Tandem chain extension-homoenolate formation: The formation of α-methylated-γ-keto esters

Article abstract of DOI:10.1021/ol016485t

matrixpresented A tandem chain extension-homoenolate formation reaction is described. The treatment of β-keto esters with the Furukawa reagent followed by exposure to a catalytic amount of trimethylsilyl chloride provides access to an ester homoenolate.

Full text of DOI:10.1021/ol016485t

ORGANIC
LETTERS
2001
Vol. 3, No. 19
3037-3040
Tandem Chain Extension-Homoenolate
Formation: The Formation of
r-Methylated-γ-Keto Esters
Ramona Hilgenkamp and Charles K. Zercher*
Department of Chemistry, UniVersity of New Hampshire,
Durham, New Hampshire 03824
ckz@christa.unh.edu
Received July 24, 2001
ABSTRACT
A tandem chain extension−homoenolate formation reaction is described. The treatment of â-keto esters with the Furukawa reagent followed
by exposure to a catalytic amount of trimethylsilyl chloride provides access to an ester homoenolate.
The formation of carbon skeletons continues to demand
significant expenditures of energy and time in organic
synthesis. The selective chain extension of easily accessed
carbon frameworks is one possible solution to the formation
of challenging structures. One strategy for chain extension
or ring expansion has been to generate strained ring systems
that upon fragmentation generate extended carbon chains.1
of R-unsubstituted-â-keto esters, since the placement of
substituents at the R-position resulted in complex reaction
mixtures due to formation of over-alkylated products. We
now report a variation on the chain extension reaction that
provides a partial solution to this problem.
Investigation of the chain extension reaction stoichiometry
revealed that formation of the enolate consumes the first
equivalent of either the Furukawa reagent or diethyl zinc.6
In an effort to minimize the amount of diethyl zinc utilized
in the reaction, we undertook an investigation of alternative
bases for the formation of the enolate 2. Formation of the
potassium enolate through addition of a 1.0 M solution of
KHMDS in toluene to â-keto ester 1, followed by transfer
to the preformed Furukawa reagent, resulted in the unex-
pected formation of a mixture of products (Scheme 2),
dominated by the appearance of the R-methylated γ-keto
ester 6. This mixture of products was in sharp contrast to
the clean reactions observed when either diethyl zinc or the
Furukawa reagent was used to initiate the reaction through
enolate formation. An intriguing observation was that even
substoichiometric amounts (0.5 equiv) of KHMDS provided
enhanced R-methylation, as high as a 9:1 ratio of 6:5 as
determined by NMR analysis of the crude reaction mixture.
We have recently reported an operationally simple ap-
proach to the chain extension of â-keto esters,2 â-keto
amides,3 and â-keto phosphonates4 that utilizes the Furukawa
reagent,5 ethyl(iodomethyl)zinc. We have proposed (Scheme
1) that the reaction proceeds through cyclopropanation of
the enolate to provide a donor-acceptor cyclopropane, which
fragments to give an intermediate ester enolate equivalent
and is quenched to provide the γ-keto ester. Practical
application of this methodology appeared limited to the use
(1) (a) Bieraugel, H.; Akkerman, J. M.; Lapierre Armand, J. C.; Pandit,
U. K. Tetrahedron Lett. 1974, 33, 2817-2820. (b) Saigo, K.; Kurihara,
H.; Miura, H.; Hongu, A.; Kubota, N.; Nohira, H. Synth. Commun. 1984,
14, 787-796. (c) Dowd, P.; Choi, S.-C. J. Am. Chem. Soc. 1987, 109,
3493-3494. (d) Dowd, P.; Choi, S.-C. J. Am. Chem. Soc. 1987, 109, 6548-
6549. (e) Dowd, P.; Choi, S.-C. Tetrahedron 1989, 45, 77-90. (f) Kunkel,
E.; Reichelt, I.; Reissig, H.-U. Liebigs Ann. Chem. 1984, 512-530. (g)
Grimm, E. L.; Reissig, H.-U. J. Org. Chem. 1985, 50, 242-244.
(2) Brogan, J. B.; Zercher, C. K. J. Org. Chem. 1997, 62, 6444-6446.
(3) Hilgenkamp, R.; Zercher, C. K. Submitted for publication.
(4) Verbicky, C. A.; Zercher, C. K. J. Org. Chem. 2000, 65, 5615-
5622.
(6) Identical results are obtained if 1 equiv of diethylzinc is used instead
of the first equivalent of ethyl(iodomethyl)zinc. In both instances enolate
formation is observed through NMR analysis with concomitant generation
of ethane gas.
(5) Furukawa, J.; Kawabata, N.; Nishimura, J. Tetrahedron 1968, 24,
53-58.
10.1021/ol016485t CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/28/2001

Scheme 1
Although the 52% isolated yield of R-methylated material
in the KHMDS reaction was not entirely satisfactory, the
unusual nature of the product warranted continued study.
1 was treated with diisopropylamine or triethylamine in the
same fashion as described above for HMDS. Although the
1H NMR spectra of crude reaction mixtures showed traces
of the R-methylated product 6, the simple chain-extended
material 5 was the major product formed. From this result it
was clear that HMDS was exerting influence over product
distribution in a fashion unrelated to its nature as a basic
amine.
Scheme 2
We concluded that KHMDS and HMDS were promoting
R-methylation through the influence of the trimethylsilyl
(TMS) group. To test this hypothesis, 0.2 equiv of trimeth-
ylsilyl chloride (TMSCl) were added to the reaction mixture
immediately after the ester substrate was combined with the
1
zinc carbenoid. Once again, the H NMR spectrum of the
crude reaction mixture showed a ratio of the R-methylated
chain-extended product 6 to the simple chain-extended 5
product of approximately 9:1.
A mechanistic description of the reaction is illustrated in
Scheme 3. After cyclopropanation and ring opening to a
Since treatment of a â-keto ester with KHMDS results in
the formation of the potassium enolate and generation of the
conjugate acid, HMDS, we intended to explore the influence
of both the counterion and the conjugate acid. Treatment of
the â-keto ester 1 with the Furukawa reagent in the presence
of substoichiometric potassium iodide (0.5 equiv) revealed
an increase in R-methylation, although the ratio of R-me-
thylated product 6 to simple chain extension product 5 was
only 3:2. Because potassium iodide is not soluble in
methylene chloride, the experiment was repeated with a
soluble metal salt, sodium tetraphenylborate. Once again, the
R-methyl chain-extended product was formed, but the simple
chain extension product was the major product; the ratio of
the two products was again approximately 3:2. These results
indicate that change in the counterion influences the R-me-
thylation reaction, although no counterions were identified
that provided the product selectivity provided by KHMDS.
The influence of the conjugate acid of KHMDS was
probed by treatment of the â-keto ester 1 with the Furukawa
reagent followed by addition of 0.2 equiv of HMDS. This
revealed that R-methylation was the dominant reaction
pathway (9:1 ratio of 6:5) in the absence of a potassium or
sodium cation and that appearance of the R-methylation
product cannot be attributed to a simple counterion effect.
To test the influence of the amine functionality, â-keto ester
Scheme 3
dimeric zinc species 4,7 the trimethylsilyl group appears to
promote fragmentation of the dimeric species and generation
of an activated nucleophile. This nucleophile could be either
TMS-ketene acetal 7 or the donor-acceptor cyclopropane
8, although the absence of any apparent Ireland-Claisen
rearrangement pathway with an allyl ester discourages
3038
Org. Lett., Vol. 3, No. 19, 2001

consideration of the ketene acetal intermediate.8 It is
important to note that trimethylsilyloxycyclopropanes, like
8, have been implicated in reactions with exceptional carbon
electrophiles,9 including zinc-carbenoids.10 Either potential
nucleophilic intermediate would be expected to attack the
electrophilic carbenoid and provide the zinc homoenolate 9.11
Anionic character at the newly incorporated methyl group
was demonstrated by quenching the reaction mixture with
D2O to provide 10.
reaction was not hindered by the presence of a bulky
substituent or aromatic group on the ester oxygen or by the
presence of amide functionality. In every case, a small
amount of the simple chain-extended product was observed
1
in the H NMR spectra of the crude reaction mixtures. The
reaction was attempted with a secondary â-keto amide,
N-cyclohexyl 3-oxo-butanamide 19,12 with very different
results. The substrate was added to 5 equiv of the zinc
carbenoid, 40 mol % of TMS-Cl was added after 30 s, and
1
the reaction was quenched after 30 min. The H NMR
A number of variables were modified to test their impact
on the efficiency of the reaction. The number of equivalents
of the zinc carbenoid were varied from four to six with no
apparent impact. The amount of TMSCl was varied from
10 mol % to 80 mol %, again with no apparent influence.
The timing of addition of TMSCl to the reaction mixture
was varied from 30 s to 10 min after addition of the substrate
to the carbenoid, and the duration of the reaction after
addition of TMSCl was varied from 10 to 45 min. In only
one case was there a clear reduction in the ratio of the
R-methyl chain-extended product to the simple chain-
spectrum of the crude reaction mixture showed that the
R-unsubstituted chain-extended product 2013 was the major
product rather than the expected R-methyl chain-extended
product 21; the ratio of the two products was approximately
3:1. Efforts were made to increase the yield of the R-methyl
chain-extended product by modifying the amount of TMSCl
and timing of the addition; however, ratio of the R-unsub-
stituted product to the R-substituted product could not be
improved.
1
extended product, determined by analysis of the H NMR
spectra of the crude reaction mixtures. When TMSCl was
added 10 min after adding the ester substrate 1 to the
carbenoid and the reaction was quenched after another 10
min, the ratio of the R-methyl product 6 to the simple chain-
extended product 5 was 3:1 rather than approximately 9:1
as usually observed. The 10-min reaction time was evidently
insufficient to achieve the higher ratio. When the same
substrate was allowed to react for 30 min after addition of
TMSCl, the R-methylated product was favored by a >9:1
ratio and isolated in 70% yield.
Scheme 5
Several R-methyl γ-keto esters and amides (12, 14, 16,
18) were prepared from â-keto esters and amides using the
tandem chain extension-homoenolate formation procedure
(Scheme 4). Yields of the major product after purification
A likely explanation for these results is that the carbon-
bound zinc intermediate 4 is partially quenched by the
secondary â-keto amide hydrogen before TMSCl transforms
it to a reactive TMS-containing species 7 or 8, thus
interfering with the R-alkylation reaction. When secondary
â-keto amides are chain-extended without the use of TMS-
Cl,3 this partial quenching of intermediate 4 would result in
formation of the same product as is generated with an
ammonium chloride quench. Quenching of intermediate 7
or 8 with the acidic amide proton prior to reaction with the
zinc carbenoid is an alternative and synthetically equivalent
explanation. Regardless of the mechanism, it is clear that
the presence of an acidic proton inhibits the R-methylation
reaction.
Scheme 4
by column chromatography varied from 57% to 73%. As
these results demonstrate, the efficiency of the tandem
To test the amide-quenching hypothesis, a chain extension
reaction (no addition of TMSCl) of secondary â-keto amide
substrate 19 was quenched after 30 min with excess D2O
(7) The dimeric nature of the intermediate has not been unequivocally
established in the present situation; however, the intermediate bears
remarkable spectroscopic and reactivity similarity to a Reformatsky reagent.
Reformatsky reagents have been shown to be dimeric in the crystalline state,
as well as through molecular weight determinations in solution. (a) Orsini,
F.; Pelizzoni, F.; Ricci, G. Tetrahedron 1984, 40, 2781. (b) Orsini, F.;
Pelizzoni, F.; Ricci, G. Tetrahedron Lett. 1982, 25, 3945.
(8) A Reformatsky-Claisen reaction of a zinc-ketene acetal would require
elevated temperatures (refluxing benzene). Baldwin, J. E.; Walker, J. A. J.
Chem. Soc., Chem. Commun. 1973, 117.
(10) Saigo, K.; Yamashita, T.; Hongu, A.; Hasegawa, M. Synth. Commun.
1985, 715.
(11) (a) Knochel, P.; Rozema, M. J.; Tucker, C. E.; Retherford, C.;
Furlong, M.; AchyuthaRao, S. Pure Appl. Chem. 1992, 64, 361-369. (b)
Crimmons, M. T.; Nautermet, P. G. Org. Prep. Proced. Int. 1993, 25, 41-
81.
(12) Garcia, M. J.; Rebolledo, F.; Gotor, V. Tetrahedron 1994, 50, 6935-
6940.
(9) Reissig, H.-U. Top. Curr. Chem. 1988, 144, 73-135.
(13) Saito, K.; Sato, T. Bull. Chem. Soc. Jpn. 1979, 52, 3601-3605.
Org. Lett., Vol. 3, No. 19, 2001
3039

and the reaction mixture was purified by column chroma-
equivalent 4 (Reformatsky-like) through the introduction of
aldehydes has been accomplished in our laboratories,14 yet
the R-methylation reaction provides a potential general
solution to the problem. Since a proposed intermediate 9 in
the R-methylation reaction is a zinc ester homoenolate, it
should be possible to trap the homoenolate through addition
of a suitable electrophile15 or by metal-mediated coupling.16
Efforts are presently underway in our laboratory to utilize
the homoenolate intermediate in a reaction that will involve
three sequential carbon-carbon bond-forming reactions.
1
tography. The H and 13C NMR spectra show clearly that
deuterium has been only partially incorporated on the
R-carbon with the estimated ratio of deuterated to non-
deuterated products being approximately 3:2. This result
supports the contention that the amide hydrogen can quench
intermediate 4 and interfere with the R-alkylation reaction,
thereby accounting at least in part for the low yield of the
R-methyl chain-extended product 21. Some reduction in yield
may also be attributable to a protic quench of the TMS-
containing intermediate 7 or 8 with the acidic hydrogen, but
no evidence for that phenomenon has been obtained.
The tandem chain-extension/R-methylation reaction of
esters and amides provides access to R-methylated γ-keto
esters and amides, compounds that were not accessible
through chain extension of R-methylated â-keto esters.
Activation of a Reformatsky-like intermediate 4 with TMSCl
appears to promote methylation through formation of a
trimethylsilyloxycyclopropane 8. Less efficient formation of
R-methylated products was observed with alkili metal
counterions. An attractive explanation is that counterions
other than zinc affect the equilibrium between the cyclo-
propyl alkoxide (3) and the open ketene acetal intermediates
(4).11b
Acknowledgment. This research was funded by a grant
from the National Institutes of Health (GM60967-01).
Supporting Information Available: Detailed experi-
mental procedures, including spectroscopic data, are available
for compounds 6, 10, 12, 14, 16, 18, and 20-22. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL016485T
(14) Lai, S.; Zercher, C. K. Manuscript in preparation.
(15) (a) Nakamura, E.; Aoki, S.; Sekiya, K.; Oshino, H.; Kuwajima, I.
J. Am. Chem. Soc. 1987, 109, 8056-8066. (b) Nakamura, E.; Oshino, H.;
Kuwajima, I. J. Am. Chem. Soc. 1986, 108, 3745-3755. (c) Armstrong, J.
D., III; Hartner, F. W., Jr.; DeCamp, A. E.; Volante, R. P.; Shinkai, I.
Tetrahedron Lett. 1992, 33, 6599-6602.
(16) (a) Tamarua, Y.; Ochiai, H.; Nakamura, T.; Yoshida, Z. Tetrahedron.
Lett. 1986, 27, 955-958. (b) Kadota, I.; Takamura, H.; Sata, K.; Yamamoto,
Y. Tetrahedron Lett. 2001, 42, 4729-4731.
Manipulation of the reaction to incorporate groups other
than methyl at the R-position would provide a general
solution to the inefficient reactivity of R-substituted â-keto
esters.2 Successful trapping of the intermediate zinc-enolate
3040
Org. Lett., Vol. 3, No. 19, 2001