Atom economy. Aldol-type products by Vanadium-catalyzed additions of allenic alcohols and aldehydes

Full text of DOI:10.1021/ja011351w

12736
J. Am. Chem. Soc. 2001, 123, 12736-12737
Scheme 1. Proposed Additon of Allenic Alcohols and
Aldehydes
Atom Economy. Aldol-Type Products by
Vanadium-Catalyzed Additions of Allenic Alcohols
and Aldehydes
Barry M. Trost,* Catrin Jonasson, and Margarita Wuchrer
Department of Chemistry, Stanford UniVersity
Stanford, California 94305-5080
ReceiVed June 4, 2001
Increasing our repertoire of simple addition reactions will
improve synthetic efficiency.1 The importance of aldol products
led us to consider nonconventional ways for their creation by
simple additions.2,3 The 1,3-transposition of allylic and propargylic
alcohols have been widely studied and are catalyzed by a wide
variety of oxo metal complexes including those derived from
vanadium,4 molybdenum,5 tungsten,6 and rhenium.7 Surprisingly,
the corresponding 1,3-transposition of the readily available allenic
alcohols has been virtually ignored. The ready availability of
allenols, such as by the LAH reduction of the mono THP ethers
of butyne-1,4-diols, makes such a strategy very attractive.10
In continuation of our program directed toward the development
of atom economical reactions catalyzed by vanadium, we initiated
a study of vanadium-catalyzed additions of allenic alcohols and
aldehydes which can generate aldol-type adducts formally derived
from an R,â-unsaturated ketone and an aldehyde, a particularly
versatile juxtaposition of functionality, a type of aldol process
that is virtually unknown.9 The proposed route for such a reaction
is given in Scheme 1. The key becomes the interception of
intermediate A by an aldehyde to give aldol B vs protonation to
enone C.
using nearly diastereomerically pure allenol and obtaining the
identical result. We only observed the E-double bond isomer
which was in accordance with the results reported by Takai.8 A
few other solvents (THF and toluene) were also screened in order
to see if the syn/anti selectivity could be improved. The reaction
in CH2Cl2, however, proved to be the best. Increasing the
concentration of the reaction did not improve the selectivity either.
Changing the catalyst to MoO2(acac)2 resulted in a mixture of
aldol product 2 and rearranged product 3 (ratio 80:20). The more
electron rich vanadium catalyst VO(OiPr)3 gave no reaction at
all. Using VO(OTMS)3 gave a much slower reaction, and aldol
product 2 could only be isolated in 21% yield after 72 h with a
syn/anti selectivity of 74/26.
Using the conditions stated above (eq 1), we explored the
generality of the reaction by varying the aldehyde (Table 1, entries
1-8).13 When we employed aromatic aldehydes (entries 1 and
2) or heteroaromatic aldehydes (entries 3-5), complete conver-
sions into aldol products 6-10 were generally observed within
36-48 h. The isolated yields were good, and usually none or a
trace amount (<10%) of the simple rearranged product 3 (eq 1)
was observed. It was necessary to protect the amine in 2-pyr-
rolecarboxaldehyde to obtain a good yield (entry 5). Running the
reaction with the free amine resulted in a complex mixture of
products. Aliphatic aldehydes also seem to be efficiently converted
to the aldol products. Performing the reaction in the presence of
butyraldehyde gave aldol product 11 in 79% yield with a syn/
anti ratio of 78/22 (Table 1, entry 6). More sterically hindered
aldehydes gave lower yields and a corresponding significant
We first studied the reaction of allenic alcohol 1 having a
phenyl group R to the alcohol since this has shown some
promising result in the aldol-type reactions with propargylic
alcohols.8 The reaction of allenic alcohol 110 (1 equiv), which is
a nearly 1:1 diastereomeric mixture, with benzaldehyde (1.2 equiv)
in the presence of 5 mol % VO(OSiPh3)3 (4) in CH2Cl2 (2.5 M)
at 55 °C was investigated (eq 1). The reaction was finished after
18 h and gave aldol product 211 (66%), together with the
rearranged product 3 (ratio 75:25). Lowering the temperature to
room temperature resulted in an improved reaction, and only the
aldol product 2 was isolated in 86% yield with a syn/anti
selectivity of 80/20.12 That this diastereoselectivity does not derive
from the diastereomeric nature of the allenol was established by
(10) The allenic alcohols were prepared according to known procedures.
(a) Kimura, M.; Tanaka, S.; Tamaru, Y. Bull. Chem. Soc. Jpn. 1995, 68, 1689.
(b) Cowie, J. S.; Landor, P. D.; Landor, S. R. J. Chem. Soc., Perkin Trans. 1
1973, 720. (c) Ma, S.; Zhao, S. J. Am. Chem. Soc. 1999, 121, 7943. Further
methods: (d) Crabbe, P. J. Chem. Soc., Chem. Commun. 1979, 859. (e)
Katsuhira, T.; Harada, T.; Oku, A. J. Org. Chem. 1994, 59, 4010. (f)
Masauyama, Y.; Watabe, A.; Ito, A.; Kurusu, Y. Chem. Commun. 2000, 2009.
(g) Creary, X. J. Am. Chem. Soc. 1977, 99, 7632. (h) Isaac, M. B.; Chan,
T.-H. Chem. Commun. 1995, 1003.
(11) New compounds have been characterized spectroscopically, and
elemental composition has been established by high-resolution mass spec-
troscopy and combustion analysis.
(12) The syn/anti selectivity was determined by comparing the coupling
constants for the syn and anti isomers with similar compounds. Examples:
(a) Danishefsky, S. J.; Larson, E.; Askin, D.; Kato, N. J. Am. Chem. Soc.
1985, 107, 1246. (b) Kobayashi, S.; Nagayama, S.; Busujima, T. Tetrahedron
1999, 29, 8739. (c) Kawakami, T.; Miyatake, M.; Shibata, I.; Baba, A. J.
Org. Chem. 1996, 61, 376.
(1) (a) Trost, B. M. Science 1991, 254, 1471. (b) Trost, B. M. Angew.
Chem., Int. Ed. Engl. 1995, 34, 259.
(2) Mukaiyama, T. Org React. 1982, 28, 203. (b) Heathcock, C. H. In
Asymmetric Synthesis; Morrison, J. D., Ed.; Academic Press: New York, 1984;
Vol 3, Part B, p 111. (c) Kim, B. M., Williams, S. F., Heathcock, C. H., Eds.;
Pergamon Press: Oxford, 1991; Vol. 2, Chapter 1.7, p 239.
(3) Trost, B. M.; Oi, S. J. Am. Chem. Soc. 2001, 123, 1230.
(4) (a) Chabardes, P.; Kuntz, E.; Varagnat, J. Tetrahedron 1977, 33, 1775.
(b) Olson, G. L.; Cheung, H. C.; Morgan, K. D.; Borer, R.; Saucy, G. HelV.
Chim. Acta 1976, 59, 567. (c) Pauling, H.; Andrews, D. A.; Hindley, N. C.
HelV. Chim. Acta 1976, 59, 1233. (d) Erman, N. B.; Aoultchanko, I. S.;
Kheifitz, L. A.; Doulova, V. G.; Novikov, Y. N.; Volpine, M. E. Tetrahedron
lett. 1976, 2981.
(5) Belgacem, J.; Kress, J.; Osborn, J. A. J. Am. Chem. Soc. 1992, 114,
1501.
(6) Hosogai, T.; Fujita, Y.; Ninagawa, Y.; Nishida, T. Chem Lett. 1982,
357.
(7) Bellemin-Laponnaz, S.; Gisie, H.; Le Ny, J. P.; Osborn, J. A. Angew.
Chem., Int. Ed. Engl. 1987, 36, 976.
(13) A general procedure follows: In a screw-cap reaction vessel with a
Miniert syringe valve, aldehyde (1.2 equiv) and allenic alcohol (1.0 equiv)
were added to a solution of VO(OSiPh3)3 (5 mol %) in CH2Cl2 (2.5 M). After
the solution was stirred for 36-48 h, the solvent was evaporated in vacuo,
and the residue was purified by flash chromatography to give pure products.
(8) Matsubara, S.; Okazoe, T.; Oshima, K.; Takai, K.; Nozaki, H. Bull.
Chem. Soc. Jpn. 1985, 58, 844.
(9) Hong, B.-C.; Chin, S.-F Synth. Commun. 1997, 27, 1191.
10.1021/ja011351w CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/27/2001

Communications to the Editor
J. Am. Chem. Soc., Vol. 123, No. 50, 2001 12737
Table 1. Vanadium-Catalyzed Additions of Allenic Alcohols and
Aldehydesa
Encouraged by this result, we subjected the nonaromatic
monosubstituted allenic alcohol 19, a type of substitution pattern
that failed in the case of propargylic alcohols, to the same condi-
tions. Initially this reaction gave only recovered starting material,
but, by increasing the temperature to 60 °C and using 10% of
VO(OSiPh3)3, we were able to push the reaction to completion,
and aldol product 20 could be isolated in 72% yield (eq 3).
It was also of interest to see if the reaction could be performed
with a more sterically hindered substituent on the allene. Thus,
allenic alcohol 17b was prepared and subjected to the standard
conditions. This gave the aldol product 18b in 57% yield together
with a substantial amount of untrapped rearranged product. The
syn/anti selectivity was 88/12 (eq 2). From this observation and
the fact that the more sterically hindered aldehydes (Table 1,
entries 7, 8) also gave a lot of untrapped rearranged product, we
can conclude that the reaction is quite sensitive to steric hindrance.
The rate of aldehyde interception decreases when the substituent
on either the allene or the aldehyde becomes too large and
protonation of the dienyl oxometalate (A, Scheme 1) becomes a
major side reaction.
In conclusion, we have presented a new synthetic strategy for
the synthesis of unusual aldol-type products consisting of both
an R,â-unsaturated ketone and a â-hydroxyketone, which cannot
easily be obtained by other methods in a highly atom economic
fashion. For example, the only report of 13 involves a circuitous
route via a phosphonate olefination14snot a direct aldol addition
of benzylideneacetone to benzaldehyde, which produces the
dehydrated product dibenzylideneacetone.15 The product 14 is a
simple natural product, (()-yashabushiketol,16 and this route
represents a simpler protocol than that previously recorded.14
Given the ease of synthesis of the allenols from aldehydes and
propargyl alcohols, this new strategy can be summarized as in
eq 4 involving a series of additions and one reduction such that
a In a typical procedure the reactions were carried out at room
temperature in dichloromethane (2.5 M) employing 5 mol % of
VO(OSiPh)3, 1.2 equiv of aldehyde, and 1.0 equiv of allenic alcohol
under an atmospheric pressure of argon. The reaction times varied from
24 to 48 h. b Isolated yield after flash chromatography. c The syn/anti
1
ratio was determined by H NMR. d The allenic alcohol was added
the starting materials are from componentssacetylene, aldehyde-
1, aldehyde-2, and either an aldehyde-3 or a ketone. Further
investigations to improve the syn/anti selectivity and to develop
the reaction into an asymmetric version are underway.
slowly over a period of 6 h.
increase in the amount of the rearranged product 3 (Table 1,
entries 7, 8). The yield of the reaction of 1 with diphenylacetal-
dehyde was, however, improved from 60% to 70% by adding
the allenic alcohol slowly over 6 h. We also examined the reaction
with an unsubstituted allenic alcohol 5 (Table 1 entries 9-12).
Using the latter conditions, a range of aldehydes was shown to
undergo the vanadium-catalyzed aldol-type reaction. Most notable,
in entry 12, when p-anisaldehyde was used as the trapping agent,
a substantial amount of dehydrated product was observed, and
the aldol product 16 was only isolated in 64% yield. This is the
only case where we have seen the dehydrated product.
Acknowledgment. We thank the National Science Foundation and
the National Institutes of Health, General Medical Sciences, for their gene-
rous support. C.J. thanks the Swedish Foundation for International Coop-
eration in Research and Higher Education for a postdoctoral fellowship.
Supporting Information Available: Experimental details and char-
acterization data for compounds 1-20 (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
JA011351W
During the course of this study, we considered the possibility
of extending the reaction to include nonaromatic allenic alcohols.
Indeed, nonaromatic disubstituted allenic alcohol 17a reacted
under the standard conditions with benzaldehyde (eq 2) to give
the aldol product 18a in 86% yield and a syn/anti ratio of 77/23.
(14) Tsuge, O.; Kanemasa, S.; Nakagawa, N.; Suga, H. Bull. Chem. Soc.
Jpn. 1987, 60, 4091.
(15) (a) Claisen, L. Chem. Ber. 1881, 14, 2471. (b) Reddy, D. B.; Reddy,
A. S.; Reddy, N. S. Indian J. Chem. Sect. B 1999, 38, 1342.
(16) (a) Asakawa, Y.; Genjida, F.; Hayashi, S.; Matsuura, T. Tetrahedron
Lett. 1969, 3235. (b) Asakawa, Y. Bull. Chem. Soc. Jpn. 1970, 43, 1970.