Efficient diastereoselective pinacol coupling reaction of aliphatic and aromatic aldehydes by using newly utilized low valent titanium bromide and iodide species

Article abstract of DOI:10.1016/S0040-4020(01)00074-6

Reductive coupling reaction of aromatic and aliphatic aldehydes proceeded under mild conditions to give the corresponding pinacols in moderate to high yields and DL-diastereoselectivities by using combinations of either low valent titanium(II) bromide and copper or titanium(IV) iodide and copper in a mixed solvent of dichloromethane and pivalonitrile. In the case of using titanium(IV) iodide and copper, pinacols were obtained in good to high yields with moderate to high diastereoselectivities irrespective of the number of substitutuents at α-position of aliphatic aldehydes.

Full text of DOI:10.1016/S0040-4020(01)00074-6

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 2499±2506
Ef®cient diastereoselective pinacol coupling reaction of aliphatic
and aromatic aldehydes by using newly utilized low valent
titanium bromide and iodide species
Teruaki Mukaiyama,p Naritoshi Yoshimura, Koji Igarashi and Akifumi Kagayama
Department of Applied Chemistry, Faculty of Science, Science University of Tokyo, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
This paper is dedicated to Professor Henri B. Kagan on the occasion of his receipt of the 1999 Tetrahedron Prize
Received 30 June 2000; revised 23 October 2000; accepted 26 October 2000
AbstractÐReductive coupling reaction of aromatic and aliphatic aldehydes proceeded under mild conditions to give the corresponding
pinacols in moderate to high yields and dl-diastereoselectivities by using combinations of either low valent titanium(II) bromide and copper
or titanium(IV) iodide and copper in a mixed solvent of dichloromethane and pivalonitrile. In the case of using titanium(IV) iodide and
copper, pinacols were obtained in good to high yields with moderate to high diastereoselectivities irrespective of the number of substitutuents
at a-position of aliphatic aldehydes. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
reducing reagents are being studied continuously by many
research groups.1
Reductive coupling reaction of carbonyl compounds that
affords vicinal diols or ole®ns, known as pinacol coupling
reaction, is one of the most important carbon±carbon bond
forming reactions. In last few decades, various low valent
metal species such as aluminum, cerium, iron, magnesium,
manganese, niobium, samarium, silicon, titanium, vana-
dium, ytterbium and zirconium were developed extensively
as reducing metal reagents for this reaction.1 Recently,
many of these coupling reactions including intramolecular
cyclizations have been employed effectively as key steps in
the total synthesis of complex natural and unnatural
products.
Concerning intermolecular pinacol coupling reactions,
recent topics are focused on how to establish high yields
and diastereoselectivities (dl or meso) under mild con-
ditions. By treating aromatic aldehydes with several kinds
of low valent metals such as titanium,3 samarium4 and
niobium,5 the corresponding homo-coupling products, 1,2-
diols, were reported to be obtained in high yields with high
dl-diastereoselectivities. Further, dl-pinacol was preferen-
tially formed from acetophenone, an aromatic ketone, by
using a combination of titanium(III) chloride, magnesium
and catechol in THF.6 There had been a few reports,
however, on highly diastereoselective coupling reaction of
aliphatic carbonyl compounds due to their low reactivities.
Recently, it was reported from our laboratory that a combi-
nation of titanium(II) chloride and zinc effectively promoted
the reductive coupling reaction of aliphatic carbonyl
compounds in a mixed solvent of dichloromethane and
pivalonitrile,7 and titanium(II) chloride proved to be a useful
reagent in the following experiment: that is, by an intra-
molecular pinacol coupling reaction using low valent
titanium species prepared in situ from titanium(II) chloride
and lithium aluminum hydride, the construction of A ring
onto BC ring system was performed successfully in our total
synthesis of antitumor agent Taxol,8 and a similar reaction
was also observed on using a combination of titanium(III)
chloride and lithium aluminum hydride. Comparing these
two conditions, the former generated low valent titanium
species in less acidic media. Then, it was further demon-
strated that a combination of titanium(II) chloride and
copper promoted the aldol reaction of a-bromo ketones
Of those reducing reagents, low valent titanium compounds
were shown to be quite effective and thus were being studied
intensively. In 1973, Mukaiyama2a reported the synthesis of
vicinal diols by pinacol coupling reaction using titanium-
(IV) chloride and zinc as well as the synthesis of ole®ns via
the above diols using titanium(IV) chloride and lithium
aluminum hydride while Tyrlik2b also reported the for-
mation of ole®ns by using titanium(III) chloride and mag-
nesium. McMurry,2c in 1974, started to study this coupling
reaction in detail by using either combination of titanium-
(III) chloride and lithium aluminum hydride or titanium(III)
chloride and zinc±copper alloy. Today, various titanium-
Keywords: coupling reactions; aldehydes; diols; diastereoselection; low
valent titanium species.
p
Corresponding author. Tel.: 181-3-3260-4271; fax: 181-3-3235-2214;
e-mail: mukaiyam@rs.kagu.sut.ac.jp.
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)00074-6

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T. Mukaiyama et al. / Tetrahedron 57 (2001) 2499±2506
Table 1. Pinacol coupling reaction of benzaldehyde by using low valent titanium chloride species
Entry
Reductanta
TiCl2
TiCl21Zn (1.0)
TiCl21Zn (1.0)
TiCl21Cu (1.0)
TiCl21Cu (1.0)
Temp (8C)
Time (h)
Yield of 2 (%)
[dl/meso]b
1
2
3
4
5
rt
0
223
rt
6
6
6
6
6
36
88
91
79
32
[90/10]
[47/53]
[45/55]
[71/29]
[90/10]
223
a
PhCHO/TiCl2/tBuCNˆ0.5/0.5/2.0 mmol in CH2Cl2 (4.0 ml). Numbers in parentheses were molar ratios of metals/Ti.
b
1
Ratios were determined by H NMR analysis of crude product mixture.
with aliphatic aldehydes with high syn-selectivities under
mild conditions.9
reaction. Here, we would like to report an ef®cient method
for the preparation of various pinacols from aromatic and
aliphatic aldehydes by using titanium(II) bromide or
titanium(IV) iodide species in their respective combinations
with copper in a mixed solvent of dichloromethane and
pivalonitrile.
It is generally known that the yields and diastereoselec-
tivities of pinacol coupling products by using low valent
titanium compounds are higher in homogeneous system
than in heterogeneous one.3b,10 In titanium(II) chloride
promoted reaction, pivalonitrile was added on the con-
sideration that the nitrile would moderately coordinate to
the low valent titanium species to form a coordinated
complex, which then increases solubility of the titanium
species and accelerates reduction step of donating the
titanium complex to the carbonyl compounds. When zinc
was combined with titanium(II) chloride, the addition of
pivalonitrile actually enhanced the solubility of low valent
titanium species and the coupling reactions proceeded to
give pinacols in high yields, but the diastereoselectivities
were rather low.7 Based on these results, titanium(II) bro-
mide11 and iodide were chosen in order to generate more
active low valent titanium species besides titanium(II)
chloride. As their atoms of titanium(II) bromide and iodide
are larger than those of chloride, it should be dif®cult for
them to form clusters. They are then expected to become
more soluble for participating effectively in the coupling
2. Results and discussion
In the ®rst place, titanium(II) chloride was facilely prepared
from titanium(IV) chloride and hexamethyldisilane accord-
ing to the previously reported procedure,12 and reductive
coupling reaction of benzaldehyde (1) was next tried by
using combinations of titanium(II) chloride and metals
such as zinc and copper in a mixed solvent of dichloro-
methane and pivalonitrile (see Table 1). When titanium(II)
chloride was used independently in a mixed solvent of
dichloromethane and pivalonitrile at room temperature,
the reductive coupling of 1 proceeded to give 1,2-diphenyl-
ethane-1,2-diol (2) in 36% yield with high dl-diastereo-
selectivity (dl/mesoˆ90/10, entry 1). When titanium(II)
chloride was combined with zinc, the reaction proceeded
smoothly to afford the corresponding pinacol in higher
Table 2. Pinacol coupling reaction of benzaldehyde by using newly utilized low valent titanium bromide species
Entry
Reductanta
TiBr2
TiBr21Zn (1.0)
TiBr21Cu (1.0)
TiBr21Cu (1.0)
TiBr21Cu (1.0)
TiBr21Cu (0.5)
TiBr21Fe (1.0)
TiBr21Mn (1.0)
TiBr21Sn (1.0)
Temp (8C)
Time (h)
Yield of 2 (%)
[dl/meso]b
1
2
3
4
5
6
7
8
9
rt
0
rt
223
240
223
rt
6
6
6
6
6
43
50
90
95
80
36
80
53
80
[.99/1]
[51/49]
[90/10]
[96/4]
[97/3]
[98/2]
[93/7]
[80/20]
[75/25]
6
18
18
3
rt
rt
a
PhCHO/TiBr2/tBuCNˆ0.5/0.5/2.0 mmol in CH2Cl2 (4.0 ml). Numbers in parentheses were molar ratios of metals/Ti.
b
1
Ratios were determined by H NMR analysis of crude product mixture.

T. Mukaiyama et al. / Tetrahedron 57 (2001) 2499±2506
2501
Scheme 1.
yield, but diastereoselectivity was not observed this time
(entries 2 and 3). On the other hand, a homo-coupling
product was obtained in a moderate yield with good dia-
stereoselectivity by adding copper at room temperature. The
above pinacol coupling was then tried at 2238C with an aim
of achieving higher diastereoselectivity; but unfortunately,
the yield of the corresponding pinacol decreased drastically
(entries 4 and 5).
species whose oxygen atoms of the two ketyl radicals are
linked side by side to the low valent titanium species and
their alkyl groups are located anti each other to minimize
the steric interaction (Scheme 1). That is: dl-pinacols are
preferentially formed by an internal carbon±carbon
coupling of `titanium-bridged' intermediate A which is
formed readily due to the highly coordinating ability of
low valent titanium species.
The application of titanium(II) bromide to the pinacol
coupling reaction was tried next. Although there are some
methods for the preparation of titanium(II) bromide from
titanium(III) bromide or titanium metal being reported, their
procedures are not quite convenient because they require
extremely high temperatures.13 A better procedure may be
provided by treating titanium(IV) bromide with hexa-
methyldisilane according to the procedure employed in
preparation of titanium(II) chloride.12 After screening
several reaction conditions, analytically pure titanium(II)
bromide was obtained in high yield as an air- and
moisture-sensitive dark brown solid when ®ve times molar
amounts of hexamethyldisilane was added dropwise into the
re¯uxing titanium(IV) bromide (at 2308C). The mixture was
further re¯uxed for 9 h, and the work up was carried out as
described in Ref. 12. Titanium(II) bromide thus prepared
was dissolved thoroughly in a mixed solvent of dichloro-
methane and pivalonitrile. As expected, 1 was smoothly
coupled at 2238C to afford 2 in 95% yield with excellent
dl-diastereoselectivity (dl/mesoˆ96/4, Table 2, entry 4)
when a combination of titanium(II) bromide and copper
was used. Next, combinations of titanium(II) bromide and
several other metals were screened (Table 2, entries 2±9). In
the case of using zinc, diastereoselectivity of 2 decreased
considerably just as in the case with titanium(II) chloride
(entries 1 and 2). When it was used together with iron or
manganese (entries 7 and 8), the rate of reductive coupling
was slow even at room temperature and the yield of 2 was
not so high. With the use of tin, the diastereoselectivity of 2
also decreased although the reduction of aldehyde
proceeded rapidly (entry 9).
In order to further improve the coupling reaction, the appli-
cation of titanium(II) iodide to the pinacol coupling reaction
was tried. Methods that have already been reported are of
the reactions carried out under extremely severe conditions
(for example, a high temperature of 800±9008C) sometimes
with the danger of explosion.13b Then, titanium(IV) iodide
was tried with hexamethyldisilane just as in the cases of
preparing titanium(II) chloride12 and bromide to aim for
the establishing
a milder preparative procedure as
previously mentioned. In spite of the careful examination
of the reaction conditions, no pure titanium(II) iodide was
successfully isolated. Then, the in situ formation of low
valent titanium iodide species was tried by adding copper,
a reducing reagent, to the titanium(IV) iodide, and the
species generated thus was applied to the pinacol coupling
reaction.14
In the ®rst place, a reductive coupling reaction of 1 was
tried by using combinations of titanium(IV) iodide or
bromide and copper (Table 3). When titanium(IV)
iodide was used in the absence of copper, coupling of
1 proceeded at room temperature and gave 2 in 43%
yield with exclusive dl-diastereoselectivity within 6 h.
In the presence of copper, on the other hand, the
coupling proceeded smoothly within 3 h at 2238C
giving 2 in high yields with excellent diastereoselec-
tivities (entries 1±4). Next, when titanium(IV) bromide
was employed instead of titanium(IV) iodide, the reduc-
tive coupling slowed down (6 h) even when copper was
used as a co-reductant, although it afforded the corre-
sponding pinacols in good to high yields with excellent dia-
stereoselectivities (entries 5±8). Incidentally, the reaction
using a combination of titanium(IV) chloride and copper
did not proceed at all (entries 10±12).
The mechanism of this dl-diastereoselection could be
explained by the initial generation of intermediate radical

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T. Mukaiyama et al. / Tetrahedron 57 (2001) 2499±2506
Table 3. Pinacol coupling reaction of benzaldehyde by using a combination of titanium(IV) iodide or bromide and copper
Entry
Reductanta
TiI4
TiI41Cu (1.0)
TiI41Cu (2.0)
TiI41Cu (3.0)
Temp. (8C)
Time (h)
Yield of 2 (%)
[dl/meso]b
1
2
3
4
rt
6
3
3
3
43
94
93
92
[.99/1]
[98/2]
[.99/1]
[.99/1]
223
223
223
5
6
7
8
9
TiBr4
rt
18
6
6
6
12
N.R.
60
74
96
±
TiBr41Cu (1.0)
TiBr41Cu (2.0)
TiBr41Cu (3.0)
Cuc
223
223
223
rt
[98/2]
[98/2]
[98/2]
±
N.R.
10
11
12
TiCl4
TiCl41Cu (1.0)
TiCl41Cu (2.0)
rt
rt
rt
18
18
18
N.R.
N.R.
N.R.
±
±
±
a
PhCHO/TiX4/tBuCNˆ0.5/0.5/2.0 mmol in CH2Cl2 (4.0 ml). Numbers in parentheses were molar ratios of Cu/Ti.
PhCHO/Cu/tBuCNˆ0.5/1.0/2.0 mmol in CH2Cl2 (4.0 ml).
b
c
1
Ratios were determined by H NMR analysis of crude product mixture.
Then, 3-phenylpropionaldehyde (3), an aliphatic aldehyde,
which is generally less reactive than an aromatic one, was
tried as a substrate in the coupling reaction using a combi-
nation of titanium(IV) iodide and copper (summarized in
Table 4). When two or three molar amounts of copper
were used with titanium(IV) iodide, the reaction proceeded
smoothly at 08C and afforded 1,6-diphenylhexane-3,4-diol
(4) in high yields with high diastereoselectivities within 6 h
(entries 1±4). On the other hand, it did not proceed at
all when each titanium(IV) iodide, copper(0) or copper(I)
iodide was used independently (entries 1,8 and 9). These
results can reasonably be explained by assuming that the
formation of active titanium(II) iodide species would take
place by the reduction of titanium(IV) iodide with two
molar amounts of copper. Here, the iodide works as an
effective reductant to give pinacols via `titanium-bridged'
intermediate A (Scheme 1). This assumption can be
supported by the following observation: that is, before the
addition of aldehyde, suspended bronze colored powder (i.e.
copper) turned into gray (probably copper(I) iodide) by
using titanium(IV) iodide in a mixed solvent of dichloro-
methane and pivalonitrile. When a combination of titaniu-
m(IV) bromide and copper was used, on the other hand, the
reactions proceeded slowly (6 h) and the yield of 4 was
rather low (entries 5 and 6). When 3 was treated with tita-
nium(II) bromide and copper for a longer time (18 h, entry
7), 4 was obtained in high yield. All these results suggested
a higher reactivity of low valent titanium iodide species in
the pinacol coupling reaction.
In the next place, reductive coupling reactions of various
aromatic and aliphatic aldehydes using newly utilized low
Table 4. Pinacol coupling reaction of 3-phenylpropionaldehyde by using low valent titanium iodide or bromide species
Entry
Reductanta
TiI4
TiI41Cu (1.0)
TiI41Cu (2.0)
TiI41Cu (3.0)
Temp (8C)
Time (h)
Yield of 4 (%)
[dl/meso]b
1
2
3
4
0
0
0
0
18
6
6
N.R.
N.R.
80
±
±
[80/20]
[81/19]
6
80
5
6
TiBr41Cu (2.0)
TiBr41Cu (3.0)
0
0
6
6
46
61
[78/22]
[81/19]
7
TiBr21Cu (1.0)
0
18
82
[80/20]
8
9
Cuc
rt
rt
18
18
N.R.
N.R.
±
±
CuIc
a
Ph(CH2)2CHO/TiXn/tBuCNˆ0.5/0.65/2.6 mmol in CH2Cl2 (4.0 ml). Numbers in parentheses were molar ratios of Cu/Ti.
Ph(CH2)2CHO/CuXn/tBuCNˆ0.5/1.3/2.6 mmol in CH2Cl2 (4.0 ml).
b
c
1
Ratios were determined by H NMR analysis of crude product mixture.

T. Mukaiyama et al. / Tetrahedron 57 (2001) 2499±2506
2503
Table 5. Pinacol coupling reaction of various aromatic and aliphatic aldehydes by using titanium(IV) iodide-copper and titanium(II) bromide-copper
Entry
Aldehyde
TiI422Cu
TiBr22Cu
Conditionsa
A, 3 h
Yield (%)
[dl/meso]b
[.99/1]
Conditionsa
A, 6 h
Yield (%)
[dl/meso]b
1
2
2 94
2 95
[96/4]
[99/1]
A, 3 h
6a 93
[.99/1]
A, 6 h
6a 97
3
4
5
A, 3 h
A, 3 h
B, 6 h
6b 76
6c 76
4 80
[98/2]
[99/1]
A, 6 h
A, 6 h
B, 18 h
6b 74
6c 80
4 82
[94/6]
[91/9]
[81/19]
[80/20]
6
7
B, 6 h
B, 6 h
6d 72
6e 85
[80/20]
[75/25]
B, 18 h
B, 18 h
6d 82
6e 75
[80/20]
[74/26]
8
B, 6 h
6f 98
[85/15]
B, 18 h
6f 75
[75/25]
9
B, 6 h
B, 6 h
C, 6 h
6g 90
6h 98
6i 92
[80/20]
[84/16]
[85/15]
B, 18 h
B, 18 h
C, 18 h
6g 54
6h 21
N.R.
[85/15]
[70/30]
[-]
10
11
a
Conditions A: aldehyde/TiI4(TiBr2)/Cu/tBuCNˆ0.5/0.5/1.0(0.5)/2.0 mmol in CH2Cl2 (4.0 ml), 2238C; B: aldehyde/TiI4(TiBr2)/Cu/tBuCNˆ0.5/0.65/
1.3(0.65)/2.6 mmol in CH2Cl2 (4.0 ml), 08C; C: aldehyde/TiI4(TiBr2)/Cu/tBuCNˆ0.5/0.65/1.3(0.65)/2.6 mmol in CH2Cl2 (4.0 ml), rt.
Ratios were determined by 1H NMR analysis of crude product mixture.
b
valent titanium iodide and bromide species, that is, TiI4±
aliphatic aldehydes. On the other hand, the number of
substituents affected the reaction in the cases of using
TiBr2±Cu; that is, yields of the corresponding pinacols
decreased when a-disubstituted aldehydes were used
while no reaction took place with the use of a-trisubstituted
ones (entries 5±11). Hirao and co-workers suggested that
the bulkiness of aliphatic aldehydes at a-position was
responsible for the diastereoselectivities of the pinacol
coupling products.15 In their reductive coupling reactions
using a catalytic amount of vanadium(IV) complex together
with excess amounts of zinc and chlorotrimethylsilane, the
observed diastereoselectivities were rather low (dl/
meso,2/1) when a-monosubstituted aldehydes, substrates
2Cu and TiBr2±Cu, were tried (see Table 5). By employing
the above two systems, aromatic and a,b-unsaturated alde-
hydes were converted to the corresponding pinacols at
2238C in good to high yields with high diastereoseletivities
(entries 1±4) within 3 and 6 h, respectively. Effects of these
two reducing systems on reductive coupling of aliphatic
aldehydes were as follows: in the cases of using TiI4±
2Cu, the pinacol coupling reactions proceeded smoothly
within 6 h at the temperatures ranging from 08C to room
temperature to give the corresponding pinacols in good to
high yields with moderate to good diastereoselectivities
irrespective of the number of substituents at a-position of

2504
T. Mukaiyama et al. / Tetrahedron 57 (2001) 2499±2506
less hindered than a-di- and a-trisubstututed ones, were
used. On the other hand, Niobium(III) chloride±1,2-
dimethoxyethane complex5b and samarium(II) iodide±
ferrocenyl ligand complex16 afforded the corresponding
pinacol, 2,2,5,5-tetramethylhexane-3,4-diol (6i), in fairly
good yields with high diastereoselectivities when pivalalde-
hyde (5i), an a-trisubstituted aldehyde, which has generally
been considered to be less reactive than a-mono- or
a-disubstituted ones because of the steric hindrance, was
used as a substrate. In the cases of using acyclic a-mono-
or a-disubstituted aliphatic aldehydes, the former afforded
the corresponding 1,3-dioxolanes as major products, which
were produced by further-reaction between the correspond-
ing pinacols and the remaining aldehydes, and the latter
afforded the pinacols in moderate to good yields. Recently,
it was reported that the reductive coupling of various
aromatic and aliphatic aldehydes by using a catalytic
amount of cerium(III) triisopropoxide together with excess
amounts of diethylzinc and chlorotrimethylsilane15e
afforded the corresponding pinacols with high diastereo-
selectivities, but the yields remained moderate to good.
Further, b-monosubstitututed aldehydes were not coupled
at all under the above reaction conditions. These results
therefore suggest that the low valent titanium iodide
species-mediated reductive coupling reactions may most
widely be applied to the reductive coupling of various
aromatic and aliphatic aldehydes to afford the correspond-
ing pinacols in good to high yields with moderate to high
diastereoserectivities under mild conditions.
lybdic acid. All reactions were carried out under argon
atmosphere in dried glassware. Dichloromethane and
pivalonitrile were distilled from diphosphorus pentoxide,
then calcium hydride, and dried over MS 4A. All substrates
were purchased from Tokyo Kasei Kogyo, Kanto Chemical,
Aldrich Chemical, Merck, or Soekawa Chemical, and were
used after puri®cation by distillation. Copper powder was
used as received. Zinc powder was activated before use by
1N HCl and washed with H2O and ether, then dried under
vacuum at 1008C. Other metals were dried under vacuum at
1008C before use.
4.2. The procedure for preparation of titanium(II)
chloride and titanium(II) bromide
Titanium(II) chloride was prepared by Nalura's pro-
cedure.12 Anal. calcd for TiCl2: Ti 40.31%, Cl 59.69%;
found: Ti 39.89%, Cl 59.28%.
Titanium(II) bromide was prepared by following procedure:
A 30 ml two-necked round-bottomed ¯ask was equipped
with a re¯ux condenser and a dropping funnel. The ¯ask
was dried and dry argon gas was introduced. Titanium(IV)
bromide 5.51 g (15 mmol) was added to the ¯ask, and
heated to 2308C with continuous stirring. To re¯uxing
titanium(IV) bromide, hexamethyldisilane 10.98 g (75
mmol) was added dropwise. The reaction mixture turned
dark brown, and a solid compound appeared, then stirred
for 9 h. And then the work up reported in Ref. 12 was
followed. A dark brown solid 2.67 g (12.9 mmol, 86%
yield) was obtained. Anal. calcd for TiBr2: Ti 23.05%, Br
76.95%, found: Ti 22.89%, Br 77.10%.
3. Conclusions
Reductive coupling reaction of aromatic and aliphatic
aldehydes proceeded smoothly to give the corresponding
pinacols in good to high yields with moderate to high
dl-diastereoselectivities by using combinations of either
low valent titanium(II) bromide and copper or titanium(IV)
iodide and copper in a mixed solvent of dichloromethane
and pivalonitrile under mild conditions. In the case of using
titanium(IV) iodide and copper, the coupling of various
aldehydes proceeded smoothly to give the corresponding
pinacols in good to high yields with moderate to high dia-
stereoselectivities irrespective of the number of sub-
stitutuents at a-position of aliphatic aldehydes.
4.3. Typical procedure for the reductive coupling
reaction of aldehyde using titanium(II) bromide and
copper in dichloromethane±pivalonitrile
To a dark brown suspension of TiBr2 0.104 g (0.5 mmol)
and Cu powder 0.032 g (0.5 mmol) in CH2Cl2 2.5 ml was
added BuCN 0.22 ml (2.0 mmol) under argon atmosphere.
t
After the resulting Cu suspended dark green solution was
cooled to 2238C, a solution of benzaldehyde 0.053 g
(0.5 mmol) in CH2Cl2 1.5 ml was added. The reaction
mixture was stirred for 6 h, then saturated aqueous NH4Cl
was added. The mixture was ®ltered and extracted with
CH2Cl2, and the organic layer was washed with saturated
aqueous NaHCO3 and brine, dried over Na2SO4. After ®l-
tration and concentration of the mixture, the crude product
was puri®ed by thin layer chromatography to afford the
desired pinacol (0.051 g, 95% yield, dl/mesoˆ96/4).
4. Experimental
4.1. General
Elemental analyses were performed by Mitsui Chemical
Analysis & Consulting Service Inc. (Kanagawa, Japan).
1H- and 13C NMR spectra were recorded on a JEOL JNM-
EX270L, and a JEOL JNM-LA400 using tetramethylsilane
(TMS) or chloroform-d (CDCl3) as internal standard. The
following abbreviations were used: sˆsinglet, dˆdoublet,
tˆtriplet, qˆquartet, mˆmultiplet, and brˆbroad. Thin
layer chromatography used routinely for puri®cation and
separation of product mixtures was performed on Wakogel
B5F. Analytical thin layer chromatography was performed
using E. Merck 0.25 mm silica gel 60 F254 plates, and
visualization was accomplished with ethanolic phosphomo-
4.4. Typical procedure for the reductive coupling
reaction of aldehyde using low valent titanium iodide
species in situ formed by titanium(IV) iodide and copper
in dichloromethane±pivalonitrile
To a reddish brown suspension of TiI4 0.361 g (0.65 mmol)
and Cu powder 0.083 g (1.3 mmol) in CH2Cl2 2.5 ml was
added BuCN 0.29 ml (2.6 mmol) under an argon atmos-
t
phere. The color changed to dark brown and the mixture
was stirred for additional 30 min at room temperature. The
resulting gray colored powder (probably CuI) suspended
reddish-dark brown solution was cooled to 08C, and a

T. Mukaiyama et al. / Tetrahedron 57 (2001) 2499±2506
2505
solution of 3-phenylpropionaldehyde 0.067 g (0.5 mmol) in
CH2Cl2 1.5 ml was added. The reaction mixture was stirred
for 6 h, and then work up was done as mentioned above. The
crude product was puri®ed by thin layer chromatography to
afford the desired pinacol (0.054 g, 80% yield, dl/mesoˆ
81/19).
CH±OH, dl), 3.49 (2H, d, Jˆ7.3 Hz, CH±OH, meso).
Assignments were made by comparing the relative areas
of carbinol proton signals at d 3.30 and 3.49, respectively.
4.5.8. dl- and meso-1,2-Dicyclohexylethane-1,2-diol
(6f).25 Colorless solid; 1H NMR (CDCl3) d: 0.97±1.80
(44H, m, cyclohexyl), 1.98±2.20 (4H, br, OH), 3.28
(2H, d, Jˆ5.7 Hz, CH, dl), 3.51 (2H, d, Jˆ8.5 Hz, CH,
meso). Assignments were made by comparing the relative
areas of carbinol proton signals at d 3.28 and 3.51,
respectively.
4.5. Diastereoselectivities of pinacols
1
400 MHz H NMR spectra assignments were used for the
determination of the dl/meso ratio of the crude pinacols
obtained.
4.5.9. dl- and meso-2,5-Diphenylhexane-3,4-diol (6g).15,26
Colorless solid; 1H NMR (CDCl3) d: 1.21 (6H, d, Jˆ6.8 Hz,
CH3, dl-A), 1.30 (6H, d, Jˆ7.1 Hz, CH3, dl-B), 1.38 (6H,
d, Jˆ7.1 Hz, CH3, meso), 1.62±2.04 (6H, br, OH), 2.87 (2H,
m, Ph±CH, dl-A), 2.96(2H, m, Ph±CH, dl-B), 3.02 (2H, m,
Ph±CH, meso), 3.20 (2H, m, CH±OH, meso), 3.32 (2H, m,
CH±OH, dl-A), 3.71 (2H, m, CH±OH, dl-B), 6.81±7.37
(30H, m, Ph-H). Assignments were made by comparing the
relative areas of carbinol proton signals at d 3.20 and 3.32,
3.71, respectively. Theoretically, there are possible three
dl-isomers (3,4-syn); i.e. (i) 2,3-syn/4,5-syn, (ii) 2,3-anti/
4,5-anti and (iii) 2,3-syn/4,5-anti isomers. However,
relative con®gurations of the isomers (i) and (ii) (C2 sym-
metry) were not assigned. Stereoselectivities were
determined by measuring a mixture of (i) and (ii) isomers
(dl-A), and (iii) (C1 symmetry) isomer (dl-B) with a
ratio of 7:3. Concerning meso isomers, only one isomer of
the three possible isomers was detected. Similar results
reported in the case of using samarium(II) iodide as
shown in Ref. 26.
4.5.1. dl- and meso-1,2-Diphenylethane-1,2-diol (2).17,18
Colorless solid; H NMR (CDCl3) d: 2.38 (2H, br, OH,
meso), 3.04 (2H, br, OH, dl), 4.65 (2H, s, CH, dl), 4.79
(2H, s, CH, meso), 7.07±7.30 (20H, m, Ph±H). Assignments
were made by comparing the relative areas of carbinol
proton signals at d 4.65 and 4.79, respectively.
1
4.5.2. dl-1,2-Bis(40-chlorophenyl)ethane-1,2-diol (6a).18,19
Colorless solid; H NMR (CDCl3) d: 2.21 (2H, br, OH),
1
4.65 (2H, s, CH), 7.06 (4H, d, Jˆ8.5 Hz, Ph±H), 7.25
(4H, d, Jˆ8.5 Hz, Ph±H).
4.5.3. dl- and meso-1,2-Bis(40-methoxyphenyl)ethane-
1
1,2-diol (6b).20 Colorless solid; H NMR (CDCl3) d: 2.17
(2H, br, OH, meso), 2.78 (2H, br, OH, dl), 3.77 (6H, s,
OCH3, dl), 3.81 (6H, s, OCH3, meso), 4.64 (2H, s, CH,
dl), 4.74 (2H, s, CH, meso), 6.74±7.06 (16H, m, Ph-H).
Assignments were made by comparing the relative
areas of carbinol proton signals at d 4.64 and 4.74,
respectively.
4.5.10. dl- and meso-2,5-Dimethylhexane-3,4-diol (6h).15,23
1
Colorless solid; H NMR (CDCl3) d: 0.87 (12H, d, Jˆ
4.5.4. dl- and meso-1,6-Diphenyl-1,5-hexadiene-3,4-diol
1
(6c).21 Colorless solid; H NMR (CDCl3) d: 2.20 (2H, br,
7.1 Hz, CH3, meso), 0.89 (12H, d, Jˆ7.1 Hz, CH3, dl),
1.79 (2H, m, CH3CH, dl), 1.97 (2H, m, CH3CH, meso),
2.27±2.31 (4H, br, OH), 3.30 (2H, d, Jˆ5.9 Hz, CH±OH,
dl), 3.49 (2H, d, Jˆ7.3 Hz, CH±OH, meso). Assignments
were made by comparing the relative areas of carbinol
proton signals at d 3.30 and 3.49, respectively.
OH, meso), 2.69 (2H, br, OH, dl), 4.26 (2H, d, Jˆ5.1 Hz,
CH, dl), 4.36 (2H, m, CH, meso), 6.25 (2H, dd, Jˆ5.1,
15.8 Hz, Ph-CHvCH, dl), 6.21±6.29 (2H, m, Ph±
CHvCH, meso), 6.71 (2H, d, Jˆ15.8 Hz, Ph±CHvCH,
dl), 6.90 (2H, d, Jˆ16.1 Hz, Ph±CHvCH, meso), 7.14±
7.57 (20H, m, Ph±H). Assignments were made by compar-
ing the relative areas of carbinol proton signals at d 4.26 and
4.36, respectively.
4.5.11. dl- and meso-2,2,5,5-Tetramethylhexane-3,4-diol
1
(6i).27 Colorless solid; H NMR (CDCl3) d: 0.92 (18H, s,
(CH3)C, dl), 1.02 (18H, s, (CH3)C, meso), 1.43 (4H, br,
OH), 3.25 (2H, d, Jˆ5.1 Hz, CH, meso), 3.32 (2H, d, Jˆ
4.9 Hz, CH, dl). Assignments were made by comparing the
relative areas of carbinol proton signals at d 3.25 and 3.32,
respectively.
4.5.5. dl- and meso-1,6-Diphenylhexane-3,4-diol (4).22
Colorless solid; H NMR (CDCl3) d: 1.76±1.87 (8H, m,
1
CH2), 2.65±2.90 (12H, m, CH21OH), 3.50 (2H, m, CH,
dl), 3.65 (2H, m, CH, meso), 7.22±7.36 (20H, m, Ph±H).
Assignments were made by comparing the relative areas of
carbinol proton signals at d 3.50 and 3.65, respectively.
References
4.5.6. dl- and meso-Decane-5,6-diol (6d).23,24 Colorless
solid; 1H NMR (CDCl3) d: 0.90±0.93 (12H, m, CH3),
1.21±1.54 (24H, m, CH2), 2.27±2.37 (4H, br, OH), 3.39
(2H, m, CH, dl), 3.60 (2H, m, CH, meso). Assignments
were made by comparing the relative areas of carbinol
proton signals at d 3.39 and 3.60, respectively.
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14. Postulated low valent titanium iodide mediated reductive
coupling of carbonyl compounds affording the corresponding