Reductions of aliphatic and aromatic nitriles to primary amines with diisopropylaminoborane

Article abstract of DOI:10.1021/jo8023329

Diisopropylaminoborane [BH₂Nf)Pr)₂] in the presence of a catalytic amount of lithium borohydride (LiBH₄) reduces a large variety of aliphatic and aromatic nitriles in excellent yields. BH ₂NOPr)₂ can be prepared by two methods: first by reacting diisopropylamineborane [(iPr)₂N)BH₃] with 1.1 equiv of n-butylhthium (n-BuLi) followed by methyl iodide (MeI), or reacting iPrN:BH ₃ with 1 equiv of n-BuLi followed by trimethylsilyl chloride (TMSCl). BH₂N(ZPr)₂ prepared with MeI was found to reduce benzonitriles to the corresponding benzylamines at ambient temperatures, whereas diisopropylaminoborane prepared with TMSCl does not reduce nitriles unless a catalytic amount of a lithium ion source, such as LiBH₄ or lithium tetraphenylborate (LiBPh₄), is added to the reaction. The reductions of benzonitriles with one or more electron-withdrawing groups on the aromatic ring generally occur much faster with higher yields. For example, 2,4-dichlorobenzonitrile was successfully reduced to 2,4-dichlorobenzylamine in 99% yield after 5 h at 25 °C. On the other hand, benzonitriles containing electron-donating groups on the aromatic ring require refluxing in tetrahydrofuran (THF) for complete reduction. For instance, 4- methoxybenzonitrile was successfully reduced to 4-methoxybenzylamine in 80% yield. Aliphatic nitriles can also be reduced by the BH₂N(iPr) ₂/cat. LiBH₄ reducing system. Benzyl cyanide was reduced to phenethylamine in 83% yield. BH₂NOPr)₂ can also reduce nitriles in the presence of unconjugated alkenes and alkynes such as the reduction of 2-hexynenitrile to hex-5-yn-l-amine in 80% yield. Unfortunately, selective reduction of a nitrile in the presence of an aldehyde is not possible as aldehydes are reduced along with the nitrile. However, selective reduction of the nitrile group at 25 °C in the presence of an ester is possible as long as the nitrile group is activated by an electron-withdrawing substituent. It should be pointed out that lithium aminoborohydrides (LABs) do not reduce nitriles under ambient conditions and behave as bases with aliphatic nitriles as well as nitriles containing acidic a-protons. Consequently, both LABs and BH₂NOPr)₂ are complementary to each other and offer methods for the selective reductions of multifunctional compounds.

Full text of DOI:10.1021/jo8023329

Reductions of Aliphatic and Aromatic Nitriles to Primary Amines
with Diisopropylaminoborane
Dustin Haddenham, Lubov Pasumansky, Jamie DeSoto, Scott Eagon, and
Bakthan Singaram*
Department of Chemistry and Biochemistry, UniVersity of California, Santa Cruz, 1156 High Street,
Santa Cruz, California 95064
singaram@chemistry.ucsc.edu
ReceiVed October 16, 2008
Diisopropylaminoborane [BH2N(iPr)2] in the presence of a catalytic amount of lithium borohydride (LiBH4)
reduces a large variety of aliphatic and aromatic nitriles in excellent yields. BH2N(iPr)2 can be prepared
by two methods: first by reacting diisopropylamineborane [(iPr)2N:BH3] with 1.1 equiv of n-butyllithium
(n-BuLi) followed by methyl iodide (MeI), or reacting iPrN:BH3 with 1 equiv of n-BuLi followed by
trimethylsilyl chloride (TMSCl). BH2N(iPr)2 prepared with MeI was found to reduce benzonitriles to the
corresponding benzylamines at ambient temperatures, whereas diisopropylaminoborane prepared with
TMSCl does not reduce nitriles unless a catalytic amount of a lithium ion source, such as LiBH4 or
lithium tetraphenylborate (LiBPh4), is added to the reaction. The reductions of benzonitriles with one or
more electron-withdrawing groups on the aromatic ring generally occur much faster with higher yields.
For example, 2,4-dichlorobenzonitrile was successfully reduced to 2,4-dichlorobenzylamine in 99% yield
after 5 h at 25 °C. On the other hand, benzonitriles containing electron-donating groups on the aromatic
ring require refluxing in tetrahydrofuran (THF) for complete reduction. For instance, 4-methoxybenzonitrile
was successfully reduced to 4-methoxybenzylamine in 80% yield. Aliphatic nitriles can also be reduced
by the BH2N(iPr)2/cat. LiBH4 reducing system. Benzyl cyanide was reduced to phenethylamine in 83%
yield. BH2N(iPr)2 can also reduce nitriles in the presence of unconjugated alkenes and alkynes such as
the reduction of 2-hexynenitrile to hex-5-yn-1-amine in 80% yield. Unfortunately, selective reduction of
a nitrile in the presence of an aldehyde is not possible as aldehydes are reduced along with the nitrile.
However, selective reduction of the nitrile group at 25 °C in the presence of an ester is possible as long
as the nitrile group is activated by an electron-withdrawing substituent. It should be pointed out that
lithium aminoborohydrides (LABs) do not reduce nitriles under ambient conditions and behave as bases
with aliphatic nitriles as well as nitriles containing acidic R-protons. Consequently, both LABs and
BH2N(iPr)2 are complementary to each other and offer methods for the selective reductions of
multifunctional compounds.
Introduction
including agrochemicals, dyes, drugs, surfactants, and plastics;
as auxiliaries for the rubber, textile, and paper industries; and
as anticorrosion agents and process chemicals for gas scrubbing.1
Examples of compounds with aliphatic amines that are used in
these industries are shown in Figure 1.
Aliphatic amines are among the most important organic
intermediates in the chemical industry with a worldwide
production in the year 2000 of several 100 000 tons per annum.1
These compounds are important in a variety of industries
Due to their interesting physiological properties, amines are
extremely important functionalities in numerous biologically
active pharmaceuticals used worldwide. For example, central
(1) Aliphatic Amines In Ullmann’s Encyclopedia of Industrial Chemistry,
7th ed.; Wiley-VCH: Weinheim, Germany, 2008; Vol. A2, p 2.
1964 J. Org. Chem. 2009, 74, 1964–1970
10.1021/jo8023329 CCC: $40.75 2009 American Chemical Society
Published on Web 02/04/2009

Reductions of Aliphatic and Aromatic Nitriles
SCHEME 1. Reduction of a Nitrile by the BH2N(iPr)2/cat.
LiBH4 Reducing System
SCHEME 2. Reduction of 2,4-Dichlorobenzonitrile with
BH2N(iPr)2 Made with 1.1 equiv of n-BuLi and MeI
FIGURE 1. Examples of aliphatic amines used in industry.
SCHEME 3. Reduction of 2,4-Dichlorobenzonitrile with
BH2N(iPr)2 Made with TMSCl
FIGURE 2. Example of CNS drugs with amine side chains.
nervous system (CNS) drugs make up the largest sector of
pharmaceuticals sold worldwide. It is interesting to look at some
of the structures of successful CNS drugs as they contain amine
side chains (Figure 2).2
SCHEME 4. Differences in the Reactivity of Aminoboranes
With the growing repertoire of biologically relevant
nitrogenous molecules, there is an emerging need for efficient
synthetic methods to prepare amines.3,4 A frequently applied
process in the pharmaceutical industry is the heterogeneous
catalytic hydrogenation of nitriles.4 Nitriles can also be
reduced utilizing a variety of hydride reducing agents which
often require transition metal salts as catalysts.5-8 However,
these methods suffer from harsh reaction conditions such as
high temperatures, pressures, use of toxic transition metal
catalysts, or pyrophoric reducing agents. Recently, we have
discovered the synthesis of the nonpyrophoric diisopropy-
laminoborane [BH2N(iPr)2] from the corresponding lithium
diisopropylaminoborohydride (iPrLAB).9-11 Herein we report
the reduction of various nitriles to the corresponding amines
by BH2N(iPr)2 in the presence of a catalytic amount of a
lithium salt, such as lithium borohydride (LiBH4) (Scheme
1).
Results and Discussion
(2) Barton, C. CNS Drug DiscoVeries: what the future holds; Espicom
Business Intelligence: West Sussex, UK, 2006; p 1.
(3) (a) Buehler, C. A.; Pearson, D. E. SurVey of Organic Synthesis; Wiley-
Interscience: New York, 1970; Vol. 1, pp 413-512. (b) Mitsunobu, O.
ComprehensiVe Organic Synthesis; Trost, R. M., Fleming, I., Eds.; Pergamon:
Oxford, UK, 1991; Vol. 6, p 65.
(4) (a) Rappoport, Z. The Chemistry of the Cyano Group; Wiley Interscience:
New York, 1970; pp 307-340. (b) March, J. AdVanced Organic Chemistry:
Reactions, Mechanisms and Structure, 4th ed.; Wiley: Toronto, Canada, 1992;
p 1276.
(5) (a) Wade, R. C. J. Mol. Catal. 1983, 18, 273. (b) Satoh, S. Tetrahedron
Lett. 1969, 10, 4555. (c) Egli, R. A. HelV. Chim. Acta 1970, 53, 47. (d) Khurana,
J. M.; Kukreja, G. Synth. Commun. 2002, 32, 1265.
(6) (a) Nystrom, F.; Brown, W. G. J. Am. Chem. Soc. 1948, 70, 3738. (b)
Amundsen, L. H.; Nelson, L. S. J. Am. Chem. Soc. 1951, 73, 242. (c) Brown,
H. C.; Weissman, P. M.; Yoon, N. M. J. Am. Chem. Soc. 1966, 88, 1458. (d)
Soffer, L. M.; Parrotta, E. W. J. Am. Chem. Soc. 1954, 76, 3580.
(7) (a) Hudlicky, M. Reductions in Organic Chemistry, 2nd ed.; ACS
Monograph 188; American Chemical Society: Washington, DC, 1996. (b) Yoon,
N. M.; Brown, H. C. J. Am. Chem. Soc. 1968, 90, 2927. (c) Brown, H. C.;
Subba Rao, B. C. J. Am. Chem. Soc. 1960, 82, 681. (d) Brown, H. C.; Yoon,
N. M. J. Am. Chem. Soc. 1966, 88, 1464.
Reductions of Nitriles by BH2N(iPr)2. During our explor-
atory investigations of the properties of BH2N(iPr)2, we have
discovered that BH2N(iPr)2, generated in situ by reacting
diisopropylamineborane [(iPr)2N:BH3] with 1.1 equiv of n-
butyllithium (n-BuLi) followed by methyl iodide (MeI), reduced
nitriles to their corresponding amines.10,11 The reduction of 2,4-
dichlorobenzonitrile 1 by 2 equiv of BH2N(iPr)2 was complete
after 5 h of stirring at 25 °C yielding 99% of the corresponding
benzyl amine 2 after a simple acid-base workup. When this
reaction was performed with 1 equiv of BH2N(iPr)2, only 49%
of the corresponding amine was obtained even after 24 h. It
was apparent that this reaction requires 2 equiv of BH2N(iPr)2
for complete reduction (Scheme 2).
We have previously shown that BH2N(iPr)2 can be synthe-
sized by other routes.10 It was of interest to see if BH2N(iPr)2
prepared by other methods could also be used in the reduction
of nitriles. Consequently, BH2N(iPr)2 was synthesized by
reacting iPrN:BH3 with 1 equiv of n-BuLi followed by trim-
ethylsilyl chloride (TMSCl), which was then reacted with 1
(Scheme 3).11 We were surprised that there was no reduction
even after 24 h and 1 was recovered unchanged. Since
aminoboranes are not isolated but prepared in situ, it is clear
(8) Pasumansky, L.; Goralski, C. T.; Singaram, B. Org. Process Res. DeV.
2006, 10, 959.
(9) Fisher, G. B.; Harrison, J.; Fuller, J. C.; Goralski, C. T.; Singaram, B.
Tetrahedron Lett. 1992, 33, 4533.
(10) Pasumansky, L.; Haddenham, D.; Clary, J. W.; Fisher, G. B.; Goralki,
C. T.; Singaram, B. J. Org. Chem. 2008, 73, 1898–1905.
(11) Pasumansky, L.; Collins, C. J.; Pratt, L. M.; Nguyen, N. V.; Ramachan-
dran, B.; Singaram, B. J. Org. Chem. 2007, 72, 971–976.
J. Org. Chem. Vol. 74, No. 5, 2009 1965

Haddenham et al.
TABLE 1. BH2N(iPr)2 Reduction of Benzonitriles at 25 °Ca
SCHEME 5. Reduction of 2,4-Dichlorobenzonitrile with
BH2N(iPr)2, Prepared from iPrLAB and TMSCl, in the
Presence of a Catalytic Amount of LiBH4
that the source of the aminoborane plays an important role in
this reaction. We postulated that BH2N(iPr)2 prepared from 1.1
equiv of n-BuLi and MeI may have a different reactivity than
BH2N(iPr)2 prepared from 1 equiv of n-BuLi and TMSCl. Upon
re-examining the 11B NMR spectra of BH2N(iPr)2 prepared by
both methods, it was observed that BH2N(iPr)2 made from 1.1
equiv of n-BuLi and MeI contained a trace amount of LiBH4.
However, BH2N(iPr)2 prepared with 1 equiv of n-BuLi and
TMSCl did not contain any LiBH4 (Scheme 4).12 This observa-
tion led us to formulate the hypothesis that LiBH4 is acting as
a catalyst in the reduction of nitriles with BH2N(iPr)2.
We have tested this hypothesis by reacting pure BH2N(iPr)2
prepared from 1 equiv of n-BuLi and TMSCl with 1 in the
presence of 10 mol % of LiBH4.12 The nitrile was completely
reduced after 18 h at 25 °C and the corresponding benzyl amine
was isolated in 90% yield (Scheme 5). These results clearly
indicate that LiBH4 is effective in catalyzing the reduction of
nitriles by BH2N(iPr)2. It should be noted that LiBH4 alone does
not reduce nitriles in THF even at 65 °C.13 This catalysis is
most likely promoted through lithium ion coordinating to the
nitrogen atom of the nitrile, thus activating the nitrile group for
reduction by BH2N(iPr)2.
a Reactions were carried out on 5 mmol scale with 1 equiv of nitrile
and 2 equiv of aminoborane made with 1.1 equiv of n-BuLi and MeI.
The generality of this reaction was investigated by reducing
a series of benzonitriles with BH2N(iPr)2 at 25 °C to obtain the
corresponding benzyl amines. Substituted benzonitriles reduced
by BH2N(iPr)2 at 25 °C furnished the corresponding benzyl
amine products in very good to excellent isolated yields (Table
1).
SCHEME 6. Reduction or Tandem Displacement/Reduction
of 4-Bromo-2-fluorobenzonitrile
Reductions of benzonitriles with one or more electron-
withdrawing groups on the aromatic ring are generally faster
and result in higher yields (Table 1, entries 1-8). For example,
2,4-dichlorobenzonitrile was successfully reduced to 2,4-dichlo-
robenzylamine in 99% yield (Table 1, entry 1). Similarly,
4-bromo-2-chlorobenzonitrile was reduced to 4-bromo-2-chlo-
robenzylamine in almost quantitative 99% yield (Table 1, entry
3). Unfortunately, selective reduction of a nitrile in the presence
of an aldehyde was not successful. During the reduction of
4-cyanobenaldehyde both the nitrile and the aldehyde were
reduced to yield [4-(aminomethyl)phenyl]methanol in 80% yield
(Table 1, entry 10). We should point out that in the case of the
o-fluorobenzonitriles the corresponding benzylamine is obtained
during the reaction with aminoboranes (Table 1, entries 2 and
4), whereas lithium aminoborohydride (LAB) reagents pre-
dominately afford the tandem displacement/reduction product,
2-(dialkylamino)benzylamine.14 Thus, the aminoborane reduc-
tion methodology is complementary to the LAB tandem
displacement/reduction reaction (Scheme 6).
During our investigation on the generality of the reduction
of nitriles with the BH2N(iPr)2/cat. LiBH4 system, we found
that benzonitriles with a sterically crowded nitrile or electron-
donating groups required higher temperatures for complete
reduction. Consequently, a series of nitriles were reduced by
(12) It should be noted that BH2N(iPr)2 can be prepared from iPrLAB and
TMSCl by using a slight excess of n-BuLi so that it contains a catalytic amount
of LiBH4. BH2N(iPr)2 prepared in this manner is also able to reduce nitriles
with no additives.
(13) Brown, H. C.; Narasimhan, S.; Choi, Y. M. J. Org. Chem. 1982, 47,
4702.
(14) (a) Thomas, S.; Collins, C. J.; Cuzens, J. R.; Spiciarich, D.; Goralski,
C. T.; Singaram, B. J. Org. Chem. 2001, 66, 1999–2004. (b) Thomas, S.; Collins,
C. J.; Goralski, C. T.; Singaram, B. Chem. InnoVation 2000, 30, 31.
1966 J. Org. Chem. Vol. 74, No. 5, 2009

Reductions of Aliphatic and Aromatic Nitriles
TABLE 2. Diisopropylaminoborane Reduction of Benzonitriles in
Refluxing THFa
TABLE 3. Diisopropylaminoborane Reduction of Aliphatic
Nitriles in Refluxing THFa
a Reactions were carried out on 5 mmol scale with 1 equiv of nitrile
and 2 equiv of aminoborane made with 1.1 equiv of n-BuLi and MeI.
b Crude yield. See ref 17. c Isolated as a benzamide.
nitriles were reduced to their corresponding amines in refluxing
THF in excellent yields (Table 3).
a Reactions were carried out on 5 mmol scale with 1 equiv of nitrile
A variety of aliphatic nitriles can be reduced by the BH2N(iPr)2/
cat. LiBH4 reducing system in refluxing THF (Table 3). Benzyl
cyanides are notoriously hard nitriles to reduce because of the
extreme acidity of the protons R to the nitrile. This acidity leads
to deprotonation instead of reduction with most reducing agents.
In contrast, the BH2N(iPr)2/cat. LiBH4 reducing system reduces
a variety of benzyl cyanides to their corresponding phenethy-
lamines in excellent yields.17 The reduction of benzyl cyanides
allows for the easy preparation of a variety of biologically active
compounds to be made from similar benzyl nitriles (Figure 2).
Aliphatic nitriles that contain an alkyne that is not conjugated
with the nitrile group can be reduced selectively without
affecting the C-C multiple bond (Table 3, entry 4). For
example, 2-hexynenitrile is reduced to the corresponding hex-
5-yn-1-amine in 80% yield after 18 h of reflux in THF. These
results demonstrate that it is possible to reduce a wide variety
of nitriles to the corresponding amines in very high yields with
this BH2N(iPr)2/cat. LiBH4 reducing system, which complements
the reduction of nitriles by BH3:THF.
Catalysis of BH2N(iPr)2 Reduction of Nitriles with Other
Lithium Ion Sources. In the previous section, we have shown
that various nitriles can be reduced by BH2N(iPr)2 in the
presence of a catalytic amount of LiBH4. The LiBH4 is thought
to activate the nitrile for reduction by BH2N(iPr)2 through
lithium ion coordination. If this reduction is indeed promoted
through lithium ion coordination, then other sources of lithium
ions should also promote the reduction. In an effort to test this
hypothesis, the reduction of 1 was attempted with pure
BH2N(iPr)2, prepared from iPrLAB made with 1 equiv of n-BuLi
and 2 equiv of aminoborane made with 1.1 equiv of n-BuLi and MeI.
BH2N(iPr)2 in refluxing THF producing the corresponding
benzylamine products in very good to excellent yields (Table
2).
Reductions of benzonitriles with electron-donating groups on
the aromatic ring require heating to 65 °C in order to go to
completion (Table 2, entries 3-6). For example, 4-methoxy-
benzonitrile was successfully reduced to 4-methoxybenzylamine
in 80% yield after 2 h of refluxing in THF (Table 2, entry 4).
Benzonitriles containing an alkene that is not conjugated with
the nitrile group can also be reduced selectively without affecting
the C-C multiple bond (Table 2, entry 6). For example,
4-(allyloxy)benzonitrile is reduced to corresponding (4-(ally-
loxy)phenyl)methanamine in 85% yield after 2 h of reflux in
THF. Additionally, 2,6-dichlorobenzonitrile was reduced to the
corresponding amine in 77% yield after 2 h of refluxing in THF
(Table 2, entry 2). The lower yield and requirement for increased
temperature is attributed to the steric hindrance around the
reduction site.
Aliphatic nitriles can also be reduced by the BH2N(iPr)2/cat.
LiBH4 system. It should be pointed out that many of the current
methods cannot reduce aliphatic nitriles even under extended
reflux.6,15,16 The reductions do not occur because the hydrogen
R to the nitrile is acidic and is deprotonated by these reagents,
thus halting the reduction. The BH2N(iPr)2/cat. LiBH4 reducing
system does not suffer from this problem and a series of aliphatic
(15) Collins, C. J.; Fisher, G. B.; Reem, A.; Goralski, C. T.; Singaram, B.
Tetrahedron Lett. 1997, 38, 529.
(16) (a) Brown, H. C.; Kim, K. C.; Krishnamurthy, S. J. J. Org. Chem. 1980,
45, 1. (b) Malek, J. Tetrahedron Lett. 1968, 9, 3303.
(17) The crude yield of phenethylamine is reported. A small amount of the
crude phenethylamine was purified by forming the oxalate salt and then
recrystalizing from methanol.
J. Org. Chem. Vol. 74, No. 5, 2009 1967

Haddenham et al.
SCHEME 7. Reduction of 2,4-Dichlorobenzonitrile with
BH2N(iPr)2, Prepared from 1 equiv of n-BuLi and TMSCl,
in the Presence of a Catalytic Amount of a Lithium Ion
Additive
SCHEME 8. Competitive Reduction of
4-Bromo-2-fluorobenzonitrile and Benzaldehyde at 25 °C
SCHEME 9. Competitive Reduction of Benzonitrile and
Ethyl Benzoate at 65 °C
TABLE 4. Reduction of Nitriles by Pure BH2N(iPr)2 in the
a
Presence of a Catalytic Amount of LiBPh4
We have found that various nitriles can be reduced by pure
BH2N(iPr)2, made with 1 equiv of n-BuLi and TMSCl, using
LiBPh4 as a catalyst (Table 4). These results further support
the hypothesis that nitriles are activated for the reduction by
BH2N(iPr)2 through lithium ion coordination.
Chemoselective Reductions of Nitriles. The development
and use of reagents that will selectively transform a given
functional group in a multifunctional compound is highly
desirable, especially in reductive transformations. To determine
the chemoselectivity in the reduction of nitriles with the
BH2N(iPr)2/LiBH4 system in the presence of other functional
groups, several experiments were conducted.
As observed with 4-cyanobenzaldehyde (Table 1, entry 10),
both nitrile and aldehyde are reduced by BH2N(iPr)2 under
standard reaction conditions. It should be noted that BH2N(iPr)2
cannot reduce aldehydes without lithium salt promotion.10 To
investigate if a nitrile can be reduced faster than an aldehyde
in an intermolecular reaction, a competitive reduction of
4-bromo-2-fluorobenzonitrile 3 and benzaldehyde was per-
formed. It was found that the very reactive benzaldehyde was
reduced to benzyl alcohol in 30 min, leaving 4-bromo-2-
fluorobenzonitrile 3 intact (Scheme 8). Ketones are also reduced
selectively by the BH2N(iPr)2/cat. LiBH4 system.10
We have previously shown that the BH2N(iPr)2/cat. LiBH4
reducing system is able to reduce esters at 65 °C.10 To determine
if it is possible to reduce a nitrile in the presence of an ester at
65 °C, a competitive reaction between benzonitrile 4 and ethyl
benzoate 5 was conducted (Scheme 9). Samples were collected
at different intervals and analyzed on a GC with use of an
internal standard (Chart 1). This demonstrated that 5 was
reduced faster then 4 at 65 °C. However, the results show that
nitriles without electron-withdrawing groups cannot be selec-
tively reduced in the presence of esters.
a Reactions were carried out on 3 mmol scale with 1 equiv of nitrile,
2 equiv of aminoborane, and 20 mol % of LiBPh4. Reaction progress
was monitored via TLC (2:1 hexanes/ethyl acetate) and IR. b See ref 18.
c Time for complete reduction to occur. d Determined by NMR.
and TMSCl, in the presence of a catalytic amount of various
lithium ion additives (Scheme 7).
Lithium salts, such as LiCl, LiBr, LiI, and LiBF4, did not
catalyze this reduction. Fortunately, lithium tetraphenylborate
(LiBPh4)18 promotes the reduction of a nitrile by BH2N(iPr)2.
We believe that the lithium ions in the other sources are bound
too tightly by their counterions, interfering with their ability to
catalyze the reduction. We also tried boron trifluoride etherate
(BF3:Et2O) and phenyllithium (PhLi), the precursors of LiBPh4,
to check their catalytic activity in this reaction. We discovered
that neither of these precursors alone promoted the reduction
of nitriles with BH2N(iPr)2. We then tested whether LiBPh4 can
catalyze the reduction of other nitriles. A representative set of
nitriles was reduced with pure BH2N(iPr)2 in the presence of a
catalytic amount of LiBPh4 (Table 4).
Earlier it was established that nitriles containing electron-
withdrawing groups, such as halogens, are readily reduced to
primary amines at 25 °C in 5 h. Consequently, it should be
possible to selectively reduce an aromatic nitrile containing an
electron-withdrawing group in the presence of an ester at
25 °C. Accordingly, a competitive reaction between 3 and 5
(18) The lithum tetraphenylborate (LiBPh4) was synthesized by reacting 4
equiv of phenyllithium (PhLi) with 1 equiv of trifluoroborane etherate (BF3:
Et2O) in tetrahydrofuran (THF) under an inert atmosphere.
1968 J. Org. Chem. Vol. 74, No. 5, 2009

Reductions of Aliphatic and Aromatic Nitriles
CHART 1. Competitive Reduction of Benzonitrile and
Ethyl Benzoate at 65 °C
trace amount of LiBH4 in the solution of BH2N(iPr)2 dramati-
cally changes its reactivity. An addition of a catalytic amount
of LiBH4 or LiBPh4 to pure BH2N(iPr)2, made with 1 equiv of
n-BuLi and TMSCl, reduces nitriles to the corresponding
primary amines. LAB, the precursor to aminoboranes, can
reduce unactivated aromatic nitriles sluggishly at 65 °C, but
gives tandem displacement/reduction with halogen activated aryl
nitriles at 65 °C. It should also be pointed out that LAB reagents
deprotonate the R-proton of aliphatic nitriles, preventing reduc-
tion. In summary, we have developed a mild and efficient
method for the reduction of aromatic and aliphatic nitriles.
Experimental Section
General Procedure for the Reduction of a Nitrile by Pure
BH2N(iPr)2 and a Catalytic Amount of LiBH4. The following
procedure for the reduction of 2,4-dichlorobenzonitrile by pure
BH2N(iPr)2 is representative. To a 50-mL round-bottomed flask
equipped with magnetic stir bar and fitted with a rubber septum
was added 2,4-dichlorobenzonitrile (0.86 g, 5 mmol). The flask was
charged with pure diisopropylaminoborane10 (10 mL, 1 M in THF,
10 mmol) and LiBH4 (0.5 mL, 2 M in THF, 20 mol %). The
reaction was complete in 18 h at 25 °C as evidenced by TLC (Hex:
EtOAc 2:1). The reaction mixture was cooled to 0 °C (ice bath)
and unreacted BH2N(iPr)2 was quenched with 3 M HCl (7 mL)
(caution: hydrogen evolution). The acidic solution was stirred for
30 min and then made basic with NaOH pellets to pH ∼10. 2,4-
Dichlorobenzylamine was extracted with 1:1 Et2O:THF (3 × 10
mL). The combined organic layers were dried over anhydrous
MgSO4, filtered, and evaporated in vacuo (25 °C, 1 Torr) to afford
2,4-dichlorobenzylamine as a light-yellow oil (90% yield).
SCHEME 10. Competitive Reduction of
4-Bromo-2-fluorobenzonitrile and Ethyl Benzoate at 25 °C
CHART 2. Competitive Reduction of
4-Bromo-2-fluorobenzonitrile and Ethyl Benzoate at 25 °C
General Procedure for the Reduction of a Nitrile by
BH2N(iPr)2, Prepared from iPrLAB and MeI. The following
procedure for the reduction of 2,4-dichlorobenzonitrile by
BH2N(iPr)2 is representative. To a 50-mL round-bottomed flask
equipped with magnetic stir bar and fitted with a rubber septum
was added 2,4-dichlorobenzonitrile (0.86 g, 5 mmol). The flask was
charged with diisopropylaminoborane (20 mL, 0.5 M in THF, 10
mmol),10 obtained from iPrLAB made with 1.1 equiv of n-BuLi
and MeI and upon addition the solution turns bright red. The
reaction goes to completion in 5 h at 25 °C, as evidenced by TLC
(Hex:EtOAc 2:1) analysis. The reaction mixture was cooled to 0
°C (ice bath) and unreacted BH2N(iPr)2 was quenched with 3 M
HCl (7 mL) (caution: hydrogen evolution). The acidic solution was
stirred for 30 min and then basified with NaOH pellets to pH ∼10.
The aqueous layer was extracted with 1:1 Et2O:THF (3 × 10 mL).
The combined organic layers were dried over anhydrous MgSO4,
filtered, and evaporated in vacuo (25 °C, 1 Torr) to afford 2,4-
dichlorobenzylamine as a light-yellow oil (99% yield).
was conducted (Scheme 10). Samples were collected at different
intervals and analyzed by GC by using an internal standard
(Chart 2). As expected, the reduction of 3 occurred faster than
5, demonstrating that selective reduction of nitriles in the
presence of esters is possible if the aryl nitrile contains an
electron-withdrawing substituent on the aromatic ring.
2,4-Dichlorobenzylamine (Table 1, entry 1): yellowish oil, 99%
1
yield; H NMR (500 MHz, CDCl3) δ 2.36 (s, 2H), 3.83 (s, 2H),
7.23 (d, 1H, J ) 8.75 Hz), 7.33 (d, 1H, J ) 8 Hz), 7.36 (d, 1H, J
) 2 Hz); 13C NMR (125 MHz, CDCl3) δ 44.1, 127.2, 129.2, 129.2,
133.5, 134.1, 138.6; exact mass m/z calcd for C7H7Cl2N, HRMS
(70 eV) m/z (M+ + 1) calcd 174.99555, found 174.99603.
2,6-Dichlorobenzylamine (Table 2, entry 1): yellowish oil, 77%
yield; 1H NMR (500 MHz, CDCl3) δ 2.35 (br s, 2H), 4.11 (s, 2H),
7.12 (t, 1H, J ) 8.5 Hz), 7.29 (d, 2H, J ) 8 Hz); 13C NMR (125
MHz, CDCl3) δ 41.2, 128.3, 128.5, 128.9, 135.2, 138.1; exact mass
m/z calcd for C7H7Cl2N, HRMS (70 eV) m/z (M+ +1) calcd
174.99555, found 174.99563.
Conclusion
We have shown that BH2N(iPr)2 in the presence of a catalytic
amount of LiBH4 reduces nitriles under exceedingly mild
reaction conditions affording the corresponding primary amines
in excellent yields. For example, treatment of 4-bromo-2-
chlorobenzonitrile with 2 equiv of BH2N(iPr)2 for 5 h at 25 °C
provides 4-bromo-2-chlorobenzylamine in 99% yield. Both
aromatic and aliphatic nitriles can also be reduced by this
method in high yields. Nitriles with electron-withdrawing groups
are reduced faster then aromatic esters.
2-(2-Bromophenyl)ethanamine (Table 3, entry 1): yellowish
oil, 80% yield; 1H NMR (500 MHz, CDCl3) δ 1.4 (br s, 2H), 2.88
(t, 2H, J ) 7 Hz), 2.97 (t, 2H, J ) 7 Hz), 7.07 (m, 1H), 7.23 (m,
2H), 7.54 (d, 1H, J ) 7.5 Hz); 13C NMR (125 MHz, CDCl3) δ
40.3, 42.1, 124.7, 127.5, 128.0, 130.9, 133.0, 139.2; exact mass
m/z calcd for C8H10BrN, HRMS (70 eV) m/z (M+ + 1) calcd
200.01224, found 200.00694.
It is important to note that BH2N(iPr)2 shows different
reactivity when prepared in situ by different methods, since a
J. Org. Chem. Vol. 74, No. 5, 2009 1969

Haddenham et al.
General Procedure for the Reduction of a Nitrile by Pure
BH2N(iPr)2 and Catalytic LiBPh4. The following procedure for
the reduction of 2,4-dichlorobenzonitrile by pure BH2N(iPr)2 and
catalytic LiBPh4 is representative. To a 50-mL round-bottomed flask
equipped with magnetic stir bar and fitted with a rubber septum
was added 2,4-dichlorobenzonitrile (0.52 g, 3 mmol) and THF (3
mL). The flask was charged with pure diisopropylaminoborane10
and then basified with NaOH pellets to pH ∼10. The aqueous layer
was extracted with 1:1 Et2O:THF (3 × 10 mL). The combined
organic layers were dried over anhydrous MgSO4, filtered, and
evaporated in vacuo (25 °C, 1 Torr) to afford 2,4-dichlorobenzy-
lamine as a light-yellow oil.
Supporting Information Available: The preparation of
BH2N(iPr)2 and spectroscopy data for all compounds character-
ized. This material is available free of charge via the Internet
at http://pubs.acs.org.
18
(6 mL, 1 M in THF, 6 mmol) and LiBPh4 (2.4 mL, 0.25 M in
THF, 20 mol %). The reaction goes to completion in 5 h at 25 °C,
as evidenced by TLC (Hex:EtOAc 2:1) and IR analysis. The
reaction mixture was cooled to 0 °C (ice bath) and unreacted
BH2N(iPr)2 was quenched with 3 M HCl (4.5 mL) (caution:
hydrogen evolution). The acidic solution was stirred for 30 min
JO8023329
1970 J. Org. Chem. Vol. 74, No. 5, 2009