Diastereoselective Syntheses of (E)-α-Trialkylsilyl α,β-Unsaturated Esters, α-Silane-Substituted Conjugated Silyl Ketene Acetals, and α,γ-Substituted Allylsilanes

Article abstract of DOI:10.1021/acs.joc.8b01209

The vicinal functionalization of propiolate esters via a catalytic carbocupration/silicon group migration sequence has been further investigated to include the syntheses of a wide variety of β-alkyl- and β-aryl-substituted (E)-α-silyl α,β-unsaturated esters. The ester substrates were transformed into their β, γ-unsaturated isomers by means of an LDA-mediated γ-deprotonation, extended silyl ketene acetal formation, and final α-protonation sequence. The silyl ketene acetal intermediates were also isolated, and their stereochemistries were established by NOE. The isolation of the intermediate extended silyl ketene acetals afforded further understanding of the lithium-extended dienolate structure and furnished additional support for Snieckus's proposed cyclic eight-membered transition state in the deprotonation of (Z)-α,β-unsaturated carbonyls with metallodialkylamides.

Full text of DOI:10.1021/acs.joc.8b01209

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Article
Diastereoselective Syntheses of (E)-#-Trialkylsilyl-#,#-
Unsaturated Esters, #-Silane Substituted Conjugated
Silyl Ketene Acetals, and #,#-Substituted Allyl Silanes
David A. Johnson, Amanda J. Mueller Hendrix, and Michael Paul Jennings
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01209 • Publication Date (Web): 25 Jul 2018
Downloaded from http://pubs.acs.org on July 26, 2018
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The Journal of Organic Chemistry
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Diastereoselective Syntheses of (E)ꢀαꢀTrialkylsilylꢀα,βꢀ
Unsaturated Esters, αꢀSilane Substituted Conjugated
Silyl Ketene Acetals, and α,γꢀSubstituted Allyl Silanes
David A. Johnson, Amanda J. Mueller Hendrix, and Michael P. Jennings*
Department of Chemistry, 250 Hackberry Lane, The University of Alabama, Tuscaloosa, AL 35487ꢀ
0336
jenningm@ua.edu
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
ABSTRACT:
The vicinal functionalization of propiolate esters via a catalytic carbocuprationꢀsilicon group
migration sequence has been further investigated to include the syntheses of a wide variety of βꢀalkyl
and aryl substituted (E)ꢀαꢀsilylꢀα,βꢀunsaturated esters. The ester substrates were transformed into their
β,γꢀunsaturated isomers by means of an LDA mediated γꢀdeprotonation, extended silyl ketene acetal
formation, and final αꢀprotonation sequence. The silyl ketene acetal intermediates were also isolated and
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their stereochemistries were established by nOe. The isolation of the intermediate extended silyl ketene
acetals afforded further understanding of the lithium extended dienolate structure and furnished
additional support for Snieckus’ proposed cyclic eightꢀmembered transition state in the deprotonation of
(Z)ꢀα,βꢀunsaturated carbonyls with metalloꢀdialkylamides.
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INTRODUCTION:
The application of siliconꢀbased reagents in organic synthesis has been well documented for more than
60 years.1 More specifically, a couple subgroups of organosilanes have received a majority of the
attention of synthetic chemists.
CuI 2LiCl
2 RMgX
MgXI, 2 LiCl
O
R2Cu- MgX+
OEt
RMgX
H
R
O
R = aryl, alkyl
-
MgX+ Cu
RCu
OEt
R
TMSO
OEt
TMSOTf
+
MgXOTf
R
H
O
R
OH
O
R'CHO
TiCl4
TFA
OEt
R'
OEt
OEt
TMSO
R
OEt
H
R
O
O
Me3Si
NH4Cl
OEt
R
R
Figure 1. TMSꢀallenolate formation via catalytic carbocupration of ethyl propiolate (1a)
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Both allylꢀand vinyl silanes have been utilized in a variety of such synthetic strategies ranging from
broadly defined HosomiꢀSakurai reactions to Pdꢀcatalyzed Hiyama crossꢀcouplings.2,3 In addition, silyl
ketene acetals, enol ethers, oxyallenes, and allenolates have been shown to be exceedingly useful
organic synthons extending from Mukaiyamaꢀtype aldol reactions, DielsꢀAlder cyclizations, and αꢀ
acylvinyl anion equivalents.4ꢀ6 Due to the frequent usage of such reagents, the development of methods
that provide stereodefined organosilanes remains a significant area of research.7,8 Coupled with our
interest in the aforementioned silane reagents for target based organic synthesis, we have been
concomitantly involved in developing a catalytic carbocupration of propiolate electrophilic substrates
utilizing Kharasch reagents combined with further manipulation of the expected TMSꢀallenolate
intermediate.9,10 Our general hypothesis for the catalytic cycle is detailed in Figure 1. Thus, the
addition of substoichiometric amounts (5ꢀ15 mol%) of CuI•2LiCl and 2 equiv. of Grignard reagent (aryl
and/or alkyl) with respect to the electrophilic substrate should allow for the formation of the in-situ
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o
formed Kharasch Reagent.11 An ensuing synꢀcarbocupration at low temp. (ꢀ78 C) of ethyl propiolate
(1a) with the diaryl(or dialkyl) magnesiocuprate should afford the moderately stable stereodefined vinyl
cuprate. In order to complete the turnover of the Cuꢀcatalyst, the vinyl cuprate would then be
transformed into the TMS allenolate, via addition of TMSOTf, coupled with a simultaneous liberation
of the organocuprate.12 Seemingly, the byꢀproduct aryl(or alkyl) cuprate would then be reꢀtransformed
into the reactive diaryl(or dialkyl) magnesiocuprate by means of RMgX addition and, in turn, complete
the Cu(I) catalytic cycle while providing the intermediate TMS allenolate product which could be
manipulated in situ into other products. In order for the catalytic cycle to be feasible, a couple of
noteworthy conditions must be met. The first is that the Cu(I) catalyst turnover must be faster than any
side reactions that the Grignard reagent might undergo (i.e. nucleophilic addition to the ester
functionality, deprotonation of the acetylenic CꢀH bond of 1a, or addition to TMSOTf). The second
condition centers on the stability of the intermediate TMS allenolate product under the reaction
conditions. We have observed that both the Cu(I) turnover is very rapid leading to minimal side
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reactions with excess Grignard reagent. In addition, the TMS allenolate is stable under the reaction
conditions and can be further manipulated into other final products, vide infra.
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With these thoughts in mind, we have recently described the divergent synthesis of both E and
Zꢀα,βꢀunsaturated esters by means of the above hypothesized catalytic carbocupration reaction process.
Interestingly, the diastereoselectivity deviates from a presumed common TMS allenolate contingent on
specific reaction conditions.13 In addition, we extended the scope of utilizing the TMS allenolate as a
nucleophile by establishing a vicinal functionalization of propiolate esters by means of a catalytic
carbocuprationꢀMukaiyama aldol reaction protocol.14 During this sequence, a tautomerization was
detected of the TMS allenolate intermediate into a stereodefined αꢀTMSꢀα,βꢀunsaturated ester upon the
addition of excess TMSOTf.15 Equipped with this intriguing silyl group migration, we elected to
further explore the reaction scope and limitations. Our complete results with respect to the synthesis of
a variety of αꢀsilylꢀα,βꢀunsaturated esters and their further transformations into stereodefined
allylsilanes and silyl ketene acetals are reported herein.16
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RESULTS AND DISCUSSION
Synthesis of vinyl silanes. Before embarking on the synthetic utility of the mentioned αꢀTMSꢀα,βꢀ
unsaturated esters as precursors to more complex allyl silanes and silyl ketene acetals, a few key
questions with respect to the catalytic carbocupration/silyl migration observation remained. The
catalytic carbocupration (5 mol% CuI•2LiCl) of ethyl propiolate (1a) and PhMgBr (1.2 equiv) coupled
with TMSOTf (1.3 equiv) afforded a 43% yield of the desired vinyl silane 2 with a d.r. of >20:1 for the
E isomer.15 Increasing the amount of TMSOTf from 1.3→3.3 equiv. provided better yields (86% and
92%) of vinyl silane 2, while preserving the d.r. of >20:1. Moreover, portionwise addition of TMSOTf
did not have a significant influence on the yield of 2 (see table 1, entries 4 and 5) or the
diastereoselectivity as delineated in Table 1.
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Table 1. Vicinal functionalization of 1a via a catalytic carbocuprationꢀsilicon group migration
sequence with various silane promoters.
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entry
R3SiX Equiv.
R3SiX
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSCl
TMSBr
TMSI
Yield%a
43c
86
E/Zb
1
2
1.3
2.3
>20/1
>20/1
>20/1
>20/1
>20/1
>20/1
>20/1
>20/1
>20/1
>20/1
3
3.3
92
4
1.3 then 1
1.3 then 2
3.3
72c
5
90
6
67c
80
7
3.3
8
3.3
89
9
3.3
TESOTf
TESCl
88
10
3.3
32c
(a) purified, isolated yield of vinyl silane. (b) E/Z ratio determined by 1H NMR (360 or 500 MHz) from
the crude reaction mixture. (c) remaining mass balance was the α,βꢀunsaturated ester from the proton
quench of the TMS allenolate or decomposed material.
In addition, the TMS halide Lewis acids ranging in acidity from TMSCl→TMSI (3.3 equiv.)
provided yields ranging from 67 to 89% for product 2. Furthermore, catalytic carbocupration exploiting
both TESCl or TESOTf afforded assorted results with respect to the TES group migration and
ultimately to the final product vinyl silane 2. The yields of the αꢀTESꢀα,βꢀunsaturated ester 3 varied
from 32% to 88%, however with mutually identical levels of diastereoselectivity (>20:1).
Unfortunately, other silane halides or triflates (i.e. TBSOTf and TBSCl) furnished no corresponding
vinyl silane product and returned mainly decomposed starting material 1a.
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Given the synthetic value of αꢀtrialkylsilylꢀα,βꢀunsaturated ester products, we were optimistic
for a general stereoselective synthetic process, as they have evaded organic chemists.17 With the scope
somewhat defined in Table 1, additional exploration of the above mentioned reaction with a series of
aromatic Grignard reagents coupled with esters 1a, 1b, and 1c was undertaken. The catalytic
carbocupration/TMSꢀtautomerization of 1a readily progressed with 5 mol% of the CuI•2LiCl catalyst
and TMSOTf (3.3 equiv.) with a variety of steric and electronic diverse aromatic Grignard reagents (1.2
equiv) to furnish compounds 4-7 in virtually identical high yields (88ꢀ92%) as highlighted in Table 2.
Furthermore, all of the βꢀaromaticꢀαꢀTMSꢀα,βꢀunsaturated esters (4-7) were isolated as a single
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stereoisomer, >20:1 for the E diastereomer.
In addition, the catalytic carbocuprationꢀTMS
tautomerization of methyl propiolate (1b) with PhMgBr furnished the αꢀTMSꢀβꢀphenylꢀα,βꢀ
unsaturated methyl ester 8 in 90% yield as a single diastereomer under identical conditions to that of
1a. Likewise, we subsequently investigated ethyl 2ꢀbutynoate (1c) as a more sterically diverse
electrophilic coupling partner under the above noted reaction conditions with PhMgBr. Pleasantly, the
catalytic carbocupration of 1c under the above described reaction conditions afforded the presumed
initial TMS allenolate intermediate and ensuing tautomerization provided the tetrasusbtituted silyl ester
9 in 85 % yield as a single diastereomer (>20:1 for the Eꢀisomer).18 Unfortunately, both alkenyl and
alkynyl Grignard reagents were not compatible under reaction conditions and afforded only
decomposed starting material.
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Table 2. Vicinal functionalization of 1a, 1b, and 1c via a catalytic carbocuprationꢀsilicon group
migration sequence with various aryl Grignard reagents and R3SiOTf.a,b
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O
O
OR1
R3SiO
R
OR1
R2
R3Si
-78 oC to rt
CuI 2LiCl (5 mol %)
R3SiOTf, R2MgBr
OR1
R
R2
9
R
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2-9
1a: R = H, R1 = Et
1b: R = H, R1 = Me
1c: R = Me, R1 = Et
product
yield, (E/Z)
Grignard
reagent
product
yield, (E/Z)
Grignard
reagent
Me
O
O
MgBr
MgBr
Me3Si
Me3Si
OEt
OEt
Me
2: 92% (E/Z > 20/1)
4: 88% (E/Z > 20/1)
O
O
MgBr
MgBr
Et3Si
OEt
Me3Si
OEt
3: 83% (E/Z > 20/1)
5: 92% (E/Z > 20/1)
O
O
MgBr
MgBr
Me3Si
OEt
Me3Si
OMe
MeO
MgBr
MgBr
OMe
6: 88% (E/Z > 20/1)
8: 90% (E/Z > 20/1)
O
O
Me3Si
Me3Si
OEt
OEt
MeO
OMe
7: 90% (E/Z > 20/1)
9: 85% (E/Z > 20/1)
(a) E/Z ratio determined by 1H NMR (360 or 500 MHz) from the crude reaction mixture. (b) yields are
of the isolated, pure compounds.
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Building on the successful catalytic carbocupration/TMSꢀtautomerization of 1a with aromatic
Grignard reagents as noted in Table 2, we looked to expand the reaction scope by investigating aliphatic
Grignard reagents under similar reaction conditions. Initially, the addition of MeMgBr to 1a in the
presence of 5 mol% of the CuI•2LiCl catalyst and 3.3 equiv of TMSOTf afforded the corresponding
product 10 in ~50% yield with a diastereoselectivity of >20:1 for the E isomer. Similarly, EtMgBr
mirrored the reactivity and outcome to that of the methyl derived Grignard reagent with 1a and
provided synthon 12 in 51% yield as a single E isomer as well. Based on these two results, it was
hypothesized that the Cu(I) turnover was more sluggish with respect to the less reactive aliphatic
Grignard regents to that of the aromatic ones. Thus, we increased the catalyst loading from 5 to 15
mol% while maintaining the 3.3 equiv of TMSOTf and observed an increase in yield from ~50% to
75% for both αꢀTMSꢀα,βꢀunsaturated esters 10 and 12 as delineated in Table 3. With the updated
reaction conditions, we further investigated a diverse series of aliphatic Grignard reagents. Much to our
delight, catalytic carbocupartiation/silyl migration utilizing 15 mol% of CuI•2LiCl of 1a with iPrMgCl,
Me3SiCH2MgCl, benzylMgCl, octylMgBr (1.3 equiv. for all Grignard reagents) and TMSOTf (3.3
equiv.) readily provided the corresponding αꢀTMSꢀα,βꢀunsaturated esters 14, 15, 17, and 18 with yields
ranging from 70ꢀ90% with diastereoselectivities of >20:1 strongly favoring the E isomer in all
examples. The lowest isolated yield of 70% was observed for benzyl ester 17 and due to the Grignard
reagent catalyzing a SET polymerization of the THF solvent, thus making isolation/purification of the
product more problematic. Similar to ester 3 from Table 1, silyl migration/tautomerization utilizing
TESOTf in place of TMSOTf was also successful with MeMgBr, EtMgBr, and Me3SiCH2MgCl upon
catalytic carbocupration of 1a to afford αꢀTESꢀα,βꢀunsaturated esters 11, 13, and 16 with yields
ranging from 33ꢀ75% with diastereoselectivities of >20:1 strongly favoring the E isomer in all
examples.
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Table 3. Vicinal functionalization of 1a and 1b via a catalytic carbocuprationꢀsilicon group migration
sequence with various aliphatic Grignard reagents and R3SiOTf.a,b
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3
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8
O
O
OEt
R3SiO
R
OEt
R1
R3Si
-78 oC to rt
CuI 2LiCl (15 mol %)
R3SiOTf, R1MgX
OEt
R
R1
9
R
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12
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10-19
1a: R = H
1b: R = Me
product
yield, (E/Z)
Grignard
reagent
product
yield, (E/Z)
Grignard
reagent
O
O
Me3Si
Me3Si
Me3Si
MgCl
MeMgBr
OEt
OEt
SiMe3
10: 75% (E/Z > 20/1)
15: 90% (E/Z > 20/1)
O
O
Et3Si
OEt
Et3Si
OEt
MeMgBr
EtMgBr
Me3Si
MgCl
SiMe3
11: 33% (E/Z > 20/1)
16: 75% (E/Z > 20/1)
O
O
Me3Si
OEt
Me3Si
Ph
MgCl
OEt
Ph
12: 75% (E/Z > 20/1)
17: 70% (E/Z > 20/1)
O
O
Et3Si
OEt
Me3Si
OEt
EtMgBr
MgBr
5
13: 44% (E/Z > 20/1)
18: 88% (E/Z > 20/1)
O
O
Me3Si
OEt
MgBr
Me3Si
OEt
Me3Si
MgCl
SiMe3
14: 82% (E/Z > 20/1)
19: 33% (E/Z > 20/1)
(a) E/Z ratio determined by 1H NMR (360 or 500 MHz) from the crude reaction mixture. (b) yields are
of the isolated, pure compounds.
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1
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8
9
It is worth noting that yields are lower across the board (i.e. 2 vs 3, 10 vs 11, 12 vs 13, and 15 vs 16)
when TESOTf is used in place of TMSOTf. Lastly, catalytic carbocupration/silyl migration of 1b with
Me3SiCH2MgCl under the standard reactions conditions did proceed, but unfortunately, only provided a
33% isolated yield of the tetrasubstituted αꢀTMSꢀα,βꢀunsaturated ester 19 with a >20:1
diastereoselectivity favoring the E isomer. An assessment of Tables 2 and 3 have revealed that both
aromatic and aliphatic Grignard regents readily undergo catalytic carbocupration/silyl group migration
(5ꢀ15 mol % of CuI•2LiCl and 3.3 equiv of R3SiOTf) of 1a to afford αꢀTMS(or TES)ꢀα,βꢀunsaturated
ester products in modest to outstanding yields coupled with excellent levels of diastereocontrol over the
olefin geometry. Generally, the aromatic Grignard reagents led to higher yields with a slightly lower
catalyst loading.
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Figure 2. Key nOe enhancements of arylꢀ and alkyl vinyl silanes for assigning olefin geometry
As described in Figure 2, the geometry of vinyl silane products 2, 9, 14, and 19 were determined by
means of 1D nOe spectroscopy. As shown above, the strong couplet from the protons resident on the
TMS moieties and the βꢀvinylic positions afforded convincing evidence for the assigned Eꢀolefin
1
geometry. Furthermore, the H NMR chemical shifts of 2-19 emulate that of structurally comparable
silane products as conveyed by Zweifel.16b Based on the noted nOe results for 2, 9, 14, and 19, the
stereochemistry of the remaining silane products, as described in tables 2 and 3, were designated as the
Eꢀisomer.
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Kinetic deconjugation of α-TMS-(E)-α,β-unsaturated esters. Zweifel and coꢀworkers previously
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8
9
described a four step synthetic process, including deconjugation of αꢀTMSꢀ(Z)ꢀα,βꢀunsaturated esters,
to obtain three higher order allylic silanes with the inconvenient dependency of HMPA as a coꢀ
solvent.16b Likewise, they also reported a five step reaction sequence, devoid of HMPA, which
included isomerization of olefin stereochemistry (from Z→E) followed by deconjugation of αꢀTMSꢀ
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(E)ꢀα,βꢀunsaturated esters, to obtain two stereochemically pure conjugated silyl ketene acetal products.
However, the enolate olefin geometries were not fully established. In addition, no further reactions of
the isolated silyl ketenes acetals were investigated. With our new method for the direct oneꢀpot
selective formation of αꢀTMSꢀ(E)ꢀα,βꢀunsaturated esters, we chose to investigate the further scope and
limitations of the deconjugation of the afore mentioned esters with the hopes of building a diverse set
functionalized allyl and crotylꢀtype silane reagents over a twoꢀstep process, while eliminating the
reliance on HMPA. Initially, we elected to examine the LDAꢀmediated deprotonation of ester 17
followed by direct protonation of the Liꢀextended enolate intermediate with the anticipation of forming
allyl silane 20. Ester 17 was selected due to the fact that the anticipated product (20) would most
likely contain a labile carbonꢀsilicon bond due to the ease of forming a further extended enolate upon
anion mediated desilylation, thus potentially making the isolation of 20 somewhat challenging.
As described in Table 4, LDA (1.1 equiv) mediated kinetic deprotonation (ꢀ78 oC in THF) of 17
at the γꢀposition seemingly formed the extended Liꢀenolate and subsequent protonation with 1M HCl
1
provided a product ratio of 21:42:37 for compounds 17, 20, and 21 as determined by H NMR in a
combined 85% yield of the crude material as further purification was not required. A few key points
merit further discussion from entry 1. The esters 20 and 21 were isolated with an excellent dr of >20:1
for the E isomer of the newly formed β,γꢀolefin as determined by 1H NMR and were a consequence of
αꢀprotonation of the extended enolate. Secondly, desilylation of the αꢀTMS group occurred during the
workꢀup, post protonation, providing a significant amount of ester 21 as we initially surmised might
transpire. Lastly, a significant amount of starting material ester 17 was recovered and attributed to
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either incomplete deprotonation, γꢀprotonation of the extended enolate, or possible olefin isomerization
of 20→17.
1
2
3
4
5
6
7
8
Table 4. LDA mediated deprotonation/Brönsted acid reprotonation of αꢀTMSꢀα,βꢀunsaturated ester 17
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Entry
H+ source
Temp., oC
Product Ratio (%) Combined Yield %b
17:20:21a
1
2
HCl (1M)
HCl (1M)
ꢀ78
ꢀ40
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
21:42:37
6:57:37
0:61:39
4:16:80
9:0:91
85
85
90
90
95
80
90
90
80
60
80
80
92
3
HCl (1M)
4
TFA (2 eq.)
5
AcOH (2 eq.)
CSA (2 eq.)
6
4:22:74
0:0:100
0:9:91
7
PTSA (2 eq.)
37% HCl (2 eq.)
H2SO4 (2 eq.)
H3PO4 (2 eq.)
48% HBF4 (2 eq.)
NH4Cl (sat.)
HBr (1.4 M)
8
9
9:0:91
10
11
12
13
0:0:100
0:0:100
0:0:100
11:44:45
(a) product ratio determined by 1H NMR (360 or 500 MHz) from the crude reaction mixture. (b) crude
combined yield of 17, 20, and 21 as further purification was not required.
We subsequently varied the protonation (1M HCl) temperatures from ꢀ78 C to ꢀ40 oC then further to ꢀ
o
o
20 C and observed significantly less product 17 (6% at ꢀ40 and ~0% at ꢀ20) while slightly improving
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The Journal of Organic Chemistry
the ratio of 20:21 (up to 61:39) while maintaining ~85ꢀ90% overall yield (entries 2 and 3). It should be
noted that only the E alkene isomer was detected in esters 20 and 21. We were pleased that complete
deprotonation of 17 had taken place and a large majority of αꢀprotonation products (20 and 21) were
identified, while being able to rule out olefin isomerization of 20→17. While holding the protonation
1
2
3
4
5
6
7
8
9
o
temperature at ꢀ20 C, a series of Brönsted acids were examined and provided mixed results. Most all
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
of the acid reagents provided deconjugated esters 20 and/or 21 (>20:1 for the E isomer) in 60ꢀ90%
yields with little to no starting material 17. Unfortunately, the major product (75ꢀ100%) in entries 4ꢀ12
was the desilylated ester 21, thus highlighting the lability of the αꢀTMS moiety resident in ester 20
during a direct protonation of the lithium extended enolate.
Unfortunately, direct protonation of the Liꢀextended enolate afforded a large majority of the
desilyled ester product 21 due to a combination of the strongly basic/nucleophilic nature of the
conjugate bases and labile siliconꢀcarbon bond αꢀto the carbonyl moiety. In an attempt to circumvent
these issues, we envisaged trapping the extended lithium enolate with TMSCl as a silyl ketene acetal
consequently affording a softer and more regioselective mechanism for protonation, thus leading to the
delivery of ester 20 in lieu of 21.19
As shown in Table 5, LDA (1.1 equiv) mediated kinetic
deprotonation (ꢀ78 oC in THF) of 17 at the γꢀposition followed by subsequent trapping of the presumed
extended enolate with TMSCl afforded the intermediate silyl ketene acetal. Ensuing protonation at ꢀ20
oC with NH4Cl furnished a product ratio of 4:9:87 for compounds 17, 20, and 21 as determined by 1H
NMR in a combined 60% yield of the crude material.
Table 5. LDA mediated deprotonation/silyl ketene formation/Brönsted acid protonation of αꢀTMSꢀα,βꢀ
unsaturated ester 17.
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1
2
3
4
5
6
7
8
9
Entry
H+ source
Temp., oC Product Ratio (%) Combined Yield %b
17:20:21a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
2
NH4Cl (sat.)
TFA (2 eq.)
HCl (1.4 M)
HCl (1.4 M)c
TFA (2 eq.)c
HCl (1.4 M)d
HCl (1.4 M)e
HCl (1.4 M)
HCl (1.4 M)f
HBr (1.4 M)e
HI (1.4 M)e
ꢀ20
ꢀ20
4:9:87
0:65:35
13:37:50
8:77:15
33:51:16
27:61:12
8:80:12
9:0:91
60
90
80
85
80
85
90
58
88
86
85
90
3
ꢀ20
4
ꢀ78
5
ꢀ78
6
ꢀ78
7
ꢀ78
8
ꢀ78→rt
ꢀ78
9
8:77:15
4:83:13
65:32:3
8:77:15
10
11
12
ꢀ78
ꢀ78
HBr (1.4 M)g
ꢀ78
(a) product ratio determined by 1H NMR (360 or 500 MHz) from the crude reaction mixture. (b) crude
combined yield of 17, 20, and 21 as further purification was not required. (c) reaction stirred for 15
min. post addition of proton source (d) reverse quench (e) reaction stirred for 2 min. post addition of
proton source (f) 1.5 equiv of LDA used (g) TMSOTf was used to form the silyl ketene acetal in place
of TMSCl.
As noted before in Table 5, the olefin stereochemistry of both 20 and 21 were >20:1 for the Eꢀisomer
Exchanging the proton source from NH4Cl to TFA provided for the first time a majority of the desired
deconjugated ester 20 (~2:1 ratio) in a 90% yield under the formerly described reaction conditions at ꢀ
o
o
20 C. As shown in entry 5, lowering the temperature from ꢀ20 to ꢀ78 C for the TFA quench of the
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intermediate silyl ketene acetal did improve the product 20:21 ratio to roughly 3:1, however a
significant of the γꢀprotonated product (i.e. ester 17) was isolated as well. Much to our delight,
utilizing HCl or HBr (entries 4, 7, 9, 10 and 12) as the proton source, while maintaining the reaction
1
2
3
4
5
6
7
8
o
and quench temperature at ꢀ78 C, provided a ~5:1 ratios of the αꢀTMS ester 20 to the desilylated
9
analogue 21 in 85ꢀ90% yields while minimizing ester 17 formation via a γꢀprotonation (<10%).
Overall, lower temperatures allowed for higher αꢀregioselecivity protonations and lower amounts of
desilylation with HCl but higher γꢀregioselectivity with TFA. A reverse quench with HCl resulted in
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
o
higher γꢀregioselectivity (entry 6), while warming the protonation from ꢀ78 C to rt afforded no desired
silylated ester 20 (entry 8).
Based on the observation that protonation of the silyl ketene acetal derived from ester 17 with
HCl or HBr at ꢀ78 oC in THF provided a maximum product ratio (~5:1) for the silylated ester 20 in lieu
of product 21, we elected to investigate the effect of nonꢀpolar solvents and sterically diverse Liꢀamide
bases on final product ratios of 20:21. An initial examination of solvent effects revealed little variance
between Et2O and THF with repect to αꢀ versus γꢀprotonation, however 5 fold greater levels of γꢀ
protonation was obseved with MTBE leading to ester 17 (entry 3) as delineated in Table 6.
Interestingly, hydrocarbon solvents, such as toluene or pentane, afforded the highest levels of
regioselectivity for the αꢀprotonated product and nearly suppressed desilylation (entries 4 and 5) while
providing yields ranging from 89ꢀ95% for ester 20.
Table 6. LDA mediated deprotonation/silyl ketene formation/HBr protonation of αꢀTMSꢀα,βꢀ
unsaturated ester 17.
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1
2
3
4
5
6
7
8
9
Entry
Solvent
Liꢀamide base Product Ratio (%) Combined Yield %b
17:20:21a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
2
3
4
5
6
7
8
THF
LDA
LDA
4:83:13
4:80:16
19:74:7
4:87:9
86
62
90
95
89
90
90
90
Et2O
MTBE
pentane
toluene
toluene
toluene
toluene
LDA
LDA
LDA
4:91:5
LiCA
0:87:13
71:21:7
77:23:0
LiTMP
LiHMDS
(a) product ratio determined by 1H NMR (360 or 500 MHz) from the crude reaction mixture. (b) crude
combined yield of 17, 20, and 21 as further purification was not required.
An ensuing examination of a few Liꢀamide based revealed that LDA afforded the highest αꢀ
regioselective pronation, however LiCA afforded
a
slightly greater amount of the
deconjugated/desilylated product 21. Finally, both LiHMDS and LiTMP appeared to be either
insufficient to appreciably deprotonate ester 17 under standard reaction conditions and/or promoted a
significant amount of γꢀprotonation, thus leading to reꢀisolation of a substantial amount (71ꢀ77%) of
starting material (entries 7 and 8).
Table 7. LDA mediated deprotonation/silyl ketene formation/protonation of αꢀTMSꢀα,βꢀunsaturated
ester 10.
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1
2
3
4
5
6
7
8
9
Entry
Solvent
Temp., oC
H+ source/workup
Product Ratio (%) Yield %b
of H+ addn.
22:10a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
1
2
3
4
pentane
THF
ꢀ78
ꢀ78
0
HBr (1.4 M)
HBr (1.4 M)
HCl (1.4 M)
2:1
2:1
80
81
95
80
THF
2:1
THF
0
NH4Cl, pentane, H2O
extraction, then HCl (1.4 M)
15:1
5
pentane
0
NH4Cl, pentane, H2O
extraction, then HCl (1.4 M)
2:1
62
(a) product ratio determined by 1H NMR (360 or 500 MHz) from the crude reaction mixture. (b) crude
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
combined yield of 22 and 10 as further purification was not required.
Based on the standardized reaction condition for the deconjugation of ester 17, we sought to further
investigate the identical reaction process on aliphatic αꢀTMSꢀα,βꢀunsaturated esters. Thus, LDA (1.1
o
equiv) mediated kinetic deprotonation (ꢀ78 C in pentane) of 10 at the γꢀposition followed by ensuing
trapping of the presumed extended enolate with TMSCl afforded the intermediate silyl ketene acetal.
Subsequent protonation at ꢀ78 oC with HBr furnished a substandard 2:1 product ratio for compounds 22
1
and 10 as determined by H NMR in a combined 80% yield of the crude material. However, no
desilylated product was observed with ester 10 as the substrate. As described in Table 7, exchanging
the reaction solvent from pentane to THF while holding the other reaction variables constant
(equivalents, temperature, and proton source) also afforded a 2:1 ratio of the deconjugated product (22)
to that of the starting material (10) in roughly the same yield (~81%). Perplexed by these two results,
the reaction medium (THF) was warmed to 0 oC, post deprotonation at ꢀ78 oC, and quenched with HCl
to provide the identical product ratio of 2:1 with a slightly greater yield of 95%. The poor αꢀ
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protonation regioselectivities were much lower than those reported by Zweifel (although this exact
1
2
3
substrate was not investigated) for the protonation of silyl ketene acetals derived from (Z)ꢀαꢀsilylꢀα,βꢀ
4
5
6
7
8
9
unsaturated esters.16b As noted by Zweifel, their γꢀdeprotonationꢀαꢀprotonation sequence with LDA
required the use of HMPA as a coꢀsolvent. Thus, prior to protonation with 1.4M HCl, a specific
reaction workup and extraction was reported in order to remove HMPA. Intrigued by this subtle
technique, we repeated the deconjugation of 10 in THF, followed the H2O/pentane workꢀup as noted
above, and observed a significant enhancement of αꢀprotonation of the silyl ketene acetal (15:1/α
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
versus γ) with 1.4M HCl leading to the desired volatile deconjugated ester 22 in 80% yield (entry 4).
Unfortunately, the repeat of entry 4 with exclusively using pentane as the solvent accompanied by the
identical brief workꢀup process afforded a ~2:1 ratio (similar to entries 1ꢀ3) of products 22 and 10 in a
lower yield of 60%. Pleased that the brief workꢀup with pentane and H2O provided high levels of αꢀ
protonation with 1.4M HCl leading to the desired product 22, we chose to further investigate the scope
of the LDAꢀmediated deconjugation/protonation reaction sequence to include a variety of αꢀsilylatedꢀ
α,βꢀunsaturated esters.
o
As delineated in Table 8, LDA (1.1 equiv) mediated kinetic deprotonation (ꢀ78 C in THF) of
11 at the γꢀposition followed by ensuing trapping of the presumed extended enolate with TMSCl
afforded the intermediate silyl ketene acetal. Subsequent H2O/pentane workꢀup, as noted above,
followed by slow addition of 1.4 M HCl at 0 oC to the organic phase provided the desired deconjugated
ester 23 in nearly quantitative yield (~99%) with no purification required of the crude material.
Likewise, under identical reaction conditions, esters 12 and 13 readily underwent deconjugation to
afford the trimethyl and triethyl allylic silanes 24 and 25 in 80 and ~99% yields, respectively. In
addition, only the E isomer of the newly formed olefin moiety (>20:1, J = 15.2 Hz) was detected by 1H
NMR of the crude material.
Table 8. LDA mediated deprotonation/silyl ketene formation/protonation of a variety of αꢀsilylꢀα,βꢀ
unsaturated esters.
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OEt
O
O
1
2
3
4
R3Si
R3Si
R3Si
LDA, -78 oC
TMSCl
OTMS
1. NH4Cl, pentane
2. 1.4 M HCl, 0 oC
OEt
OEt
5
6
R1
10-17
R1
20, 22-28
R1
7
8
9
product
yield, (E/Z)
product
yield, (E/Z)
vinyl silane
O
vinyl silane
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
O
O
O
Me3Si
22
Me3Si
Me3Si
Me3Si
OEt
OEt
OEt
OEt
SiMe3
26
15
10
SiMe3
80%
O
99% (E/Z > 20/1)
O
O
O
O
Et3Si
OEt
Et3Si
23
Et3Si
Et3Si
OEt
OEt
OEt
OEt
OEt
SiMe3
27
11
12
16
17
14
SiMe3
99%
O
99% (E/Z > 20/1)
O
O
O
Me3Si
Me3Si
Me3Si
OEt
Me3Si
Me3Si
OEt
Ph
24
20
Ph
80% (E/Z > 20/1)
99% (E/Z > 20/1)
O
O
O
Me3Si
OEt
Et3Si
Et3Si
OEt
OEt
OEt
25
28
13
90%c
99% (E/Z > 20/1)
(a) E/Z ratio determined by 1H NMR (360 or 500 MHz) from the crude reaction mixture. (b) yields are
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
of the isolated, pure compounds. (c) deprotonation carried out at ꢀ40 oC.
As noted above, the crude esters 24 and 25 were sufficiently pure and did not require any type of further
purification. In addition, LDA mediated γꢀdeprotonation of bisꢀsilyl esters 15 and 16 provided the
corresponding silyl ketene acetal intermediates upon addition of TMSCl and an ensuing brief pentaneꢀ
H2O workup/HCl protonation furnished the vinyl silylꢀdeconjugated esters 26 and 27 in nearly
1
quantitative yields with only a single olefin isomer (>20:1, E) observed by H NMR. Much to our
delight, the current procedure also afforded the sought after TMSꢀdeconjugated product ester 20 in
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~99% as a single diastereomer post deprotonation/workꢀup/αꢀprotonation of starting material 17.
1
2
3
4
o
Lastly, the (E)ꢀαꢀTMSꢀβꢀisopropyl ester 14 readily underwent LDA deprotonation at ꢀ40 C (the
reaction was quite sluggish when carried out at ꢀ78 oC) and subsequent workꢀup/αꢀprotonation provided
the gemꢀdimethyl allyl silane ester 28 in 90% isolated yield. Interestingly, Zweifel had noted previously
that a similar Zꢀisomer (βꢀcyclohexyl versus βꢀisopropyl ester 14) variant which contained a tertiary
allylic hydrogen could not be deprotonated with LDA and HMPA.16b As noted above, no further
purification was required of the product esters 20, 22-28 and yields were consistently high at 80ꢀ99%.
Synthesis and isolation of α-silane substituted conjugated silyl ketene acetals. Zweifel and
coworkers were able to isolate two silyl ketene acetal intermediates derived from the deprotonation of
(E)ꢀαꢀtrimethylsilylꢀα,βꢀunsaturated esters in the absence of HMPA with a nonꢀaqueous workup.16b
Moreover, only one stereoisomer was detected and the enolate geometry tentatively assigned (but not
confirmed) as C1ꢀC2ꢀE, C3ꢀC4ꢀE based on a previously reported extended silyl ketene acetal. Along this
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
line, we unexpectedly isolated a 3:1 ratio, as determined by H NMR integration, of the intermediate
silyl ketene acetal and product allyl silane 28 due to an incomplete acidic hydrolysis post the standard
pentane/H2O work up starting from ester 14. Based on this observation, we chose to investigate the
possibility of isolating the extended silyl ketene intermediates prior to acidic hydrolysis with the
anticipation of confirming the enolate stereochemistry by 1D nOe.
As shown in Table 9, the deprotonation of (E)ꢀαꢀtrimethylsilylꢀα,βꢀunsaturated ester 10 with
o
LDA in THF at ꢀ78 C followed by an ensuing trapping of the pendent enolate with TMSCl afforded
the crude extended silyl ketene acetal intermediate. A subsequent quench and workꢀup with NH4Cl,
1
pentane, and H2O furnished the pure acetal 29 a single diastereomer as observed by H NMR in 93%
isolated yield. As noted above with respect to the allyl silanes in Table 8, no further purification was
required. Likewise, treatment of the triethyl silyl ester variant 11 under identical reaction and workꢀup
conditions provided the extended conjugated silyl ketene acetal 30 in 85% yield with a dr of >20:1.
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The Journal of Organic Chemistry
Table 9. LDA mediated deprotonation and isolation of extended silyl ketene acetals from a variety of
αꢀsilylꢀα,βꢀunsaturated esters.a,b
1
2
3
4
5
6
7
8
>20:1 E/Z
OEt
OLi
OEt
1
O
R3Si
R3Si
R3Si
LDA
TMSCl
NH4Cl
OSiMe3
2
3
OEt
9
4
R1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
R1
R1
>20:1 E/Z
29-34
10-15
product
yield, (E/Z)
product
yield, (E/Z)
vinyl silane
vinyl silane
O
OEt
OEt
O
Me3Si
Me3Si
Me3Si
29
Me3Si
OEt
OEt
OSiMe3
OSiMe3
OEt
32
12
10
11
14
93% (C1-C2: E/Z > 20/1)
91% (C1-C2: E/Z > 20/1)
O
O
OEt
OEt
O
O
Et3Si
Et3Si
Et3Si
Et3Si
OSiMe3
OSiMe3
OEt
OEt
30
33
13
85% (C1-C2: E/Z > 20/1)
89% (C1-C2: E/Z > 20/1)
OEt
OEt
Me3Si
Me3Si
Me3Si
Me3Si
OEt
OSiMe3
OSiMe3
SiMe3
15
34
31
SiMe3
91% (C1-C2: E/Z > 20/1)
99% (C1-C2: E/Z > 20/1)
OEt
OEt
Me3Si
32
Me3Si
OSiMe3
OSiMe3
H
1D nOe enhancements
H
H
29
CH3
1
(a) C1ꢀC2 and C3ꢀC4 olefin E/Z ratios determined by H NMR (360 or 500 MHz) from the crude
reaction mixture. (b) yields are of the isolated, pure compounds.
o
Additionally, deprotonation of ester 14 with LDA at ꢀ40 C followed by addition of TMSCl afforded
the silyl ketene acetal 31 in quantitative yield while maintaining the >20:1 E/Z ratio of the newly
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formed tetra substituted alkene moiety after the standard workꢀup process. Similar to esters 10 and 11,
1
2
3
o
deprotonation of esters 12, 13, and 15 with LDA at ꢀ78 C furnished the extended dienolate
4
5
6
7
8
9
intermediates followed by an ensuing addition of TMSCl provided silyl ketene acetals 32, 33, and 34 in
very good yields ranging from 89ꢀ91% while affording very high levels of dr (>20:1) for both the C1ꢀC2
and C3ꢀC4 olefin moieties.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
As shown in Table 9, the C1ꢀC2 and C3ꢀC4 olefin geometries of silyl ketene acetal 32 were
1
determined by means of H NMR. The strong 1D nOe couplet for the C2ꢀsilane methyl groups and
ethoxy protons resident on C1 provided convincing proof for the assigned C1ꢀC2 enolate (E)ꢀolefin
geometry. Additionally, a strong 1D nOe signal for the vinylic proton on C3 and the terminal methyl
group on C4 furnished persuasive evidence (combined with a C3ꢀC4 J = 16.0 Hz) of the C3ꢀC4ꢀ(E)ꢀ
alkene stereochemical assignment. Furthermore, the C1ꢀC2 olefin geometry of silyl ketene acetal 29
was also investigated and based on the compelling nOe data, the stereochemistry of the C1ꢀC2 olefin
was assigned as the Eꢀisomer. Based on the nOe experimental results for 29 and 32, the C1ꢀC2 (and
additional C3ꢀC4, where applicable) stereochemistries of the remaining extended silyl ketene acetals 30,
31, 33, and 34 were assigned as the Eꢀisomer by analogy, thus confirming Zweifel’s previous tentative
stereochemical assignments.16b
A few key observations from Tables 7ꢀ9 merit further discussion. It has been established that
an β,γꢀunsaturated ester product is a consequence of a selective αꢀprotonation typically under kinetic
conditions of an extended enolate or silyl ketene acetal.19 The αꢀpositions of the extended silyl ketene
acetals (i.e. 29-34) derived from substrates 10ꢀ19 are more sterically hindered and less accessible than
that of the γꢀposition. However, the αꢀposition is significantly more nucleophilic based on the tetraꢀ
substitution patterns of the C1ꢀC2 carbon atoms coupled with anion stabilization by the silyl group via
negative hyperconjugation.20 Thus, the competition of steric hindrance versus electronic effects during
the process of protonation of the intermediate silyl ketene acetals was quite sensitive depending on
reaction conditions. Direct protonation of the intermediate extended silyl ketene acetals in THF at
o
either ꢀ78 or 0 C was believed to be nearly instantaneous and provided a significant amount of the
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The Journal of Organic Chemistry
thermodynamically more stable product as shown in Table 7, entries 2 and 3. It would appear, based on
the results, that the sterically more accessible γꢀcarbon site was preferred under homogenous
protonation conditions irrespective of temperature. As noted above, Zweifel and coworkers utilized an
aqueous workup prior to protonation in order to remove the HPMA coꢀsolvent.16b In actuality, the
extraction step (pentane, NH4Cl, and H2O) is critically essential to exert kinetic control over the
regioselective protonation, due to the fact that it functioned as a method of both purification and
significant dilution of the extended silyl ketene acetal. At the conclusion of the reaction prior to
protonation, the crude reaction mixture was partition between aqueous and hydrocarbon layers. Most
likely, a large majority of THF, LiCl, and iPr2NH were drawn into the aqueous layer leaving the crude,
but considerably pure, extended silyl ketene acetal with a trace amount of THF in the hydrocarbon
(pentane) layer. The removal of iPr2NH during the partition helped to clarify the truly active proton
donor (HCl versus iPr2NHꢀHCl). Moreover, upon addition of an aqueous 1.4M HCl solution to the
hydrocarbon phase, the presence of trace amounts of THF most likely operated as a phase transfer
catalyst, shuttling protons into the hydrocarbon layer. Thus, this heterogeneous process allowed the
protonations to proceed under highly dilute concentrations and proved to be quite regioselective for the
αꢀposition of the extended silyl ketene acetal intermediates leading to the observed αꢀtrialkylsilylꢀβ,γꢀ
unsaturated ester products in high yield (nearly quantitative in most examples) as delineated in Table 8.
The complexedꢀinduced proximity effect (CIPE), initially introduced by Beak and Meyers, has
been used to explain deprotonations/lithiations occurring at remote positions in relation to Lewis basic
functional groups capable of an initial coordination.21,22 Typically, a deprotonation/substitution
sequence involves an association of the organolihium or lithium amide species with the substrate to
provide the prelithiation complex followed by a subsequent remote deprotonation of an acidic
hydrogen. This in turn would furnish a new lithiated species which can further undergo an ensuing
transformation with an electrophile. The CIPE model has been cited for chemoselective deprotonations
of Zꢀα,βꢀunsaturated carbonyls, particularly the high kinetic preference for γꢀZ deprotonations over γꢀE
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
deprotonations when the βꢀposition was disubstituted.22,23 Under such kinetic conditions,
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deprotonations of Zꢀα,βꢀunsaturated carbonyls generally provide C1ꢀC2ꢀ(Z) and C3ꢀC4ꢀ(E) extended
dienolates. Thus, Snieckus proposed eight membered transitions states to help rationalize the observed
stereoselectivities for both C1ꢀC2 and C3ꢀC4 olefins.23,24
1
2
3
4
5
6
7
8
9
Based on the observed products derived from the deprotonation of (E)ꢀαꢀtrimethylsilylꢀα,βꢀ
unsaturated esters, we envisaged two possible transition states that would account for high levels of dr
for both the C1ꢀC2 and C3ꢀC4 olefins as highlighted in Figure 3. Constructed from the Snieckus model
utilizing an eight membered transition state, the initial olefin C2ꢀC3 stereochemistry of ester 12 should
facilitate a CIPE intramolecular deprotonation at the γꢀposition (C4) thus providing the C1ꢀC2ꢀ(E)ꢀ
enolate stereochemistry in both TS1 and TS2. Without the CIPE, one would most likely expect a
mixture of C1ꢀC2 enolate geometries and/or competitive Michael addition of LDA in the absence of
HMPA, which was not observed experimentally. The cyclic eightꢀmembered transition state ensures
high diastereoselectivity of the C1ꢀC2ꢀolefin. In addition, the stereochemistry of the C3ꢀC4 olefin was
established during the CIPE deprotonation. The selectivity for the C3ꢀC4 olefin can be depicted as a
competition between two transition states (TS1 and TS2) with respect to A1,3 and A1,2 strain.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
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The Journal of Organic Chemistry
Figure 3. Competing transition states during the deprotonation of ester 12 leading to stereochemically
pure extended silyl ketene acetal 32.
1
2
3
4
5
6
7
8
As shown in TS1, the methyl group resident on C4 of ester 12 would eclipse the πꢀsystem causing
significant A1,3ꢀstrain (but minimal A1,2 strain via eclipsing H atoms) during the deprotonation
leading to the C3ꢀC4ꢀ(Z) stereochemistry (which was not detected in the final product silyl ketene
acetal). However in the competing TS2, the H atom on C4 of ester 12 would eclipse the πꢀsystem
minimizing A1,3ꢀstrain during deprotonation while the methyl group would eclipse the H atom on C3
leading to A1,2 strain and thus afford the C3ꢀC4ꢀ(E) stereochemistry of the final product 32 (as
observed in a >20:1 E/Z ratio). Based on the experimental ratios of E/Z for the C1ꢀC2 and C3ꢀC4 olefin
geometries in all of the isolated silyl ketene acetals 24-30, it appears that TS2 (in lieu of TS1) must be
in operation during the CIPE γꢀdeprotonations of (E)ꢀαꢀtrimethylsilylꢀα,βꢀunsaturated esters.
CONCLUSION
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In conclusion, we have presented an expansion of the scope for the catalytic carbocupration of
alkynoates in the presence of excess trialkylsilyl triflates to include several βꢀalkyl substituted (E)ꢀαꢀ
silylꢀα,βꢀunsaturated esters. These substrates were converted to their β,γꢀunsaturated constitutional
isomers via a γꢀdeprotonationꢀαꢀprotonation sequence. Kinetic protonations with aq. HCl of the
intermediate silyl ketene acetals in a biphasic solution were required to illicit high levels of
regioselectivity. The extended silyl ketene acetal intermediates were also isolated and their
stereochemistries were confirmed by nOe to be C1ꢀC2ꢀ(E), C3ꢀC4ꢀ(E). The observed stereochemistry
provided insight into the lithium extended dienolate structure resulting from CIPE deprotonations and
afforded additional support for an eightꢀmembered transition state in the deprotonation of (Z)ꢀα,βꢀ
unsaturated carbonyls with metallo dialkylamides. Future directions of investigation will include further
utilization of both the prepared allyl silanes and extended silyl ketene acetals in target driven synthesis.
In addition, a novel approach to enantioenriched allyl silanes by means of a chiral protonation of the
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described extended silyl ketene acetal intermediates is currently ongoing. Results from these studies
will be reported in due course.
1
2
3
4
5
6
7
8
EXPERIMENTAL SECTION
9
All of the reactions were performed under Ar in flameꢀdried glassware. Anhydrous tetrahydrofuran
(THF) was obtained from a commercial source and used without purification. Copper(I) iodide (98%
purity) and lithium chloride (LiCl, 99%+, ACS) were used without any purification. The NMR spectra
were recorded with either a 360 or 500 MHz Bruker spectrometer. 1H spectra were obtained using
CDCl3 or C6D6 as the solvent with chloroform (CHCl3: δ = 7.26 ppm) or benzene (C6H6: δ = 7.16 ppm)
as the internal standard. 13C spectra were obtained using CDCl3 or C6D6 as the solvent with chloroform
(CDCl3: δ = 77.0 ppm) or benzene (C6D6: δ = 128.1 ppm) as the internal standard. Highꢀresolution
mass spectra were recorded on an EBE sector instrument using electron ionization (EI) at 70 eV.
Column chromatography was performed using 60ꢀ200 ꢀm silica gel. Analytical thin layer
chromatography was performed on silica coated glass plates with Fꢀ254 indicator. Visualization was
accomplished by UV light (254 nm) and KMnO4.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General Experimental Procedure for the TMSOTf-Promoted Catalytic Carbocupration of 1a
with aromatic Grignard Reagents: CuI (0.029 g, 0.15 mmol) and LiCl (0.013 g, 0.30 mmol) was
placed in a 100 mL round bottom flask (flame dried under vacuum) under Ar. Dry THF (20 mL) was
added and the mixture was stirred at rt for a period of 0.5 h until complete dissolution had occurred.
The clear, light yellow homogeneous solution was cooled to –78 °C, and 1a (0.294 g, 3.0 mmol) was
added, followed by TMSOTf (3.3 eq., 1.8 mL, 9.9 mmol). After 5 minutes at –78 °C, the aryl Grignard
reagent (1.2 eq., 1.2 mL, 3.6 mmol) was added dropwise via syringe, and the solution was stirred at –78
°C for 1 h and allowed to warm to rt. The reaction was quenched with H2O and the product extracted
with Et2O (3 X 25 mL), and the combined organic layers were washed with deionized H2O followed by
saturated NH4Cl. The organic layer was separated, dried with MgSO4, and concentrated in vacuo to
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The Journal of Organic Chemistry
give the crude product, which was then analyzed by 1H NMR spectroscopy to determine
diastereoselectivity. Column chromatography of the crude material (3% ethyl acetate in hexanes)
afforded the pure vinyl silane products.
1
2
3
4
5
6
7
8
1
Ethylꢀ(E)ꢀ3ꢀphenylꢀ2ꢀ(trimethylsilyl)acrylate (2): Yield: 0.684 g, 92%: H NMR (500 MHz, CDCl3) δ
9
13
7.25 (m, 5H), 6.77 (s, 1H), 4.15 (q, J = 7.2 Hz, 2H), 1.16 (t, J = 7.2 Hz, 3H), 0.19 (s, 9H). C NMR
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(125 MHz, CDCl3) δ 171.9, 141.3, 138.7, 136.6, 128.4, 128.3, 128.1, 60.4, 14.1, ꢀ1.7. IR (CH2Cl2):
2954, 1711, 1601, 1490, 1213, 1028, 852, 753, 696 cmꢀ1. Rf = 0.66, 20% EtOAc in hexanes. HRMS
(EIꢀEBE Sector) m/z: [M]+ Calcd for C14H20O2Si 248.1233; Found: 248.1239.
1
Ethylꢀ(E)ꢀ3ꢀphenylꢀ2ꢀ(triethylsilyl)acrylate (3): Yield: 0.722 g, 83%: H NMR (360 MHz, CDCl3) δ
7.31 (m, 5H), 6.79 (s, 1H), 4.18 (q, J = 7.2 Hz, 2H), 1.21 (t, J = 7.2 Hz, 3H), 1.01 (t, J = 7.6 Hz, 9H),
0.75 (q, J = 7.6 Hz, 6H). 13C NMR (125MHz, CDCl3) δ 172.1, 142.1, 136.7, 136.1, 128.3, 128.3, 128.1,
60.3, 14.0, 7.1, 3.0. IR (CH2Cl2): 2957, 2872, 1708, 1601, 1456, 1190, 1006, 740, 696 cmꢀ1. Rf = 0.77,
20% EtOAc in hexanes. HRMS (EIꢀEBE Sector) m/z: [MꢀC2H5]+ Calcd for C17H26O2Si 261.1311;
Found 261.1312.
1
Ethylꢀ(E)ꢀ3ꢀ(oꢀtolyl)ꢀ2ꢀ(trimethylsilyl)acrylate (4): Yield: 0.692 g, 88%: H NMR (500 MHz, CDCl3) δ
7.15 (m, 4H), 7.03 (s, 1H), 4.08 (q, J = 7.2 Hz, 2H), 2.31 (s, 3H), 1.09 (t, J = 7.2 Hz, 3H), 0.25 (s, 9H).
13C NMR (125 MHz, CDCl3) δ 171.4, 142.2, 139.5, 136.7, 135.7, 129.9, 128.1, 127.6, 125.6, 60.1,
19.6, 14.0, ꢀ1.5. IR (CH2Cl2): 2958, 1703, 1605, 1369, 1198, 1030, 760, 669cmꢀ1. Rf = 0.81, 20%
EtOAc in hexanes. HRMS (EIꢀEBE Sector) m/z: [M]+ Calcd for C15H22O2Si 262.1389; Found
262.1392.
1
Ethylꢀ(E)ꢀ3ꢀmesitylꢀ2ꢀ(trimethylsilyl)acrylate (5): Yield: 0.801 g, 92%: H NMR (500 MHz, CDCl3) δ
6.99 (s, 1H), 6.80 (s, 2H), 3.95 (q, J = 7.2 Hz, 2H), 2.25 (s, 3H), 2.14 (s, 6H), 0.98 (t, J = 7.2 Hz, 3H),
0.26 (s, 9H). 13C NMR (125 MHz, CDCl3) δ 170.1, 146.1, 140.8, 136.3, 134.8, 134.5, 127.7, 59.7, 21.0,
20.0, 13.9, ꢀ1.3. IR (CH2Cl2): 2957, 2912, 1712, 1605, 1442, 1327, 1242, 1190, 1043, 855 cmꢀ1. Rf =
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0.77, 20% EtOAc in hexanes. HRMS (EIꢀEBE Sector) m/z: [M]+ Calcd for C17H26O2Si 290.1702;
Found 290.1707.
1
2
3
4
5
6
7
8
9
Ethylꢀ(E)ꢀ3ꢀ(3ꢀmethoxyphenyl)ꢀ2ꢀ(trimethylsilyl)acrylate (6): Yield: 0.734 g, 88%: 1H NMR (500
MHz, CDCl3) δ 7.23 (t, J = 7.8 Hz, 1H), 6.93 (d, J = 8.3 Hz, 1H), 6.89 (s, 1H), 6.83 (dd, J = 8.3, 3.0
Hz, 1H), 6.78 (s, 1H), 4.21 (q, J = 7.2 Hz, 2H), 3.79 (s, 3H), 1.23 (t, J = 7.2 Hz, 3H), 0.24 (s, 9H). 13C
NMR (125 MHz, CDCl3) δ 171.9, 159.5, 141.0, 139.0, 138.0, 129.3, 120.7, 114.5, 113.1, 60.4, 55.2,
14.2, ꢀ1.7. IR (CH2Cl2): 2961, 2898, 1704, 1597, 1579, 1468, 1250, 1194, 1035, 847, 777, 688 cmꢀ1. Rf
= 0.68, 20% EtOAc in hexanes. HRMS (EIꢀEBE Sector) m/z: [M]+ Calcd for C15H22O3Si 278.1338;
Found 278.1338.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ethylꢀ(E)ꢀ3ꢀ(4ꢀmethoxyphenyl)ꢀ2ꢀ(trimethylsilyl)acrylate (7): Yield: 0.751 g, 90%: 1H NMR (500
MHz, CDCl3) δ 7.30 (d, J = 8.5 Hz, 2H), 6.83 (d, J = 8.5 Hz, 2H), 6.74 (s, 1H), 4.22 (q, J = 7.2 Hz,
13
2H), 3.80 (s, 3H), 1.25 (t, J = 7.2 Hz, 3H), 0.23 (s, 9H). C NMR (125 MHz, CDCl3) δ 172.2, 159.8,
140.9, 135.8, 129.8, 129.2, 113.7, 60.3, 55.2, 14.2, ꢀ1.6. IR (CH2Cl2): 2961, 2894, 1704, 1608, 1509,
1257, 1202, 1039, 995, 851 cmꢀ1. Rf = 0.68, 20% EtOAc in hexanes. HRMS (EIꢀEBE Sector) m/z: [M]+
Calcd for C15H22O3Si 278.1338; Found 278.1346.
1
Methylꢀ(E)ꢀ3ꢀphenylꢀ2ꢀ(trimethylsilyl)acrylate (8): Yield: 0.632 g, 90%: H NMR (500 MHz, CDCl3)
13
δ 7.30 (m, 5H), 6.82 (s, 1H), 3.71 (s, 3H), 0.24 (s, 9H). C NMR (125 MHz, CDCl3) δ 172.4, 141.5,
138.2, 136.5, 128.4, 128.3, 128.0, 51.4, ꢀ1.8. IR (CH2Cl2): 2957, 1716, 1605, 1428, 1209, 1021, 946,
843, 758, 696 cmꢀ1. Rf = 0.73, 20% EtOAc in hexanes. HRMS (EIꢀEBE Sector) m/z: [M]+ Calcd for
C13H18O2Si 234.1076; Found 234.1085.
Ethylꢀ(E)ꢀ3ꢀphenylꢀ2ꢀ(trimethylsilyl)butꢀ2ꢀenoate (9): Yield: 0.668 g, 85%: 1H NMR (500 MHz,
CDCl3) δ 7.26 (m, 5H), 3.86 (q, J = 7.2 Hz, 2H), 2.19 (s, 3H), 0.92 (t, J = 7.2 Hz, 3H), 0.28 (s, 9H). 13C
NMR (125 MHz, CDCl3) δ 172.1, 152.0, 144.2, 135.0, 128.0, 127.3, 126.6, 59.9, 24.0, 13.9, ꢀ0.24. IR
(CH2Cl2): 2961, 2902, 1704, 1597, 1442, 1261, 1209, 1091, 1035, 839, 754, 702 cmꢀ1. Rf = 0.48, 20%
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EtOAc in hexanes. HRMS (EIꢀEBE Sector) m/z: [M]+ Calcd for C15H22O2Si 262.1389; Found
262.1387.
1
2
3
4
5
6
7
8
9
General Experimental Procedure for the TMSOTf-Promoted Catalytic Carbocupration of 1a
with aliphatic Grignard Reagents: CuI (0.11 g, 0.6 mmol) and LiCl (0.050 g, 1.2 mmol) was flame
dried under vacuum in a 100 mL round bottom flask under Ar. Dry THF (20 mL) was added and the
mixture was stirred at RT for a period of 0.5 h until complete dissolution had occurred. The clear, light
yellow homogeneous solution was cooled to – 78 °C, and 1a (0.39 g, 0.40 mL, 4.0 mmol) was added,
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followed by TMSOTf (3.3 equiv, 2.4 mL, 13.2 mmol). After 10 minutes at – 78 °C, the aliphatic
Grignard Reagent (1.4 equiv, 5.6 mmol) was added dropwise via syringe, and the solution was stirred at
–78 °C for 2 hr and allowed to warm to RT for 2 hrs. The reaction was quenched with H2O and the
product extracted with Et2O (3x25 mL), and the combined organic layers were washed with brine. The
organic layer was separated, dried with MgSO4, and concentrated in vacuo to give the crude product,
1
which was then analyzed by H NMR spectroscopy to determine diastereoselectivity. The crude
material was then submitted to column chromatography and purified using 1% diethyl ether in hexane.
1
Ethylꢀ(E)ꢀ2ꢀ(trimethylsilyl)butꢀ2ꢀenoate (10): Yield: 0.558 g, 75%: H NMR (360 MHz, CDCl3) 6.30
(q, J = 6.8 Hz, 1H), 4.20 (q, J = 7.2 Hz, 2H), 1.97 (d, J = 6.8 Hz, 3H), 1.30 (t, J = 7.2 Hz, 3H), 0.13 (s,
9H). 13C NMR (125 MHz, CDCl3) δ 170.0, 146.2, 137.0, 59.6, 17.4, 14.2, ꢀ1.6. IR (CH2Cl2): 2957,
1716, 1612, 1339, 1198, 1032, 847 cmꢀ1. Rf = 0.53, 20% EtOAc in hexanes. HRMS (EIꢀEBE Sector)
m/z: [MꢀCH3]+ Calcd for C8H15O2Si 171.0841; Found 171.0839.
1
Ethylꢀ(E)ꢀ2ꢀ(triethylsilyl)butꢀ2ꢀenoate (11)25: Yield: 0.301 g, 33%: H NMR (360 MHz, CDCl3)
δ 6.22 (q, J = 6.7 Hz, 1H), 4.19 (q, J = 7.2 Hz, 2H), 1.94 (d, J = 6.6 Hz, 3H), 1.30 (t, J = 7.2 Hz, 3H),
0.92 (t, J = 8.0 Hz, 9H), 0.64 (q, J = 8.0 Hz, 6H).
Ethylꢀ(E)ꢀ2ꢀ(trimethylsilyl)pentꢀ2ꢀenoate (12): Yield: 0.600 g, 75%: 1H NMR (500 MHz, CDCl3)
δ 6.14 (t, J = 7.1 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 2.37 (m, 2H), 1.29 (t, J = 7.1 Hz, 3H), 1.03 (t, J =
7.6 Hz, 3H), 0.13 (s, 9H). 13C NMR (125 MHz, CDCl3) δ 170.5, 153.0, 135.5, 59.9, 25.0, 14.4, 13.5, ꢀ
29
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