Efficient diastereoselective pinacol reaction of aliphatic and aromatic aldehydes by combined use of newly utilized titanium(II) bromide and copper

Article abstract of DOI:10.1246/cl.2000.336

Newly utilized low-valent titanium reductant, titanium(II) bromide, was conveniently prepared by treating titanium(IV) bromide with hexamethyldisilane. The pinacol reaction of aromatic and aliphatic aldehydes including primary aldehydes proceeded smoothly in dichloromethane-pivalonitrile at temperatures ranging from -23 to 0 °C by the combined use of soluble titanium(II) bromide and copper to give 1,2-diols in good to high yields with good to high dl-selectivities.

Full text of DOI:10.1246/cl.2000.336

336
Chemistry Letters 2000
Efficient Diastereoselective Pinacol Reaction of Aliphatic and Aromatic Aldehydes
by Combined Use of Newly Utilized Titanium(II) Bromide and Copper
Teruaki Mukaiyama, Akifumi Kagayama, and Koji Igarashi
Department of Applied Chemistry, Faculty of Science, Science University of Tokyo, Kagurazaka, Shinjuku-ku, Tokyo 162-8601
(Received December 27, 1999; CL-991102)
Newly utilized low-valent titanium reductant, titanium(II)
bromide, was conveniently prepared by treating titanium(IV)
bromide with hexamethyldisilane. The pinacol reaction of
aromatic and aliphatic aldehydes including primary aldehydes
proceeded smoothly in dichloromethane-pivalonitrile at temper-
atures ranging from -23 to 0 °C by the combined use of soluble
titanium(II) bromide and copper to give 1,2-diols in good to
high yields with good to high dl-selectivities.
Reductive coupling of carbonyl compounds using low-
valent metal species, known as pinacol reaction, is one of the
most important methods for carbon-carbon bond formation, and
many kinds of reducing reagent, especially low-valent titanium
species, have been employed in this reaction.1 Of these reac-
tions, pinacols can be formed easily when aromatic aldehydes
are used while yields and diastereoselectivities (dl and meso) of
pinacols are usually found to be rather low in cases of aliphatic
aldehydes. Recently, it was reported from our laboratory that
a combination of titanium(II) chloride and zinc effectively
promoted pinacol reaction of aliphatic carbonyl compounds in
dichloromethane-pivalonitrile.2 Under the condition, however,
the diastereoselectivities of products were rather low, and com-
binations of titanium(II) chloride and other metals such as mag-
nesium or copper were not effective for these reactions. Very
recently, Matsubara and co-workers reported on enantioselective
pinacol reaction of benzaldehyde using two moles of
titanium(II) chloride and four moles of chiral diamines.3 In
order to find more efficient low-valent titanium species other
than titanium(II) chloride, titanium(II) bromide was chosen and
its preparation and its application to pinacol reaction were studied.
A few methods for the preparation of titanium(II) bromide
from titanium(III) bromide or titanium metal have been reported,
but these procedures are not convenient because the reactions
are carried out at extremely high temperature (400 °C) or dan-
gerous ignition was sometimes observed.4 In our trial to develop
a better procedure, titanium(IV) bromide was treated with hexa-
methyldisilane similar to that employed in the preparation of
titanium(II) chloride.5 After screening several reaction condi-
tions, it was found that analytically pure titanium(II) bromide6
was obtained as an air and moisture sensitive dark brown solid
in high yield when five moles of hexamethyldisilane was added
dropwise into the refluxing titanium(IV) bromide (at 230 °C).
The mixture was further refluxed for additional 9 h, and the
work up was carried out as mentioned in ref. 5.
diastereoselectivity were rather low when the reaction was carried
out using a suspended titanium(II) chloride in the above mixed
solvent (Table 1, entries 1, 2). In order to improve the coupling
reaction, combinations of titanium(II) bromide with several
metals8 were tried (entries 3-11). When zinc was used as co-
reductant, the aldehyde was consumed rapidly, but the
diastereoselectivity decreased extremely in the case of using
either titanium(II) bromide or chloride. On the contrary,
combination of titanium(II) bromide and copper exhibited high
reactivity in this reductive coupling reaction and sufficient
diastereoselectivity was attained at -23°C (entry 7).9 In this
reaction, copper powder did not react with titanium(II) bromide
in the mixed solvent unless aldehyde was added. After adding
the aldehyde, copper disappeared soon. This observation
suggested that copper(0) would help titanium(II) bromide to
reduce aldehyde and there would be a one-to-one complex of
titanium and copper because the yield decreased extremely
when a half amount of copper was used (entry 8). On the other
hand, zinc powder reacted with titanium(II) bromide in the
absence of aldehydes and the solution turned into dark brown,
suggesting that lower (zero or one) -valent titanium species
would be produced. In the case of using iron or manganese, the
reaction proceeded slowly even at room temperature and the
yield of pinacol was rather low. In the case of using tin, the
diastereoselectivity decreased though the aldehyde was reduced
rapidly (entries 9-11).
Thus prepared titanium(II) bromide dissolved thoroughly
in dichloromethane-pivalonitrile and the solution turned into a
dark green. When an equimolar amount of benzaldehyde was
added to this solution, the reductive coupling proceeded
smoothly to give the corresponding pinacol in increased yield
and diastereoselectivity.7 On the other hand, the yield and
The yields and diastereoselectivities of the pinacol reaction
Copyright © 2000 The Chemical Society of Japan

Chemistry Letters 2000
337
good to higher diastereoselectivities. These results may be
explained by considering initial formation of a titanium-bridged
intermediate which can be readily formed by the interaction of
an aldehyde with titanium(II) bromide soluble in the above
mentioned solvent. By reductive coupling of the above inter-
mediate on the surface of copper metal, titanium alcoholate and
copper complex were in turn produced as sketched in Scheme 1.13
Thus dl-selective pinacol reaction of several aldehydes
including primary aliphatic aldehydes was effectively achieved
by combined use of titanium(II) bromide and copper in
dichloromethane-pivalonitrile.
This work was supported by Grant-in-Aids for Scientific
Research from the Ministry of Education, Science, Sports and
Culture.
References and Notes
1
Review articles, see: a) G. M. Robertson, in "Comprehensive
Organic Synthesis," ed. by B. M. Trost and I. Fleming,
Pergamon Press, Oxford(1991), Vol. 3, p 563. b) T. Wirth,
Angew. Chem., Int. Ed. Engl., 35, 61 (1996). c) A. Fürstner and
B. Bogdanovic, Angew. Chem., Int. Ed. Engl., 35, 2442 (1996).
T. Mukaiyama, A. Kagayama, and I. Shiina, Chem. Lett., 1998,
1107.
S. Matsubara, Y. Hashimoto, T. Okano, and K. Utimoto,
Synlett, 1999, 1411.
a) R. C. Young and W. M. Leaders, Inorg. Synth., 2, 116
(1965). b) G. Brauer, "Handbook of Preparative Inorganic
Chemistry," vol. 2, p 1185 (1965).
2
3
4
of several aldehydes using titanium(II) bromide and copper
are summarized in Table 2. Aromatic and α,β-unsaturated
aldehydes were transformed to the corresponding pinacols in
high yields with high diastereoselectivities (entries 1-4).
In the cases of aliphatic aldehydes, the corresponding pina-
col coupling products were obtained at 0 °C, along with a small
amount of 1,3-dioxolanes 2 produced from initially formed
pinacols and remaining aldehydes (entries 5-8). Concerning
high diastereoselective pinacol reaction of primary aliphatic
aldehydes, Szymoniak et al. isolated pinacols as their dioxolane
compounds like 2 with high diastereoselectivities (dl / meso ~ 9
/ 1) using low-valent niobium reagent.11 Hirao et al. improved
pinacol reactions of aliphatic aldehydes without producing 1,3-
dioxolanes using catalytic amount of vanadium(IV) complex
together with excess amounts of zinc and chlorotrimethylsilane,
but diastereoselectivities of these reactions using primary
aldehydes were rather low (dl / meso < 2 / 1).12 In the present
reaction of using titanium(II) bromide and copper, pinacols
were obtained mainly as 1,2-diol in good to high yields with
5
6
S. P. Narula and H. K. Sharma, Inorg. Synth., 24, 181 (1985).
Elemental Anal. of titanium(II) bromide, Found: Br 77.10%, Ti
22.89%. Calcd for TiBr2: Br 76.95%, Ti 23.05%.
7
It was reported that soluble low-valent titanium species
improved the diastereoselectivity because of the readiness of
forming the titanium-bridged intermediate: A. Clerici, L.
Clerici, and O. Porta, Tetrahedron Lett., 37, 3035 (1996).
Copper powder was purchased from Soekawa Chemical Co.,
Ltd. and used as received. Zinc powder was activated before
use by 1 M aqueous HCl and washed with H2O and ether, then
dried under vacuum at 100 °C. Other metals were dried under
vacuum at 100 °C.
8
9
Benzaldehyde was reduced slowly at -23 °C by using the com-
bination of titanium(II) chloride and copper: T. Mukaiyama, A.
Kagayama, K. Igarashi, and I. Shiina, Chem. Lett., 1999, 1157.
10 A typical procedure for the pinacol coupling reaction: To a sus-
pension of TiBr2 (0.5 mmol) and Cu powder (0.5 mmol) in
t
CH2Cl2 (1.0 mL) was added BuCN (2 mmol) under argon
atmosphere. After the resulting Cu suspended dark green solu-
tion was cooled to –23 °C, a solution of benzaldehyde (0.5
mmol) in CH2Cl2 (0.8 mL) was added. The reaction mixture
was stirred for 6 h, then the work up was carried out as men-
tioned in ref. 2. The crude product was purified by TLC to
afford the desired pinacol (95%).
11 J. Szymoniak, J. Besançon, and C. Moïse, Tetrahedron, 50,
2841 (1994).
12 a) T. Hirao, M. Asahara, Y. Muguruma, and A. Ogawa, J. Org.
Chem., 63, 2812 (1998). For similar reactions using catalytic
amount of titanium(III) complex, see: b) T. A. Lipski, M. A.
Hilfiker, and S. G. Nelson, J. Org. Chem., 62, 4566 (1997).
13 The reductive coupling also proceeded when titanium(IV) bro-
mide was employed instead of titanium(II) bromide. However,
complex mixtures were produced and yields of the pinacols
were poor. For example, in the case of using benzaldehyde or
3-phenylpropanal as a substrate, the yield of pinacol was 60%
or 14%, respectively.