Hetero [4 + 2] cycloadditions of (trialkylsilyl)vinylketenes. Synthesis of α,β-unsaturated δ-valerolactones and -lactams

Article abstract of DOI:10.1021/ol9907217

(Matrix presented) Hetero Diels-Alder reactions of (trialkylsilyl)vinylketenes (TAS-vinylketenes) with carbonyl and imino dienophiles are described. TAS-vinylketenes participate as electron-rich dienes in [4 + 2] cycloadditions with diethyl ketomalonate t

Full text of DOI:10.1021/ol9907217

ORGANIC
LETTERS
1999
Vol. 1, No. 4
641-644
Hetero [4 + 2] Cycloadditions of
(Trialkylsilyl)vinylketenes. Synthesis of
r,â-Unsaturated δ-Valerolactones and
-Lactams
Dawn M. Bennett, Iwao Okamoto, and Rick L. Danheiser*
Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
danheisr@mit.edu
Received June 7, 1999
ABSTRACT
Hetero Diels−Alder reactions of (trialkylsilyl)vinylketenes (TAS-vinylketenes) with carbonyl and imino dienophiles are described. TAS-vinylketenes
participate as electron-rich dienes in [4 + 2] cycloadditions with diethyl ketomalonate to afford r,â-unsaturated δ-valerolactones in good
yield. Nonenolizable N-alkyl- and N-(trimethylsilyl)imines combine with TAS-vinylketenes to furnish r,â-unsaturated δ-valerolactams. In contrast
to most Diels−Alder reactions involving unactivated imines, these cycloadditions do not require promotion by Lewis acids and in general
proceed with a high degree of stereoselectivity.
The utility of vinylketenes1 in organic synthesis is well-
established. Research in our laboratory has shown that [2 +
2] cycloadditions of vinylketenes can serve as triggering steps
in powerful “pericyclic cascade” strategies for the synthesis
of six- and eight-membered carbocyclic compounds.2 In
related studies, we have demonstrated that (trialkylsilyl)-
vinylketenes (TAS-vinylketenes) are remarkably stable ketenes
which exhibit reactivity that is complementary to other
vinylketenes in many reactions.3,4 Silyl substitutents5 suppress
the tendency of vinylketenes to undergo dimerization and
[2 + 2] cycloaddition, allowing them to express their
underlying reactivity as electron-rich conjugated dienes and
permitting them to serve as building blocks in novel synthetic
routes to five- and six-membered rings.3,4,6 In this Letter we
now report the extension of this chemistry to include hetero
Diels-Alder reactions of TAS-vinylketenes with electron-
deficient carbonyl compounds and N-alkyl- and N-(trialkyl-
silyl)imines (eq 1).
(1) Reviewed in: Tidwell, T. T. Ketenes; Wiley: New York, 1991.
(2) (a) Danheiser, R. L.; Martinez-Davila, C.; Sard, H. Tetrahedron 1981,
37, 3943. (b) Danheiser, R. L.; Gee, S. K.; Sard, H. J. Am. Chem. Soc.
1982, 104, 7670. (c) Danheiser, R. L.; Gee, S. K. J. Org. Chem. 1984, 49,
1672. (d) Danheiser, R. L.; Brisbois, R. G.; Kowalczyk, J. J.; Miller, R. F.
J. Am. Chem. Soc. 1990, 112, 3093.
(3) (a) Danheiser, R. L.; Sard, H. J. Org. Chem. 1980, 45, 4810. (b)
Loebach, J. L.; Bennett, D. M.; Danheiser, R. L. J. Org. Chem. 1998, 63,
8380.
(4) Loebach, J. L.; Bennett, D. M.; Danheiser, R. L. J. Am. Chem. Soc.
1998, 120, 9690.
(5) For reviews on the chemistry of silylketenes, see ref 1 and the
following: (a) Pommier, A.; Kocienski, P.; Pons, J.-M. J. Chem. Soc., Perkin
Trans. 1 1998, 13, 2105. (b) Schaumann, E.; Scheiblich, S. In Methoden
der Organischen Chemie (Houben-Weyl); Kropf, E., Schaumann, E., Eds.;
Thieme: Stuttgart, Germany, 1993; Vol. E15, Part 2.
The TAS-vinylketenes (1-4) required for this study were
prepared by two methods: (1) the photochemical Wolff
(6) For related reactions involving silylated bisketenes, see: Colomvakos,
J. D.; Egle, I.; Ma, J.; Pole, D. L.; Tidwell, T. T.; Warkentin, J. J. Org.
Chem. 1996, 61, 9522.
10.1021/ol9907217 CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/08/1999

rearrangement of R′-silyl-R′-diazo-R,â-unsaturated ketones3b
and (2) the 4π-electrocyclic ring opening of 2-silylcyclobuten-
ones3b,6 (eq 2). The requisite photo Wolff substrates were
acetonitrile with 1.5 equiv of CO(CO2Et)2 (6) for 15 min
provided the desired valerolactone 7 in 94% yield after silica
gel chromatography.11 Cycloaddition with the more sterically
demanding vinylketene 3 proceeded similarly in 2 h to afford
bicyclic lactone 8. As predicted, in these regiospecific
cycloadditions the carbonyl oxygen of the TAS-vinylketene
functions as a powerful electron donor substituent to direct
the regiochemical course of the reaction.
The oxa Diels-Alder reaction can also be carried out by
generating TAS-vinylketenes in situ via electrocyclic ring
opening of cyclobutenones. For example, heating cyclobuten-
one 5 and 1.5 equiv of CO(CO2Et)2 in acetonitrile at reflux
for 15 h furnished lactone 9 in 92% yield. Protodesilylation
of this cycloadduct was readily achieved in quantitative yield
upon exposure to methanesulfonic acid in dichloromethane
(eq 3).12
synthesized by silylation7 of the corresponding diazo ketones
which were obtained by employing our detrifluoroacetylative
diazo transfer procedure.8 Cyclobutenone 53b was prepared
via the [2 + 2] cycloaddition of dichloroketene with (triethyl-
silyl)phenylacetylene followed by reductive dechlorination.9
“Oxa Diels-Alder reactions” of carbonyl compounds and
conjugated dienes provide valuable synthetic routes to 5,6-
dihydropyrans and other six-membered oxygen ring com-
pounds.10 The most common variants of this cycloaddition
process involve reactions of electron-deficient carbonyl
groups and cycloadditions of simple aldehydes and ketones
activated by coordination with Lewis acids. We tested the
feasibility of conducting oxa Diels-Alder reactions with
TAS-vinylketenes by first examining their reaction with
commercially available diethyl ketomalonate. As summarized
in Table 1, heating a solution of TAS-vinylketene 1 in
Attempts to extend oxa [4 + 2] cycloadditions of TAS-
vinylketenes to include unactivated carbonyl compounds as
dienophiles have not been fruitful. Heating vinylketene 1 with
pivaldehyde resulted in no detectable reaction, and attempts
to promote the cycloaddition using Lewis acids such as
Me2AlCl and BF3‚OEt2 led only to slow decomposition of
the ketene.
We next turned our attention to examining the application
of TAS-vinylketenes in hetero [4 + 2] cycloadditions leading
to nitrogen heterocycles. Aza Diels-Alder reactions of imino
dienophiles have found considerable use in recent years as
methods for the synthesis of tetrahydropyridines, 4-piperi-
dones, and other six-membered N-heterocycles.10 Especially
valuable are the reactions of electron-deficient N-sulfonyl
and N-acyl imines and immonium salts. Neutral, unactivated
imines fail to engage in hetero [4 + 2] cycloadditions unless
paired with electron-deficient dienes (inverse electron de-
mand cycloadditions) or with highly electron-rich dienes in
the presence of Lewis acids. We focused our initial studies
on unactivated imines which we hoped would combine with
TAS-vinylketenes to provide expeditious routes to R,â-
unsaturated 2-piperidones (δ-valerolactams).
Table 1. Cycloadditions of TAS-vinylketenes and Diethyl
Ketomalonate (6)a
(7) (a) Maas, G.; Bru¨ckmann, R. J. Org. Chem. 1985, 50, 2801. (b)
Bru¨ckmann, R.; Schneider, K.; Maas, G. Tetrahedron 1989, 45, 5517.
(8) (a) Danheiser, R. L.; Miller, R. F.; Brisbois, R. G.; Park, S. Z. J.
Org. Chem. 1990, 55, 1959. (b) Danheiser, R. L.; Miller, R. F.; Brisbois,
R. G. Org. Synth. 1995, 73, 134.
(9) (a) Danheiser, R. L.; Sard, H. Tetrahedron Lett. 1983, 24, 23. (b)
Danheiser, R. L.; Savariar, S. Tetrahedron Lett. 1987, 28, 3299. (c)
Danheiser, R. L.; Savariar, S.; Cha, D. D. Organic Syntheses; Wiley: New
York, 1993; Collect. Vol. VIII, pp 82-86.
(10) For reviews on the hetero Diels-Alder reaction, see: (a) Tietze, L.
F.; Kettschau, G. Top. Curr. Chem. 1997, 189, 1. (b) Boger, D. L.; Weinreb,
S. M. Hetero Diels-Alder Methodology in Organic Synthesis; Academic
Press: San Diego, 1987. (c) Weinreb, S. M. Heterodienophile Additions to
Dienes. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I.,
Eds.; Pergamon: Oxford, 1991; Vol. 5, p 401.
(11) Infrared, 1H NMR, 13C NMR, and elemental analyses were fully
consistent with the assigned structures (see Supporting Information).
(12) Attempted desilylation of 9 with n-Bu4NF in THF (25 °C, 30 min)
led to a complex mixture of products.
642
Org. Lett., Vol. 1, No. 4, 1999

We initially examined reactions involving N-(trimethyl-
silyl)imines13 in the hope that these derivatives might serve
as stable equivalents for imines of the general type R2CdNH.
Barluenga has shown that N-(trimethylsilyl)imines will
combine with highly electron-rich 2-aminobutadienes in the
presence of the Lewis acid promoter zinc chloride.14 As
summarized in Table 2, we have found that nonenolizable
N-(trimethylsilyl)imines readily engage in [4 + 2] cyclo-
additions with TAS-vinylketenes simply upon heating in
acetonitrile or at room temperature in the case of reactions
conducted without solvent. No Lewis acid is required to
promote these hetero Diels-Alder reactions. The initial
cycloadducts, which are either N- or O-(trimethylsilyl)
derivatives, undergo protodesilylation upon silica gel chro-
matography to afford the desired lactams 15-23 in good to
excellent yield.11 Particularly noteworthy is the stereoselec-
tivity of these cycloadditions. Reactions involving ketenes
1 and 2 (entries 1, 2, and 5) afforded in each case a single
cis-substituted product, while reactions of cyclohexenylketene
3 led to the sterically less crowded exo products 17, 20, and
23.15
Table 2. Cycloadditions of TAS-vinylketenes with
N-(Trimethylsilyl)imines
Attempts to extend this chemistry to include enolizable
N-(trimethylsilyl)imines (e.g., CH3CHdNSiMe3) have not
been successful, probably due to the instability of these
imines at the temperatures necessary for cycloaddition.
Efforts to employ TAS-ketenimines (R3SiNdCdCR1R2) as
dienophiles also led to complex mixtures of products. On
the other hand, simple N-alkylimines do function as reactive
dienophiles in cycloadditions with TAS-vinylketenes, as
illustrated with the reaction of N-(methyl)benzaldimine
outlined in eq 4. Interestingly, this cycloaddition produced
predominantly the trans-substituted cycloadduct, in contrast
to the reactions of 1 with N-(trimethylsilyl)imines 11 and
12. Finally, attempts thus far to engage more sterically
demanding imines such as N-((S)-R-methylbenzyl)benz-
aldimine and 2-phenyl-1-pyrroline in these hetero Diels-
Alder reactions have not been successful, and no reaction
was observed in attempts to react TAS-vinylketenes with
certain amidine, hydrazone, and imidate derivatives.
Protodesilylation of the aza Diels-Alder cycloadducts was
best achieved by treatment with 5 equiv of methanesulfonic
acid in dichloromethane at reflux; under these condi-
tions triethylsilyl-substituted cycloadducts undergo clean
(13) For the synthesis and chemistry of N-silyl imines, see: Panunzio,
M.; Zarontonello, P. Org. Process Res. DeV. 1998, 1, 49.
(14) (a) Barluenga, J.; Aznar, F.; Valde´s, C.; Cabal, M.-P. J. Org. Chem.
1993, 58, 3391. (b) Barleunga, J.; Aznar, F.; Valde´s, C.; Mart´ın, A.; Garc´ıa-
Granda, S.; Mart´ın, E. J. Am. Chem. Soc. 1993, 115, 4403.
(15) Stereochemical assignments were made on the basis of 1H NMR
difference NOE experiments.
desilylation in excellent yield (e.g., eq 5). Under similar con-
ditions triisopropylsilyl derivatives also undergo desilyl-
Org. Lett., Vol. 1, No. 4, 1999
643

ation; however, in these cases the resulting lactams were
found to be difficult to separate from byproducts of the
reaction.
Two observations suggest that an analogous stepwise
pathway represents a plausible alternative for the reactions
of TAS-vinylketenes and imines. First, it is reasonable to
expect that nucleophilic addition of imines to TAS-vinyl-
ketenes can take place under our cycloaddition conditions
since we have observed that Et2NH adds to vinylketene 2 in
acetonitrile at 50 °C in 20 min to afford the expected mixture
of isomeric unsaturated amides. Also noteworthy are the
results of experiments carried out with N-(silyl)imine 11 and
TIPS-ketene 27.17 Under conditions where [4 + 2] cyclo-
addition of this imine with TAS-vinylketene 1 is complete,
no reaction with 27 occurs, although a good yield of the [2
+ 2] cycloadduct 28 is obtained by reaction without solvent
at higher temperature (eq 6). This observation can be
Further studies will be necessary to develop a full
understanding of the mechanistic basis of the stereochemical
course of these cycloadditions. The Diels-Alder reactions
of TAS-vinylketenes with electron-deficient alkenes studied
previously in our laboratory3 were found to proceed supra-
facially with respect to the dienophile and to afford endo
cycloadducts, in accord with a concerted [4 + 2] mechanism.
We likewise favor a concerted mechanism for the reactions
of TAS-vinylketenes with diethyl ketomalonate; however,
at this time we do not believe it is possible to distinguish
between concerted and stepwise pathways (Scheme 1) in the
explained by the operation of different mechanisms for the
two types of cycloadditions: stepwise [2 + 2] for 27 and
concerted [4 + 2] for the much more facile reaction of
vinylketene 1. Alternatively, both reactions may proceed via
stepwise mechanisms in which the rate-determining 6π
electrocyclic closure in the [4 + 2] process occurs faster
than the 4π electrocyclization involved in the [2 + 2] reaction
of 27. Further studies are planned to resolve this mechanistic
issue and to explore the further application of these hetero
Diels-Alder reactions in organic synthesis.
Scheme 1
Acknowledgment. We thank the National Institutes of
Health (Grant GM 28273) and the Pharmacia & Upjohn
Company for generous financial support. D.M.B. was sup-
ported in part as a National Science Foundation Predoctoral
Fellow, and I.O. was supported as a J.S.P.S. Research Fellow.
case of the imine cycloadditions. Note that the indicated
stepwise pathway is reminiscent of the mechanism generally
accepted for the [2 + 2] cycloadditions of ketenes and imines
(the Staudinger reaction).16 In those [2 + 2] processes,
nucleophilic addition of an imine to a ketene produces a
zwitterionic intermediate which undergoes conrotatory 4π
electrocyclic ring closure to afford a â-lactam.
Supporting Information Available: Experimental pro-
cedures, characterization data, and H NMR spectra for all
cycloaddition products. This material is available free of
charge via the Internet at http://pubs.acs.org.
1
OL9907217
(17) The [2 + 2] cycloaddition of N-silyl imines with silylketenes has
not been reported previously, although Staudinger reactions of silyl imines
with ketenes (generated by dehydrochlorination of acyl chlorides) have been
studied extensively by Panunzio and co-workers. See: Bacchi, S.; Bongini,
A.; Panunzio, M.; Villa, M. Synlett 1998, 843 and references therein.
(16) For a review on [2 + 2] cycloadditions of imines and ketenes, see:
Georg, G. I.; Ravikumar, V. T. In The Organic Chemistry of â-Lactams;
Georg, G. I., Ed.; VCH: New York, 1993; pp 295-368.
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Org. Lett., Vol. 1, No. 4, 1999