides often involve silyl group migration to form enoxysilanes (15). This tendency is even more pronounced in the transformations offluorinatedacylsilanes, giving fluorinated enoxysilanes as the major product (Figure 10) (16). However, no information on the influence of the nature of trialkylsilyl group on the reaction pathway has previously been reported.

FC 3

SiPh

3

P / 3C

YJ

Figure 10. Wittig reaction offluorinatedacylsilanes


386 Wittig reaction of difluoroacetyltrialkylsilanes (3)


Wittig reaction of difluoroacetyltriethylsilane (3a) with triphenylphosphonium methylide produced two fluorinated compounds: the expected alkene (8a), and as consequence of Brook rearrangement, the fluorinated enoxysilane (9a) (Figure 11, Table V). However, a similar reaction with difluoroacetyl-fm-butyldiphenylsilane (3c) yielded only fluorinated enoxysilane (9b). Furthermore, when (3a) was allowed to react with a resonance-stabilized triphenylphosphonium benzylide, the only product isolated was the normal Wittig product (8c). '9 JL HF C^SiR 3 2

R'T, S!R %=/ C F H 8 y

+ R'H=PPh

·*

3

3

E t 2

3

+

n

0

H

2

R'x OSiR >===< H C F H 9

3

2

Figure 11. Wittig reaction of difluoroacetyltrialkylsilanes (2)

Table V. Wittig reaction of (3) Entry 3 1 3a 2 3c 3 3a

StR SiEt Si'BuPh SiEt

Time (h) R H 1 H 2 24 Ph

3

3

2

3

Yield (%)"Yield (%) 9a (25) 8a (21) 9b (63) 8b (0) 9c (0) 8c (75)

Source: Reproduced with permissionfromJ. Fluorine Chem. 2002,117,207. Copyright 2002.

It is clear that both the reactivity of ylides and the nature of substituents on silicon affected on the outcome of the reaction. Horner-Emmons reaction of difluoroacetyltrialkylsilanes (3) Reaction of (3) with stabilized ylides (17), Horner-Emmons type reagents, was also investigated (Figure 12) and results are summarized in Table VI. Jl^ HF C

χ SiR

2

3

+ 3

^ OEt

π-BuLI

^QEt

Et O,0°C 2

χ

γ

Η

HF C^SiR 10 2

3

Figure 12. Horner-Emmons reaction of (3)


387 Table VI. Horner-Emmons reaction of (3)


Entry 1 2 3 4 5 6

3 3a 3b 3c 3a 3b 3c

Time (h) 1 4 1 1 1 1

X C(0)OEt C(0)OEt C(0)OEt CN CN CN

Yield (%) 10a (61) 10b (52) 10c (59) lOd (76) 10e(59) 10f(42)

E/Z 99/1 99/1 99/1 78/22 99/1 99/1

Reaction of (3) with the phosphonate anion, generated by deprotonation of either triethyl phosphonoacetate or diethyl (cyanomethyl)phosphonate, in diethyl ether at 0 °C gave only the normal Horner-Emmons product (10) with no isomerized product detected. These results are in agreement with those obtained with triphenylphosphonium benzylide, another stabilized ylide. The reaction of difluoroacetyltriisopropylsilane (3b) with triethyl phosphonoacetate (Table VI, entry 2) required longer reaction times than compounds (3a) and (3c), principally as a consequence of steric obstruction of the carbonyl carbon by the alkyl silane. With only one exception, reaction of (3a) with diethyl (cyanomethyl)phosphonate (Table VI, entry 4), the reaction was highly stereoselective as indication by the observation of only one vinyl proton around δ 6 ppm in *H NMR spectrum and a singlefluorineresonance at δ -110 ppm in F NMR. Extensive studies to determine an absolute stereochemistry of the product (10) by both NMR spectroscopy and single crystal X-ray diffraction studies revealed the absolute stereochemistry as (£). The stereoselective formation of the (£)-isomer can be rationalized by the steric influences observed in the transition state model shown in Figure 13. The oxyanion and phosphonate have to occupy a synperiplanar relationship for synelimination. As steric congestion between silyl group and X (CN and C(O)OEt) in transition state [IV] is greater than between the silyl group and hydrogen in [III] path a is favored leading to the selective formation of the (E)-isomer. 19

F>(0)(OEt)

P(OKOEt)

2

Η

\X

-

2

Η

R Sr^CF H 3

path a favored

HF C^SiR

2

2

X = C(0)OEt, CN

R sr^CF H 3

E-isomer major

2

3

pathb disfavored

R SK^CF H 3

2

Z-isomer minor

Figure 25. Transition state model for rational of stereoselectivity


388


Reaction of mono- (4) and difluoroacetyltrialkylsilanes (3) with sulfur ylides In reactions of mono- (4) and difluroacetyltrialkylsilanes (3) with sulfur ylides (Figure 14), the least bulky silyl derivative, difluoroacetyltriethylsilane (3a), reactions with dimethylsulfonium methylide under various reaction conditions produced complexfluorinatedmixtures. On the other hand, reactions with dimethylsulfoxonium methylide, in THF at 0 °C, cleanly formed a single fluorinated product. Dimethylsulfoxonium methylide reacted with all fluorinated acylsilanes (3 and 4) examined to give exclusively the enoxysilane products (9 and 11) in good yields (Table VII). The rearrangement was insensitive to either the steric demand of silyl group or the extent offluorinationof α-carbon. The low isolated yield of compound (11a) may be a consequence of the volatility of the compound. Unfortunately, monofluoroacetyltriethylsilane (4a) did not undergo reaction in a manner that lead to facile isolation of the product. u Ρ A i R H F. C SiH n

3

n

+

H C=S(0)(CHa) 2

2

3

— * >=< THF,0°C H CF . H 9:n = 1 11:n = 2 3

n

n

Figure 14. Reaction offluorinatedacylsilanes (3) and (4) with sulfur ylides Reaction pathways for the formation of alkenes and enoxysilanes are depicted in Figure 15. Addition of the ylide to the fluorinated acylsilane would result in the formation of intermediate [V]. In cases where the ylides were stabilized by either resonance or the electron withdrawing effect of substituents(Y), such as phenyl (Table V, entry 3), carbonyl (Table VI, entries 13), or cyano groups (Table VI, entries 4-6), reaction path b is favored forming alkenes. On the other hand, reaction of ylides with substituents (Y) with no

Table VIL Reaction offluorinated acylsilanes (3) and (4) with sulfur ylides Yield (%) sm3 SiEt 9a (31) 9d (70) Si'Pr 9b (84) Si'BuPh lib (69) SiT>r 11c (67) Si'BuPh Source: Reproduced with permissionfromJ. Fluorine Chem. 2002,117,207. Copyright 2002. Entry 1 2 3 4 5

η 1 1 1 2 2

3

3

2

3

2

substituents (Y) with no stabilizing influence, underwent Brook réarrangeaient to give the enoxysilanes (path a) (Table VII). Moreover, the effect of silicon


389 substituents on the reaction pathways was clear. Reaction with a more electrophilic silyl group favored reaction path a and the enoxysilane major product (Table V, entry 2), whereas, reaction with less electrophilic silyl group preferred path b resulting in formation of the alkene (Table V, entry 1). ΓθΧί - R Si J J

ο

Ο

H F . cAsiR n

3 n

+ 3

Y H = X

R St 3

I

HnFa-nC

X

H

nP3-n

C

R SiO 3

Η

3

Η >=

Synthesis and Utility of Fluorinated Acylsilanes - ACS Symposium

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