Transfer hydrogenation of nitriles with 2-propanol and Raney nickel

Article abstract of DOI:10.1081/SCC-120023995

Raney nickel in refluxing 2-propanol containing 2% KOH is an effective catalytic system for reducing nitriles to amines.

Full text of DOI:10.1081/SCC-120023995

This article was downloaded by: [University of Hawaii at Manoa]
On: 08 September 2013, At: 11:19
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House,
37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
Transfer Hydrogenation of Nitriles with 2-Propanol and
Raney® Nickel
Robert C. Mebane a , David R. Jensen a , Kerry R. Rickerd a & Benjamin H. Gross a
a Department of Chemistry, University of Tennessee at Chattanooga, Chattanooga,
Tennessee, USA
Published online: 15 Aug 2006.
To cite this article: Robert C. Mebane , David R. Jensen , Kerry R. Rickerd & Benjamin H. Gross (2003) Transfer Hydrogenation
of Nitriles with 2-Propanol and Raney® Nickel, Synthetic Communications: An International Journal for Rapid Communication
of Synthetic Organic Chemistry, 33:19, 3373-3379
To link to this article: http://dx.doi.org/10.1081/SCC-120023995
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the
Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and
should be independently verified with primary sources of information. Taylor and Francis shall not be liable for
any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever
or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of
the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 19, pp. 3373–3379, 2003
Transfer Hydrogenation of Nitriles with
2-Propanol and RaneyÕ Nickel
*
Robert C. Mebane, David R. Jensen, Kerry R. Rickerd,
and Benjamin H. Gross
Department of Chemistry, University of Tennessee at
Chattanooga, Chattanooga, Tennessee, USA
ABSTRACT
Raney nickel in refluxing 2-propanol containing 2% KOH is an
effective catalytic systemfor reducing nitriles to amines.
Key Words: Transfer hydrogenation; Nitrile reduction; Raney1
nickel.
The reduction of nitriles to amines is an important reaction in
synthetic chemistry[1,2] and is of value in industrial chemistry.[3] Of the
various methods for performing this reaction which include catalytic
hydrogenation,[4] metal hydride reduction,[5] dissolving metal reduction[6]
*Correspondence: Robert C. Mebane, Department of Chemistry, University
of Tennessee at Chattanooga, 615 McCallie Ave., Chattanooga, Tennessee
37403-2598, USA; Fax: 423/425-4709; E-mail: Robert-Mebane@utc.edu.
3373
DOI: 10.1081/SCC-120023995
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
3374
Mebane et al.
and electrochemical reduction,[7] catalytic hydrogenation appears to be
most widely employed. A commonly used catalyst for these catalytic
reductions is Raney nickel, a versatile catalyst for effecting reductive
transformations of organic compounds.[8] Less well known and utilized
is Raney nickel’s ability to catalyze reductions using hydrogen donors
instead of molecular hydrogen.[9,10] First described by Kleiderer and
Kornfield,[11] Raney nickel catalyzed transfer hydrogenations (CTH)
have been reported for the reduction of olefins,[12] ketones,[12–14]
phenols,[12] aromatic nitro compounds,[15,16] and certain aromatic hydro-
carbons.[12,17] Recently, we reported on the hydrogenolysis of aromatic
alcohols[18] and the deiodination of iodolactones[19] using Raney nickel
and 2-propanol as a hydrogen donor. Herein we describe a novel catalytic
transfer hydrogenation procedure for converting nitriles into amines
using 2-propanol and Raney nickel. In contrast to traditional catalytic
hydrogenation, this new method employs mild conditions, is less
hazardous, and leads to N-isopropylidene amines (2a–h) which are
easily hydrolyzed to primary amines.
The experimental procedure for the CTH of nitriles is simple and
straightforward and affords reduced products in excellent yields. The
overall reaction is described in Fig. 1 and a summary of our results is
presented in Table 1. In a typical run, the nitrile (2.0 g) was refluxed in a
−
Cl
Raney nickel
i) 10% HCl
ii) KOH
R
N
R
CN
R
NH3+
2-propanol,
2% KOH, reflux
1a-i
2a-h
iii) HCl, Et O
2
4a-h
Figure 1. Reduction of nitriles by catalytic transfer hydrogenation.
Table 1. Transfer hydrogenation of nitriles with RaneyÕ nickel and 2-propanol.
Nitrile
R
Product
Yield (%)
1a
1b
1c
1d
1e
1f
n-butyl
n-pentyl
n-hexyl
n-heptyl
4a
4b
4c
4d
4e
4f
97
94
94
88
88
91
98
96
89
Isopropyl
t-butyl
1g
1h
1i
Cyclohexyl
Norborn-2-yl
Norborn-5-en-2-yl
4g
4h
4h

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
2-Propanol and RaneyÕ Nickel
3375
magnetically stirred suspension of Raney nickel (5 g) in 2-propanol
(30 mL) containing 2% KOH (w/v) for 1 h while open to the atmosphere.
At this stage the N-isopropylidene amine could be isolated after suitable
workup as described in the experimental section. Isolated yields of the
imines were excellent (>90%) except for the lower molecular weight, and
thus more volatile, N-isopropylidene amines.[20] Acid hydrolysis followed
by a base workup afforded the free amines of 4 which gave NMR and
mass spectra identical to authentic samples. The yields in this study are
reported for the hydrochloride salts of the corresponding primary amines
due to the volatility of the lower molecular weight amines.
The optimal substrate to catalyst ratio (w/w) for the reduction of
nitriles by CTH was found to be 2:5. Although an excess of nickel
catalyst is required, we did find that the catalyst retains its activity
after repeated use.[21] While Raney cobalt has been used successfully in
the reduction of nitriles with molecular hydrogen under pressure,[22] we
found this catalyst incapable of reducing nitriles by CTH with 2-propanol
as the hydrogen donor. We also found that benzonitrile and benzyl
cyanide are recovered unchanged when subjected to CTH with Raney
nickel in 2-propanol. An explanation for this may be that strong adsorp-
tion of the aromatic ring on the nickel surface may prevent the nitrile
group fromcoming into contact with the active sites of the catalyst. As
seen with nitrile 1i, double bonds may also reduced be under the reaction
conditions.
It appears reasonable to assume that the formation of the
N-isopropylidene amines is the result of condensation between the
primary amines arising from nitrile reductions and acetone resulting
fromthe oxidation of 2-propanol during the CTH reaction. Further
reduction of the imines is not observed as long as the reaction is
performed in the presence of the 2% KOH which was determined to
be an optimal amount of base. Reducing the amount of KOH in the
CTH reactions leads to reduction of the N-isopropylidene amines to
give N-isopropyl amines and symmetrical dialkyl amines (vide infra)
with the former products being major. We attempted to find general
reaction conditions which favored the formation of N-isopropyl
amines while suppressing the reaction leading to the symmetrical
secondary amines. By performing the CTH reactions in the presence
of only 0.07% KOH we were able to effectively reduce nitriles 1d–i to
their respective N-isopropyl amines. Reaction times for complete
conversion varied from3 h ( 1d) to over 40 h (1e). In contrast,
reduction of nitriles 1a–1c was not nearly as clean giving instead
mixtures consisting of N-isopropylidene amines, N-isopropyl amines
and symmetrical dialkyl amines.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
3376
Mebane et al.
The formation of symmetrical dialkyl amines is a common side
reaction encountered in the conventional metal catalyzed hydrogenation
of nitriles and imines with molecular hydrogen.[23–26] The secondary
amine results from addition of primary amine to an imine intermediate
followed by hydrogenolysis of an –NH2 group.[26] In this study we found
that if the CTH is performed without added base a mixture of
N-isopropyl-N-alkyl amine and symmetrical secondary amine results
with the former product being major.
The role KOH plays in these CTH reactions was not elucidated in
this study. It is clear fromour results that KOH suppresses the reduction
N-isopropylidene amines and the formation of the symmetrical dialkyl
amines. In traditional hydrogenation of nitriles with hydrogen gas
and metal catalysts it is known that dialkyl amine formation can be
minimized by performing the reductions in the presence of ammonia or
[26]
sodiumhydroxide.
In conclusion, catalytic transfer hydrogenation with Raney nickel,
2-propanol as the hydrogen donor and containing 2% KOH is an effective
method for the reduction of aliphatic nitriles to primary amines. The
primary amines are converted in the reaction into N-isopropylidene
amines by condensation with acetone formed in the reaction. The
N-isopropylidene amines can be isolated as such or conveniently hydro-
lyzed to primary amines with dilute HCl. This mild and cost-effective
method of reduction is a viable alternative to conventional catalytic
hydrogenation utilizing molecular hydrogen since neither hydrogen
containment nor a pressure vessel is required.
EXPERIMENTAL
RaneyÕ 2800 nickel was obtained fromW. R. Grace Company,
Chattanooga Davison. The catalyst was washed prior to use with distilled
water (6Â) and 2-propanol (3Â) and stored in 2-propanol. 1H and
13C NMR spectra were recorded on a Varian Gemini 300 spectrometer
using tetramethylsilane as internal reference. Mass spectra were recorded
on a Perkin Elmer Ion Trap GC-MS. The NMR and mass spectra of the
amines prepared in this work were identical to known spectra.
As an illustrative example of the hydrogenation procedure, nitrile 1a
(2.0 g, 24.1 mmol) was refluxed in a magnetically stirred suspension of
Raney nickel (5 g) in 2-propanol (30 mL) containing 2% KOH (w/v) for
1 h with the condenser open to the atmosphere. After cooling to room
temperature the organic layer was decanted from the Raney nickel[27] and
the catalyst was washed with diethyl ether (3 Â 10 mL). The combined

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
2-Propanol and RaneyÕ Nickel
3377
organic layers were filtered through Celite and concentrated by rotatory
evaporation. The residue was stirred with 10% HCl (20 mL) for 15 min to
hydrolyze the N-isopropylidene pentanamine. The reaction mixture was
made basic with 10% KOH (10 mL), cooled, and extracted with diethyl
ether (4 Â 20 mL). The combined ether layers were dried (potassium
carbonate), filtered, and concentrated by rotatory evaporation. To this
residue was added HCl in diethyl ether (1.0 M, 30 mL). The mixture was
concentrated by rotatory evaporation, filtered, washed with cold diethyl
1
ether and dried to give 2.88 g (97%) of 4a as a white solid. The H and
13C NMR spectra and the mass spectra of the free amine of 4a were
identical to spectra of authentic pentanamine.
ACKNOWLEDGMENTS
The authors gratefully acknowledge financial support fromthe
University of Chattanooga Foundation and the Grote Chemistry
Fund. In addition, we are indebted to the W. R. Grace Company,
Chattanooga for the generous donation of RaneyÕ Nickel catalyst.
REFERENCES
1. For general references, see: (a) Freifelder, M. Practical Catalytic
Hydrogenation; John Wiley and Sons: New York, 1971; Chapter 12;
(b) Rabinovitz, M. The Chemistry of the Cyano Group; Rappoport, Z.,
Ed.; John Wiley and Sons: New York, 1970; Chapter 7; (c) Smith,
P.A.S. The Chemistry of Open-Chain Organic Nitrogen Compounds;
W.A Benjamin, Inc.: New York, 1965; Vol. 1, pp. 218–219.
2. For synthetic applications, see; (a) Verraest, D.L.; Zitha-Bovens, E.;
Peters, J.A.; Van Bekkum, H. Carbohydr. Res. 1998, 310, 109–115;
(b)Bergeron, R.J.; Garlich, J.R. Synthesis1984, 782–784; (c)Galan, A.;
de Mendoza, J.; Prados, P.; Rojo, J.; Echavarren, A. J. Org. Chem.
1991, 56, 452–454.
3. For industrial examples, see: (a) Weigert, F.J. US Patent 5,237,088,
1993; (b) Besson, M.; Cordier, G.; Fouiloux, P.; Masson, J. US
Patent 5,801,286, 1998; (c) Cordier, G.; Fouilloux, P.; Laurain, N.;
Spindler, J.-F. US Patent 5,777,166, 1998.
4. Ref.[1b] pages 320–325 and references therein.
5. Some leading references on metal hydride reduction of nitriles
include: (a) Gribble, G.W. Chem. Soc. Rev. 1998, 27, 395–404; (b)
Fisher, G. B.; Harrison, J.; Fuller, J.C.; Goralski, C.T.; Singaram, B.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
3378
Mebane et al.
Tetrahedron Lett. 1992, 33, 4533–4536; (c) Prasad, A.S.B.; Kanth,
J.V.B.; Periasamy, M. Tetrahedron 1992, 48, 4623–4628; (d)
Akabori, S.; Takanohaski, Y. J. Chem. Soc., Perkin Trans. 1991,
1, 379–482; (e) Heinzman, S.W.; Ganem, B. J. Am. Chem. Soc.
1982, 104, 6801–6802.
6. (a) Doumaux, A.R. J. Org. Chem. 1972, 37, 508–510; (b)Kamochi, Y.;
Kudo, T. Chem. Pharm. Bull. 1994, 42, 402–404.
7. Reed, R.C.; Wightman, R.M. Encyclopedia of Electrochemistry of
the Elements; Bard, A.J., Ed.; Marcel Dekker, Inc.: New York, 1984;
Vol. 15, pp. 1–165.
8. House, H.O. Modern Synthetic Reactions, 2nd Ed.; W.A. Benjamin,
Inc.: Menlo Park, 1972; p. 1.
9. Brieger, G.; Nestrick, T. Chem. Rev. 1974, 74, 567.
10. Johnstone, R.A.W.; Wilby, A.H. Chem. Rev. 1985, 85, 129.
11. Kleiderer, E.C.; Kornfeld, E.C. J. Org. Chem. 1948, 13, 455.
12. Andrews, M.J.; Pillai, C.N. Indian J. Chem. 1978, 16B, 465.
13. Stevovic, L.S.; Soskic, V.; Juranic, I.O. J. Serb. Chem. Soc. 1995,
60, 1071.
14. Gonikberg, E.M.; le Noble, W.J. J. Org. Chem. 1995, 60, 7751.
15. Banerjee, A.A.; Mukesh, D. J. Chem. Soc., Chem. Commun.
1988, 1275.
16. Kuo, E.; Srivastava, S.; Cheung, C.K.; le Noble, W.J. Synth.
Commun. 1985, 15, 599.
17. Srivastava, S.; Minore, J.; Cheung, C.K.; le Noble, W.J. J. Org.
Chem. 1985, 50, 394.
18. Gross, B.H.; Mebane, R.C.; Armstrong, D.L. J. Applied Catalysis
A: General 2001, 219, 281.
19. Mebane, R.C.; Grimes, K.D.; Jenkins, S.R.; Deardorff, J.D.; Gross,
B.H. Synth. Commun. 2002, 32, 2049.
20. Yields of all N-isopropylidene amines (2) as determined by glc were
essentially quantitative.
21. It was found that the Raney catalyst retained activity through at
least six reductions of nitrile 1d. In each reduction 1d was completely
converted into 2d within 1 h. The used catalyst was washed with
fresh 2-propanol (3 Â 10 mL) prior to reuse.
22. Reeve, W.; Christian, J. J. Am. Chem. Soc. 1956, 78, 860.
23. Augustine, R.L. Heterogeneous Catalysis for the Synthetic Chemist;
Marcel Dekker, Inc.: New York, 1996; pp. 491–493.
24. Yada, S.; Hyamizu, M.; Takagi, Y. Nippon Kagaku Kaishi 1998,
8, 525.
25. Thomas-Pryor, S.N.; Manz, T.A.; Liu, Z.; Koch, T.A.; Sengupta,
S.K.; Delgass, W.N. Chem. Ind. 1998, 75, 195.

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
2-Propanol and RaneyÕ Nickel
3379
26. Ref.[1a] page 238.
27. Raney nickel is paramagnetic and sticks to the magnetic stir bar
which facilitates the decantation.
Received in the USA April 17, 2003

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016
©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.