The Baylis-Hillman condensation of α,β-conjugate cycloketones with aldehydes using diethylaluminum iodide alone as the promoter

Article abstract of DOI:10.1039/b206736f

The Baylis-Hillman condensation of three types of α,β-conjugate cycloketones with aldehydes was successfully performed by using diethylaluminum iodide as the Lewis acid promoter alone without the direct use of a Lewis base. The reaction proceeded to compl

Full text of DOI:10.1039/b206736f

The Baylis–Hillman condensation of a,b-conjugate cycloketones with
aldehydes using diethylaluminum iodide alone as the promoter†
Wei Pei, Han-Xun Wei and Guigen Li*
Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409-1061, USA.
E-mail: qeggl@ttu.edu
Received (in Corvallis, OR, USA) 8th July 2002, Accepted 3rd September 2002
First published as an Advance Article on the web 20th September 2002
The Baylis-Hillman condensation of three types of a,b-
conjugate cycloketones with aldehydes was successfully
performed by using diethylaluminum iodide as the Lewis
acid promoter alone without the direct use of a Lewis base.
The reaction proceeded to completion at 0 °C in CH2Cl2
within 24 h to give modest to good yields (53–72%).
intermediates derived from conjugate addition of Et2AlI onto
a,b-unsaturated cycloketones can be both aromatic and ali-
phatic aldehydes. Meanwhile, all three common kinds of a,b-
unsaturated cycloketones (2-cyclopeten-1-one, 2-cyclohexen-
1-one and 2-cyclohepten-1-one) proved to be the effective
Michael-type acceptors giving good yield (up to 69%, entries
1–4). As measured by GC or TLC, these a,b-unsaturated
cycloketones showed similar reaction rates. When a,b-un-
saturated acycloketones were employed, the reaction stopped at
the stage of halo aldols under current conditions. Regarding
aromatic aldehydes, both electron-withdrawing and electron-
donating substrates showed similar effectiveness. It is note-
worthy that the strong electron-donating p-methoxybenzalde-
hyde can give 53% yield (entry 5). As anticipated, the
electron-withdrawing property of p-nitrobenzaldehyde benefits
the chemical yield (72%, entry 6).
The Baylis–Hillman and related processes have become
increasingly important in synthetic organic chemistry because
the resulting adducts have an array of multifunctional groups
which can be subjected to numerous transformations.1 These
reactions usually require the direct use of Lewis bases, such as
DABCO, Ph3P and chalcogen species.2–5 Recently, we found
that the Baylis–Hillman-type reaction of a,b-unsaturated cyclo-
ketones with aldehydes can occur in the presence of TiCl4
without the use of any Lewis bases.6,7 Unfortunately, this
reaction is limited to the use of aliphatic aldehydes or those
aromatic aldehydes with strong electron withdrawing groups
(e.g., –NO2, –CF3). The limitation also exists for a,b-
unsaturated Michael acceptors. For example, when the reaction
substrates were changed to a,b-unsaturated acyclic ketones, the
reaction resulted in (Z)-2-(halomethyl)vinyl ketones.3a The later
reactions were also confirmed by using Lewis acid/Lewis base
co-promoters under different conditions.8
A slightly excess amount of a,b-unsaturated cycloketones
was found necessary to achieve the complete consumption of
aldehydes and optimized yields. There was no improvement on
Table 1 Results of Et2AlI-mediated B-H type reaction11
In the past few years, we have made many efforts to
overcome the above serious limitations. In this communication
we would like to report that the Baylis–Hillman condensation of
three types of a,b-conjugate cycloketones with aldehydes
which failed to give any products under the previous TiCl4-
based conditions can now be successfully performed by using
diethylaluminum iodide as the Lewis acid promoter alone,
without the direct use of a Lewis base. The three types of a,b-
conjugate cycloketones include a,b-unsaturated 2-cyclopeten-
1-one, 2-cyclohexen-1-one and 2-cyclohepten-1-one, as de-
scribed in Scheme 1.
Yield
(%)
Entry R-
Product
1
1
65
The reaction was carried out under the protection of nitrogen
gas, and is easy to run by simply adding the dichloromethane
solution of diethylaluminium iodide into the mixture of
aldehyde and a,b-unsaturated cycloketone. The reaction pro-
ceeded to completion at 0 °C in dichloromethane within 24 h to
give Baylis–Hillman adducts in modest to good chemical yields
which are summarized in Table 1.
2
3
2
3
56
69
As revealed in Table 1, the current reaction showed the good
scope of substrates for both Michael-type acceptors and
electrophiles. The electrophiles to react with aluminum enolate
4
5
6
7
4
5
6
7
61
53
72
61
Scheme 1
† Electronic supplementary information (ESI) available: experimental
details. 1H NMR data for compounds 1–7. See http://www.rsc.org/
suppdata/cc/b2/b206736f/
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This journal is © The Royal Society of Chemistry 2002

yields by loading more a,b-unsaturated cycloketones. Attempts
to use a substoichiometric amount of diethylaluminium iodide
(0.25 and 0.5 equiv. respectively) proved to be unsuccessful due
to the slow reaction rate: a considerable amount of aldehyde
remained even after a long period ( > 24 h). In addition, keeping
the reaction temperature low (0 °C) is also crucial. In fact, when
the reaction was carried out at room temperature, more
unknown side products were generated.
Unlike our previous TiCl4-based system, this effective
reaction is attributed to the irreversible deprotonation step
during the reaction process (step D of Scheme 2). The release of
CH3CH3 acts as a strong driving force and makes the reaction
irreversible. This step conceivably benefits both the chemical
yields and the reaction rate. This hypothesis can distinguish
diethylaluminium iodide9 from most other Lewis acids which
have been examined so far. Similarly to our TiCl4-promoted
system, the first step proceeded via the intermolecular Michael-
type pathway, which is governed by the rigid characteristic of
a,b-unsaturated cycloketones. In contrast, the Et2AlI-promoted
reaction using a,b-unsaturated thioester as the substrate is more
likely to occur through an intramolecular pathway in the
Michael-type addition step due to the flexible structure of the
a,b-unsaturated thioester.10 The later intramolecular pathway is
similar to that of haloaldol reaction promoted by TiCl4–nEt4NI
as proposed by Oshima.8a
counterparts. The use of acyclic ketones for this reaction under
new conditions will be investigated later.
In summary, the Baylis–Hillman-type reaction of a,b-
unsaturated cycloketones with various aldehydes has been
smoothly performed by using diethylaluminium iodide as the
promoter without the direct use of any Lewis bases. The
reaction showed the extended scope for both aldehydes and a,b-
unsaturated cycloketones.
We gratefully acknowledge the National Institutes of Health,
General Medical Sciences (R15-GM-60261) and the Robert A.
Welch Foundation (D-1361) for the generous support of this
work and the National Science Foundation (CHE-9808436) for
partial funding of the 500 MHz NMR spectrometer.
Notes and references
1 (a) For reviews regarding the Baylis–Hillman reaction see: E. Ciganek,
Org. React., 1997, 51, 201; (b) D. Basavaiah, P. D. Rao and R. S. Hyma,
Tetrahedron, 1996, 52, 8001; (c) For a review regarding b-branched
Baylis–Hillman adduct synthesis see: G. Li, J. Hook and H.-X. Wei, in
Recent Research Developments in Organic & Bioorganic Chemistry,
Transworld Research Network, 2001, vol. 4, p. 49.
2 (a) B. M. Trost, H. C. Tsui and F. D. Toste, J. Am. Chem. Soc., 2000,
122, 3534; (b) L. J. Brzezinski, S. Rafel and J. M. Leahy, J. Am. Chem.
Soc., 1997, 119, 4317; (c) A. G. C. Barrett, A. S. Cook and A.
Kamimura, Chem. Commun., 1998, 2533; (d) Y. Iwabuchi, M.
Nakatani, N. Yokoyama and S. Hatakeyama, J. Am. Chem. Soc., 1999,
121, 10219; (e) M. Kawamura and S. Kobayashi, Tetrahedron Lett.,
1999, 40, 1539.
3 (a) G. Li, H.-X. Wei, B. S. Phelps, D. W. Purkiss and S. H. Kim, Org.
Lett., 2001, 3, 823; (b) G. Li, H.-X. Wei, B. R. Whittlesey and N. N.
Batrice, J. Org. Chem., 1999, 64, 1061; (c) V. K. Aggarwal, A. M. M.
Castro, A. Mereu and H. Adams, Tetrahedron Lett., 2002, 43, 1577.
4 (a) V. K. Aggarwal and A. Mereu, Chem Commun., 1999, 2311; (b) P.
V. Ramachandran, M. V. R. Reddy and M. T. Rudd, Chem Commun.,
1999, 1979; (c) P. V. Ramachandran, M. V. R. Reddy and M. T. Rudd,
Chem Commun., 2001, 757; (d) M. Shi, C. Q. Li and J. K. Jiang, Chem
Commun., 2001, 833; (e) B. Alcaid, P. Almendros and C. Aragoncillo,
J. Org. Chem., 2001, 1612; (f) C. Yu, B. Liu and L. Hu, J. Org. Chem.,
2001, 5413.
This mechanism can also account for the observation that a
substoichiometric amount of diethylaluminium iodide failed to
drive the reaction to completion. Other two factors which could
benefit the reaction include the stability of the resulting cyclic
a,b-conjugate Baylis–Hillman structures and the greater re-
activity of halogeno aluminum enolates than their titanium
5 (a) T. Kataoka, T. Iwama, T. Iwamura, S. Kinoshita, Y. Tsujiyama, S.
Iwamura and S. Watanabe, Synlett, 1999, 2, 197; (b) T. Kataoka, S.
Kinoshita, H. Kinoshita, M. Fujita, T. Iwamura and S. Watanabe, Chem.
Commun., 2001, 1958.
6 (a) G. Li, H.-X. Wei and T. D. Caputo, Tetrahedron Lett., 2000, 41, 1;
(b) G. Li, J. Gao, H.-X. Wei and M. Enright, Organic Letters, 2000, 2,
617; (c) D. Basavaiah, B. Screenivasulu and J. S. Rao, Tetrahedron
Lett., 2001, 42, 1147.
7 (a) H. X. Wei, T. D. Caputo, D. W. Purkiss and G. Li, Tetrahedron,
2000, 56, 2397; (b) T. Kataoka, H. Kinoshita, S. Kinoshita, T. Iwamura
and S. Watanabe, Angew. Chem., Int. Ed., 2000, 39, 2358.
8 (a) S. Uehira, Z. Han, H. Shinokubo and K. Oshima, Org. Lett., 1999,
1, 1383; (b) M. Shi, J. K. Jiang, S. C. Cui and Y. S. Feng, J. Chem. Soc.,
Perkin Trans 1, 2001, 390.
9 (a) For the pioneering work on the application of Et2AlI for C(sp3)–
C(sp2) bond formation: M. Taniguchi, T. Hino and Y. Kishi,
Tetrahedron Lett., 1986, 39, 4767; (b) A. Itoh, S. Pzawa, K. Oshima and
H. Nozaki, Bull. Chem. Soc. Jpn., 1981, 54, 274.
10 W. Pei, H.-X. Wei and G. Li, Chem. Commun., 2002, 1856.
11 For typical procedure and analytic data see EPI.
Scheme 2
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