The use of borane-amine adducts as versatile palladium-catalyzed hydrogen-transfer reagents in methanol

Article abstract of DOI:10.1016/S0040-4039(01)00300-8

The scope of borane-amine adducts as reducing agents is broadened through palladium-catalyzed methanolysis capable of reducing a wide variety of functional groups. Hence, borane mediated reduction of a benzamide followed by a tandem methanolysis/hydrogenolysis of the resulting borane-benzylamine adduct allows chemoselective removal of an N-benzoyl in the presence of an O-benzoyl.

Full text of DOI:10.1016/S0040-4039(01)00300-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2763–2766
The use of borane–amine adducts as versatile
palladium-catalyzed hydrogen-transfer reagents in methanol
Michel Couturier,* Brian M. Andresen, John L. Tucker, Pascal Dube´, 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 19 February 2001; accepted 20 February 2001
Abstract—The scope of borane–amine adducts as reducing agents is broadened through palladium-catalyzed methanolysis capable
of reducing a wide variety of functional groups. Hence, borane mediated reduction of a benzamide followed by a tandem
methanolysis/hydrogenolysis of the resulting borane–benzylamine adduct allows chemoselective removal of an N-benzoyl in the
presence of an O-benzoyl. © 2001 Elsevier Science Ltd. All rights reserved.
Borane–amine complexes are an important class of
hydroborating as well as reducing agents and have
found several applications in organic synthesis1 and
industrial processes.2 Although over a dozen borane–
amine complexes are commercially available,3 some on
a tonnage scale,4 their scope in organic synthesis has
been limited relative to the loosely bound borane–Lewis
base complexes (such as borane–tetrahydrofuran (BH3–
THF) and borane–dimethyl sulfide (BMS)).5 As a result
of a tighter boronꢀnitrogen bond, the reactivity of
amineꢀboranes is somewhat diminished, and harsher
reaction conditions are often required. Unlike common
hydride reducing agents, however, borane–amine
adducts are generally hydrolytically and thermally sta-
ble, soluble in both protic and aprotic solvents, and
often crystalline compounds that offer safe handling
convenience.6 Significant efforts have therefore been
put forth to activate these stable borane reagents. For
instance, the activity of borane–amine adducts has been
shown to increase in the presence of Brønsted7 and
Lewis acids.8 Pyridine–borane adsorbed on solid sup-
ports exhibits enhanced reducing properties as well.9 In
hopes of finding more reactive amine–borane reagents,
Brown10 and Soderquist11 have designed borane carriers
incorporating sterically demanding tertiary amines. The
less basic aniline derivatives also form weaker and
hence more reactive adducts with borane.12 However,
the structural modifications needed for greater activity
result in higher boiling free-amine by-products which
encumber product isolation when compared to tradi-
tional amine–boranes. To increase the synthetic poten-
tial of borane carriers made from volatile amines, it
would be a desirable advantage to activate these other-
wise stable/inert hydride sources in neutral conditions
through transition metal catalysis.
In this context, we recently disclosed that palladium
and Raney nickel activate the methanolic cleavage of
stable borane–amine complexes.13 Since palladium
hydride is a likely transient species prior to molecular
hydrogen liberation, we further envisioned the use of
commercially available amine–boranes in methanol as
novel, palladium-catalyzed, hydrogen-transfer reagents.
We first reported the application of this concept to the
reduction of nitroaryls to anilines.14 Others have also
employed borane–amine adducts as hydride sources in
palladium-catalyzed systems such as reductive opening
of diene-ester derived monoepoxides,15 aryl triflate
reductions16 and N-alloc deprotections.17 Herein, we
report on the scope of the palladium catalyzed
methanolysis of amine–boranes as a reducing system
for various functional groups.
Representative examples of catalytic transfer hydro-
genations of substrates, unreactive with amine–boranes
alone, are illustrated in Table 1.18,19 For instance,
olefins do not react with t-butylamine–borane at room
temperature, but will undergo hydroboration at ele-
vated temperatures with isomerization.1b Using 1.2
equivalents of t-butylamine borane and 10% Pd–C in
methanol, trans-stilbene (entry 1), ethyl cinnamate
(entry 2) and a propargylic alcohol (entry 5) were all
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00300-8

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M. Couturier et al. / Tetrahedron Letters 42 (2001) 2763–2766
Table 1. Reduction of representative functional groups with t-BuNH2·BH3/10% Pd–C/methanol systema
Entry
1
Substrate
Product
Time (h)
4
Yield %
93
CO2Et
CO2Et
8
94
2
4
92b
3
4
5
N
H
N
81c
97b
16
O
OH
OH
OH
-
9
O
O
120
11
6
7
82
Cl
83d
EtO2C
OTf
EtO2C
BnO
OBn
OH
1
90
8
BnO
O
O
a Reactions were conducted in a sealed vessel at room temperature on 50 mmol of substrate in 30 mL of methanol with 20 mmol of t-BuNH2·BH3
and 174 mg of 10% Pd–C, unless otherwise noted. b As in a, except on 25 mmol of substrate. c Regioselectivity is 24:1 in favour of the secondary
alcohol. Determined by 1H NMR. d Reaction performed in ethanol to avoid transesterification.
hydrogenated in yields greater than 90%.20 Although
pyridine–borane has been shown to reduce quinoline in
acetic acid, the reaction also leads to N-acetyl and
N-ethyl tetrahydroquinoline derivatives when the reac-
tion is run at reflux.21 Using our procedure, t-butyl-
amine borane can accomplish the desired transforma-
tion cleanly, under milder neutral conditions, in high
yield (entry 3). Hydrogenolysis type reductions have
also been explored. Reductions of epoxides have been
reported and are limited to allylic systems using
borane–dimethylamine. Under the present conditions,
reductive opening of 1-epoxydecane led to the sec-
ondary alcohol in a 24:1 ratio. Interestingly, the
regioselectivity is superior to the reported 4:1 ratio
obtained using hydrogen gas and Pd–C in methanol.22
Reductive cleavage of aryl chloride (entry 6) and triflate
(entry 7) worked well in the presence of both electron-
withdrawing and donating groups. As compared to
Lipshultz’s method, the current procedure does not
require triphenylphosphine and base as additive, and
can be carried out at room temperature. An attractive
feature of the present procedure is that, after removal
of the palladium catalyst, the desired product can be
isolated by simple removal of methanol, t-butylamine
and trimethylborate by evaporation. The last example
illustrates the chemoselective hydrogenolysis of a benzyl
ester in the presence of a benzyl ether, again in high
yield. Unlike amine–borane activation precedents,
which have been sporadic and require very specific
reaction conditions, the examples above demonstrate
the versatility and mildness of the method.
The utility of this procedure can be further extended to
cases where the amine–borane is an integral part of the
molecule to be reduced. In Scheme 1, a two-step
sequence involving borane mediated amide reduction of
benzamide 1,23 followed by a tandem methanolysis/
hydrogenolysis of the resulting borane–benzylamine
adduct 2,24,25 allows deprotection of an N-benzoyl in
the presence of an O-benzoyl blocking group.
BzO
BzO
BzO
Pd/C
MeOH
75%
BH3-THF
THF
93%
N
N
N
H
Bn BH3
Bz
1
2
3
Scheme 1.
In conclusion, the palladium-catalyzed methanolysis of
borane–amine adducts provides efficient hydrogen-
transfer conditions capable of reducing a wide range of
functional groups in excellent overall yields. The scope
of amine–borane in organic synthesis is therefore
broadened through palladium catalysis, in a unified
methodology. Combined with a straightforward isola-
tion method, this is an attractive procedure that may

M. Couturier et al. / Tetrahedron Letters 42 (2001) 2763–2766
2765
17. Gomez-Martinez, P.; Dessolin, M.; Guibe, F.; Albericio,
F. J. Chem. Soc., Perkin Trans. 1 1999, 20, 2871.
18. A representative experimental procedure is as follows: To
a mixture of trans-stilbene (9.01 g, 50.0 mmol) and 10%
palladium-on-carbon (740 mg, 50% wet) in methanol (15
mL) was added a solution of borane t-butylamine (1.74 g,
20.0 mmol) in methanol (15 mL) and the vessel was
immediately sealed and heated to 30°C. Upon reaction
completion (4 h, monitored by a constant pressure read-
ing), the reaction mixture was cooled to room tempera-
ture, filtered over Celite, rinsed with methanol, and
concentrated under reduced pressure. Purification of the
crude material by silica gel chromatography using
dichloromethane gave bibenzyl (8.46 g, 93%) as a white
crystalline solid.
19. It is noteworthy that the rates of reductions are generally
slower than extrusion of hydrogen from the catalytic
surface. As a consequence, the pressure of hydrogen
increases in the reaction vessel and the requisite equiva-
lent of hydrogen is ultimately consumed in the time
indicated in the Table 1.
20. The current methodology is not limited to aromatic sub-
stitution since 1-hexene was utilized as hydrogen scav-
enger in the palladium-catalyzed decomplexation of
borane–benzylamine complexes (see Ref. 13).
lead to further palladium-catalyzed applications of
borane–amine complexes.
Acknowledgements
The authors thank Professors Dave Collum (Cornell)
and Steven Ley (Cambridge) for insightful discussions.
References
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23. Experimental procedure: To an ice-cold solution of N,O-
bis(benzoyl)-3-pyrrolidinol (1.98 g, 6.68 mmol) in tetra-
hydrofuran (15 mL), was added
a
solution of
borane–tetrahydrofuran (13.4 mL, 13.4 mmol, 1 M in
THF) and the resulting mixture was stirred for 1 h at
room temperature. The reaction was then cooled to 0°C,
quenched with methanol (10 mL) and immediately con-
centrated to dryness at 25°C under reduced pressure.
Purification of the residual material by silica gel chro-
matography using 10% ethyl acetate in hexane provided a
diastereomeric mixture of borane–amine complexes (1.83
g, 93%) as a white crystalline solid. Major isomer: 1H
NMR (400 MHz, CDCl3) d 7.76 (d, J=8.0 Hz, 2H), 7.55
(t, J=8.0 Hz, 1H), 7.45–7.25 (m, 7H), 5.55 (brs, 1H), 4.16
(s, 2H), 3.65 (dd, J=6.0, 12.5 Hz, 1H), 3.30–3.15 (m,
3H), 2.83 (m, 1H), 2.20–1.40 (m, 4H); 13C NMR (100
MHz, CDCl3) d 165.96, 133.55, 132.99, 131.55, 129.77,
129.63, 129.29, 128.70, 128.61, 74.61, 66.17, 63.52, 57.19,
1
31.01. Minor isomer: H NMR (400 MHz, CDCl3) d 8.03
(d, J=8.5 Hz, 2H), 7.56 (t, J=8.5 Hz, 1H), 7.45–7.20 (m,
7H), 5.30 (m, 1H), 4.09 (s, 2H), 3.55 (dd, J=7.0, 13.0 Hz,
1H), 3.25–3.15 (m, 2H), 3.12 (m, 1H), 2.37 (m, 1H),
2.25–1.60 (m, 4H); 13C NMR (100 MHz, CDCl3) d
166.52, 133.56, 132.65, 131.80, 130.02, 129.75, 129.60,
128.91, 128.68, 73.31, 66.62, 63.91, 58.02, 31.19.
24. Experimental procedure: To a mixture of borane–amine
complex 2 (2.95 g, 10 mmol) and 10% palladium-on-car-
bon (1.18 g, 50% wet) was added methanol (30 mL). The
reaction vessel was quickly sealed and the contents stirred
at room temperature for 4 days. The resulting reaction
mixture was filtered over Celite, rinsed with methanol
and concentrated to dryness. Flash chromatography of
the residual material using 5% methanol in
dichloromethane provided the desired secondary amine
13. Couturier, M.; Tucker, J. L.; Andresen, B. M.; Dube, P.;
Negri, J. T. Org. Lett. 2001, 3, 465.
14. Couturier, M.; Andresen, B. M.; Tucker, J. L.; Dube´, P.;
Breneck, S.; Negri, J. T. Tetrahedron Lett. 2001, 42, 2285.
15. David, H.; Dupuis, L.; Guillerez, M.-G.; Guibe´, F. Tet-
rahedron Lett. 2000, 41, 3335.
16. Lipshutz, B. H.; Buzard, D. J.; Vivian, R. W. Tetra-
hedron Lett. 1999, 40, 6861.
.

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M. Couturier et al. / Tetrahedron Letters 42 (2001) 2763–2766
(1.43 g, 75%) as a colorless oil. 1H NMR (400 MHz,
130.45, 129.76, 129.68, 128.53, 76.66, 53.84, 46.15, 33.55.
25. The reaction rate of the tandem methanolysis/
hydrogenolysis is comparable to the standard hydrogena-
tion of the corresponding free-base when performed in
similar reaction conditions.
CDCl3) d 7.96 (d, J=7.5 Hz, 2H), 7.56 (t, J=7.5 Hz,
1H), 7.45–7.20 (t, J=7.5 Hz, 2H), 5.37 (m, 1H), 3.10–
3.00 (m, 3H), 2.87 (m, 1H), 2.25 (brs, 1H), 2.15–1.85 (m,
2H); 13C NMR (100 MHz, CDCl3) d 166.49, 133.18,
.