Alkynoate synthesis through the vinylogous reactivity of rhodium(II) carbenoids

Article abstract of DOI:10.1002/anie.201204047

Siloxy group migration: A rhodium(II) carbenoid approach has been developed for the synthesis of alkynoates (see scheme). This transformation combines the addition of enol ethers at the vinylogous position of ?-siloxy-substituted vinyldiazo derivatives with a siloxy group migration to give the products as single diastereomers.

Full text of DOI:10.1002/anie.201204047

Angewandte
Chemie
DOI: 10.1002/anie.201204047
Rhodium Catalysis
Alkynoate Synthesis through the Vinylogous Reactivity of
Rhodium(II) Carbenoids**
Damien Valette, Yajing Lian, John P. Haydek, Kenneth I. Hardcastle, and Huw M. L. Davies*
2-Alkynoates represent a versatile class of synthetic inter-
mediates in the field of organic synthesis[1] and are useful
precursors to numerous biologically active compounds.[2]
Despite significant interest from the synthetic community,
facile incorporation of an alkynecarboxylate moiety remains
a challenge. The difficulty associated with the direct alkyla-
tion of 2-alkynoates is due to their tendency to isomerize
under basic conditions into the corresponding allenes, which
are then prone to undergo conjugate addition.[3] In practice,
commonly reported procedures require a multistep reaction
sequence.[4] A reasonably direct alternative approach to
introduce the alkynecarboxylate group is the Nicholas
reaction,[5] which allows the functionalization of propargylic
sites with a variety of nucleophiles.[6] This approach requires
the use of stoichiometric dicobalt reagents as well as the need
to perform an oxidative decomplexation to regenerate the
alkyne moiety following substitution. Herein, we describe
a new stereoselective approach that allows a straightforward
access to highly functionalized alkyl 2-alkynoates by means of
a rhodium-catalyzed transformation between silyl enol ethers
and 3-siloxy 2-diazobutenoates [Eq. (1)].
tandem cyclopropanation/Cope rearrangement,[10] leading to
the synthesis of three-, five-, or seven-membered carbocycles.
The combination of siloxy a-diazoacetates with cinnamalde-
hydes offers access to complementary motifs.[11] More
recently, the addition of nitrones to the vinylogous position
of this carbenoid as well as a number of unusual trans-
formations have been reported.[12] The key transformation
behind the 2-alkynoate alkylation protocol also involves
reaction at the vinylogous position of a vinylcarbenoid, but
this is then followed by an unprecedented siloxy group
migration.
We extensively investigated the scope of substrates that
undergo selective vinylogous addition over carbenoid-type
transformations.[8] During these studies, we discovered that
the [Rh2(esp)2][13]-catalyzed reaction of 1-(trimethylsiloxy)-
cyclohexene (1) with 3-siloxy 2-diazobutenoate (2) unexpect-
edly led to the formation of alkyne 3 as a single diastereomer
in 53% yield (Scheme 1). The structure of compound 3 was
unambiguously confirmed by single-crystal X-ray diffrac-
tion.[14]
The successful development of the aforementioned alkyl-
ation protocol is based on the discovery of an unusual
transformation of rhodium-stabilized vinylcarbenoids. Tran-
sient vinylcarbenoids undergo a wide variety of synthetically
useful reactions,[7] and their chemistry is particularly rich
because they display electrophilic character at both the
carbenoid site and the vinylogous position.[8] Especially
versatile vinylcarbenoids are those derived from 3-siloxy 2-
diazobutenoates. Reactions initiated at its carbenoid site have
been used for stereoselective cyclopropanation[9] and the
Scheme 1. X-ray crystal structure of product 3 formed from 3-siloxy 2-
diazobutenoate (2) and 1-(trimethylsiloxy)cyclohexene (1).
esp=a,a,a’,a’-tetramethyl-1,3-benzenedipropionate, TBS=tert-butyldi-
methylsilyl, TMS=trimethylsilyl.
This reaction was intriguing, not only because the
formation of 3 occurred by vinylogous addition, but also
because the disiloxy ketal functional group arose from the
migration of the OTBS group from the vinylcarbenoid to the
cyclohexyl moiety. To the best of our knowledge, such
migration is unprecedented in the literature about carbenoids.
In order to evaluate the stereospecificity of the transforma-
tion, the reaction between the siloxy cyclohexene and b-siloxy
vinyldiazoacetate was repeated with the TBS and TMS
substituents interconverted (Table 1, entry 1). The diastereo-
mer to 3 was obtained in a highly stereoselective manner.
[*] Dr. D. Valette, Dr. Y. Lian, J. P. Haydek, Dr. K. I. Hardcastle,
Prof. Dr. H. M. L. Davies
Department of Chemistry, Emory University
1515 Dickey Drive, Atlanta, GA 30322 (USA)
E-mail: hmdavie@emory.edu
Homepage: http://www.chemistry.emory.edu/
[**] This research was supported by the National Institutes of Health
(GM099142). The crystallographic data was supplied by the X-ray
diffraction laboratory at the Department of Chemistry, Emory
University.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201204047.
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À
Table 1: Substrate scope.
acceptor carbenoids and silyl enol ethers favors C H
insertion[16] or the combined C H functionalization/Cope
À
rearrangement[17] over cyclopropanation. In this particular
alkynoate transformation, we rationalize that the open/
unsubstituted vinylogous position of the vinylcarbenoid is
responsible for the vinylogous addition by the silyl enol ether.
In addition, the use of sterically demanding nucleophiles,
essentially tri- and tetrasubstituted olefins, is certainly
accountable for the enhancement of vinylogous reactivity.[8e,g]
A plausible mechanism for the alkynoate formation is
detailed in Scheme 2. Addition of the silyl enol ether to the
Entry
Enol
Diazo
Product
Yield[a] [%]
compd
1
2
3
4
2
2
49[b]
79[b]
61[b]
4
2
69[b]
5
6
2
5
33[c]
84[d]
7
8
2
5
51[c,e]
98[d]
9[f]
2
2
56
10[f]
53[b]
[a] Yields of isolated products. [b] d.r.>20:1. [c] R4 =Me. [d] R4 =tBu.
[e] Yield refers to the isolated alkynoate product, which was separated
from the cyclopropanated by-product by column chromatography.
[f] Reaction was run at reflux.
Scheme 2. Proposed mechanism.
unsubstituted g-position of the activated b-siloxy vinylcarbe-
noid would result in the formation of the zwitterionic
intermediate 14. Subsequent direct [1,4]-siloxy group transfer
or stepwise addition to the oxocarbenium ion via intermedi-
ate 15 followed by b-elimination would lead to the alkynoate
product. Previous studies have shown that rhodium-stabilized
b-siloxy vinylcarbenoids have a strong preference for the s-cis
conformation, in which the siloxy group points away from the
“wall” of the catalyst.[17,18] We postulate that this conforma-
tional preference would be consistent with the rhodium
carboxylate and the siloxy group adopting an anti-periplanar
conformation, which would then facilitate the b-elimination
to afford the alkynoate product.
The X-ray structure of alkynoate 3 unambiguously shows
that both the alkynyl side chain and the siloxy migrating
group are on the same face of the cyclohexane. This led us to
propose that the siloxy migration could be considered as an
intramolecular transfer process that would preferentially
occur in a suprafacial manner (path a vs. b in Scheme 3).
Having established the basic propargylation method,
studies were then conducted to determine the synthetic
potential of the transformation. One obvious application
would be to use the disiloxy ketal as a carbonyl protecting
group. Indeed the alkynoate products generated are readily
converted into the corresponding ketones in high yield by
simple treatment with tris(dimethylamino)sulfonium difluo-
The scope of this transformation was then explored with
a range of cyclic enol ethers. The reaction proceeded in
moderate to excellent yields, and in all cases only a single
diastereomer of the product was generated. With certain
substrates, such as siloxy indene and siloxy cyclobutene, the
potentially competing products derived from carbenoid
reactivity became apparent and resulted in lower isolated
yields of the alkynoate products (Table 1, entries 5 and 7). We
have demonstrated that increasing the size of the ester group
in the vinylcarbenoid enhances the vinylogous reactivity.[8c,e]
Indeed, when the reactions on these substrates were repeated
using tert-butyl 3-siloxy 2-diazobutenoate 5, alkynoates 10
and 11 were isolated as the sole products in 84 and 98% yield,
respectively (entries 6 and 8). The vinylogous reactions to the
carbenoid derived from 3-butenediazoacetate 2 are also
applicable to tetrasubstituted vinyl ethers and led to the
formation of alkynoates containing two adjacent quaternary
centers (entries 9 and 10). The relative configuration of
products 6–13 was assigned by analogy to alkynoate 3,
because an equivalent migration is presumed to be involved
in the formation of those compounds.
It is well established that donor/acceptor carbenoids are
more selective than their acceptor-only homologs.[15] We have
previously demonstrated that the reaction between donor/
2
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products 20–22 as single diastereomers that bear three
contiguous stereogenic centers. The relative configuration of
20 was determined by 1D-NOE NMR studies and extended
by analogy to compounds 21 to 22. This result is consistent
with a nucleophilic addition of the silyl enol ether anti to the
3-substituent, followed by intramolecular siloxy group migra-
tion syn with respect to the alkyne moiety.
Scheme 3. Rationale for the diastereoselectivity.
To demonstrate the practicality of this reaction, the above
transformation was repeated with the enantioenriched silyl
enol ether (À)-19 (Scheme 6, 98% ee). As anticipated,
Scheme 4. Access to 1,6-dicarbonyl compound 16. DMF=N,N-dime-
thylformamide.
rotrimethylsilicate (TASF); ketone 16 was isolated in 94%
yield (Scheme 4).
Scheme 6. Alkynoate formation with conservation of enantioenrich-
An exploratory study was then conducted to determine
whether an enantioselective version of this transformation
was feasible. Extensive experimentation showed that the use
of [Rh2(S-PTAD)4] at À258C in TFT were the optimal
conditions (see the Supporting Information for further
discussion on the optimized conditions). Representative
examples are summarized in Table 2. Moderate levels of
ment.
product (+)-22 was isolated as a single diastereomer with
complete transfer of stereochemical information. As chiral 3-
substituted silyl enol ethers, such as (À)-19, are readily
obtained by asymmetric conjugate addition to unsaturated
carbonyl compounds,[19] this allows the propargylation proce-
dure to be effectively used for the synthesis of highly
enantioenriched products that contain three contiguous
stereogenic centers.
Table 2: Asymmetric alkynoate synthesis.
In summary, we have developed a highly diastereoselec-
tive method for the rapid access to highly functionalized 2-
alkynoates in a single step using cyclic silyl enol ethers and
siloxy vinylcarbenoids under rhodium(II) catalysis. Further
studies are in progress to extend this reaction to acyclic enol
ethers and to find systems that will give higher levels of
asymmetric induction. These studies underscore the rich
chemistry of rhodium-stabilized vinylcarbenoids, which has
led to their broad application in a number of novel synthetic
transformations.
Entry
R
n
Yield[a] [%]
d.r.[b]
ee[c] [%]
1
2
3
4
H
H
1
2
2
3
87
53
49
69
>20:1
>20:1
>20:1
>20:1
50
60
46
70
O(CH2)2O
H
[a] Yields of isolated products. [b] Determined from 1H NMR spectra of
the crude reaction mixture. [c] Determined by HPLC analysis on a chiral
stationary phase after hydrolysis of the disiloxy ketal. (S)-ptad=(S)-
(+)-(1-adamantyl)-(N-phthalimido)aceto, TFT=trifluorotoluene.
Experimental Section
enantioinduction were observed, which demonstrated that
the chiral catalyst was capable of limited facial selectivity.
Interestingly, the enantiomeric excess of the products
increased proportionally with the size and flexibility of the
ring (Table 2, entries 1, 2, and 4).
The study was then extended to 3-substituted silyl enol
ethers (Scheme 5). The [Rh2(esp)2]-catalyzed reactions of
siloxy vinyldiazoacetate 2 with compounds 17–19 generated
General procedure: A solution of siloxy vinyldiazoacetate (1.0 mmol,
2.0 equiv) in dried, degassed CH2Cl2 (6 mL) was added by syringe
pump over three hours to a flame-dried 25 mL flask containing
[Rh2(esp)2] (7.7 mg, 0.02 equiv) and enol ether (0.5 mmol, 1.0 equiv)
in dried, degassed CH2Cl2 (6 mL) at room temperature under an
argon atmosphere. The solution was stirred at room temperature for
an additional hour. The mixture was concentrated under reduced
pressure and purified by flash chromatography (see the Supporting
Information for eluents) on silica gel to give the product.
Received: May 24, 2012
Revised: June 14, 2012
Published online: && &&, &&&&
Keywords: 2-alkynoates · carbenoids · migration · rhodium ·
.
Scheme 5. Scope of a-substituted silyl enol ethers.
vinyldiazo compounds
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4
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Communications
Rhodium Catalysis
D. Valette, Y. Lian, J. P. Haydek,
K. I. Hardcastle,
H. M. L. Davies*
&&&& — &&&&
Siloxy group migration: A rhodium(II)
carbenoid approach has been developed
for the synthesis of alkynoates (see
scheme). This transformation combines
the addition of enol ethers at the vinyl-
ogous position of b-siloxy-substituted
Alkynoate Synthesis through the
Vinylogous Reactivity of Rhodium(II)
Carbenoids
vinyldiazo derivatives with a siloxy group
migration to give the products as single
diastereomers.
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