Morita-Baylis-Hillman reaction and cyclization of 1-(p-toluenesulfonyl)-1, 3-butadiene with aldimines

Article abstract of DOI:10.1021/ol050658n

(Chemical Equation Presented) Aldimines 2 underwent Morita-Baylis-Hillman reaction with 1-(p-toluenesulfonyl)-1,3-butadiene (3) in the presence of 3-hydroxyquinuclidine (HQD) to afford adducts 4. The 5-isomers of the products cyclized to the corresponding

Full text of DOI:10.1021/ol050658n

ORGANIC
LETTERS
2005
Vol. 7, No. 12
2377-2379
Morita
Cyclization of
−Baylis−Hillman Reaction and
1-(p-Toluenesulfonyl)-1,3-butadiene with
Aldimines
Thomas G. Back,* Danica A. Rankic, Jovina M. Sorbetti, and Jeremy E. Wulff
Department of Chemistry, UniVersity of Calgary, Calgary, AB, Canada, T2N 1N4
tgback@ucalgary.ca
Received March 28, 2005
ABSTRACT
Aldimines 2 underwent Morita−Baylis−Hillman reaction with 1-(p-toluenesulfonyl)-1,3-butadiene (3) in the presence of 3-hydroxyquinuclidine
(HQD) to afford adducts 4. The E-isomers of the products cyclized to the corresponding functionalized piperidines 8 under base-catalyzed
conditions. Simultaneous equilibration of (E)-4 and (Z)-4 was effected by photoisomerization to improve the efficiency of the cyclization.
The Morita-Baylis-Hillman reaction1 has been widely
investigated as an effective carbon-carbon bond-forming
method.2 In its original and most common variation, an
alkene containing an electron-withdrawing group (EWG)
undergoes a conjugate addition of a tertiary phosphine1a or
amine1b catalyst and the resulting zwitterion adds to the
carbonyl group of an aldehyde. Elimination of the amine
then regenerates the alkene double bond, resulting in the
formation of the corresponding adduct 1, as shown in Scheme
1.
Scheme 1. Morita-Baylis-Hillman Reactiona
More recent studies have resulted in numerous variations
of this useful process. For example, chalcogenides in the
presence of Lewis acids have proved to be effective
replacements for tertiary phosphines or amines as nucleo-
philic catalysts.3 Furthermore, several reports have indicated
that imines4 can be employed in lieu of aldehydes in Scheme
1. Although diverse types of electron-deficient alkenes have
a EWG ) electron-withdrawing group; Y ) P or N.
been used in the Morita-Baylis-Hillman reaction, there are
only a few reports of vinyl sulfones5 in this context.
(4) For examples of the use of imines with carbonyl compounds or nitriles
in Morita-Baylis-Hillman reactions, see: (a) Perlmutter, P.; Teo, C. C.
Tetrahedron Lett. 1984, 25, 5951-5952. (b) Campi, E. M.; Holmes, A.;
Perlmutter, P.; Teo, C. C. Aust. J. Chem. 1995, 48, 1535-1540. (c)
Bertenshaw, S.; Kahn, M. Tetrahedron Lett. 1989, 30, 2731-2732. (d)
Ku¨ndig, E. P.; Xu, L. H.; Schnell, B. Synlett 1994, 413-414. (e) Yamamoto,
K.; Takagi, M.; Tsuji, J. Bull. Chem. Soc. Jpn. 1988, 61, 319-321. (f)
Takagi, M.; Yamamoto, K. Tetrahedron 1991, 47, 8869-8882. (g) Cyrener,
J.; Burger, K. Monatsh. Chem. 1995, 126, 319-331. (h) Shi, M.; Xu,
Y.-M. J. Org. Chem. 2003, 68, 4784-4790.
(1) (a) Morita, K.; Suzuki, Z.; Hirose, H. Bull. Chem. Soc. Jpn. 1968,
41, 2815. (b) Baylis, A. B.; Hillman, M. E. D. Ger. Offen. 2,155,113, 1972;
Chem. Abstr. 1972, 77, 34174q.
(2) For recent reviews, see: (a) Basavaiah, D.; Rao, A. J.; Satyanarayana,
T. Chem. ReV. 2003, 103, 811-891. (b) Basavaiah, D.; Rao, P. D.; Hyma,
R. S. Tetrahedron 1996, 52, 8001-8062. (c) Ciganek, E. Org. React. 1997,
51, 201-350. (d) Langer, P. Angew. Chem., Int. Ed. 2000, 39, 3049-3052.
(e) Drewes, S. E.; Roos, G. H. P. Tetrahedron 1988, 44, 4653-4670.
(3) Kataoka, T.; Kinoshita, H. Eur. J. Org. Chem. 2005, 45-58.
10.1021/ol050658n CCC: $30.25
© 2005 American Chemical Society
Published on Web 05/11/2005

As part of our general interest in the chemistry of
unsaturated sulfones,6,7 we decided to investigate Morita-
Baylis-Hillman reactions between aldimines 2 and the
conjugated dienyl sulfone 3. To our knowledge, the Morita-
Baylis-Hillman chemistry of dienyl sulfones, or other
similarly activated dienes, has not yet been explored, and
the anticipated products 4 comprise potentially useful func-
tionalized allylic amine derivatives. Moreover, the regener-
ated dienyl sulfone moiety provides possibilities for further
transformations.
Table 1. Morita-Baylis-Hillman Reactions of Aldimines 2
with Dienyl Sulfone 3a,b
A series of imines 2 were prepared from the corresponding
aldehydes by a standard procedure,8 and 1-(p-toluenesulfon-
yl)-1,3-butadiene (3) was obtained by a literature method.9
To optimize the conditions for the Morita-Baylis-Hillman
reaction, the imine 2a (R ) Ph) was treated with 3 in the
presence of DBU, DABCO, DMAP, triethylamine, triphen-
ylphosphine, and 3-hydroxyquinuclidine (HQD) in a variety
of solvents. The best results were typically obtained in the
presence of 25 mol % HQD10 in DMF at room temperature
for ca. 5 h. These conditions were then similarly applied to
imines 2b-j, and the results are shown in Table 1. In some
cases the imine 2 was employed in excess over the sulfone
3 to compensate for its partial hydrolysis during the reaction.
However, equimolar amounts of 2 and 3 afforded comparable
yields of 4 if rigorously anhydrous conditions were main-
tained. Although the dienyl sulfone 3 was prepared as the
E-isomer, the adducts 4 were obtained as E/Z mixtures,
presumably because of free rotation prior to elimination of
HQD in the product-forming step. The method is compatible
with both electron-withdrawing and -donating substituents
on the aryl moiety of the imine. Exceptions were observed
with the nitro- and cyano-substituted derivatives 2f and 2h,
respectively, which reacted very rapidly in DMF to afford
(5) For examples of the reaction of vinyl sulfones with aldehydes in
Morita-Baylis-Hillman reactions, see: (a) Auvray, P.; Knochel, P.;
Normant, J. F. Tetrahedron Lett. 1986, 27, 5095-5098. (b) Auvray, P.;
Knochel, P.; Normant, J. F. Tetrahedron 1988, 44, 6095-6106. (c)
Hoffmann, H. M. R.; Weichert, A.; Slawin, A. M. Z.; Williams, D. J.
Tetrahedron 1990, 46, 5591-5602. (d) Weichert, A.; Hoffmann, H. M. R.
J. Org. Chem. 1991, 56, 4098-4112.
(6) (a) For an overview of sulfone chemistry, see: Simpkins, N. S.
Sulphones in Organic Synthesis; Pergamon Press: Oxford, 1993. (b) For a
review of vinyl sulfones, see: Simpkins, N. S. Tetrahedron 1990, 46, 6951-
6984. (c) For a review of acetylenic and allenic sulfones, see: Back, T. G.
Tetrahedron 2001, 57, 5263-5301. (d) For a review of dienyl sulfones,
see: Ba¨ckvall, J. E.; Chinchilla, R.; Na´jera, C.; Yus, M. Chem. ReV. 1998,
98, 2291-2312.
a All reactions were performed in DMF at room temperature for 4-6 h,
except the preparations of 4f and 4h, which were carried out in THF for 16
and 20 h, respectively. b All reactions were performed in the presence of
25 mol % HQD except in the case of 4e, where 50 mol % was used.
(7) For recent examples, see: (a) Back, T. G.; Nakajima, K. J. Org.
Chem. 1998, 63, 6566-6571. (b) Back, T. G.; Nakajima, K. Org. Lett.
1999, 1, 261-264. (c) Back, T. G.; Nakajima, K. J. Org. Chem. 2000, 65,
4543-4552. (d) Back, T. G.; Hamilton, M. D. Org. Lett. 2002, 4, 1779-
1781. (e) Back, T. G.; Parvez, M.; Wulff, J. E. J. Org. Chem. 2003, 68,
2223-2233. (f) Back, T. G.; Parvez, M.; Zhai, H. J. Org. Chem. 2003, 68,
9389-9393. (g) Back, T. G.; Hamilton, M. D.; Lim, V. J. J.; Parvez, M. J.
Org. Chem. 2005, 70, 967-972.
complex mixtures of products, and with the more hindered
mesityl derivative 2j, which failed to react under all
attempted conditions. The additions to 2f and 2h were
achieved in THF, in which the reaction proceeded at a
significantly slower rate compared to DMF.
The major product in each successful example in Table 1
proved to be the corresponding E-isomer. This was estab-
lished unequivocally for 4a by NMR experiments. Thus,
when a D2O exchange was performed, the doublet at δ 5.91
ppm collapsed to a singlet, establishing it as the benzylic
proton R to the sulfonamide moiety. This signal showed a
strong NOE (16%) when the multiplet at δ 6.64, assigned
to the proton γ to the sulfone group in the diene moiety,
(8) Vishwakarma, L. C.; Stringer, O. D.; Davis, F. A. Org. Synth. 1988,
66, 203-210.
(9) Barluenga, J.; Mart´ınez-Gallo, J. M.; Na´jera, C.; Fan˜ana´s, F. J.; Yus,
M. J. Chem. Soc., Perkin Trans. 1 1987, 2605-2609.
(10) It is possible that the particular efficacy of HQD in this process is
due to stabilization of the zwitterion formed by its addition to the 2-position
of 3 through hydrogen-bonding between the HQD hydroxyl group and a
sulfone oxygen atom. Similar hydrogen-bonding effects have been postulated
in the additions of HQD to other activated alkenes. (a) Ameer, F.; Drewes,
S. E.; Freese, S.; Kaye, P. T. Synth. Commun. 1988, 18, 495-500. (b)
Drewes, S. E.; Freese, S. D.; Emslie, N. D.; Roos, G. H. P. Synth. Commun.
1988, 18, 1565-1572.
2378
Org. Lett., Vol. 7, No. 12, 2005

was irradiated, and vice versa (14%). This established that
the vinyl substituent and the R-aminobenzyl side chain are
cis oriented. The similarity of the NMR signals of the diene
moieties and of the benzylic protons in the major isomers
of the other products in Table 1 when compared to (E)-4a
indicates that they too possess the E-configuration. In each
example in Table 1, the yield refers to the total of both
geometrical isomers. However, careful flash chromatography
of the mixtures permitted the isolation of the pure, less polar
E-isomers, while the Z-isomers generally could not be
obtained completely free from the corresponding E-isomers.
The identities and amounts of the Z-isomers were inferred
from the NMR spectra of the unseparated E/Z mixtures.
Attempts to employ the more sterically hindered methyl-
substituted dienyl sulfones 5,9 6,11 or 79 (Figure 1) in place
of 3 with imine 2a (R ) Ph) failed under similar conditions.
Z-isomers to adopt a conformation compatible with the
6-centered transition state required for the cyclization.
We also attempted to cyclize the unseparated E/Z mixture
of 4a to 8a under conditions designed to promote the in situ
equilibration of the geometrical isomers, thereby allowing
the otherwise inert Z-isomer to cyclize via its E-counterpart.
First, we observed in separate experiments that pure (E)-4a
and a 40/60 mixture of (E)- and (Z)-4a afforded identical
70/30 mixtures of the two geometrical isomers when irradi-
ated with 300 nm UV light. This experiment established that
photoisomerization of 4a is possible and that the 70/30 E/Z
ratio represents the mixture at equilibrium. Attempts at
equilibration in the presence of the HQD catalyst for
extended periods or at elevated temperatures gave less
satisfactory results. Finally, an unseparated 65/35 mixture
of (E)- and (Z)-4a was treated under the usual cyclization
conditions (K2CO3, DMF-H2O) while being irradiated with
UV light at 300 nm, affording 8a in 84% yield (Scheme 3),
Scheme 3. Photoisomerization and Cyclization of 4a
Figure 1. Substituted dienyl sulfones 5-7.
When the pure E-isomers of the representative Morita-
Baylis-Hillman adducts 4a, 4b, and 4h were dissolved in
DMF-water (10/1) containing K2CO3 at room temperature,
intramolecular conjugate additions of the sulfonamide func-
tionalities to the terminal positions of the diene substituents
occurred to afford the corresponding piperidine derivatives
8a, 8b, and 8h, respectively, in high yield (Scheme 2). Not
comparable to what had been obtained earlier by cyclization
of the pure E-isomer. This demonstrates the feasibility of a
one-pot photoisomerization and cyclization protocol for the
conversion of both isomers to the final cyclized product.
Attempts to perform [4 + 2]-cycloadditions of 2a with 3
to afford 8a in one step by heating in various solvents or in
the presence of Lewis acids (e.g., BF3‚OEt2, TiCl4) have so
far proved to be fruitless.
These experiments demonstrate that aldimines 2 undergo
relatively facile Morita-Baylis-Hillman reaction with dienyl
sulfone 3 in the presence of HQD to afford E/Z mixtures of
the adducts 4. Moreover, the dominant E-isomers of 4 can
be cyclized to the corresponding 2-substituted piperidines
8. Alternatively, cyclization of a mixture of both geometrical
isomers can be effected by photoisomerization that permits
their in situ equilibration. The presence of the vinyl sulfone
moiety in the products 8 offers potential for further useful
transformations.
Scheme 2. Cyclization of Morita-Baylis-Hillman Adducts 4
Acknowledgment. We thank the Natural Sciences and
Engineering Research Council of Canada (NSERC) for
financial support. D.A.R. thanks NSERC for an Undergradu-
ate Summer Research Assistantship. J.M.S. acknowledges
receipt of Postgraduate Scholarships from NSERC and the
Alberta Ingenuity Fund. J.E.W. thanks NSERC, the Alberta
Heritage Foundation for Medical Research, and the Killam
Foundation for Postgraduate Scholarships.
surprisingly, treatment of the corresponding Z-isomers under
similar conditions failed to afford significant amounts of the
cyclized products. The difference in behavior between the
geometrical isomers is attributed to the inability of the
Supporting Information Available: Experimental pro-
cedures, characterization data, and 1H and 13C NMR spectra
of compounds 4a-i, 8a, 8b, and 8h. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL050658N
(11) Bordwell, F. G.; Mecca, T. G. J. Am. Chem. Soc. 1972, 94, 4, 5829-
5837.
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