A new method for the preparation of silyl enol ethers from carbonyl compounds and (trimenthylsily)diazomethane in a regiospecific and highly stereoselective manner

Article abstract of DOI:10.1021/ja027061c

The reaction of lithium (trimethylsilyl)diazomethane with aldehydes and ketones has been investigated, and it has been found that quenching at low temperature with MeOH followed by addition of Rh₂(OAc)₄ gave silyl enol ethers in high yields. Quenching with other electrophiles (e.g., deuterium, MeI) gave terminal and substituted silyl enol ethers with complete control over regio- and stereochemistry. The mechanism of this novel process has been mapped out through a combination of deuterium labeling, ReactIR, and isolation of reaction intermediates. Copyright

Full text of DOI:10.1021/ja027061c

Published on Web 08/10/2002
A New Method for the Preparation of Silyl Enol Ethers from Carbonyl
Compounds and (Trimethylsilyl)diazomethane in a Regiospecific and Highly
Stereoselective Manner
Varinder K. Aggarwal,*,† Chris G. Sheldon,† Gregor J. Macdonald,‡ and William P. Martin‡
School of Chemistry, UniVersity of Bristol, Cantock’s Close, Bristol BS8 1TS, UK and GlaxoSmithKline,
New Frontiers Science Park (North), Third AVenue, Harlow, Essex CM19 5AW, UK
Received May 27, 2002
Scheme 1. Pathways in the Reaction of LTMSD with RCHO
Silyl enol ethers are fundamental building blocks in organic
synthesis,1 but their synthesis in a regio- and especially stereo-
defined manner can be problematic.2 In the case of unsymmetrical
ketones bearing similar groups it is difficult to control the
regioselectivity in enolization, and therefore alternative strategies
have to be employed. In this communication we describe a new
method for converting aldehydes into silyl enol ethers in a
regiospecific and highly stereoselective manner.3
We considered the reaction of lithium(trimethylsilyl)diazo-
methane (LTMSD) 1 with an aldehyde, a reaction which normally
furnishes alkynes 4.4 We reasoned that if the initial alkoxide addition
product 2 could be captured by a transition metal catalyst either
before or after a protonation event to give 6, subsequent 1,2-hydride
migration5 would then furnish the silyl enol ether 7 (Scheme 1).
To achieve our synthesis of silyl enol ethers we required a Brook
rearrangement6 to intervene prior to the protonation/metal carbene
1,2-hydride migration event. However, literature precedent was not
encouraging as it had been reported that quenching adduct 2 with
AcOH led to the silyl diazo compound 5.7 Furthermore, the product
of Brook rearrangement 6 was required not to eliminate LiOSiMe3,
otherwise alkyne formation would result via 3. Both of these
processes were unprecedented.
In the event, when cyclohexane carboxaldehyde was reacted with
LTMSD at -78 °C followed by addition of MeOH and Rh2(OAc)4
and then slow warming to 0 °C, the terminal silyl enol ether was
obtained as the sole product. The reaction was found to be general
for a range of aliphatic aldehydes (Table 1) and could even be used
with base-sensitive aldehydes (entry 6) without racemization.
Aldehydes prone to enolization (e.g., phenylacetaldehyde (entry 7))
could also be employed and furnished the terminal silyl enol ether
in high yield. Despite a number of attempts, it has proved impossible
to generate this silyl enol ether regioselectively by deprotonation
of the corresponding ketone,2c,8 thus demonstrating the unique
advantage of the current methodology. Aromatic aldehydes (entry
8) were also suitable substrates, although unexpectedly, phenyl
migration competed with and dominated hydride migration.5a,b,9 In
addition, the methodology could be extended to include aromatic
ketones (entry 9). In this case, exclusive migration of the phenyl
group was observed, leading to the silyl enol ether in good yield
and with very high stereoselectivity (vide infra).
Table 1. Formation of Silyl Enol Ethers from Carbonyl
Compounds
entry
substrate
product yield (%)a
1
2
3
4
5
6
7
8
9
cyclohexane carboxaldehyde
octaldehyde
valeraldehyde
3-phenylpropanol
pivaldehyde
N-(BOC)-D-prolinal
phenylacetaldehyde
benzaldehyde
84
81
71
74
77
70
83
74b
75c
acetophenone
a Isolated yield after Kugelrohr distillation. b 92:1:7 mixture of E- and
Z-1-phenyl-2-(trimethylsiloxy)ethene, and 1-phenyl-1-(trimethylsiloxy) ethene.
c 96:4 mixture of E- and Z-1-phenyl-2-(trimethylsiloxy)propene.
Scheme 2. Synthesis of Labeled Silyl Enol Ethers
stereoselectivity (96:4) and in high yield (82%) by reacting
deuteriocyclohexane carboxaldehyde under the same conditions, but
quenching with MeOH.
These experiments provide not only a unique synthetic method
for the stereo-controlled synthesis of labeled silyl enol ethers which
would otherwise be extremely difficult to prepare but also useful
insights into the mechanism of the process. The two experiments
unequivocally show that one of the two protons of the terminal
silyl enol ether originate from the quench and the other from the
aldehyde C-H. Furthermore, they illustrate that the 1,2-hydride/
deuteride migration occurs with very high stereoselectivity.
Quenching the reaction with CD3OD instead of MeOH gave the
mono-deuterated silyl enol ether 8 with essentially complete
stereoselectivity in favor of the Z-isomer (Scheme 2). The corre-
sponding E-isomer could be obtained, again with very high
* To whom correspondence should be addressed. E-mail: v.aggarwal@
bristol.ac.uk.
† University of Bristol.
‡ GlaxoSmithKline.
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10.1021/ja027061c CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Scheme 4. Formation of Substituted Silyl Enol Ethers
Scheme 3. Mechanism Determined by ReactIR
bulkier R group. To test this proposition, the deuterium-labeling
experiment shown in Scheme 2 was repeated with pivaldehyde,
and this time a 68:32 ratio of silyl enol ethers was obtained with
the E-isomer dominating. Thus when R ) t-Bu, transition state A
is destabilized due to very severe steric hindrance, and the reaction
preferentially occurs via transition state B. The strength of the
electronic repulsion is still evident though, as over 30% of the
reaction occurs via the severely sterically hindered transition state
A.
Having established the mechanism of this novel process we
sought to exploit this chemistry further by preparing more
substituted silyl enol ethers in a regio- and stereo-defined manner.
This was achieved by quenching the reaction with MeI instead of
MeOH. To our delight, the corresponding silyl enol ethers were
produced with complete regio- and stereoselectivity (Scheme 4).
In conclusion we have discovered a new synthesis of terminal
and substituted silyl enol ethers with complete control over regio-
and stereochemistry. The mechanism of this novel process has been
mapped out through a combination of deuterium labeling, ReactIR,
and isolation of reaction intermediates.
Having established a novel transformation which converted
aldehydes into silyl enol ethers we wished to determine the
mechanism and the precise order of events of this process. ReactIR
was employed to unravel the sequence of events as shifts in the
diazo stretching frequency provide characteristic information on
the reaction intermediates (see Supporting Information). From this
analysis we concluded that the mechanism shown in Scheme 3 was
operative. Following addition of LTMSD to the aldehyde, a Brook
rearrangement occurred to give 9. This species was in equilibrium
with 2 as quenching with AcOH at low temperature, as described
by Scho¨llkopf,7 gave the alcohol derived from 2, whereas quenching
with MeOH gave 10. Neither 9 nor 10 reacted with Rh2(OAc)4 at
low temperature. Upon warming 10 in the presence of Rh2(OAc)4,
N2 was evolved, and the silyl enol ether 12 was formed presumably
via the metal carbene 11. Intermediate 10 was isolated, where R )
t-Bu and Ph, and subjected to Rh2(OAc)4, and the same silyl enol
ether products were obtained as in entries 5 and 8 (Table 1), proving
the intermediacy of this species.
The E/Z selectivity of the silyl enol ethers originates from the
1,2-hydride migration step and can be rationalized by considering
the possible stereoelectronically required conformations A and B
(Figure 1) which place the migrating group parallel with the empty
p orbital on carbon.9a,b,10 Of the two conformations, B is likely to
be disfavored because of electronic repulsions between the acetate
ligands attached to rhodium and the oxygen of the silyl ether. Thus,
rearrangement is proposed to occur via transition state A which
leads to the observed Z-isomer.
Acknowledgment. We gratefully thank the EPSRC and Glaxo-
SmithKline for a CASE Award to C.G.S.
Supporting Information Available: Experimental procedures,
compound characterization data, and ReactIR data (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
References
(1) (a) Brownbridge, P. Synthesis 1983, 1. (b) Brownbridge, P. Synthesis 1983,
85.
(2) For notable contributions see: (a) Nakamura, E.; Hashimoto, K.; Kuwa-
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(3) Brookhart recently described the one carbon homologation of aromatic
aldehydes to silyl enol ethers with TMSD using a Rh(I) complex, but the
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Figure 1. Model for stereoselectivity.
This model accounts not only for the deuterium experiments
above but also for the E/Z selectivities observed in entries 8 and 9.
Furthermore, it also accounts for the preferred migration of the
phenyl group over hydride migration (entry 8). In this case, as H
and Ph can both migrate with almost equal ease, conformers A
and C need to be considered, and C suffers less steric hindrance
than A, thus leading to the unusual preference for phenyl migration.
A corollary of the above model is that the electronic repulsion
shown in transition state B must be very severe as transition state
A suffers from a significant steric hindrance between the wall of
ligands around rhodium and the cyclohexyl group and yet A is
strongly preferred over B. If the above model is indeed correct, it
should be possible to destabilize transition state A by using an even
(6) For a review see: Moser, W. H. Tetrahedron 2001, 57, 2065.
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(8) Gaudemar, M.; Bellassoued, M. Tetrahedron Lett. 1989, 30, 2779.
(9) In this type of rearrangement, hydrogen usually migrates more readily
than a phenyl group: (a) Ikota, N.; Takamura, N.; Young, S. D.; Ganem,
B. Tetrahedron Lett. 1981, 22, 4163. (b) Taber, D. F.; Herr, R. J.; Pack,
S. K.; Geremia, J. M. J. Org. Chem. 1996, 61, 2908. For a discussion
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