Re-entry of tin in N-alkylation: First example of a homogeneous heterobimetallic Pd-Sn catalyst for base and additive free alkylation of amine and surrogates with alcohol

Article abstract of DOI:10.1016/j.tetlet.2016.05.018

The N-alkylation of amines, and amides with benzyl alcohols is catalyzed by bimetallic catalyst [Pd(COD)(SnCl₃)Cl] in o-xylene. The reaction does not require additional base, additive or ligand, and is insensitive toward air and moisture and involves minimal work-up. These features make the reaction attractive, simple, and practical.

Full text of DOI:10.1016/j.tetlet.2016.05.018

Accepted Manuscript
Re-entry of Tin in N-alkylation: First Example of a Homogeneous Heterobi-
metallic Pd-Sn Catalyst for Base and Additive Free alkylation of Amine and
Surrogates with Alcohol
Anuradha Mohanty, Sujit Roy
PII:
S0040-4039(16)30531-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.05.018
TETL 47636
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
10 April 2016
3 May 2016
4 May 2016
Please cite this article as: Mohanty, A., Roy, S., Re-entry of Tin in N-alkylation: First Example of a Homogeneous
Heterobimetallic Pd-Sn Catalyst for Base and Additive Free alkylation of Amine and Surrogates with Alcohol,
Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.05.018
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Re-entry of Tin in N-alkylation: First Example of
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for Base and Additive Free alkylation of Amine
and Surrogates with Alcohol
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Anuradha Mohanty and Sujit Roy*
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1
Tetrahedron Letters
Re-entry of Tin in N-alkylation: First Example of a Homogeneous Heterobimetallic
Pd-Sn Catalyst for Base and Additive Free alkylation of Amine and Surrogates with
Alcohol
Anuradha Mohanty and Sujit Roy*
aOrganometallics & Catalysis Laboratory, School of Basic Sciences, Indian Institute of Technology, Bhubaneswar 751013, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The N-alkylation of amines, and amides with benzyl alcohols is catalyzed by bimetallic catalyst
[Pd(COD)(SnCl3)Cl] in o-xylene. The reaction does not require additional base, additive or
ligand, and is insensitive towards air and moisture and involves minimal work-up. These
features make the reaction attractive, simple and practical
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
N-alkylation
Palladium
Tin
Amine
Alcohol
Amines find widespread application in both the bulk and fine
chemical industries as basic intermediates, additives, dyes, and
agrochemicals, as well as in the pharmaceutical industry.1 The
development of simple methods for the selective formation of C-
N bonds is therefore of great importance. The best known
method for the alkylation of amines is their nucleophilic
substitution reaction with haloalkanes.2 However, this method
can be problematic due to over alkylation and toxic nature of
many alkyl halides and related alkyl agents and also produce
large amount of inorganic salt. The so-called “borrowing
hydrogen methodology”3 or “hydrogen auto transfer reaction”4
has aroused great interest in recent years and is an excellent
protocol for the selective alkylation of amines using simple,
nontoxic alcohols.5 The use of alcohols as alkylating agents make
the process relatively greener since the by-product is only water.
In past few years many homogenous transition metal complexes
such as ruthenium, iridium, rhodium, platinum, gold, nickel,
copper, and iron catalysts are used for the synthesis of N-
alkylation of amines with alcohols.6-15 However these catalysts
require the use of co-reagents such as a base, a promoter or an
additive. While an additive free N-alkylation strategy in the
homogeneous regime is yet to emerge, a few heterogeneous
nobel-metal catalysts (Pd, Ru, Ag, Au, and Pt)16-20 have been
reported. Yet many of these catalysts require high pressure (5 atm
of N2), H2 atmosphere or co-catalyst/support. We presume that
development of an efficient catalyst for direct N-alkylation will
be rewarding.
carbon-carbon bond-forming cross couplings.22 In 1994,
Buchwald and Hartwig independently reported the catalytic
amination reactions of aryl halide with palladium complexes with
Tin amide.23 They used ex-situ or in-situ generated tin amide in
stoichiometric amount. Due to the toxicity of tin amides and
related disposal problems, alternative routes were explored,
which led to the development of Buchwald-Hartwig amination in
the absence of tin reagent, but utilizing stoichiometric amount of
strong bases such as LiN(SiMe3)2, NaO-t-Bu and Cs2CO3.
Use of an alcohol instead of a halide in the N-alkylation of
amines has been attempted by various groups. In this regard
recent reports on the use of benzylic and aliphatic primary
alcohols as alkylating agent by homogenous16e-f or
heterogeneous16a-d palladium based catalyst are noteworthy. In
continuation of our success with bimetallic catalysis for carbon–
carbon bond formation,24 here we report a homogenous
heterobimetallic ‘Pd–Sn’ catalyst which promotes the C-N bond
formation through N-alkylation of anilines with alcohol under
base and additive free condition.
The N-alkylation of aniline with benzyl alcohol in the absence
of base and additive was explored using various Lewis acids,
monometallic salts, and bimetallic complexes as catalysts. In
model studies, we examined the reaction of aniline 1 (0.25 mmol)
º
with benzyl alcohol 2 (0.25 mmol) at 140 C for 24h leading to
the formation of N-benzyl aniline 3 as the desired product
varying the solvents and catalysts (3 mol%) (table 1). To our
delight,
the
heterobimetallic
catalyst
namely
[Pd
Thirty years ago Migita and co-workers noted that palladium
compounds can catalyze the regiospecific N-alkylation from aryl
halides and stoichiometric tin amides.21 This hetero cross-
coupling is remarkable, considering its relationship to Stille type
(COD)(SnCl3)Cl] showed excellent catalytic efficiency in o-
xylene as solvent under reflux giving rise to the desired product 3
(table 1, entry 9). The reaction did not require exclusion of air or

2
Tetrahedron Letters
moisture (entry 10). The distinct importance of the bimetallic
The condensation reaction of o-substituted (–NH2 or –SH or –
OH) anilines with aldehydes is the most commonly used method
for the synthesis of benzazoles. The synthesis of benzazoles
directly from alcohols is also reported. Interestingly we found
that our catalyst also showed good efficiency for the synthesis of
benzazoles from alcohols. In order to explore the scope of the
present method, the reactions of o-substituted (–NH2 or –SH or –
OH) anilines were explored with a variety of alcohols (table 3).
The reaction of o-phenylenediamine with benzyl alcohol and 4-
methyl benzyl alcohol proceeded smoothly to give the desired
product in high yield (table 3, entries 1, 2). Reaction of
substituted benzyl alcohols with 2-aminothiophenol afforded the
desired 2-substituted benzothiazoles in excellent yields (table 3,
entry 5, 6). In the case of benzyl alcohol (table 3, entry 5) and 4-
methyl benzyl alcohol (table 3, entry 6) good yields of the
coupling product were observed. The present protocol was also
applied for the synthesis of 2-phenylbenzoxazole from 2-
aminophenol and benzyl alcohol (table 3, entry 3) or 4-methyl
benzyl alcohol (table 3, entry 4).
catalyst may be understood from the fact that individually
[Pd(COD)Cl2] was inactive (entry 5), while SnCl2 (entry 2) and
the other bimetallic ‘Pd–Sn’ catalyst (table 1, entry 8) showed
poor reactivity. Under similar reaction condition, catalysts such
as AlCl3, FeCl3, PdCl2, Pd(OAc)2 were also poorly efficient (table
1, entries 1-5). It may be noted that heterobimetallic Pd-Sn
catalyst generated in-situ from [Pd(COD)Cl2] with SnCl2 was
equally efficient but a mere combination of PdCl2 with SnCl2 was
not so (entries 6, 7). Furthermore toluene, dichloroethane,
acetonitrile and water as solvents were ineffective (entries 11-
14).
Table 1. Catalyst Screening and Optimization
Converstion
Yield of 3
#
Catalyst
Solvent
While mechanistic explorations are underway, taking cue
from the “borrowing hydrogen methodologies”, it may be
anticipated that the present process undergoes a three-step
pathway involving alcohol oxidation, imine formation, followed
by imine hydrogenation. In independent experiments (Scheme 1)
we found that in the absence of amine, the oxidation of benzyl
alcohol to benzaldehyde takes place in presence of stoichiometric
Pd-Sn complex, confirming the first step. With catalytic Pd-Sn
complex and in presence of amine, when the reaction was carried
out at low temperature (110 °C) or stopped in between, imine
was observed as the major product, which confirms the second
step. The hydrogenation of the imine afforded the corresponding
amine under the present reaction conditions, which further
confirmed the third step.
(%)b
<5
<10
<20
<5
<10
0
(%)c
1
AlCl3
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
Toluene
DCE
-
2
FeCl3
-
3
SnCl2
15
-
4
PdCl2
5
Pd(OAC)2
-
6
PdCl2(PPh3)2
PdCl2(COD)
PdCl2+SnCl2
PdCl2(COD)+ SnCl2
Pd(PPh3)2ClSnCl3
Pd(COD)ClSnCl3
Pd(COD)ClSnCl3
Pd(COD)ClSnCl3
Pd(COD)ClSnCl3
Pd(COD)ClSnCl3
Pd(COD)ClSnCl3
0
5
0
0
6
70
60
87
20
90
88
-
7
95
8
<30
>98
95
9
a)
10d
11
12
13
<10
0
0
water
0
0
14
acetonitrile
0
0
a
b)
Reaction condition: Aniline (0.25 mmol), benzyl alcohol (0.25 mmol),
b
catalyst (3 mol%) in 3 mL of solvent at reflux temperature for 24 h; From
1H NMR; c Isolated yield of pure product; d argon atmosphere
Having established the optimum condition, we tested the
scope and limitation of the N-alkylation reaction using various
amine and surrogates with other benzyl alcohols. The C-N
coupling between aniline 1 and substituted benzyl alcohols 2
afforded the desired product 3 in moderate to excellent yields
(table 2). For example with alcohol variation, 88–94% yields of
desired product 3b, 3c, and 3d were obtained from 3-methyl
benzyl alcohol, 3-methoxy benzyl alcohol, and 2-methoxy benzyl
alcohol as the alkylation reagents (table 2, entries 2-4). On the
other hand, with alcohols bearing halogen substituent, the
corresponding products 3e-3h were isolated in 60-75% yields.
Amines such as 2, 3, 5-trimethyl aniline, 4-floroaniline could also
react with benzyl alcohol to afford the N-benzyl amine 3k and 3l
in >85% yields (entries 11, 12). The alkylation of carboxamide
with alcohol was further explored. With benzamide as the
starting material, the coupling reactions could be realized by
using benzyl alcohol (entry 10). To our delight, it was also
observed that Pd-Sn catalyst was also active for the N-alkylation
of sulfonamides. Sulfonamides such as p-toluene sulfonamide
and benzene sulfonamide reacted with benzyl alcohol to generate
the corresponding N-alkylated products 3m and 3n in excellent
yields (entries 13, 14).
Scheme-1: (a) oxidation of alcohol; (b) hydrogenation of
imine
We therefore propose that [Pd(COD)(SnCl3)Cl] promotes the
oxidation of the alcohols to aldehydes, followed by the formation
of imine and finally to N-alkylated product. A tentative outline of
the mechanistic proposal is presented in Scheme 2. This involves
initial coordination of alcohol to Pd-Sn catalyst followed by the
formation of the hydridopalladium(II) species along with the
aldehyde. The imine formed in situ from aldehyde and amine is
activated by the bimetallic core in Pd-Sn catalyst. We have
earlier shown that the Sn(IV) center in TM-Sn system is a hard
Lewis acidic center.24 Thus coordination of the hard nitrogen to
tin(IV) is expected. Formation of the final organic product is a
result of internal rearrangement as shown. The detailed
mechanistic description, in particular the role of the two metals in
the bimetallic catalyst must await further studies.

3
Table 2. Pd–Sn catalyzed N-Alkylation of Anilines with Benzylic Alcohols: Substrate Scope a
#
A niline
Alcohol
Product
Yield(%)b
1
9 0
2 a
1 a
3 a
3 b
2
3
8 8
1 a
1 a
2 b
9 4
2c
3 c
4
5
9 0
7 8
1 a
1 a
2 d
3 d
2 e
2 f
3 e
6
6 5
1 a
1 a
3 f
7
8
7 0
6 5
2g
3 g
1 a
1 a
2 h
3 h
3 i
9
7 8
6 8
2 i
1 0
2 a
1 b
3 j

4
Tetrahedron
1 1
8 4
2 a
2 a
1 c
3 k
1 2
1 3
6 0
7 5
1 d
3 l
2 a
1 e
3 m
1 4
7 0
2 a
1 f
3 n
a Unless otherwise mentioned, reaction conditions are as follows: 1 (0.25 mmol), 2 (0.25 mmol), catalyst (3 mol%); b refers to isolated yield
Table 3: N-Alkylation of O-substituted anilines with benzyl alcohols a,b
Entry
Aniline
Alcohol
Product
Yield(%)
1
80
2a
4a
5aa
2
85
2b
4a
4b
4b
4c
4c
5ab
5ba
3
4
5
6
70
72
75
73
2a
2b
5bb
5ca
2a
2b
5cb
a All the reactions were carried out with o-substituted aniline (0.25 mmole), benzyl alcohol (0.25 mmole) and catalyst (3 mol%) in 2mL o-xylene at 140 ºC

5
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Acknowledgments
Financial support from DST (to SR), and UGC (Fellowship to
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Highlights
 N-alkylation of amines and amides is achieved with benzyl alcohols using
[Pd(COD)(SnCl3)Cl] as a heterobimetallic catalyst.


The major advantage of the protocol is that it does not require any co-catalyst, base,
additive, or external ligand.
The catalyst is insensitive to air and moisture.