A novel, solventless reductive coupling of carbonyl compounds by alkali metals, catalysed by bromobenzene

Article abstract of DOI:10.1039/b210966b

Catalysed by bromobenzene, alkali metals including Li, Na, and K can mediate the reductive coupling of carbonyl compounds under mild, solventless conditions to furnish the corresponding pinacol products.

Full text of DOI:10.1039/b210966b

A novel, solventless reductive coupling of carbonyl compounds by alkali
metals, catalysed by bromobenzene
Hui Zhao, De-Jin Li, Lan Deng, Lei Liu†* and Qing-Xiang Guo*
Department of Chemistry, University of Science and Technology of China, Hefei 230026, P. R. China.
E-mail: qxguo@ustc.edu.cn; Fax: 86-551-360-6689; Tel: 86-551-360-7466
Received (in Cambridge, UK) 7th November 2002, Accepted 15th January 2003
First published as an Advance Article on the web 23rd January 2003
Catalysed by bromobenzene, alkali metals including Li, Na,
and K can mediate the reductive coupling of carbonyl
compounds under mild, solventless conditions to furnish the
corresponding pinacol products.
bromobenzene, the coupling can be conducted under very mild
conditions (solventless, room temperature, no inert gas protec-
tion). Such reaction conditions should be compared to the
previously reported reductive coupling of acetone mediated by
sodium or lithium metal, which is conducted in liquid ammonia
or THF.5
The required reaction time decreases in the order Li > Na >
K. This order is consistent with the order of reactivity of each
alkali metal. Nevertheless, because of the high reactivity, use of
K usually leads to lower yield of the desired products. The
yields for the use of Li and Na are similar. The diaster-
eoselectivity of the catalytic reductive coupling is mostly quite
high. Comparing entries 2, 3, and 4 of Table 1, we can see that
a faster reaction is favourable for the dl products. For aromatic
ketones and aldehydes, electron-withdrawing substituents on
the phenyl ring are favourable for the dl products, whereas
electron-donating substituents are favourable for the meso
products (entry 5–11). Cyclohexanone shows less reactivity
than the aromatic ketones in the reductive coupling.
Reductive coupling of carbonyl compounds is one of the most
important reactions for the formation of carbon–carbon bonds.1
Its mechanism and applications have been intensively studied
2
for many years. Recently the reductive coupling of carbonyl
compounds have been used in the synthesis of HIV-protease
3
4
inhibitors and some natural products such as taxol.
5
6
7
8
2
9
2
10
Metals including Na, Zn, Mg, Mn, In, Ti, Sm, Al,
and Ce11 have been found to be able to mediate the reductive
coupling of carbonyl compounds. Organic solvents such as
6
12
dichloromethane, tetrahydrofuran,
and dimethoxyethane
(
DME)13 are generally used in these reactions. For economic
and ecological reasons the use of aqueous media to conduct
reductive carbonyl couplings has recently attracted consider-
able interest.6
,14
We sought to find the conditions for a cleaner reductive
carbonyl coupling. Therefore, we attempted to conduct car-
bonyl coupling in a solventless and catalytic fashion. Inter-
estingly, we found that catalysed by bromobenzene, alkali
metals including Li, Na, and K can mediate the reductive
coupling of carbonyl compounds under mild, solventless
conditions. Using this method, the yield as well as the
diastereoselectivity of the coupling is quite high.
Interestingly, although the reductive coupling can be con-
ducted without any inert gas protection, use of nitrogen
protection significantly increases diastereoselectivity of the
coupling (entry 12 and 13). The cause of this observation
remains to be clarified.
Use of organic solvents does not favour the coupling. In fact,
when the coupling is conducted in tetrahydrofuran or in N,N-
dimethylformamide, the yield of the coupling of PhCOCH
decreases to 8% or 2%.
3
Typical procedures for the reductive coupling are as follows:
to a mixture of 3.5 ml of benzophenone (30 mmol) and a
catalytic amount of bromobenzene (3 mmol) is added 0.9 g of
small pieces of sodium (39 mmol). The reaction mixture is
Other metals such as Mg powder or pieces, which could also
be used in the reductive coupling of carbonyl compounds, do
not provide any product under the present reaction condition
2
stirred at ambient temperature for 5 h. Inert gas (N or Ar)
protection is not necessary in the reaction. After the reaction is
completed, 1 ml of ethanol was added into the mixture to
quench the remaining sodium. The mixture is neutralized with
Table 1 Products and yields of the reductive coupling of aldehydes or
ketones
2
M hydrochloric acid (Scheme 1). The products are separated
Yield
(%)
using flash column chromatography over silica gel. The detailed
results for the reductive couplings of different substrates are
summarized in Table 1.
According to Table 1, it can be seen that in the absence of
bromobenzene, the yield of the coupling is very low (14%). In
comparison, when bromobenzene is added the yield of the
coupling improves. In addition, the added bromobenzene could
be fully recovered after the reaction. Therefore, bromobenzene
is a catalyst for the coupling. Because of the catalytic effect of
Metala
b
dl+mesoc
Entry
Carbonyl compounds
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
PhCOCH
PhCOCH
PhCOCH
PhCOCH
3
3
3
3
Lid
Li
Na
K
Li
Na
Li
14
87
93
47
77
86
90
81
75
84
84
75
84
54
52
34
69+31
74+26
77+23
84+16
25+75
meso only
dl only
dl only
dl only
96+4
p-CH
p-CH
3
C
6
H
4
COCH
3
3
OC
6
4
H COCH
3
2,4-Cl
o-ClC
PhCHNCHCOCH
p-ClC COCH
p-BrC COCH
C
2 6
H
CHO
3
CHO
H
4 4
Li
Li
3
1
1
1
1
1
1
1
a
H
6 4
3
Na
Na
Li
H
6 4
3
99+1
PhCHO
PhCHO
Cyclohexanone
Cyclohexanone
Cyclohexanone
65+35
99+1
—
—
—
e
Li
Li
Na
K
The reaction time is 6–8 hours for Li, 2–4 hours for Na, and 1 hour for K,
respectively. b Isolated yield. c Ratios were determined from H NMR (400
MHz) and GC-MS analyses of the isolated products. Reaction performed
in the absence of bromobenzene. e Reaction performed under nitrogen
protection.
1
Scheme 1
d
†
Current address: Department of Chemistry, Columbia University, New
York, NY 10027. E-mail: leiliu@chem.columbia.edu
5
06
CHEM. COMMUN., 2003, 506–507
This journal is © The Royal Society of Chemistry 2003

even after prolonged reaction time (48 h). This may be due to
the fact that the alkali metals are much more electropositive than
other metals. Magnesium oxide on the surface of magnesium
metal may also obstruct the reaction.
Chlorobenzene and iodobenzene can also catalyse the
reductive coupling, but their efficiency is slightly worse than
that of bromobenzene. For example, for the coupling of
PhCOCH the yields associated with chlorobenzene, iodo-
3
benzene, and bromobenzene are 76%, 74%, and 87%, re-
spectively. Another catalyst we found for the reductive coupling
coupling products as discussed before.16 Bromobenzene makes
the reaction more efficient because the electron transfer rate is
higher between the alkali metal and bromobenzene than
between the alkali metal and carbonyl compound.
In summary, we found a novel bromobenzene-catalysed
reductive coupling reaction of carbonyl compounds. The
reaction can be conducted under very mild conditions. The
yields are usually good. The diastereoselectivity is mostly high.
A single electron transfer mechanism is proposed for the
coupling.
is naphthalene. However, for the coupling of PhCOCH
3
using
We thank NSFC for the financial support.
naphthalene as the catalyst can only give a yield of 24%.
Addition of p-dinitrobenzene completely inhibits the cou-
pling, as it can capture the electron and turn into a radical anion
as indicated by the electron paramagnetic resonance (ESR)
spectrum (Fig. 1).15 Interestingly, this ESR signal does not
appear if either bromobenzene or the metal is not added to the
reaction mixture. We could not observe the ESR spectrum of
bromobenzene radical anion in the reaction, possibly because
this radical anion is too reactive. However, as long as both metal
and bromobenzene are added, the ESR signal appears in the
absence of the carbonyl compound. All these observations
indicate that p-nitrobenzene inhibits the reaction because it
captures the electron carried by the bromobenzene radical
anion.16 (Scheme 2).
Notes and references
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mechanism for the catalytic reductive coupling (Scheme 3).
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electron from the alkali metal and becomes a radical anion.
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1
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