An efficient synthesis of tertiary amines from nitriles in aprotic solvents

Article abstract of DOI:10.1016/j.tetlet.2012.06.044

Tertiary amines are utilized extensively as non-nucleophilic proton scavengers for a number of organic transformations. Herein we report the efficient syntheses of tertiary alkyl amines from their corresponding alkyl nitriles in the presence of a heterogeneous palladium catalyst and a source of dihydrogen in aprotic solvents. The reaction is atom economic, the conditions are mild, and the isolated yields are virtually quantitative. The degree of amine alkylation shows some solvent dependency; in polar protic solvents such as ethanol or methanol, the reaction affords a mixture of products with the secondary alkyl amine as the major product.

Full text of DOI:10.1016/j.tetlet.2012.06.044

Tetrahedron Letters 53 (2012) 4426–4428
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An efficient synthesis of tertiary amines from nitriles in aprotic solvents
⇑
Jonathan Shares, Jenna Yehl, Amanda Kowalsick, Philip Byers, Michael P. Haaf
Ithaca College, 953 Danby Rd., Ithaca, NY 14850, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Tertiary amines are utilized extensively as non-nucleophilic proton scavengers for a number of organic
transformations. Herein we report the efficient syntheses of tertiary alkyl amines from their correspond-
ing alkyl nitriles in the presence of a heterogeneous palladium catalyst and a source of dihydrogen in
aprotic solvents. The reaction is atom economic, the conditions are mild, and the isolated yields are
virtually quantitative. The degree of amine alkylation shows some solvent dependency; in polar protic
solvents such as ethanol or methanol, the reaction affords a mixture of products with the secondary alkyl
amine as the major product.
Received 19 May 2012
Revised 7 June 2012
Accepted 8 June 2012
Available online 18 June 2012
Keywords:
Tertiary amines
Nitrile reduction
Catalytic hydrogenation
Reaction mechanism
Ó 2012 Elsevier Ltd. All rights reserved.
Tertiary amines are utilized extensively as non-nucleophilic
proton scavengers for a number of organic transformations, and
are common starting materials in the synthesis of quaternary
ammonium-based ionic liquids.1 In addition, many alkaloids of
interest (e.g. quinine, atropine, castanospermine, swainsonine,
and aspidospermidine) also contain tertiary amine centers.2,3
Herein we report of the efficient synthesis of tertiary alkyl amines
from their corresponding alkyl nitriles. As shown in Figure 1, the
tertiary amines were formed in the presence of a source of H2
(ammonium formate or H2(g)) and a catalytic amount of Pd/C in
aprotic solvents. This reaction is reasonably atom economic, pro-
ceeds at room temperature, and is complete within 48–72 h.4
The reduction of nitriles to amines is a well-known transforma-
tion.5 However, the products formed can depend strongly on the
solvent used, and tertiary amines are usually formed as minor
products, if at all.6 Reactions run in aprotic solvents (pentanes,
hexane, THF, toluene) produce exclusively tertiary amines, while
reactions run in protic solvents (ethanol, methanol, etc.) afford
mostly secondary amines. Table 1 lists the results of the reaction
of alkyl nitriles with a catalyst (Pd/C, 5 wt% of metal content) and
a source of dihydrogen (ammonium formate). These reactions were
conducted in a variety of solvents at room temperature. Reaction
times varied, but all were complete between 48 and 72 h.
followed by removal of the solvent by distillation. In most cases, the
tertiary amine needed no further purification. However, trimethyl-
acetonitrile (entry 5) afforded exclusively a secondary amine (1),
demonstrating a steric limitation to this process. Benzonitrile (entry
6) and phenylacetonitrile (entry 7) did not yield an amine, but were
reduced to toluene and ethylbenzene, respectively. Interestingly,
isobutyronitrile (entry 8) in ethanol yielded mostly (80%) secondary
amine (1) and had a smaller (20%) yield of tertiary amine (2). Propi-
onitrile in ethanol (entry 9) yielded only secondary amine (1). These
entries highlight a strong solvent dependence on the outcome of
this reaction.
Hydrogenations using ammonium formate are routinely per-
formed at temperatures above 20 °C.7 Indeed, we observed an
accelerated consumption of alkyl nitrile at elevated temperature,
and some reactions were complete in under 2 h. However, we also
observed a mixture of secondary and tertiary amines, and addi-
tional uncharacterized reaction products appeared as well. As such,
ambient temperature is preferred to maximize selectivity, despite
longer reaction times.
The putative mechanism proposed in Figure 2 is broadly consis-
tent with those previously reported.8 It involves the initial reduc-
tion of the alkyl nitrile to a primary amine (II), via an imine
intermediate (I).
Reductions of acetonitrile (entry 1), propionitrile (entry 2),
butyronitrile (entry 3), and isobutyronitrile (entry 4) resulted in a
virtually quantitative conversion to their respective tertiary amines
(2) in aprotic solvents. Isolation of the tertiary amine product in-
volved simply filtering the reaction mixture through a bed of celite,
NH4HCO2
Pd/C (5 mol%)
R
R
+ 2 NH3
R
CN
3
R
N
aprotic solvent
R = Me, Et, Pr, iPr
⇑
Corresponding author.
E-mail address: mhaaf@ithaca.edu (M.P. Haaf).
Figure 1. Formation of tertiary amines from nitriles.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.044

J. Shares et al. / Tetrahedron Letters 53 (2012) 4426–4428
4427
Table 1
H2
Pd
R
N
C
+
R
N
CHR
R
NH
R
R
N
N
C
R
Scope and selectivity of the overall reaction
Pd
(IV)
(VII)
R
NH
R
R
NH4HCO2
R
R
Pd/C (5% wt.)
R
N
CH
R
+
H2
Pd
R
N
H2
Pd
R
N
R
R
CN
R
N
H
R
R
solvent
CH
R
1
2
NH2
R
NH3
Entry4
Nitrile
Solventa
1b (%)
2b (%)
(VIII)
1
2
3
4
5
6
7
8
9
Acetonitrile
Propionitrile
Butyronitrile
Isobutyronitrile
Trimethylacetonitrile
Benzonitrile
Phenylacetonitrile
Isobutyronitrile
Propionitrile
i, ii, iii
i, ii, iii
i, ii, iii
i, ii, iii, iv
i, ii
i, ii
i, ii
v
v, vi
Trace
Trace
Trace
Trace
>99
0
0
80
>99
>99
>99
>99
>99
Trace
0
0
20
Trace
Figure 4. Mechanism of tertiary amine formation.
Table 2
Effects of nitrile concentration on reaction selectivity
NH4HCO2
Pd/C (5% wt)
a
i = Hexanes,
v = ethanol, vi = methanol.
Identification and quantification of the products were determined by GC/MS
analysis, relative conversions were determined by peak area ratio analysis.
ii = pentane,
iii = tetrahydrofuran, iv = dimethylformamide,
+
CN
N
H
N
solvent
b
Entry
Concn of nitrile (M)
% Diisobutylamine
% Triisobutylamine
1
2
3
4
5
0.2
1
2
3
Neat
38
6
9
Trace
Trace
62
94
91
>99
>99
H2
Pd
H2
Pd
R
CH NH
R
CH2 NH2
(II)
NH
R
C
N
(I)
R
C N
H2
R
NH2
CH2
(II)
R
NH C R
(III)
Pd
Pd
H
N
H2
Pd
+
+
+
NH2
NHCHR
N
H
70%
N
NH2
CN
R
R
N
CHR
13%
17%
NH3
(IV)
Figure 5. Reaction of ethylamine with isobutyronitrile.
Figure 2. Putative mechanism for imine formation.
concentration of isobutyronitrile must be at or above M to be
exclusively selective for the tertiary amine. It is noteworthy that
this reaction can proceed with the same degree of selectivity with-
out any solvent at all (Table 2, entry 5). These results are consistent
with our proposed mechanism.
Although a primary amine was not observed directly in our
reactions, a primary amine such as ethyl amine can be reacted with
a nitrile to afford unsymmetrical, secondary and tertiary amines
under our reducing conditions (Fig. 5).
Similarly, reaction of a secondary amine (diethylamine) with an
alkyl nitrile yields the anticipated amine products (Fig. 6). These
results are also consistent with the proposed mechanism in Figure 4.
In the interest of ring formation, a primary amine (ethyl amine)
and a dinitrile were reacted under our reducing conditions (Fig. 7).
The reaction yielded the anticipated five member ring, 1-ethylpyrr-
olidine. In addition, the reaction also affords a small quantity of
N-ethylpyrrole, presumably from the dehydrogenation of the
saturated cycle to yield an aromatic moiety.
The amine subsequently reacts with a second nitrile moiety,
yielding an amidine intermediate (III).9 Now, activated by the Pd
catalyst, the amidine reduces to form an imine (IV).
Alternatively, the mechanism may follow a slightly different
pathway proposed in Figure 3. In this proposed mechanism, the
primary amine (II) attacks the imine (I) to form compound (V). This
compound undergoes a proton transfer, then forms compound (IV).
Further, especially in aprotic solvents, this process can repeat to
form a tertiary amine (VII), as shown in Figure 4. This sequence of
steps occurs to a lesser extent in protic solvents, wherein the sec-
ondary amine is the major product.
It is reasonable to hypothesize that the solvent dependency on
the degree of alkylation emerges from the protic solvents’ ability to
stabilize amines via hydrogen bonding interactions. In such cases,
the reaction beyond the formation of the secondary amine (VII) is
sluggish. The amine function lacks this stabilization in aprotic
solvents and thus behaves as a stronger nucleophile, allowing for
further reaction to the tertiary amine.
H2
+
The concentration of the starting nitrile in aprotic solvents also
has an effect on the outcome of the reaction. For example, the
N
+
N
N
H
H
Pd
CN
NH
H+ transfer
R
CH2 NH2
R
CH NH
Figure 6. Reaction of diethylamine with isobutyronitrile.
R
NH2
(V)
R
(I)
(II)
NH2
NH CHR
(VI)
H2
Pd
CN
R
N
R
N
CHR
+
+
N
NH2
NC
(IV)
NH3
Figure 7. Formation of 1-ethylpyrrolidine and N-ethylpyrrole from an ethylamine
Figure 3. Alternate mechanism for imine formation.
and succinonitrile.

4428
J. Shares et al. / Tetrahedron Letters 53 (2012) 4426–4428
3. Zhao, H.; Hans, S.; Chemg, X.; Mootoo, D. R. J. Org. Chem. 2001, 66, 1761.
In summary, we have developed a protocol for the Pd-catalyzed
4. General reaction procedure for the reduction of an alkyl nitrile. A dried, vented
round bottom flask containing a stir bar was charged with alkyl nitrile (typically
ꢀ5 mL, 1 molar equiv), 5% mole of 5% wt Pd on activated carbon, a source of
hydrogen gas (ammonium formate, 2.1 molar equiv), and a solvent (ꢀ20 mL).
The reaction was stirred at room temperature until the starting nitrile was
consumed. Reaction progress was monitored by GC/MS. Once complete, the
excess Pd/C was filtered on a bed of celite and the remaining solvent was
removed via distillation to afford a pure product. 1H and 13C NMR (CDCl3,
400 MHz JEOL spectrometer) were collected and compared to spectra obtained
from authentic, commercially available samples.
reduction of alkyl nitriles to their corresponding tertiary amines.
This reaction requires mild conditions and aprotic solvents to
afford high yields of the product. The reaction of primary and
secondary amines with nitriles affords products consistent with pro-
posed mechanisms. The successful formation of N-substituted pyr-
rolidines and aromatic pyrroles under our reaction conditions was
a promising progression and further investigations are underway.
5. For example: (a) Gould, F. E.; Johnson, G. S.; Ferris, A. F. J. Org. Chem. 1960, 25,
1658; (b) Greenfield Ind. Eng. Chem. Res. Dev. 1967, 6, 142. and references
therein.
Acknowledgments
6. For example: Sajiki, H.; Ikawa, T.; Hirota, K. Org. Lett. 2004, 6, 4977.
7. For example: Ram, S.; Spicer, L. D. Synth. Commun. 1992, 22, 2683.
8. For a general review of proposed mechanisms of catalytic hydrogenations of
nitriles, see: Huang, Y.; Sachtler, W. M. H. Appl. Catal., A: Gen., 1999, 182, 365, and
mechanisms reported in references therein.
9. Similarly, imidates have been shown to form from the combination of nitriles
and alcohols under acidic conditions: Caron, S.; Wei, L.; Douville, J.; Ghosh, A. J.
Org. Chem. 2010, 75, 945.
We would like to thank Ithaca College and the Ithaca College
Dana Student Fellowship program for supporting this research.
References and notes
1. For a review, see: (a) Petchkova, N. V.; Seddon, K. R. Chem. Soc. Rev. 2008, 37,
123; (b) Welton, T. Chem. Rev. 1999, 99, 2071.
2. Toczko, M. A.; Heathcock, C. H. J. Org. Chem. 2000, 65, 2642.