Reductive N-alkylation of aromatic amines and nitro compounds with nitriles using polymethylhydrosiloxane

Article abstract of DOI:10.1016/j.tetlet.2007.02.050

The potential utility of polymethylhydrosiloxane (PMHS) as a reducing agent for reductive N-alkylation of aromatic amines and nitro compounds using nitriles as an alkylating agent and Pd(OH)₂/C as a catalyst is described. The application of this method for the synthesis of several heterocyclic compounds is also reported.

Full text of DOI:10.1016/j.tetlet.2007.02.050

Tetrahedron Letters 48 (2007) 2765–2768
Reductive N-alkylation of aromatic amines and nitro
compounds with nitriles using polymethylhydrosiloxaneI
Ch. Raji Reddy,* K. Vijeender, P. Bibhuti Bhusan, P. Phani Madhavi
and S. Chandrasekhar
Organic Division-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 24 November 2006; revised 31 January 2007; accepted 7 February 2007
Available online 15 February 2007
Abstract—The potential utility of polymethylhydrosiloxane (PMHS) as a reducing agent for reductive N-alkylation of aromatic
amines and nitro compounds using nitriles as an alkylating agent and Pd(OH)2/C as a catalyst is described. The application of this
method for the synthesis of several heterocyclic compounds is also reported.
Ó 2007 Elsevier Ltd. All rights reserved.
The development of new reduction procedures using
safe and practically useful reducing agents is of great
importance. Existing reducing agents such as H2 (gas),
NaBH4, LiAlH4 and DIBAL-H, although efficient in
producing good yields of the desired products, require
precautions in handling. The title reagent, namely, poly-
methylhydrosiloxane (PMHS) is being investigated as a
safe, easy-to-handle, cheap and environmentally benign
reagent for the reduction of organic functional groups.1
This reagent is very inert making it safe-to-handle, but
in the presence of an activator, it acts as an excellent
reducing agent. In continuation of our interest in
exploring the potential use of PMHS as a reducing
agent,2 herein we report a new and efficient method
for the reductive mono N-alkylation of nitro
compounds and amines with nitriles as an alkylating
agent using PMHS in the presence of Pd(OH)2/C as a
catalyst (Scheme 1).
H
N
NX2
PMHS-20% Pd(OH)2/C
EtOH, rt
R
NCCH2R
X= H, O
R= H, CO2Et, CONH2
Scheme 1.
agent with hydrogen (gas) as a reductant in the presence
of different types of catalysts, but only a few examples of
selective mono N-alkylation have been reported.7 Some
of these procedures are limited to only a few substrates,
require large quantities of amine and elevated hydrogen
pressure and/or higher temperature or longer reaction
times. Recently, Hudson et al. have used ammonium
formate as
a reducing agent for this reductive
alkylation.8
Traditional methods for this transformation are base
mediated N-alkylation using toxic and corrosive alkyl-
ating agents,3 reductive amination,4 alkylative amination5
and other alkylation methods,6 but most of these suffer
from disadvantages. There are reports on reductive
alkylation of amines using nitriles as the alkylating
Initially, aniline 1a and acetonitrile were reacted in the
presence of polymethylhydrosiloxane and 10% Pd/C in
ethanol as solvent at room temperature and the forma-
tion of N-ethylaniline 2a was observed in 82% yield
(entry 1). A similar reaction in the presence of 20%
Pd(OH)2/C (20 mg/mmol)9 gave the mono N-alkylated
product in 86% yield (entry 2). To rationalize this find-
ing, various anilines were alkylated with acetonitrile in
the presence of PMHS and 20% Pd(OH)2/C in ethanol
to give the corresponding N-ethyl products in reason-
ably good yields (entries 3–5). The debrominated
product was isolated in the case of entry 5. Alkylation
of anilines 1a and 1d were also studied using ethyl
Keywords: Alkylation; Amines; Nitro compounds; Nitriles; Poly-
methylhydrosiloxane.
q IICT Communication No. 061019.
*
Corresponding author. Tel.: +91 40 27193128; fax: +91 40
27160512; e-mail: rajireddy@iict.res.in
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.02.050

2766
Ch. R. Reddy et al. / Tetrahedron Letters 48 (2007) 2765–2768
Table 1. Reductive N-alkylation of aromatic amines and nitro compounds
Entry
1
Substrate
Nitrile
Time (h)
4
Producta
Yieldb (%)
82c
H
N
NH2
NH2
CH3CN
1a
1a
2a
2a
H
N
2
3
CH3CN
CH3CN
2
4
86
64
NH2
HN
2b
1b
H
N
MeO
NH2
MeO
4
5
CH3CN
CH3CN
5
75
88
2c
2a
1c
OMe
OMe
H
N
NH2
0.5
1d
Br
H
N
NH2
NH2
OEt
OEt
NH2
NH2
OEt
NC
O
6
7
3
68
75
76
74
72
73
69
1a
1d
2d
2d
O
O
O
O
H
N
OEt
NC
O
2
Br
H
N
NH2
NH2
NH2
2e
NC
O
8
4
1a
1d
H
N
NH2
2e
NC
O
9
3
Br
H
N
NO2
NO2
10
11
12
CH3CN
CH3CN
0.5
1
2a
2f
1e
1f
H
N
H3C
H3C
H3C
H
N
NO2
NO2
OEt
OEt
NC
O
1.5
1f
1f
O
O
2g
H3C
H
N
NH2
NH2
NC
O
13
14
2
65
63
2h
H3C
H3C
H
N
NH2
CH3CN
0.5
1g
2i
F
F
a All the products were characterized by 1H NMR, mass and IR spectroscopy.
b Isolated yields.
c 10% Pd/C was used as the catalyst.

Ch. R. Reddy et al. / Tetrahedron Letters 48 (2007) 2765–2768
2767
cyanoacetate and cyanoacetamide to afford the products
2d and 2e in good yields without affecting the ester and
amide functionalities (entries 6–9). Debromination of 1d
(entries 5, 7 and 9) is, however, noted as a limitation. We
next turned our attention to alkylation of nitro com-
pounds. Accordingly, nitrobenzene 1e was treated with
acetonitrile in the presence of polymethylhydrosiloxane
and 20% Pd(OH)2/C in ethanol at room temperature
to give N-ethylaniline 2a in 72% yield. Similarly, p-nitro-
toluene was alkylated with acetonitrile, ethyl cyano-
acetate and cyano acetamide under similar conditions
to yield 2f, 2g and 2h (Table 1, entries 11–13). Substrate
1g having an electron-withdrawing substituent also
underwent reaction with the present reagent system to
provide the corresponding mono alkylated product 2i
in 63% yield (Table 1, entry 14). An attempt was made
to reuse the catalyst, but was unsuccessful.
General experimental procedure: To a stirred solution of
substrate (1 mmol) in ethanol (5 mL) was added the
nitrile (1 mmol), polymethylhydrosiloxane (180 mg,
3 mmol) and 20% Pd(OH)2/C (ꢀ20 mg) and the reaction
mixture was stirred at room temperature for the given
time (see Tables 1 and 2). After completion of the
reaction, the mixture was filtered through Celite and
the filtrate was evaporated in vacuo. The residue was
purified by column chromatography on silica gel to give
the corresponding N-alkylated products.10
Acknowledgement
K.V., P.B.B. and P.P.M. are thankful to the CSIR, New
Delhi, for fellowships.
In order to demonstrate the scope of this method, we
have prepared several starting materials possessing nitro
and cyano groups and studied the intramolecular reduc-
tive N-alkylation reaction. Accordingly, compound 3a
was subjected to PMHS in the presence of 20%
Pd(OH)2/C in ethanol at room temperature to give the
corresponding 3,4-dihydro-2H-1,4-benzoxazine (4a) in
73% yield. Similarly, 3b gave the corresponding benz-
oxazine 4b in 67% yield. When compound 3c was
subjected to the present reductive N-alkylation
conditions, 3-substituted-1,2-dihydroquinoline 4c was
obtained in 72% yield.
References and notes
1. For an exhaustive review on PMHS, see: (a) Lawrence, N.
J.; Drew, M. D.; Bushell, S. M. J. Chem. Soc., Perkin
Trans. 1 1999, 3381–3391; and also see: (b) Senapati, K. K.
Synlett 2005, 1960–1961.
2. (a) Chandrasekhar, S.; Chandrashekar, G.; Vijeender, K.;
Reddy, M. S. Tetrahedron Lett. 2006, 47, 3475–3478; (b)
Chandrasekhar, S.; Chandrashekar, G.; Babu, B. N.;
Vijeender, K.; Venkatram Reddy, K. Tetrahedron Lett.
2004, 45, 5497–5499; (c) Chandrasekhar, S.; Babu, B. N.;
Ahmed, Md.; Reddy, M. V.; Srihari, P.; Jagadeesh, B.;
Prabhakar, A. Synlett 2004, 1303–1305; (d) Chandra-
sekhar, S.; Reddy, Ch. R.; Babu, B. N. Tetrahedron Lett.
2003, 44, 2057–2059; (e) Chandrasekhar, S.; Reddy, Ch.
R.; Babu, B. N. J. Org. Chem. 2002, 67, 9080–9082.
3. Larock, R. C. Comprehensive Organic Transformations,
2nd ed.; Wiley-VCH: New York, 1999; pp 789–792.
4. Larock, R. C. Comprehensive Organic Transformations,
2nd ed.; Wiley-VCH: New York, 1999; pp 835–846.
5. (a) Alvaro, G.; Savoia, D. Synlett 2002, 651–673; (b)
Bloch, R. Chem. Rev. 1998, 98, 1407–1438; (c) Enders, D.;
Reinhold, U. Tetrahedron: Asymmetry 1997, 8, 1895–
1946.
6. Ono, Y. Pure Appl. Chem. 1996, 68, 367–375.
7. (a) Chen, W.; Liu, B.; Yang, C.; Xie, Y. Tetrahedron Lett.
2006, 47, 7191–7193; (b) Sajiki, H.; Ikawa, T.; Hirota, K.
Org. Lett. 2004, 6, 4977–4980; (c) Fujita, K.-i.; Li, Z.;
Ozeki, N.; Yamaguchi, R. Tetrahedron Lett. 2003, 44,
2687–2690; (d) Vink, M. K. S.; Schortinghuis, C. A.;
Mackova-Zabelinskaja, A.; Fechter, M.; Pochaluer, P.;
Marianne, A.; Castelijns, C. F.; van Maarseveen, J. H.;
Hiemstra, H.; Griengl, H.; Schoemaker, H. E.; Rutjes, F.
P. J. T. Adv. Synth. Catal. 2003, 345, 483–487; (e) Gangjee,
A.; Adair, O. O.; Queener, S. F. J. Med. Chem. 2003, 46,
5074–5082; (f) Blackburn, L.; Taylor, R. J. K. Org. Lett.
2001, 3, 1637–1639; (g) Zhang, J.; Chang, H.-M.; Kane, R.
R. Synlett 2001, 643–645; (h) Selva, M.; Tundo, P.;
Perosa, A. J. Org. Chem. 2001, 66, 677–680, and references
cited therein.
In conclusion, we have demonstrated that PMHS is a
versatile reducing agent for reductive mono N-alkyl-
ation of aromatic amines and nitro compounds with
nitriles as alkylating agents. The applicability of this
method for the synthesis of 3,4-dihydro-2H-1,4-benzox-
azines and dihydroquinolines is also described and fur-
ther applications towards expanding the substrate
scope are underway. We believe that the reagent system
described herein may find wide applicability in organic
synthesis due to its efficiency, economy, simplicity and
safety.
Table 2. Intramolecular reductive N-alkylation
Entry Substrate
Time Producta
(h)
Yieldb
(%)
O
O
CN
1
0.5
73
67
72
N
H
4a
4b
NO2
3a
O
CN
O
2
3
0.5
NO2
N
3b
H
CH3
CH3
8. Nacario, R.; Kotakonda, S.; Fouchard, D. M. D.;
Tillekeratne, L. M. V.; Hudson, R. A. Org. Lett. 2005,
7, 471–474.
CO2Et
CO2Et
9. Reactions using 20% Pd(OH)2/C in smaller quantities
(10 mg or 15 mg/mmol) did not proceed to completion
even after longer reaction times.
1
CN
NO2
N
H
4c
3c
a All the products were characterized by 1H NMR, mass and IR
spectroscopy.
b Isolated yields.
10. Spectral data: Compound 2g: 1H NMR (CDCl3,
300 MHz): d 6.96–6.87 (m, 2H), 6.53–6.46 (m, 2H), 4.14
(q, J = 7.2 Hz, 2H), 3.39 (t, J = 6.4 Hz, 2H), 2.55 (t,

2768
Ch. R. Reddy et al. / Tetrahedron Letters 48 (2007) 2765–2768
J = 6.0 Hz, 2H), 2.22 (s, 3H), 1.26 (t, J = 7.2 Hz, 3H); IR
1121 cmÀ1; ESI-MS: m/z 201 (M+Na)+; HRMS (EI): m/z
calcd for C10H14N2ONa 201.2207 [M+Na]+, found
201.2201. Compound 4b: 1H NMR (CDCl3, 300 MHz):
d 6.61–6.48 (m, 3H), 4.18 (t, J = 4.5 Hz, 2H), 3.44 (t,
J = 4.5 Hz, 2H), 2.08 (s, 3H); IR (KBr): m 3410, 2924,
1485, 1281, 765 cmÀ1; ESI-MS: m/z 150 (M+H)+; HRMS
(EI): m/z calcd for C9H12NO 150.1977 [M+H]+, found
150.1972.
(KBr): m 3415, 1729, 1602, 1518, 1281, 1182 cmÀ1; ESI-
MS: m/z 230 (M+Na)+; HRMS (EI): m/z calcd for
C12H17NO2Na 230.2586 [M+Na]+, found 230.2591. Com-
1
pound 2h: H NMR (CDCl3, 200 MHz): d 6.95–6.84 (m,
2H), 6.54–6.48 (m, 2H), 5.75 (br s, 1H), 5.65 (br s, 1H),
3.41 (t, J = 5.5 Hz, 2H), 2.47 (t, J = 5.9 Hz, 2H), 2.22 (s,
3H); IR (KBr): m 3353, 3347, 3195, 1666, 1518, 1409,