Palladium catalyzed activation of borane-amine adducts: Rate enhancement of amine-borane methanolysis in the reduction of nitrobenzenes to anilines

Article abstract of DOI:10.1016/S0040-4039(01)00166-6

Hydrolytically stable borane-amines can be activated in situ through palladium catalysis and perform reductions not possible otherwise. Hence, borane-trimethylamine is an efficient hydrogen-transfer reagent for the open vessel reduction of nitroaryls to anilines. Likewise, the palladium catalyzed methanolysis/decomplexation of stable borane-amine adducts is accelerated by the action of nitrobenzene.

Full text of DOI:10.1016/S0040-4039(01)00166-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2285–2288
Palladium catalyzed activation of borane–amine adducts: rate
enhancement of amine–borane methanolysis in the reduction of
nitrobenzenes to anilines
Michel Couturier,* John L. Tucker, Brian M. Andresen, Pascal Dub e´ , Steven J. Brenek and
Joanna T. Negri
Chemical Research and Development, Pfizer Global Research and Development, Eastern Point Road, PO Box 8013, Groton,
CT 06340-8013, USA
Received 26 January 2001; accepted 29 January 2001
Abstract—Hydrolytically stable borane–amines can be activated in situ through palladium catalysis and perform reductions not
possible otherwise. Hence, borane–trimethylamine is an efficient hydrogen-transfer reagent for the open vessel reduction of
nitroaryls to anilines. Likewise, the palladium catalyzed methanolysis/decomplexation of stable borane–amine adducts is
accelerated by the action of nitrobenzene. © 2001 Elsevier Science Ltd. All rights reserved.
Borane adducts with amines are an important class of
reducing agents with several applications in organic
amines. To further broaden the reducing capabilities of
borane carriers made from volatile amines, it would be
a desirable advantage to activate these otherwise stable/
inert hydride sources in neutral conditions through
transition metal catalysis.
1
2
synthesis and industrial processes. In fact, over a
dozen borane–amine complexes are commercially
3
available and some are even prepared on a tonnage
4
scale. Unlike common hydride reducing agents,
borane–amine adducts are generally hydrolytically and
thermally stable, soluble in both protic and aprotic
solvents and most often crystalline compounds that
In this regard, we recently disclosed that palladium and
Raney nickel activate the methanolic cleavage of stable
14
borane–amine complexes. In this process, palladium
hydride is a likely transient species prior to molecular
hydrogen liberation. Hence, we envisioned the use of
commercially available borane–amines in methanol as a
novel palladium catalyzed reducing system. It is note-
worthy that borane–amine adducts have recently been
5
offer safe handling convenience over the former. As
expected, their reactivity is somewhat diminished, and6
some can even be utilized in aqueous acidic solutions.
In consequence, their scope in organic synthesis has
been limited relative to loosely bound borane–Lewis
base complexes such as borane–tetrahydrofuran (BH –
employed as hydride sources in palladium catalyzed
3
7
15
THF) and borane–dimethyl sulfide (BMS). However,
systems such as epoxide openings,
aryl triflate
16
17
the activity of borane–amine adducts has been shown
reductions and N-alloc deprotections. We report
herein on the palladium catalyzed reduction of
nitroaryls to anilines using commercially available
borane–amine complexes.
8
to increase in the presence of Bronsted and Lewis
9
acids. Pyridine–borane adsorbed on solid supports
10
exhibits enhanced reducing properties as well. In
hopes of finding more reactive amine–borane reagents,
1
1
12
Brown and Soderquist have designed borane carriers
incorporating sterically demanding tertiary amines. The
less basic aniline derivatives also form weaker and
To gain better understanding of the kinetics of the
palladium-catalyzed methanolysis, the reaction rate was
measured by profiling the pressure of hydrogen released
over time. For this purpose, commercially available
borane t-butylamine was decomplexed in methanol
using 10% Pd/C, and the corresponding plot is illus-
trated in Fig. 1. The linearity of rate suggests an
apparent zero-order kinetic profile under these reaction
conditions. This implies that the concentration of
borane t-butylamine is not rate determining, and the
1
3
hence more reactive adducts with borane. However,
these structural modifications make the product isola-
tion from the resulting higher boiling free-amine more
cumbersome as compared to traditional borane–
*
0
Corresponding author.
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00166-6

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M. Couturier et al. / Tetrahedron Letters 42 (2001) 2285–2288
Figure 1. Pressure of hydrogen released by methanolysis of t-BuNH –BH as a function of time.
2
3
Figure 2. Pressure of hydrogen released by methanolysis of Me N–BH as a function of time.
3
3
limiting factor would be either protonolysis and/or
extrusion of hydrogen from the catalytic surface.
Indeed, under these favorable conditions, the reduction
of nitrobenzene was milder and under control with a
reaction time of 15 minutes. It is noteworthy that the
palladium-catalyzed methanolysis takes 20 hours to
Based on this observation, it is conceivable that
borane–amines would act as hydrogen-transfer
reagents, provided that the reduction is faster than
hydrogen liberation. If this requirement is met, then a
reduction could be carried out in an open vessel with-
out loss of molecular hydrogen. To further expand on
the synthetic utility of borane–amines, we sought sub-
strates that would be reduced exclusively by the cata-
lytic action of palladium. Nitroaryls were chosen as
substrates for reduction to anilines since they are
known to be inert towards borane–amines
1
4
complete in the absence of nitrobenzene (Table 1).
Hence, the palladium catalyzed decomplexation of
borane–amines is further accelerated by the action of
nitrobenzene, and substantiates the fact that extrusion
Table 1. Comparative rates of borane–trimethylamine
methanolysis at room temperature with Pd/C and
a
nitrobenzene
additive
M
e
N
·
B
H
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢁ
a
m
i
n
e
+
B
(
O
M
e
)
3
3
3
MeOH
8
c,11b,13a,18
alone.
Although t-butylamine-borane itself is
19
unreactive with nitrobenzene, the addition of less than 1
mol% of Pd/C led to an uncontrollable exothermic reac-
tion! In light of this high reactivity, a system with
reduced reactivity would be preferable in the hope of
controlling the reaction rate. Based on our previous
experience, borane–trimethylamine is the least reac-
tive in palladium catalyzed methanolysis, and, as illus-
trated in Fig. 2, does not exhibit a first-order behavior.
Entry
Additive
Time (h)
1
2
3
None
10% Pd/C
10% Pd/C+PhNO2
6800
20
0.25
1
4
a
Reaction of a 1 M solution of borane–trimethylamine in methanol
using 1 mol% of Pd/C and 1.2 equiv. of nitrobenzene at rt.

M. Couturier et al. / Tetrahedron Letters 42 (2001) 2285–2288
2287
Table 2. Palladium catalyzed reduction of nitroaromatics using trimethylamine–borane in methanol
Me3N-BH3, Pd(OH)2/C
R
NO2
R
NH2
MeOH
1
2
Entry
1,2 a–x
R=
Temperature
Time (h)
Yield (%)a
1
2
3
4
5
6
7
8
9
a
b
b
c
d
e
f
g
h
i
H
CH3
CH3
CO Me
CN
CH CN
CH OH
OH
Rt
Rt
Reflux
Rt
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Rt
6.0
22.0
0.5
0.7
1.5
0.7
2.0
0.2
0.7
3.5
12
90
95
95
\99
\99
\99
94
98
98
99
99
2
2
2
OCH3
NHAc
F
1
1
0
1
j
a
Isolated yields.
of hydrogen from the surface of the catalyst is slower
than the actual nitro reduction. Chemoselective reduc-
tion of nitroaryls to the corresponding anilines is of
importance in synthetic organic chemistry. Methods are
Besides producing anilines in high yield, the present
method favorably compares to alternate means to
reduce nitroaryls in terms of its operationally simple
work-up procedure. In fact, in this salt-free, non-
aqueous process, the resulting aniline can be isolated
from the trimethylamine and trimethylborate by-prod-
2
0
numerous and commonly utilized procedures, which
do not require molecular hydrogen, include tin chlo-
2
1
22
34
ride, formic acid or triethylammonium formate–
ucts by simple concentration. This is in sharp con-
2
3
24
palladium
and cyclohexene–palladium.
Several
trast, for example, with the sodium borohydride–Pd/C
procedure which requires acidification with aqueous
HCl and a series of extractions to isolate the amine.
recent methods have also been reported using formic
2
5
acid–Raney nickel under sonication,
samarium–
2
6
ammonium chloride, decaborane–acetic acid–palla-
zirconium chloride–sodium
borohydride, electrochemically generated nickel in
27
dium in methanol,
In conclusion, we have demonstrated that stable
borane–amine adducts can be activated through palla-
dium catalysis and act as hydrogen-transfer reagents for
the reduction of nitrobenzenes to anilines. The present
procedure is high yielding and compatible with various
functional groups. More importantly, the safety and
handling convenience of borane–amines coupled with
an operationally simple and straightforward work-up
makes it an attractive procedure. We are currently
investigating the synthetic utility of a tandem borane
mediated reduction–methanolysis–hydrogenation seq-
uence, a concept which will be exemplified in a forth-
coming manuscript.
2
8
2
9
30
31
DMF, samarium–iodine, diethyl chlorophosphite,
32
and indium–ammonium chloride in ethanol. Each
procedure has its own advantages and disadvantages.
In general, their main drawbacks are lack of chemose-
lectivity, extended reaction times, functional group
incompatibility and complicated work-up procedures.
After our successful reduction of nitrobenzene to ani-
line, we wanted to explore the scope and limitations of
the present procedure.
In this exercise, we challenged the generality of this
concept by reducing a wide variety of functionalized
nitrobenzenes. As illustrated in Table 2, the atmo-
spheric pressure reductions were performed using 1.2
hydride equivalents and 1 mol% of Pearlman’s cata-
Acknowledgements
3
3
lyst. In some cases, the substrates were insoluble in
methanol, which slowed the reduction time. However,
we found that the reaction rate is increased when the
reductions are performed at reflux, without concomi-
tant loss of hydrogen. Upon reaction completion, the
excess borane–amine reagent is simply consumed by
methanolysis. The present procedure has been found to
be tolerant of benzylic functionalities and performs
equally well for both electron-donating and electron-
withdrawing groups with isolated yields >90%. A limi-
tation is found with aryl chlorides which were also
reduced in the process. Not unexpectedly, however, aryl
fluoride 2j was resistant to reduction.
The authors thank Professors Dave Collum (Cornell)
and Steven Ley (Cambridge) for helpful discussions.
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3. General procedure. To a stirred solution/suspension of
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3
of B(OMe) in the azeotropic mixture.
3
.
.