Convenient synthesis of protected primary amines form nitriles

Article abstract of DOI:10.1016/S0040-4039(00)00410-X

Investigations into the use of nickel chloride and sodium borohydride for the reduction of nitriles showed the secondary amine dimers to be the major products under normal conditions. The addition of a suitable trapping agent, such as di-tert-butyl dicarbonate, allowed the isolation of the protected primary amines. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00410-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3513–3516
Convenient synthesis of protected primary amines from nitriles
a,∗
a
b
Stephen Caddick, Alexandra K. de K. Haynes, Duncan B. Judd and
a
Meredith R. V. Williams
a
The Chemistry Laboratory, University of Sussex, Falmer, Brighton, BN1 9QJ, UK
b
Lead Design, Glaxo Wellcome Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK
Received 16 February 2000; accepted 7 March 2000
Abstract
Investigations into the use of nickel chloride and sodium borohydride for the reduction of nitriles showed the
secondary amine dimers to be the major products under normal conditions. The addition of a suitable trapping
agent, such as di-tert-butyl dicarbonate, allowed the isolation of the protected primary amines. © 2000 Published
by Elsevier Science Ltd. All rights reserved.
Keywords: dimerisation; nickel boride; nitriles; reduction.
During ongoing investigations it became necessary for us to uncover a selective and, more importantly,
a generally applicable procedure for the reduction of nitriles. Due to its chemical robustness the cyano
group is ordinarily reduced using either catalytic hydrogenation or a strong hydride donor, such as
1
lithium aluminium hydride, which leaves little scope for selectivity. Sodium borohydride is generally not
2
3
strong enough to bring about reduction, although exceptions do exist. However, the addition of various
transition metal salts to reaction mixtures has long been known to dramatically improve the reactivity
4
of hydride donors. Cobalt(II) salts have found repeated application in the reduction of nitriles and of
particular note is the use of cobalt chloride in conjunction with sodium borohydride. Mechanistically,
5,6
7
this reaction is thought to occur with initial formation of cobalt boride through the reaction of cobalt
chloride and sodium borohydride.5 Subsequent coordination of the nitrile group to the boride surface
then leaves it open to hydride attack from excess borohydride. Related reactions using nickel boride
and hydrogen have also appeared in the literature with excellent chemo-selectivities being recorded in
,8
9
,10
11
some cases.
Confusion as to the exact nature of these reagents has meant that no generally applicable
procedure has been developed. In this paper we describe a new procedure for the transformation of nitriles
to protected primary amines as a single-step operation using sodium borohydride and nickel chloride.
We began our investigations by treating benzyl cyanide with nickel chloride and an excess of sodium
borohydride in methanol. We were pleased to find complete reduction of the nitrile triple bond.12
∗
Corresponding author. http://www.cpes.sussex.ac.uk/faculty/sc
0
040-4039/00/$ - see front matter © 2000 Published by Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00410-X
tetl 16690

3
514
However, close scrutiny of the reaction product revealed that we had in fact isolated the symmetrical
secondary amine 4 as a result of dimerisation, a common side product in the hydrogenation of nitriles.1
,13
It seems that addition of the primary amine 1 to the intermediate imine species 2 is faster than
hydride attack. The resulting hemiaminal 3 can then extrude an equivalent of ammonia to give an imine
which is further reduced to deliver the final product 4. Varying degrees of this type of coupling have
previously been noted in other metal boride mediated reductions of nitriles.9 The stoichiometry of
the reagents obviously plays a critical role in the determination of the reaction products. In our hands
only the secondary amines were formed (Table 1)15 and longer reaction times (up to 24 h) seemed to
give the best conversions. A large excess of reducing agent was also found to be necessary to bring about
complete transformation, presumably due to the instability of sodium borohydride in methanol. Although
quantitative conversions of secondary amines were achieved in some cases, yields did vary considerably.
Simple alkyl nitriles, in particular, gave poor yields possibly as a result of stronger complexation of these
products to the nickel boride catalyst (Table 1).
,14
Table 1
To circumvent the problem of dimerisation we reasoned that if we were able to trap the initially formed
primary amine in situ, by acylation for example, then the reduced nucleophilicity of the resultant amide
would prevent further reaction with the intermediate imine. Such a strategy should then provide a direct
route from the starting nitrile to a protected primary amine. Indeed, the addition of acetic anhydride
(
Ac O) to the reaction mixtures resulted in formation of the N-acetylamines (Table 2, entries 1–6).
2
16
By extension, the use of di-tert-butyl dicarbonate (BOC O) delivers the tert-butyl-carbamates, which
2
obviously offer greater synthetic versatility due to their facile deprotection (Table 2, entries 7–18). Yields
of the protected amines were generally found to be greater than the corresponding secondary amine
products above, although very good conversions still proved elusive for some alkyl nitriles (entry 5, Table
2). Similarly, nitriles containing pyridines gave poor conversions (entries 6 and 14, Table 2). Again, we
can only speculate that this is either due to chelation of the pyridine nitrogen to nickel reducing the
efficiency of product extraction or as a result of the formation and reduction of a pyridinium species.
Nitro groups were also found to reduce under the reaction conditions (entries 17, 18, Table 2) as was the
double bond of acrylonitrile (entry 16, Table 2).
In conclusion we have found that a combination of nickel chloride and sodium borohydride efficiently
reduces nitrile groups. The procedure seems to offer reasonable selectivity with esters, acetals, amides
and carbamates apparently remaining unchanged under the reaction conditions. Furthermore, the addition
of a suitable trapping agent such as Ac O or BOC O allows the isolation of the protected primary amine
2
2
thus avoiding the formation of the secondary amine dimers.

3
515
Table 2
Acknowledgements
We would like to thank Glaxo Wellcome for their generous financial support of this work. We also
thank Dr. Abdul Sada and Dr. Tony Avent for their assistance. Additionally we acknowledge the EPSRC
mass spectrometry service at Swansea.
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5
mmol) were added to a round bottom flask. NaBH
4
at 0°C, vigorous effervescence was accompanied by the formation of a black solid. The reaction mixture was left to stir
at room temperature for 20 h. The methanol was then removed under reduced pressure, leaving a black precipitate. The
precipitate was then dissolved in EtOAc and NaHCO
3
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2
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101–1107.
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K.; Goubitz, K.; Hiemstra, H.; van Zanden, M. N. A. Tetrahedron: Asymmetry 1996, 7, 515–524.
6. Preparation of N-BOC-phenethylamine: NaBH
mmol), BOC O (1.31 g, 6 mmol) and benzyl cyanide (0.32 ml, 3 mmol) in MeOH (25 ml) at 0°C (vigorous reaction with
the formation of a black precipitate). Once the reaction had subsided the mixture was left to stir, at room temperature, for
4 h. Methanol was removed under reduced pressure and the precipitate dissolved in EtOAc and NaHCO , filtered and
repeatedly washed with EtOAc. The combined organic phases were dried (Na SO ) and concentrated to yield N-BOC-
, 300 MHz) δ 7.22–7.08 (5H, m, ArH), 4.64 (1H, br, s, NH), 3.30
4 2
(0.79 g, 21 mmol) was cautiously added to a solution of NiCl (0.71 g, 3
2
2
3
2
4
1
phenethylamine (99%) Mp: 59.1°C. H NMR (CDCl
(
3
1
3
2 2 3
2H, q, J=7.0 Hz, CH NH), 2.69 (2H, t, J=7.0 Hz, CH Ar), 1.34 (9H, s, t-Bu). C NMR (CDCl , 75 MHz) δ 156.36,
39.47, 129.24, 128.98, 126.80, 42.25, 36.64, 28.85. MS(EI) m/z 165, 104, 91, 77. IR νmax/cm 3447, 3055, 2985, 1708,
−1
1
1
506.