Interfacial hydrogenation and deamination of nitriles to selectively synthesize tertiary amines

Article abstract of DOI:10.1039/c4cc05132g

A novel one-pot method has been developed for the interfacial hydrogenation of nitriles to synthesize asymmetrical tertiary amines. The active Pt NWs allow for the preparation of a series of tertiary amines in excellent yields (up to 99.0%) and a mixed solvent is vital for the adjustment of the yield. And also, the reaction proceeded under mild conditions and is environmentally friendly.

Full text of DOI:10.1039/c4cc05132g

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
Interfacial hydrogenation and deamination of
nitriles to selectively synthesize tertiary amines†
Cite this: Chem. Commun., 2014,
50, 11110
Shuanglong Lu, Chao Li, Jiaqing Wang, Yue Pan, Xueqing Cao and Hongwei Gu*
Received 4th July 2014,
Accepted 30th July 2014
DOI: 10.1039/c4cc05132g
www.rsc.org/chemcomm
A novel one-pot method has been developed for the interfacial nanoparticles9 to promote the selective synthesis of tertiary
hydrogenation of nitriles to synthesize asymmetrical tertiary amines from alcohol and urea.10 Both of these methods are
amines. The active Pt NWs allow for the preparation of a series of novel and efficient. One limitation associated with these systems
tertiary amines in excellent yields (up to 99.0%) and a mixed solvent is that a large excess of relatively expensive alcohols is needed.
is vital for the adjustment of the yield. And also, the reaction
proceeded under mild conditions and is environmentally friendly.
Herein, we report an entirely new Pt nanowire (Pt NW)
catalyzed reduction amination process for the preparation of
a series of tertiary amines from the corresponding nitriles. The
Tertiary amines are an extremely important class of compounds ultrathin Pt NWs were synthesized from acidic etching of FePt
from the drug discovery perspective. Indeed, no less than a quarter NW and they can be recycled easily through simple centrifuga-
of registered drugs contain tertiary amines.1 They are particularly tion, which was reported in our previous work.11
common in drugs which are active within the central nervous
Inspired by our last work12 where secondary amines have been
system.2 Tertiary amines are also important building blocks in obtained from the reduction of nitriles with additional primary
organic synthesis and routinely serve as synthons for pharma- amines, we substituted the primary amine with secondary amine
ceuticals, herbicides, agricultural chemicals, and functionalized as the additional reagent to get the tertiary amine. Nitriles are
materials.3 A number of catalytic and non-catalytic procedures, for easily available and asymmetrical tertiary amines can be prepared
example (1) N-alkylation of amines with alkyl halides or alcohols,4 without any wasteful salts and it can be a very atom-efficient
(2) reductive amination of carbonyl compounds,5 (3) amination of catalytic transformation (Scheme 1).
arylhalides,6 and (4) hydroamination of unsaturated hydrocarbons
As far as we have known, almost no paper has been
with amines7 have been developed for the synthesis of tertiary published in the preparation of a tertiary amine directly from
amines. However, problems, such as the use of expensive starting a nitrile13 for the reason that the cyan group is relatively stable
materials, tedious workup procedures, low selectivity, and for- and the selectivity of several products (self-coupling to di- or
mation of large amounts of wasteful salts may occur here. Also, tri-amines and imines) are hard to be controlled. It seems
most of the traditional methods are homogeneous systems and impossible that an unsymmetrical tertiary amine can be
have shortcomings in the catalyst/product separation and recycling obtained from the hydrogenation of nitriles in the presence
of expensive metal catalysts. N. Mizuno et al. developed the of other secondary amines.
heterogeneous catalytic N-arylation using Ru(OH)x supported
At the beginning of the investigation, we evaluated the possibi-
on TiO2 as a catalyst.8 The Cao group used supported gold lity of hydrogenation of nitriles with piperidine as the added
secondary amine for accessing tertiary amines in different solvents.
However, the results (shown in Table 1) were not that satisfactory.
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry,
Chemical Engineering and Materials Science, Science & Collaborative Innovation
Center of Suzhou Nano Science and Technology, Soochow University, Suzhou,
215123, China. E-mail: hongwei@suda.edu.cn; Fax: +86-65880905;
Tel: +86-65880905
† Electronic supplementary information (ESI) available: Experimental procedures
include a synthetic protocol for the construction of the Pt NWs, optimization of
the reaction conditions, catalytic activities with different Pt morphologies, and
upscaled results for this system. And also, catalytic stability of the Pt NW and full
Scheme 1 Asymmetrical tertiary amine formation from the hydrogena-
tion reaction of benzonitrile.
spectroscopy data for all compounds are provided (23 pages). See DOI: 10.1039/
c4cc05132g
11110 | Chem. Commun., 2014, 50, 11110--11113
This journal is ©The Royal Society of Chemistry 2014

View Article Online
Communication
ChemComm
Table 1 Formation of tertiary amines from benzonitrile in a series of
reaction conditionsa
Table 2 Formation of tertiary amine in a series of reaction conditionsa
Entry
Catalyst
H2(bar)
n(a)/n(b)
M
T (1C)
Yieldb (%)
Sel.b (%)
Conv.b (%) TA DA DI
1
2
3
4
5
6
7
8
Pt NW
Pt NW
Pt NW
Pt NW
Pt NW
Pt NW
Pt NW
Pt NW
Pt NW
Pt NW
Pt NW
Pt NW
Pt NW
—
1
1
1
1
1
1
1
1
1
1
1
1
1
1
—
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
2
1
1
1
1
2
3
5
7
9
1/3
1/7
1
1
3
100
80
60
92.6
65.8
75.1
40.5
95.3
96.1
95.5
94.2
77.6
91.5
78.3
97.7
98.5
N.D.c
N.D.c
Entry n(b) : n(a) T (1C) Solvent
1
2
3
4
5
6
7
8
2
2
2
2
2
2
2
2
2
2
2
2
2
2
80
100
80
100
80
100
40
40
80
80
80
60
Toluene
Toluene
Xylene
Xylene
1,4-Dioxane
1,4-Dioxane
Methanol
Acetic acid
100
100
100
100
100
100
100
100
45.0 33.0 21.0
72.2 23.0 2.4
16.6 74.4 9.0
33.5 55.7 9.0
51.6 31.1 17.3
41.9 36.6 21.5
23.3 58.6 16.6
36.8 25.9 30.6
38.6 44.5 16.8
13.3 1.9 83.4
64.4 32.2 3.4
74.3 23.0 2.6
62.9 3.0 4.8
84.8 1.3 8.1
40
100
100
100
100
100
100
100
100
100
100
100
9
10
11
12
13
14
15
9
Triethylamine 98.8
10
11
12
13
14
Heptane
Ethanol
Ethanol
Water
100
100
100
100
100
5
1.1
1.1
Pt NW
3
80
100
a
Water
All Reactions were carried out with 0.005 mmol Pt NW at the
appropriate temperature, mixed solvent (2.0 mL), 1 bar H2 pressure
a
Reaction conditions: 0.005 mmol Pt NWs, 1 bar H2 pressure in
corresponding temperature and solvent (2.0 mL). GC yield.
b
c
for 24 h. GC yield. Not detected.
b
Both the aprotic (heptane, toluene, xylene, 1,4-dioxane, etc.) and functional groups was towards water molecules, which
protic (water, ethanol, methanol, etc.) solvents cannot afford high decreased the chance for nitriles to couple with each other
selectivity for the tertiary amine. And also, acidic and basic condi- and it became easier for the piperidine to approach the nitrile.
tions are applied to run the model reaction (entries 8 and 9). For another, a part of nitrile molecules was concealed inside
Obviously, the yield of tertiary amine was not enhanced much. the droplet, restricting a further increase in the selectivity.
Therein, the main problem was the side reaction where the nitriles
To further enhance the yield of tertiary amines, 1,4-dioxane
tend to interact with themselves instead of with the added piper- was chosen as the additional reagent to form a mixed solvent.
idines, which was consistent with the fact that the hydrogenation of 1,4-Dioxane is miscible with water and it can dissolve the
nitriles under vigorous hydrogenation conditions over platinum hydrophobic part well.
metal catalysts is favorable for self-hydrogenation.14
In accordance with our conjecture, the mixed solvent shows
However, one interesting point we noted was that even excellent performance in the selective synthesis of tertiary
though water is a poor solvent for benzonitrile (10 mg mLÀ1 amines from hydrogenation of nitriles (Table 2, entry 1). Further
in 100 1C), the selectivity of the tertiary amine in it was investigation of different proportions of the two different
surprisingly higher than those which dissolved nitriles well. solvents used (entries 5–11 in Table 2) revealed that when the
Because of the nature of benzonitrile’s solubility in water, the volume ratio of water and 1,4-dioxane was 3, a balance was
reaction mixtures were always in emulsion (shown in Fig. 1). reached and the highest yield of tertiary amine was obtained.
The two corresponding sides may contribute to the selectivity The reaction temperature also had a noticeable impact on the
of the tertiary amine in water. For one thing, due to the selectivity of the reaction, and a higher temperature was found to
interaction of cyan groups with water, the orientation of these exhibit better selectivity for the generation of tertiary amines.
Besides, more additional amine contributed to a higher
yield of the desired products. Also, when the reaction was
conducted in the absence of the catalyst or hydrogen, the
tertiary amine could not be detected, which indicates that the
Pt NW and hydrogen gas were critical to the success of this
transformation.
We proposed the interfacial interaction and organic mecha-
nism in Fig. 1 based on our experiment and previous
research.14,15 Aromatic nitriles formed microdroplets in water
and 1,4-dioxane used prevented them from being submerged
inside (shown in Fig. 1).
Benzoimine is the most important intermediate got through
partial hydrogenation of benzonitrile. It would react with the
added piperidine preferentially, subsequent elimination of
ammonia from which would lead to tertiary amine as the major
product. Benzylamine obtained from further hydrogenation
Fig. 1 Proposed mechanism (the solvent for reaction mixture a is dioxane,
the solvents for reaction mixture b are water and dioxane).
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun., 2014, 50, 11110--11113 | 11111

View Article Online
ChemComm
Communication
will react with the initial imine to give both symmetrical nitrile, 1.1 mmol added secondary amine) in hand, we proceeded
secondary amine and imine as byproducts, which is unfavor- to investigate the scope of the reaction using a wide range of
able according to the interfacial interaction shown in Fig. 1. nitriles and secondary amines. Obviously, almost all of the
Herein, the Pt NW plays a vital role in the hydrogenation and substrates gave the desired tertiary amines in good to excellent
elimination of NH3.
yields. The substituents on the phenyl rings of the substrates did
With the optimal reaction conditions (1 bar H2, 100 1C, not appear to have a significant influence on the outcome of the
mixed solvent 2 mL (1.5 mL water, 0.5 mL 1,4-dioxane), 1 mmol reaction, but steric hindrance exerted an influence on the
reaction yield (entries 5 and 6). Also the results in entries 7
and 8 demonstrated that the system was also valid for hetero-
Table 3 Tertiary amines prepared using different nitriles and secondary
cyclic and aliphatic nitriles. Weaker H-bonding between amines
and water contributes to higher selectivity of desired products
(entries 9–17, compared with piperidine). Interestingly, when
piperazine was used as an added secondary amine, the C–N
coupling could be reached on both sides of it (entry 18).
The reaction can be upscaled successfully and Pt NWs show
great superiority in achieving high conversion and selectivity
compared with other Pt catalysts with different morphologies
(shown in the ESI†) (Table 3).
In conclusion, a series of tertiary amines have been success-
fully synthesized from the interfacial hydrogenation of nitriles
in one pot using highly active and stable Pt NWs as the catalyst.
A mixed solvent was applied here to adjust the solubility of
aromatic nitriles, as a result of which the yield of tertiary amine
could reach up to 99.0%. The idea of this reaction is novel,
efficient and environmentally friendly. Further study of this
catalytic system for wider application is under investigation in
our laboratory.
amines over Pt NWsa
Entry
Nitriles
Amines
Product
Yieldb (%)
85.5(83.0)
94.3(89.0)
1
2
3
4
5
90.1(86.3)
83.2(79.5)
75.3
6
7
8
42.3
73.6(68.8)
83.8
H.W.G. acknowledges financial support from the National
Natural Science Foundation of China (No. 21373006), the Key
Project of the Chinese Ministry of Education (No. 211064), and a
project funded by the Priority Academic Program Development
of Jiangsu Higher Education Institutions. J. Q. W. acknowledges
financial support from the Scientific Innovation Research of
College Graduate in Jiangsu province (CXLX13_818).
9
87.9(85.7)
92.3(90.2)
89.7(86.3)
10
11
Notes and references
1 A. R. Brown, D. C. Rees, Z. Rankovic and J. R. Morphy, J. Am. Chem.
Soc., 1997, 119, 3288–3295.
2 D. Menche, S. Bohm, J. Li, S. Rudolph and W. Zander, Tetrahedron
Lett., 2007, 48, 365–369.
12
13
14
15
82.0(80.1)
99.3(96.2)
99.0(97.2)
87.3(85.2)
3 (a) K. P. C. Vollhardt and N. E. Schore, Organic Chemistry: Structure
and Function, W. H. Freeman and Company, USA, 3rd edn, 1999;
(b) S. A. Lawrence, Amines: Synthesis Properties, and Applications,
Cambridge University, Cambridge, 2004; (c) A. A. NfflÇez Magro,
G. R. Eastham and D. J. Cole-Hamilton, Chem. Commun., 2007,
3154–3156.
4 (a) R. N. Salvatore, C. H. Yoon and K. W. Jung, Tetrahedron, 2001, 57,
7785–7811; (b) R. N. Salvatore, A. S. Nagle and K. W. Jung, J. Org. Chem.,
2002, 67, 674; (c) C. Chiappe, P. Piccioli and D. Pieraccini, Green Chem.,
2006, 8, 277–281; (d) C. B. Singh, V. Kavala, A. K. Samal and B. K. Patel,
Eur. J. Org. Chem., 2007, 1369–1377; (e) M. H. S. Hamid, P. A. Slatford
and J. M. J. Williams, Adv. Synth. Catal., 2007, 349, 1555;
( f ) A. C. Bissember, R. J. Lundgren, S. E. Creutz, J. C. Peters and
G. C. Fu, Angew. Chem., Int. Ed., 2013, 52, 5129–5133.
5 G. Hughes, P. N. Devine, J. R. Naber, P. D. O’Shea, B. S. Foster,
D. J. McKay and R. P. Volante, Angew. Chem., 2007, 119, 1871–1874
(Angew. Chem., Int. Ed., 2007, 46, 1839–1842).
6 (a) J. P. Wolfe, H. Tomori, J. P. Sadighi, J. Yin and S. L. Buchwald,
J. Org. Chem., 2000, 65, 1158; (b) S. Shekhar, P. Ryberg, J. F. Hartwig,
J. S. Mathew, D. G. Blackmond, E. R. Strieter and S. L. Buchwald,
J. Am. Chem. Soc., 2006, 128, 3584; (c) O. Navarro, N. Marion, J. Mei
and S. P. Nolan, Chem. – Eur. J., 2006, 12, 5142.
16
97.0
17
18c
a
86.6(84.5)
73.0
Reaction conditions: 1 mmol nitrile, 1.1 mmol secondary amine,
0.005 mmol Pt NWs, 100 1C, water (1.5 mL), 1,4-dioxane (0.5 mL), 1 bar
H2 pressure for 24 h. GC yield. 2 mmol nitrile, 1 mmol piperazine. The
values in the parentheses are the yields of the isolated products.
b
c
11112 | Chem. Commun., 2014, 50, 11110--11113
This journal is ©The Royal Society of Chemistry 2014

View Article Online
Communication
ChemComm
7 (a) K. C. Hultzsch, D. V. Gribkov and F. Hampel, J. Organomet.
Chem., 2005, 690, 4441–4452; (b) A. M. Johns, M. Utsunomiya,
C. D. Incarvito and J. F. Hartwig, J. Am. Chem. Soc., 2006,
17, 14283; (b) F. Q. Qi, L. Hu, S. L. Lu, X. Q. Cao and H. W. Gu, Chem.
Commun., 2012, 48, 9631–9633; (c) L. Y. Shi, L. Hu, J. Q. Wang, X. Q. Cao
and H. W. Gu, Org. Lett., 2012, 14, 1876–1879.
128, 1828; (c) B. D. Stubbert and T. J. Marks, J. Am. Chem. Soc., 12 S. L. Lu, J. Q. Wang, X. Q. Cao, X. M. Li and H. W. Gu, Chem.
2007, 129, 4253–4271. Commun., 2014, 50, 3512–3515.
8 (a) J. L. He, J. W. Kim, K. Yamaguchi and N. Mizuno, Angew. Chem., 13 J. Shares, J. Yehl, A. Kowalsick, P. Byers and M. P. Haaf, Tetrahedron
2009, 121, 10072–10076 (Angew. Chem., Int. Ed., 2009, 48, Lett., 2012, 53, 4426–4428.
9889–9893); (b) K. Yamaguchi, J. L. He, T. Oishi and N. Mizuno, 14 (a) H. Sajiki, T. Ikawa and K. Hirota, Org. Lett., 2004, 6, 4977–4980;
Chem. – Eur. J., 2010, 16, 7199–7207.
(b) R. Reguillo, M. Grellier, N. Vautravers, L. Vendier and S. Sabo-
Etienne, J. Am. Chem. Soc., 2010, 132, 7854–7855; (c) D. Srimani,
M. Feller, Y. Ben-David and D. Milstein, Chem. Commun., 2012, 48,
11853–11855.
9 X. Liu, L. He, Y. M. Liu and Y. Cao, Acc. Chem. Res., 2014, 47, 793–804.
10 L. He, Y. Qian, R. S. Ding, Y. M. Liu, H. Y. He, K. N. Fan and Y. Cao,
ChemSusChem, 2012, 5, 621–624.
11 (a) L. Hu, X. Q. Cao, D. H. Ge, H. Y. Hong, Z. Q. Guo, L. Chen, X. H. Sun, 15 S. K. Sharma, J. Lynch, A. M. Sobolewska, P. Plucinski, R. J. Watsonc
J. X. Tang, J. W. Zheng, J. M. Lu and H. W. Gu, Chem. – Eur. J., 2011,
and J. M. J. Williams, Catal. Sci. Technol., 2013, 3, 85–88.
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun., 2014, 50, 11110--11113 | 11113