Claisen-type condensation of vinylogous acyl triflates

Article abstract of DOI:10.1021/ol0527781

(Chemical Equation Presented) The Claisen-type condensation reaction of cyclic vinylogous carboxylic acid triflates with lithium enolates and their analogues produces acyclic alkynes bearing a 1,3-diketone-type moiety. The present transformation is proposed to proceed via a 1,2-addition of the enolate to the vinylogous acyl triflate, followed by fragmentation of the aldolate intermediate.

Full text of DOI:10.1021/ol0527781

ORGANIC
LETTERS
2006
Vol. 8, No. 1
175-177
Claisen-Type Condensation of
Vinylogous Acyl Triflates
Shin Kamijo* and Gregory B. Dudley*
Department of Chemistry and Biochemistry, Florida State UniVersity,
Tallahassee, Florida 32306-4390
gdudley@chem.fsu.edu
Received November 16, 2005
ABSTRACT
The Claisen-type condensation reaction of cyclic vinylogous carboxylic acid triflates with lithium enolates and their analogues produces
acyclic alkynes bearing a 1,3-diketone-type moiety. The present transformation is proposed to proceed via a 1,2-addition of the enolate to the
vinylogous acyl triflate, followed by fragmentation of the aldolate intermediate.
The Claisen condensation is one of the hallmark reactions
of organic chemistry.1 The first report on the Claisen con-
densation dates back more than a century and describes the
homocoupling reaction of esters in the presence of an excess
amount of base to yield 1,3-ketoesters (eq 1). This mecha-
1 with lithium enolates derived from 2 proceeds to give
3, â-dicarbonyls tethered to alkynes (eq 2). This reaction
appears to be a direct mechanistic analogue of the Claisen
condensation using a vinylogous carboxylic acid ester as a
starting material.
The fragmentation event also calls to mind the process
developed by Eschenmoser and Tanabe (eq 3),3,4 although
the reaction protocols are distinctly different (vide infra).
nistic pathway extends to the cross-coupling reactions of
esters with a variety of enolates and enolate analogues.
During the course of our investigations on the reaction
between cyclic vinylogous acyl triflates (1) and organolith-
ium reagents,2 we found that the cross-coupling reaction of
Herein, we report a Claisen-type condensation of vinylogous
acyl triflates, which appears to proceed via a fragmentation
pathway and is, to the best of our knowledge, unprecedented.
We chose triflate 1a (R ) Me, n ) 1 in eq 2) and the
lithium enolate of acetophenone (2a, R′ ) Ph in eq 2) as
(1) For reviews on the Claisen condensation, see: (a) Davis, B. R.;
Garratt, P. J. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon: Oxford, 1991; Vol. 2, pp 795-863. (b) Hauser, C. R.;
Hudson, D. E. Org. React. 1942, 1, 266. (c) Hauser, C. R.; Swamer, F. W.;
Adams, J. T. Org. React. 1954, 8, 59. For a review on the Dieckman
condensation, see: (d) Schaefer, J. P.; Bloomfield, J. J. Org. React. 1967,
15, 1.
(2) (a) Kamijo, S.; Dudley, G. B. J. Am. Chem. Soc. 2005, 127, 5028.
10.1021/ol0527781 CCC: $33.50
© 2006 American Chemical Society
Published on Web 12/13/2005

of 3a (Table 1). The reaction of triflate 1a with 1.4 equiv of
2a and 1.2 equiv of LiHMDS (lithium hexamethyldisilazide)
gave 3a in 56% yield along with recovered 1a (entry 1).
Treatment of 1a with 2.4 equiv of 2a and 2.2 equiv of
LiHMDS furnished the product (3a) in 85% isolated yield
(entry 2). When 1a was treated with 1.2 equiv of 2a and 2.2
equiv of LiHMDS, 3a was obtained in 70% yield (entry 3).
This stoichiometric requirement is consistent with the
traditional Claisen condensation, wherein the relatively acidic
dicarbonyl product consumes 1 equiv of base as it is formed.
We next examined the Claisen-type condensation of the
vinylogous acyl triflate 1a with various nucleophiles derived
from analogues of 2 (Table 2). As mentioned above, the
reaction between triflate 1a and acetophenone (2a, pretreated
with LiHMDS) in THF afforded acyclic alkynyl-1,3-diketone
3a5 in 85% yield (entry 1). The lithium enolate derived from
acetone gave diketone 3b in moderate yield (entry 2). The
ethyl acetate enolate produced ketoester 3c in 88% yield
(entry 3). The anion of dimethyl sulfone (2d) reacted with
1a to furnish â-ketosulfone 3d in moderate yield (entry 4),
along with a small amount of the diyne 3d′. A similar
reaction using dimethyl methylphosphonate (2e) provided
â-ketophosphonate 3e in low yield (entry 5).
Table 1. Claisen-Type Condensation of the Vinylogous Acyl
Triflate 1a with Nucleophilic Derivatives of 2aa
triflate 1a,
equiv
acetophenone 2a,
LiHMDS,
equiv
yield,
%
b
entry
equiv
1
2
3
1.0
1.0
1.0
1.4
2.4
1.2
1.2
2.2
2.2
56c
85d
70
a The triflate 1a was reacted with acetophenone 2a (pretreated with
LiHMDS) in THF at -78 to 60 °C within 80 min. b 1H NMR yield using
anisole as an internal standard unless otherwise noted. c The recovery of
1a was observed. d Isolated yield.
the prototype, and we screened to find optimal conditions
for the formation of the acyclic alkynyl-1,3-diketone 3a. The
reaction stoichiometry had a significant effect on the yield
We then explored the Claisen-type condensation using
various triflates 1 and the lithium enolate of acetophenone
(Table 3). Triflate 1b afforded the corresponding diketone
Table 2. Claisen-Type Condensation of the Vinylogous Acyl
Triflate 1a with Nucleophilic Derivativesa
Table 3. Claisen-Type Condensation of Triflates 1 with
Acetophenonea
a Triflate 1a (0.5 mmol) was reacted with the pre-nucleophile (1.2 mmol,
pretreated with 1.1 mmol of LiHMDS) in 2 mL of THF at -78 to 60 °C
within 80 min. b Isolated yield. c n-BuLi was used instead of LiHMDS.
d Diyne 3d′ was obtained in 8.4% yield.
a Triflate 1 (0.5 mmol) was reacted with acetophenone (2a, 1.2 mmol,
pretreated with 1.1 mmol of LiHMDS) in 2 mL of THF at -78 to 60 °C
within 80 min. b Isolated yield. c Decomposition of 1c.
176
Org. Lett., Vol. 8, No. 1, 2006

3f in excellent yield (entry 1). The six-membered triflates
1c-e bearing a geminal dimethyl group were next examined.
The reaction of triflate 1c, which bears a sterically congested
quaternary center R to the carbonyl group, resulted in
decomposition; no desired product (3g) was obtained (entry
2). On the other hand, the triflates such as 1d and 1e, in
which the carbonyl groups are progressively less hindered,
furnished the corresponding products 3h and 3i in 45% and
80% yield, respectively (entries 3 and 4). Accordingly, the
reaction seemed to be sensitive to the steric demands of the
substrates.6 The seven-membered triflate 1f gave the desired
product 3j in high yield (entry 5).
and the prolonged exposure of triflate 1 to the reaction
conditions would lead to its decomposition. The Grob-type
fragmentation effects C-C bond cleavage along with extru-
sion of LiOTf to give intermediate B.2 Subsequently, a
second equivalent of the enolate abstracts a proton from the
newly formed active methylene moiety to furnish intermedi-
ate C, which yields 3 upon aqueous workup.7
In summary, we describe the first examples of the Claisen-
type condensation reaction of vinylogous acyl triflates (1)
with lithium enolates and their analogues to form acyclic
alkynes bearing a 1,3-diketone-type moiety (3). The present
transformation contains an intriguing C-C bond cleavage
process initiated by the nucleophilic addition of the lithium
enolates to the carbonyl group of triflates 1.
The mechanistic pathway for this novel Claisen-type
condensation of vinylogous acyl triflates 1 with lithium
enolates generated from 2 is proposed as shown in Scheme
1. Initially, 1,2-addition of the lithium enolate to the carbonyl
Acknowledgment. This research was supported by a
grant from the James and Ester King Biomedical Research
Program, Florida Department of Health, an award from
Research Corporation, and by the FSU Department of
Chemistry and Biochemistry. S.K. is a recipient of the
Postdoctoral Fellowship for Research Abroad (2004) from
the Japan Society for the Promotion of Science (JSPS). We
thank all of these agencies for their support. We thank Dr.
Joseph Vaughn for assistance with the NMR facilities, Dr.
Umesh Goli for providing the mass spectrometry data, and
the Krafft Lab for access to their FT-IR instrument.
Scheme 1. Proposed Mechanistic Pathway for the
Claisen-Type Condensation of Vinylogous Acyl Triflates 1 with
Lithium Enolates
Supporting Information Available: Experimental pro-
cedures, characterization data for products 3, and details of
a deuterium-labeling experiment in support of the mechanism
proposed in Scheme 1. This material is available free of
charge via the Internet at http://pub.acs.org.
OL0527781
(4) (a) Grob, C. A.; Schiess, P. W. Angew. Chem., Int. Ed. Engl. 1967,
6, 1. (b) Grob, C. A. Angew. Chem., Int. Ed. Engl. 1969, 8, 535. (c) Wharton,
P. S.; Hiegel, G. A. J. Org. Chem. 1965, 30, 3254. (d) Weyerstahl, P.;
Marschall, H. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon: Oxford, 1991; Vol. 6, pp 1041-1070.
(5) 1,3-Diketones 3a, 3b, 3f, and 3h-k exist predominantly in the enol
form in CDCl3. See Supporting Information for details.
(6) The reactions of enolates derived from more hindered esters such as
ethyl valerate and ethyl isobutyrate with triflate 1a did not proceed well.
In the former case, we could detect the corresponding product in the crude
mixture by mass spectrometry (ESI, C14H2203Na; M+ ) 261.1); however,
the yield was quite low and we could not isolate the desired product in
acceptable purity. In the latter case, the reaction resulted in decomposition
of triflate 1a, and a significant amount of ethyl isobutyrate was recovered.
(7) An alternative pathway, enolization of 1 and fragmentation to provide
a ketene intermediate, is inconsistent with a deuterium-labeling experiment.
See the Supporting Information for details.
group of triflate 1 generates intermediate A. Steric congestion
around the reacting site would retard this addition process,
(3) (a) Eschenmoser, A.; Felix, D.; Ohloff, G. HelV. Chim. Acta 1967,
50, 708. (b) Felix, D.; Shreiber, J.; Ohloff, G.; Eschenmoser, A. HelV. Chim.
Acta 1971, 54, 2896. (c) Tanabe, M.; Crowe, D. F.; Dehn, R. L. Tetrahedron
Lett. 1967, 3943. (d) Tanabe, M.; Crowe, D. F.; Dehn, R. L.; Detre, G.
Tetrahedron Lett. 1967, 3739.
Org. Lett., Vol. 8, No. 1, 2006
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