Reactions of (Trialkylsilyl)vinylketenes with lithium ynolates: A new benzannulation strategy

Article abstract of DOI:10.1021/ol051307b

(Chemical Equation Presented) (Trialkylsilyl)vinylketenes react with lithium ynolates to produce highly substituted phenols in a new benzannulation strategy that proceeds via the 6π electrocyclization of an intermediate 3-(oxido)dienylketene.

Full text of DOI:10.1021/ol051307b

ORGANIC
LETTERS
2005
Vol. 7, No. 18
3905-3908
Reactions of (Trialkylsilyl)vinylketenes
with Lithium Ynolates: A New
Benzannulation Strategy
Wesley F. Austin, Yongjun Zhang, and Rick L. Danheiser*
Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
danheisr@mit.edu
Received June 3, 2005
ABSTRACT
(Trialkylsilyl)vinylketenes react with lithium ynolates to produce highly substituted phenols in a new benzannulation strategy that proceeds
via the 6 electrocyclization of an intermediate 3-(oxido)dienylketene.
π
Vinylketenes1 function as versatile four-carbon building
blocks in a variety of useful methods for the synthesis of
carbocyclic and heterocyclic compounds. For example,
research in our laboratory has shown that [2 + 2] cyclo-
additions of vinylketenes can serve as triggering steps in
several “pericyclic cascade” strategies for the synthesis of
six- and eight-membered carbocyclic compounds.2 Like most
ketenes, however, vinylketenes are rarely isolable species
and generally must be generated as transient intermediates
for in situ trapping with ketenophilic π bonds. In previous
studies, we have demonstrated that (trialkylsilyl)vinylketenes
(“TAS-vinylketenes”) are remarkably stable ketenes and
exhibit reactivity complementary to other vinylketenes in
many useful synthetic reactions. In these transformations,
the silyl substituent3 suppresses the tendency of vinylketenes
to undergo dimerization and [2 + 2] cycloaddition, allowing
them to express their underlying reactivity as electron-rich
dienes in Diels-Alder cycloadditions4 and as reactive
carbonyl compounds in [4 + 1] annulation reactions.5,6 In
this Letter we now report a new transformation of these
versatile synthons: the reaction of TAS-vinylketenes with
lithium ynolates in a new benzannulation strategy for the
synthesis of substituted phenols (eq 1).
(1) ) Reviewed in: Tidwell, T. T. Ketenes; Wiley: New York, 1995.
(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) For reviews of the chemistry of silylketenes, see ref 1 and (a)
Pommier, A.; Kocienski, P.; Pons, J.-M. J. Chem. Soc., Perkin Trans. 1
1998, 2105. (b) Schaumann, E.; Scheiblich, S. In Methoden der Organischen
Chemie (Houben Weyl); Kropf, E., Schaumann, E., Eds.; Thieme: Stuttgart,
Germany, 1993; Vol. E15, parts 2 and 3. (c) Pons, J.-M.; Kocienski, P. J.
In Science of Synthesis: Houben Weyl Methods of Molecular Transforma-
tions; Fleming, I., Ed.; Thieme: Stuttgart, Germany; Vol. 4; section 4.31.
The TAS-vinylketenes 6a-6d required for this investiga-
tion were prepared via the photochemical Wolff rearrange-
(4) (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. (c) Bennett, D. M.; Okamoto, I.; Danheiser, R. L. Org. Lett. 1999, 1,
641.
(5) (a) Loebach, J. L.; Bennett, D. M.; Danheiser, R. L. J. Am. Chem.
Soc. 1998, 120, 9690. (b) Dalton, A. M.; Zhang, Y.; Davie, C. P.; Danheiser,
R. L. Org. Lett. 2002, 4, 2465. (c) Rigby, J. H.; Wang, Z. Org. Lett. 2003,
5, 263. (d) Davie, C. P.; Danheiser, R. L. Angew. Chem., Int. Ed. In press.
10.1021/ol051307b CCC: $30.25
© 2005 American Chemical Society
Published on Web 08/12/2005

ment of R′-silyl-R′-diazo-R,â-unsaturated ketones4b (Scheme
1). The requisite photo-Wolff substrates (5a-5d) were
Scheme 2 .
Scheme 1
a 9a: ref 10. b 9b: Danheiser, R. L.; Helgason, A. L. J. Am.
Chem. Soc. 1994, 116, 9471. c 9d: Zang, L.; Kozmin, S. A. J. Am.
Chem. Soc. 2004, 126, 10204. d 9e: Sweis, R. F.; Schramm, M.
P.; Kozmin, S. A. J. Am. Chem. Soc. 2004, 126, 7442.
in one step from readily available acetylenes or esters. As
shown in Scheme 2, siloxy alkynes 9d-9g were thus
prepared in 69-90% yield employing the method of Julia,12
and alkynes 9a-9c were obtained via the Kowalski homolo-
gation of esters 7a-7c.10,13 As noted previously, these TIPS
ynol ethers can be purified by distillation or careful chro-
matography and are stable to extended storage in solution
at 0 °C.
a
For the prior preparation of 4a,b, 5a,b, and 6a,b, see ref 4b.
synthesized by silylation7 of the corresponding diazo ketones
(4a-4d), which were obtained employing our detrifluoro-
acetylative diazo transfer procedure.8 As noted previously,
TAS-vinylketenes are remarkably robust ketenes, stable at
25 °C and at mildly elevated temperatures, and amenable to
purification using conventional silica gel chromatography.
Scheme 3 outlines the mechanistic pathway envisaged for
the proposed ynolate benzannulation as well as several of
the possible side reactions that we anticipated might compete
with the desired reaction. C-Acylation of the ynolate by the
TAS-vinylketene was expected to produce intermediate 10,
with addition to the ketene occurring anti to the bulky
trialkylsilyl group to afford the indicated (Z)-enolate. Several
modes of cyclization for this densely functionalized inter-
mediate are then conceivable. The addition of ynolates to
aldehydes and ketones leads to the formation of â-lactone
enolates,9 and an analogous reaction in this case would give
rise to products of type 12. An alternative mode of ring
closure would generate the four-membered carbocycle 13,
an enolate derivative of a substituted 1,3-cyclobutanedione.
Our expectation, however, was that intermediate 10 would
most likely undergo facile 6π electrocyclic ring closure to
afford the desired cyclohexadienone 11.14-16 Favoring this
mode of cyclization is the (Z)-enolate geometry of 10, which
enforces close proximity between the C-1 and C-6 carbon
atoms at which bond formation is desired to occur. Also
As shown in eq 1, lithium ynolates (1) serve as the second
reaction partner in the proposed benzannulation. Recent
studies have demonstrated that “ynolate anions” function as
valuable synthetic intermediates in a number of useful
transformations, and several reliable methods are now
available for their preparation.9 For our initial studies, we
focused our attention on the generation of lithium ynolates
via the cleavage of siloxy alkynes (“silyl ynol ethers”) with
methyllithium. This method, first described by Kowalski,10
is a variant of the well-known strategy for the regiospecific
generation of enolates introduced by Stork and Hudrlik.11
For our purposes, this process offered the attraction that it
takes place under mild conditions and produces only inert
tetraalkylsilanes as byproducts. In addition, the siloxy alkynes
that serve as ynolate precursors can be conveniently prepared
(6) For related reactions involving silylated bisketenes, see: (a) Colom-
vakos, J. D.; Egle, I.; Ma, J.; Pole, D. L.; Tidwell, T. T.; Warkentin, J. J.
Org. Chem. 1996, 61, 9522. (b) Huang, W.; Tidwell, T. T. Synthesis 2000,
457. (c) Allen, A. D.; Huang, W.-W.; Moore, P. A.; Far, A. R.; Tidwell, T.
T. J. Org. Chem. 2000, 65, 5676.
(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. Organic Syntheses; Wiley: New York, 1998; Collect. Vol. IX, p
197.
(12) Julia, M.; Saint-Jalmes, V. P.; Verpeaux, J.-N. Synlett 1993, 233.
(13) Siloxy alkyne 9c (see Supporting Information) was prepared using
a two-step variant of the Kowalski reaction; see: (a) Kowalski, C. J.; Fields,
K. W. J. Am. Chem. Soc. 1982, 104, 321. (b) Smith, A. B., III; Adams, C.
M.; Kozmin, S. A.; Paone, D. V. J. Am. Chem. Soc. 2001, 123, 5925.
(14) The possibility that intermediate 11 might form via a concerted
[4 + 2] cycloaddition of 1 and TAS-vinylketene 2 cannot be excluded.
(15) For a discussion of the 6π electrocyclization of 3-oxido-1,3,5-
hexatrienes, see: Magnus, P. NouV. J. Chem. 1978, 2, 555.
(16) For prior examples of 6π electrocyclization reactions involving
enolate derivatives, see: (a) White, J. D.; Skeean, R. W. J. Am. Chem.
Soc. 1978, 100, 6296. (b) White, J. D.; Skeean, R. W.; Trammell, G. L. J.
Org. Chem. 1985, 50, 1939. (c) Magomedov, N. A.; Ruggiero, P. L.; Tang,
Y. J. Am. Chem. Soc. 2004, 126, 1624. (d) Magomedov, N. A.; Ruggiero,
P. L.; Tang, Y. Org. Lett. 2004, 6, 3373 and references therein.
(9) For reviews of the chemistry of ynolates, see: (a) Shindo, M.
Synthesis 2003, 2275. (b) Shindo, M. Chem. Soc. ReV. 1998, 27, 367.
(10) Kowalski, C. J.; Lal, G. S.; Haque, M. S. J. Am. Chem. Soc. 1986,
108, 7127.
(11) Stork, G.; Hudrlik, P. F. J. Am. Chem. Soc. 1968, 90, 4464.
3906
Org. Lett., Vol. 7, No. 18, 2005

Scheme 3
important is the significant increase in charge stabilization
that should develop in the transition state leading to the 1,3-
dicarbonyl enolate system in 11. It was our expectation that
these factors would suffice to favor the desired mode of ring
Table 1. Benzannulation via Reaction of TAS-Vinylketenes with Lithium Ynolates
a Isolated yield of products purified by column chromatography.
Org. Lett., Vol. 7, No. 18, 2005
3907

closure over alternative cyclization pathways and inter-
molecular condensation reactions.
for the TIPS derivative 9f as the ynolate precursor (entry
8). Cleavage of this siloxy alkyne with MeLi is complete
within minutes, and upon reaction with TAS-vinylketene 6b
the desired benzannulation product 22 is obtained in good
yield.
The feasibility of the benzannulation was initially inves-
tigated using TAS-vinylketene 6a and the ynolate derived
from the siloxy hexyne 9e. Exposure of 9e to 1 equiv of
methyllithium in THF at room temperature led to complete
consumption of the siloxy alkyne within 3 h as monitored
by TLC analysis. Upon addition of TAS-vinylketene 6a, a
new aromatic product rapidly appeared that was isolated in
62% yield after purification by silica gel chromatography.
Interestingly, this benzannulation product was identified as
the silyl ether 15 (Table 1) rather than the originally expected
resorcinol of type 14. We speculate that the initially formed
electrocyclization product 11 isomerizes under the conditions
of the benzannulation to produce a 6-silyl-2,4-cyclohexadi-
enone intermediate that aromatizes via a 1,3 carbon f
oxygen silyl shift. 1,3-Silyl shifts in R-silyl ketones to form
silyl enol ethers are well-known processes,17 and related
rearrangements involving silylcyclohexadienones have been
observed in our laboratory4b and others.18
In summary, TAS-vinylketenes react with lithium ynolates
in a regiocontrolled benzannulation process that provides
efficient access to highly substituted aromatic compounds.
We anticipate that these annulation products should serve
as useful intermediates in a variety of further synthetic
transformations. Phenols such as 21 and 22 are of particular
interest, as the unsaturated ortho substitutents can provide
the basis for subsequent cyclization reactions to form a
variety of oxygen heterocycles including benzofurans and
benzopyrans.22 For example, as illustrated in Scheme 4,
Previous studies in our laboratory have demonstrated that
TAS-vinylketenes behave as electron-rich dienes in Diels-
Alder reactions and react best with electron-deficient
dienophiles.4b,c In view of these prior observations, we were
not surprised to find that no reaction occurs upon heating
TAS-vinylketene 6a and siloxy alkyne 9e in refluxing
toluene, and attempted reaction in the presence of Lewis and
Bronsted acids (e.g., ZnI2, TiCl4, AgNTf2, HNTf2) resulted
only in complex mixtures of products.
Table 1 delineates the scope of the ynolate benzannulation
reaction. Optimization studies revealed methyllithium to be
the most effective agent for the generation of ynolates from
siloxy alkynes 9a-9g, and low yields of the desired
benzannulation products were obtained when TBAF, TBAT,
or KOEt19 were substituted for MeLi in the reaction. A
variety of siloxy alkynes and vinylketenes participate in the
benzannulation, and branching is accommodated on either
annulation component. Unfortunately, attempts thus far to
extend the reaction to include TAS-arylketenes have not been
successful. In addition, low yields of the desired product were
obtained upon attempted benzannulation with the allyl-
substituted acetylene 9f, apparently as a result of competitive
metalation at the methylene carbon by MeLi during the
ynolate generation step.20 This problem was easily circum-
vented, however, by substituting the TBDMS ynol ether 2321
Scheme 4
treatment of 22 with catalytic PdCl2(MeCN)2 in the presence
of benzoquinone and LiCl23 furnished the tetrahydronaph-
thofuran 24 in good yield.
Acknowledgment. We thank the National Institutes of
Health (GM 28273) and Merck Research Laboratories for
generous financial support. Y.Z. was supported by a Po Ting
Ip Fellowship.
Supporting Information Available: Experimental pro-
cedures and characterization data for 4c,d, 5c,d, 6c,d, 9c,f,g,
and 15-24. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL051307B
(20) The metalation of 1-phenyl-4-penten-1-yne with MeLi has previously
been reported: Klein, J.; Brenner, S.; Medlik, A. Isr. J. Chem. 1971, 9,
177.
(21) The TBDMS siloxy alkyne 23 was prepared from allylacetylene
by employing the method of Julia (see Supporting Information). In general,
however, the use of TIPS derivatives is preferred because of their increased
stability to purification and storage.
(22) Reviewed in: Zeni, G.; Larock, R. C. Chem. ReV. 2004, 104, 2285.
(23) These conditions have been employed by Hegedus for the cyclization
of 2-allylanilines to indoles. See: Hegedus, L. S.; Allen, G. F.; Bozell, J.
J.; Waterman, E. L. J. Am. Chem. Soc. 1978, 100, 5800.
(17) For a recent theoretical study and leading references, see: Takahashi,
M.; Kira, M. J. Am. Chem. Soc. 1999, 121, 8597.
(18) (a) Moser, W. H.; Sun, L.; Huffman, J. C. Org. Lett. 2001, 3, 3389.
(b) Chamberlin, S.; Wulff, W. D. J. Org. Chem. 1994, 59, 3047. (c) Fogel,
L.; Hsung, R. P.; Wulff, W. D.; Sommer, R. D.; Rheingold, A. L. J. Am.
Chem. Soc. 2001, 123, 5580.
(19) Yu, W.; Jin, Z. Tetrahedron Lett. 2001, 42, 369.
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