Stereoselective crossed aldol reaction via boron enolate generated from α-iodoketones and 9-BBN-H

Article abstract of DOI:10.1246/cl.2002.698

Boron enolates were in situ generated smoothly by treating α-iodo ketones with 9-BBN-H, and aldols were produced in highly diastereoselective manner by successive reaction with various aldehydes at low temperature.

Full text of DOI:10.1246/cl.2002.698

698
Chemistry Letters 2002
Stereoselective Crossed Aldol Reaction via Boron Enolate
Generated from ꢀ-Iodoketones and 9-BBN-H
Teruaki Mukaiyama,ꢀ Shouhei Imachi, Keiko Yamane, and Masahiro Mizuta
The Kitasato Institute, Center for Basic Research, TCI, 6-15-5 Toshima, Kita-ku, Tokyo 114-0003
(Received April 11, 2002; CL-020309)
Boronenolateswere in situgenerated smoothly by treating ꢀ-
ꢁ78 ꢂC in toluene, and the desired aldol was obtained in 92%
iodo ketones with 9-BBN-H, and aldols were produced in highly
diastereoselective manner by successive reaction with various
aldehydes at low temperature.
yield though diastereoselection was quite low. When the reaction
was carried out at 0 ꢂC using 9-BBN-H, on the other hand, the
corresponding aldol was obtained in 45% yield with high
diastereoselectivity. Further, in order to complete the generation
of boron enolate from 2-iodopropiophenone at room temperature,
2,6-lutidine was used as a hydroiodic acid accepter. Then, the
desired aldol was obtained in 85% yield with high diastereo-
selectivity. The combined use of 2,6-lutidine and THF afforded
the corresponding aldol in the highest yield with high diastereo-
selectivity.
Aldol reaction is frequently employed in organic synthesis as
one of the most important and useful tools for carbon-carbon bond
formation. The reaction is generally carried out under basic or
acidic conditions by generating active enolates from donor
carbonyl compounds or by activating acceptor carbonyl com-
pounds, respectively. It was reported from our laboratory in 1973
that boron enolates reacted smoothly with aldehydes and gave the
aldol adducts under neutral conditions.1
Metal enolates were generated under nearly neutral condi-
tions with high regioselectivities by reduction of ꢀ-halo carbonyl
compounds with low-valent metals as is represented in the
Reformatsky and related reactions.2 ꢀ-Halo carbonyl compounds
afforded the corresponding aldols in stereoselective manner on
treatment with acceptor carbonyl compounds by using a variety of
metals or low-valent metals such as Sn,3 Co,4 Cr,5 or Sm.6 It was
recently reported from our laboratory that the aldol reactions of
titanium enolates generated from ꢀ-halo carbonyl compounds
and low valent titanium compounds such as TiCl2 gave the
corresponding aldols with high diastereoselectivities.7 In these
cases, however, difficulty in preparing reducing metallic reagents
which were employed in the generation of key enolates and also
limitation concerning the substrates were pointed out.
A proposed reaction mechanism is shown in Figure 1: i.e., ꢀ-
iodoketone was reduced with 9-BBN-H to generate boron enolate
in the presence of 2,6-lutidine. The formation of boron enolates
from ꢀ-iodoketones and boron hydrides was confirmed by the
NMR measurement.12
It was then considered that highly regioselective and
diastereoselective aldol reaction would be achieved if boron
enolates were generated from ꢀ-halo carbonyl compounds under
mild conditions since boron enolates were known to react with
aldehydes resulting in the formation of the corresponding aldols.8
The aldol reaction of ꢀ-iodoketones with several aldehydes by
using Et3B as a reductant was already reported9 although
satisfactory results were not shown concerning the diastereos-
electivities.
Figure 1.
The yields and diastereoselectivities of aldol products by the
present procedure are summarized in Table 1. Both aromatic and
aliphatic ꢀ-iodo ketones reacted smoothly with acceptor
aldehydes to give the corresponding syn-aldol products pre-
dominantly in high yields.
In this communication, we would like to describe highly
diastereoselective aldol reaction of several aldehydes and boron
enolates, generated by hydride reduction of ꢀ-iodoketones with
9-BBN-H.
In the first place, the following evidences were confirmed; 1)
generation of boron enolate on treating pinacolborane10 and 2-
iodopropiophenone where boron hydride coordinated to the
carbonyl oxygen first, and hydride reduction spontaneously took
place to form the enolate along with hydroiodic acid (Figure 1),11
2) reduction of various aldehydes by the boron hydrides did not
proceed under the reaction conditions.
The regioselectivity of the reaction is shown by the following
example (Scheme 1). Treatment of 2-iodo-5-phenyl-3-pentanone
and benzaldehyde with 9-BBN-H and 2,6-lutidine expectedly
gave ꢁ-hydroxy ketone as a single product without contaminating
the opposite regioisomer at all.
A typical procedure is described for the reaction of 2-
iodopropiophenone with benzaldehyde: To a solution of 2-
iodopropiophenone (0.3 mmol) and 2,6-lutidine (0.4 mmol) in
THF (5.0 ml) at room temperature was added 0.8 ml of a 0.5 M
solution of 9-BBN-H (0.4 mmol) in THF underargon atmosphere.
After the resulted solution was stirred for 3 h at the same
temperature, it was cooled down to ꢁ78 ꢂC and benzaldehyde was
added. Then stirring was continued another for 5 h and the
The aldol reaction of 2-iodopropiophenone with benzalde-
hyde was tried in the presence of catecholborane and K2CO3 at
Copyright Ó 2002 The Chemical Society of Japan

Chemistry Letters 2002
699
Table 1. Aldol reaction of ꢀ-iodo ketones with aldehydes in the
presence of 9-BBN-H and 2,6-lutidine
ether. The combined organic layer was washed with saturated
aqueous sodium hydrogencarbonate and brine, dried over
Na2SO4, and the solvent was removed. The crude product was
purified by TLC to afford the syn- and anti-3-hydroxy-2-methyl-
1,3-diphenyl-1-propanone (95%, syn/anti ¼ 99=1).
Reaction conditions described here are not yet sufficiently
been optimized, and further studies on scope and limitation of
these reactions are in progress.
The present work was partially supported by Grant-in-Aids
for Scientific Research from the Ministry of Education, Culture,
Sports, Science and Technology, Japan.
References and Notes
1
2
3
T. Mukaiyama, K. Inomata, and M. Muraki, Bull. Chem. Soc.
Jpn., 46, 1807 (1973).
A. Furstner, Synthesis, 1989, 571, and references cited
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therein.
a) T. Harada and T. Mukaiyama, Chem. Lett., 1982, 161. b) T.
Harada and T. Mukaiyama, Chem. Lett., 1982, 467. c) S.
Fukuzawa, T. Tsuruta, T. Fujinami, and S. Sakai, J. Chem.
Soc., Perkin Trans. 1, 1987, 1473.
4
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F. Orsini, J. Org. Chem., 62, 1159 (1997).
J.-E. Dubois, G. Axiotis, and E. Bertounesque, Tetrahedron
Lett., 26, 4371 (1985).
6
7
8
A. Krief and A.-M. Laval, Chem. Rev., 99, 745 (1999), and
references cited therein.
T. Mukaiyama, A. Kagayama, K. Igarashi, and I. Shiina,
Chem. Lett., 1999, 1157.
B. M. Kim, S. F. Williams and S. Masamune, in ‘‘Compre-
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Fleming, Pergamon Press, Oxford (1991), Vol. 2, p 239.
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9
10C. E. Trucker, J. Davidson, and P. Knochel, J. Org. Chem., 57,
3482 (1992).
11 In the presence of pyridine, the boron enolate was formed
from pinacholborane and 2-iodopropiophenone, and was
isolated by distillation in vacuo under argon. bp 91 ꢂC/
0.1 mmHg. 1H NMR (C6D6, 270MHz): ꢂ 0.91 (s, 12H), 1.71
(d, 6.9 Hz, 3H), 5.40(q, 6.9 Hz, 1H), 7.1 (m, 3H), 7.5 (d,
8.1 Hz, 2H); 13C NMR (C6D6, 67.5 MHz): ꢂ 11.4, 24.5, 83.1,
106.5, 124.7, 127.7, 128.5, 137.5, 149.1. Several boron
enolates were stereoselectively formed by oxidation of
vinylboronates and were isolated by bulb to bulb distillation.
See: R. W. Hoffmann and K. Ditrich, Tetrahedron Lett., 25,
Scheme 1.
reaction mixture was poured into phosphate buffer of pH 7.0
(5.0ml) and was extracted with ether. Next, ether was removed,
and methanol (2.0ml) and 30% H O2 (2.0ml) were added at 0 C
2
1781 (1984). R. W. Hoffmann, K. Ditrich, and S. Froch,
¨
Liebigs Ann. Chem., 1987, 977.
ꢂ
12 The NMR spectrum of the reaction mixture showed a signal at
ꢂ 5.20assigned to a vinyl proton of the boron enolate.
and was left for 15 min. The mixture was concentrated in vacuo in
order to remove most of the methanol and then was extracted with