Stereoselective Michael-Aldol Tandem Reaction of Phenylselenomagnesium Bromide with Acetylenic Sulfones and Aldehydes. An Efficient Synthesis of Polyfunctionalized Allylic Alcohols

Article abstract of DOI:10.1021/ol025628o

(Matrix Presented) A mixture of phenylselenomagnesium bromide, an acetylenic sulfone, and an aldehyde in THF/CH₂Cl₂ afforded Michael-aldol tandem adduct, i.e., (Z)-β-phenylseleno-α-(p-tolylsulfonyl)allylic alcohol, in good yield with

Full text of DOI:10.1021/ol025628o

ORGANIC
LETTERS
2002
Vol. 4, No. 8
1331-1334
Stereoselective Michael−Aldol Tandem
Reaction of Phenylselenomagnesium
Bromide with Acetylenic Sulfones and
Aldehydes. An Efficient Synthesis of
Polyfunctionalized Allylic Alcohols
Xian Huang*,†,‡ and Meihua Xie†
Department of Chemistry, Zhejiang UniVersity, Xi-xi Campus, Hangzhou 310028,
P. R. China, and State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, P. R. China
huangx@mail.hz.zj.cn
Received January 26, 2002
ABSTRACT
A mixture of phenylselenomagnesium bromide, an acetylenic sulfone, and an aldehyde in THF/CH Cl2 afforded Michael−aldol tandem adduct,
2
i.e., (Z)-â-phenylseleno-r-(p-tolylsulfonyl)allylic alcohol, in good yield with high stereoselectivity. The stereoselectivity greatly depended on
solvent.
The tandem reaction has recently been of interest for organic
synthesis because it offers a convenient and economical
method to prepare desired organic molecules.1 The Michael
addition and the aldol reaction are acknowledged as useful
tools for constructing complex organic molecules, and
combining the two reactions in one pot has attracted much
attention in organic synthesis.2
The stereoselective synthesis of multifunctional alkenes
is an important goal in organic chemistry and is still being
actively explored because of the fact that many biologically
active compounds have the structure of substituted alkenes.3
Difunctional group reagents, which have two different
functional groups linked to the olefinic carbon atoms (such
as Sn-Si, Sn-Mg, Sn-Zr, Sn-Se, Se-Zr, Se-Al, and Se-
Cu), are useful intermediates in developing convenient
methods for the synthesis of various alkenes.4 Organomag-
nesium reagents5 and vinyl selenides6 have been widely used
as building blocks in organic chemistry. However, to the best
of our knowledge, there are no reports on the synthesis of
functionalized alkenes from Se-Mg difunctional reagent.
Acetylenic sulfones are known as electrophiles,7 whereas
(3) (a) Huang, X.; Sun, A. M. J. Org. Chem. 2000, 65, 6561. (b) Wei,
H. X.; Kim, S. H.; Caputo, T. D.; Purkiss, D. W.; Li, G. G. Tetrahedron
2000, 56, 2397.
(4) (a) Mitchell, T. N.; Wickenkamp, R.; Amamria, A.; Dicke, R.;
Schneider, U. J. Org. Chem. 1987, 52, 4868. (b) Hibino, J. I.; Matsubara,
S.; Morizawa, Y.; Oshima, K.; Nozaki, H. Tetrahedron Lett. 1984, 25, 2151.
(c) Lipshutz, B. H.; Keil, R.; Barton, J. C. Tetrahedron Lett. 1992, 33,
5861. (d) Huang, X.; Ma, Y. Synth. Commun. 1997, 27, 2407. (e) Dabdoub,
M. J.; Cassol, T. M.; Barbosa, S. L. Tetrahedron Lett. 1996, 37, 831. (f)
Brage, A. L.; Reckzigel, A.; Silveira, C. C. Synth. Commun. 1994, 24, 1165.
(5) (a) Inoue, A.; Kitagawa, K.; Shinokubo, H.; Oshima, K. J. Org. Chem.
2001, 66, 4333. (b) Thibonnet, J.; Knochel, P. Tetrahedron Lett. 2000, 41,
3319.
† Zhejiang University.
‡ Chinese Academy of Sciences.
(1) For review of tandem reaction, see: (a) Posner, G. H. Chem. ReV.
1986, 86, 831. (b) Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed. Engl.
1993, 32, 131. (c) Bunce, R. A. Tetrahedron 1995, 48, 13103. (d) Tietze,
L. F. Chem. ReV. 1996, 96, 115.
(2) (a) Sibi, M. P.; Lu, J. J. Org. Chem. 1997, 62, 5864. (b) Fleming. I.;
Sarkar, A. K. J. Chem. Soc., Chem. Commun. 1986, 1199. (c) Tsukada, N.;
Shimida, T.; Gyoung, Y. S.; Asao, N.; Yamamoto, Y. J. Org. Chem. 1995,
60, 143. (d) Barrett, A. G. M.; Kamimura, A. J. Chem. Soc., Chem. Commun.
1995, 1755.
(6) Commasseto, J. V.; Ling, L. W.; Petragnani, N.; Stefani, H. A.
Synthesis 1997, 373.
10.1021/ol025628o CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/22/2002

selenolate and its analogues are good nucleophiles8 for
Michael addition. Therefore we studied the Michael addition
of magnesium selenolate with acetylenic sulfone to obtain
the Se-Mg difunctional reagent, which was captured with
aldehyde. Herein, we wish to report our preliminary results
of the Michael-aldol tandem reactions and provide a simple
and efficient one-pot protocol for the synthesis of function-
alized tetrasubstituted alkenes, (Z)-â-phenylseleno-R-(p-
tolylsulfonyl)allylic alcohols.
with good stereoselectivity when the reaction was carried
out in THF or THF/CH2Cl2 (1/4 v/v) (entries 3 and 4, Table
1). So THF or THF/CH2Cl2 is the optimal solvent for the
tandem reaction.
We further investigated the reaction of magnesium sele-
nolate 2 with p-chlorobenzaldehyde 3a. By adding 3a directly
to the solution of 2 in THF/CH2Cl2 at -20 °C and stirring
for 3h, no adduct was formed because there are no proton
1
signals of methyne and hydroxy in the H NMR spectrum
1-Phenyl-2-(p-tolylsulfonyl)ethyne (1a), phenylselenom-
agnesium bromide (2), and p-chlorobenzaldehyde (3a) were
chosen to optimize the tandem reaction conditions. The
results are summarized in Table 1. At -20 °C, 1a was added
of the crude reaction mixture. This result suggests that
phenylselenomagnesium bromide 2 can react with 1a selec-
tively when 1a, 2, and 3a were added in one pot. So it is
possible for 3a to capture alkenylmagnesium intermediate
immediately when the intermediate formed by adding 1a, 2,
and 3a simultaneously in solvent (method B). Fortunately,
both the yield and the Z/E selectivity were greatly improved
by this method (entries 5 and 6, Table 1).
Table 1. Reaction of 1-Phenyl-2-(p-tolylsulfonyl)ethyne,
Phenylselenomagnesium Bromide, and p-Chlorobenzaldehyde
The present reaction conditions were compatible with the
reaction of phenyl or aliphatic acetylenic sulfones with other
aromatic, aliphatic aldehydes or R,â-unsaturated aldehydes,
giving Z-type tandem adducts in good yields. The results
are summarized in Table 2.
The configuration of the product 4b was determined as
Z-type by single-crystal X-ray diffraction analysis 9 (Figure
1). The NOESY spectrum of 4k also shows that CH(OH)-
time
methoda (min)
yield
(%)b
entry
solvent
ratio of Z/Ec
1
2
3
4
5
6
THF/CH3CN
THF/Toluene
THF
THF/CH2Cl2
THF
A
A
A
A
B
B
90
90
70
80
60
60
30
29
70
75
81
87
62/38
85/15
70/30
73/27
88/12
>96/4
THF/CH2Cl2
a The reaction was carried out at -20 °C using 1a (0.5 mmol), 2 (0.6
mmol), and 3a (0.5 mmol). Method A: 4a was added after the Michael
addition of 2 with 1a was complete. Method B: 1a, 2, and 3a were added
simultaneously in solvent. b Determined by 1H NMR based on 1a using
CH2Br2 as an internal standard. c Determined by 400 MHz 1H NMR analysis
based on the methyne proton of 4a.
Figure 1. The crystal structure of 4b.
C6H4-Cl-p group is in a cis orientation with n-C5H11. The
fact that all of the products shared almost the same NMR
patterns suggests the stereochemistry of these compounds
to be identical. Therefore, the double bond in compounds 4
is in Z-configuration.
Vinyl selenides6 and unsaturated sulfones10 have numerous
uses in organic synthesis. Certain â-selenovinyl sulfones are
known to undergo substitution reactions of the selenium
moiety with organocuprates and other nucleophiles, as well
as syn-elimination reactions of their corresponding selenox-
to the solution of magnesium selenolate 2 in THF/acetonitrile
(1/4 v/v), which was prepared in situ from phenylmagnesium
bromide and powder selenium. When the Michael addition
was complete (monitored by TLC), 3a was added to the
reaction mixture. The reaction mixture was maintained at
-20 °C for 90 min (method A). The desired Michael-aldol
adduct Z-4a and E-4a were obtained in 30% yield with the
ratio of Z/E ) 62:38 (ratio of Z/E determined by 400 MHz
1H NMR spectrum based on the methyne proton of 4a) (entry
1, Table 1). When acetonitrile was replaced by toluene,
similar yield and higher stereoselectivity were obtained (entry
2, Table 1). However, the yield was dramatically improved
(9) Crystal data for 4b: C28H24O3SSe, MW ) 519.49, monoclinic, space
group P21/n, a ) 7.0710(4), b ) 14.6604(9), c ) 24.3432(5) Å; R ) 90°,
â ) 94.7550(10)°, γ ) 90°. V ) 2514.8(3) Å3, T ) 293 K, Z ) 4, Dc )
1.372 g cm-1, µ ) 1.603 mm-1, λ ) 0.71073 Å; F(000) 1064, 4688
independent reflections (Rint ) 0.0754), 13113 reflections collected;
refinement method, full-matrix least-squares on F2; goodness-of-fit on
F2 ) 0.657; final R indices [ I > 2σ(I)] R1 ) 0.0371, wR2 ) 0.0499.
(10) (a) Simpkins, N. S. Sulphones in Organic Synthesis; Pergamon
Press: Oxford, 1993. (b) Fuchs, P. L.; Braish, T. F. Chem. ReV. 1986, 86,
903.
(7) Fuchs, P. L.; Braish, T. F. Chem. ReV. 1986, 86, 903;
(8) (a) Kamimura, A.; Mitsudera, H.; Asano, S.; Kidera, S.; Kakehi, A.
J. Org. Chem. 1999, 64, 6353 and references therein. (b) Mitsudera, H.;
Kakehi, A.; Kamimura, A. Tetrahedron Lett. 1999, 40, 7389.
1332
Org. Lett., Vol. 4, No. 8, 2002

Table 2. Reaction of Acetylenic Sulfones with Phenylselenomagnesium Bromide and Aldehydesa
a The reaction was carried out at -20 °C by adding 1 (0.5 mmol), 2 (0.6 mmol), and 3 (0.5 mmol) simultaneously in THF/CH2Cl2 (1/4 v/v). b Isolated
1
yield of purified Z-4 based on 1. The ratio of Z/E was determined by 400 MHz H NMR spectra of the unpurified reaction mixture.
ides.11 Therefore, it is predictable that the tandem adducts 4
can be useful building blocks in organic synthesis. We also
found an efficient method for the synthesis of heteroatom-
substituted 1,3-dienes from 4. Heteroatom-substituted 1,3-
dienes are useful precursors to construct highly functionalized
ring systems in Diels-Alder reactions.12 Our experimental
results show that the treatment of 4k with Ac2O/BF3‚Et2O
can give 2-(p-tolylsulfonyl)-3-phenylselenoocta-1,3-diene 5
in high yield (96%) with high stereoselectivity (isomer purity
protons and the NOE correlation between H1 and p-
tolylsulfonyl protons were observed, indicating the stereo-
chemistry of 5 is 1E,3E.
In summary, we have developed a one-pot method for the
synthesis of â-phenylseleno-R-(p-tolylsulfonyl)allylic alco-
hols 4 efficiently and stereoselectively. The method is
convenient, starting from easily available materials. Tandem
adducts 4 obtained from aliphatic acetylenic sulfones can
be readily converted to heteroatom substituted 1,3-dienes in
1
>95%, determined by H NMR) (Scheme 1). The configu-
ration of 5 was verified by the 1H-1H 2D NOESY spectrum.
Scheme 1
The strong NOE correlation between H4 and 3-phenylseleno
(11) Back, T. G.; Bethell, R. J.; Parvez, M.; Wehrli, D. J. Org. Chem.
1998, 63, 7908 and references therein.
(12) (a) Padwa, A., Harrison, B., Murphree, S. S., Yeske, P. E. J. Org.
Chem. 1989, 54, 4232. (b) Yoshimatsu, M., Hasegawa, J. J. Chem. Soc.,
Perkin Trans. 1 1997, 211.
Org. Lett., Vol. 4, No. 8, 2002
1333

high yield and high stereoselectivity. Further application of
the â-seleno alkenylmagnesium intermediate formed in
Michael addition and the tandem adducts 4 in organic
synthesis are now in progress in our laboratory.
Supporting Information Available: Experimental pro-
cedures and spectral data for compounds prepared. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. Supported by the National Natural
Science Foundation of China (project 29772007).
OL025628O
1334
Org. Lett., Vol. 4, No. 8, 2002