Cyclometalated palladium pre-catalyst for N-alkylation of amines using alcohols and regioselective alkylation of sulfanilamide using aryl alcohols

Article abstract of DOI:10.1016/j.tet.2017.03.001

Simple pyrazole based palladacycle-phosphine with a high turnover has been developed and applied for the N-alkylation of amines and sulfanilamide using alcohols as substrates by hydrogen borrowing strategy. N-alkylation of primary and secondary amines resulted in high isolated yields at 100–130 °C, under solvent free conditions. More challenging secondary aliphatic as well as aromatic alcohols were also successfully utilized as alkylating agents under similar reaction conditions. The turn over number reached up to 43000 for N-benzylation of aniline using benzyl alcohol. Notably, regioselective N-alkylation of 2-aminobenzothiazole and 4-aminobenzenesulfonamide to the corresponding 2-N-(alkylamino)azoles and 4-amino-(N-alkyl)benzenesulfonamides using alcohols as alkylating agents have been achieved using our new pre-catalyst-phosphine system.

Full text of DOI:10.1016/j.tet.2017.03.001

Accepted Manuscript
Cyclometalated palladium pre-catalyst for N-alkylation of amines using alcohols and
regioselective alkylation of sulfanilamide using aryl alcohols
Ramesh Mamidala, Vanga Mukundam, Kunchala Dhanunjayarao, Krishnan
Venkatasubbaiah
PII:
S0040-4020(17)30215-6
10.1016/j.tet.2017.03.001
TET 28507
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 24 November 2016
Revised Date: 27 February 2017
Accepted Date: 1 March 2017
Please cite this article as: Mamidala R, Mukundam V, Dhanunjayarao K, Venkatasubbaiah K,
Cyclometalated palladium pre-catalyst for N-alkylation of amines using alcohols and regioselective
alkylation of sulfanilamide using aryl alcohols, Tetrahedron (2017), doi: 10.1016/j.tet.2017.03.001.
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Cyclometalated Palladium Pre-catalyst for
N-alkylation of Amines using Alcohols and
Regioselective Alkylation of Sulfanilamide
using Aryl Alcohols
Leave this area blank for abstract info.
Ramesh Mamidala, Vanga Mukundam, Kunchala Dhanunjayarao and Krishnan Venkatasubbaiah*
School of Chemical Sciences, National Institute of Science Education and Research (NISER), HBNI,
Bhubaneswar-752050, Orissa (India).

1
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Tetrahedron
journal homepage: www.elsevier.com
Cyclometalated Palladium Pre-catalyst for N-alkylation of Amines using
Alcohols and Regioselective Alkylation of Sulfanilamide using Aryl Alcohols
Ramesh Mamidala, Vanga Mukundam, Kunchala Dhanunjayarao and Krishnan Venkatasubbaiah*
School of Chemical Sciences,National Institute of Science Education and Research (NISER), HBNI, Bhubaneswar-752050, Orissa (India). Fax: (+) 091-674-
2494165, E-mail: krishv@niser.ac.in
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Simple pyrazole based palladacycle-phosphine with a high turnover has been developed and
applied for the N-alkylation of amines and sulfanilamide using alcohols as substrates by
hydrogen borrowing strategy. N-alkylation of primary and secondary amines resulted in high
isolated yields at 100-130 C, under solvent free conditions. More challenging secondary
aliphatic as well as aromatic alcohols were also successfully utilized as alkylating agents under
similar reaction conditions. The turn over number reached up to 43000 for N-benzylation of
aniline using benzyl alcohol. Notably, regioselective N-alkylation of 2-aminobenzothiazole and
4-aminobenzenesulfonamide to the corresponding 2-N-(alkylamino)azoles and 4-amino-(N-
alkyl)benzenesulfonamides using alcohols as alkylating agents have been achieved using our
new pre-catalyst-phosphine system.
Available online
Keywords:
Palladacycle
N-alkylation of amines
Cyclometalated Palladium
2009 Elsevier Ltd. All rights reserved.
in toluene as the solvent. Using benzylic alcohols as the
alkylating agent, up to 99% yield of the alkylated amine was
1. Introduction
reported. However, this system was not active under the
optimized conditions when aliphatic or secondary alcohols were
used as the alkylating agents. In 2013, Seayad and co-workers5c
reported (Scheme 2) PdCl2 as a catalyst in the presence of dppe
or Xantphos(t-Bu) as the ligand for the N-alkylation of primary
and cyclic secondary amines, with TON up to 900 using neat
reagents (no solvent) at temperatures of 90-150 C. It is
noteworthy to mention that an improved TON of about 46000
was reported using supported-palladium NiXantphos complex.5b
Keeping these reported results in mind we focused our efforts in
developing more active homogenous catalysts for the N-
alkylation of amines using alcohols.
Metal catalyzed carbon-carbon and carbon-heteroatom reactions
are powerful tools that are widely utilized by the synthetic
chemist in a great number of syntheses.1 Key to the success of
such catalytic reactions is the development of new
methodologies, ligands and (or) pre-catalysts. N-alkylation of
amines is an important class of reactions2 applied in the synthesis
of pharmaceuticals, pesticides and functional materials.
Traditionally, reactive alkyl halides have been used for the
production of N-alkylated amines which often produces over-
alkylated products. This method not only reduces the overall
yield of the product but also produces stoichiometric amounts of
waste. On the other hand use of alcohols as alkylating reagents
has emerged as an interesting greener approach, owing to the fact
that it produces only water as a byproduct by using “hydrogen
2
borrowing” methodology . As alluded in the literature,2,5c the
R'
R'
poor electrophilic alcohols are activated to more active carbonyl
intermediates by temporary removal of hydrogen from the
alcohols. In the presence of amine the insitu formed carbonyl is
converted into imine, which upon hydrogenation forms the final
alkylated amine by transferring the borrowed hydrogen (Scheme
1).
R''
NH2
R
OH
R
O
Good
Poor
electrophile
electrophile
H
H
[M]
[M]
R'
R'
R''
R''
H2O
R
N
R
N
Various catalytic systems using different metals have been
developed and used for the N-alkylation of amines using
alcohols.2-7 However in comparison with the Ru3 and Ir4 based
catalysts, there are limited studies on the development of Pd-
based5 catalysts or pre-catalysts, especially homogeneous5c,5e pre-
catalysts for N-alkylation of amines using alcohols. Recently
Ramón and co-workers5e reported Pd(OAc)2 (1 mol %) in the
presence of 100 mol % of CsOH at temperatures of 130−150 °C
H
Scheme 1. C-N bond formation by hydrogen borrowing

2
Tetrahedron
ACCEPTED MANUSCRIPT
coefficients. The H atoms were placed at calculated positions and
were refined as riding atoms. Crystallographic data for the
structure of palladacycle-1 and compound 49 have been
deposited with the Cambridge Crystallographic Data Centre as
supplementary publication no. CCDC- 1446359, 1526743.
Copies of the data can be obtained free of charge on application
to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: (+44)
1223-336-033; email: deposit@ccdc.cam.ac.uk).
2.2 General procedure for N-alkylation of amines using benzyl
alcohol
An oven dried Schlenk tube was charged with amine (3.0 mmol),
alcohol (3.6 mmol),LiOH (1.5 mmol), palladacycle (6.0 x10-
3mmol, 0.20 mol %), P(2-Fur)3 (12.0 x10-3mmol, 0.40 mol %)
and activated 4 Å MS (100 mg) in argon atmosphere. The
o
reaction mixture was stirred at 100 C for 24 h. The reaction
mixture was cooled to room temperature, diluted with ethyl
acetate (10 mL), and washed with water followed by brine
solution. The organic phase was dried over anhydrous sodium
sulphate. After removal of the solvent, the crude was subjected to
column chromatography on silica gel using ethyl acetate and n-
hexane mixtures to afford the N-alkylated product.
Scheme 2. Palladium mediated N-alkylation of amines using
alcohols, a comparison
Palladacycles8 are the most promising and versatile catalysts (or)
pre-catalyst in carbon-carbon and carbon-heteroatom bond
forming reactions. Owing to their facile synthesis, easy handling
and possibility of tuning electronic and steric properties many
research groups have devoted their efforts in synthesizing new
palladacycles and studying their applications in catalysis, organic
synthesis, materials and medicinal chemistry. Among the
different types of palladacycles, pyrazole-based palladacycles are
scarcely studied8d for their applications towards catalysis. Grigg
and co-workers showed that pyrazole-based palladacycles could
effectively be used for C-C bond formation. In a recent study
we8e showed the synthesis of 1,3,5-triphenylpyrazole palladium
dimer and its catalytic activity towards Mizoroki-Heck and
Suzuki-Miyaura cross-coupling reactions. Although ample
reports exist for the dehydrogenation of alcohols,8c C-N and C-C
bond formations using alkyl or aryl halides as reagents and
palladacycles as catalyst or pre-catalyst,9 surprisingly to the best
of our knowledge none of the palladacycle based pre-catalysts
have been tested for the N-alkylation of amines and sulfanilamide
using alcohols as reagent. Herein, we report a new palladacycle
which is stable in air- and moisture and highly active towards N-
alkylation of amines and sulfanilamide.
2.3 General procedure for N-alkylation of amines using primary
and secondary alcohols
A similar protocol as mentioned for N-alkylation of amines using
benzyl alcohol was used. The quantities involved are as follows:
Amine (3.0 mmol), alcohol (6.0 mmol), LiOH (1.5 mmol), pre-
catalyst (1.5 X 10-2 mmol 0.50 mol %), P(2-Fur)3 (1.5 X 10-2
mmol, 1.00 mol%) and activated 4 Å MS (100 mg). The reaction
mixture was stirred at 120 – 130 oC for 24 - 48 h.
2.4 Procedure for N-alkylation of 2-aminobenzothiazole using
aryl alcohols
An oven dried Schlenk tube was charged with LiOH (1.5 mmol),
pre-catalyst (6 x 10-3 mmol, 0.20 mol %), P(2-Fur)3 (12 x 10-3
mmol, 0.40 mol%) and activated 4 Å MS (100 mg). The tube was
connected to a vacuum line under argon and purged three times.
To the reaction mixture, 2-aminobenzothiazole (3.0 mmol) and
alcohol (6.0 mmol) were added. The Schlenk tube was closed
o
with PTFE stopper and the reaction mixture was stirred at 100 C
for 24 h. At the end of the reaction time, the reaction mixture was
cooled to room temperature, diluted with methanol (5 mL), and
the tube was washed with methanol three more times (3x2 mL).
The methanol solution was concentrated under vacuum and the
crude was subjected to column chromatography on silica gel
using ethyl acetate and n-hexane mixtures to afford the N-
alkylated product.
2. Experimental
2.1 General
All reagents and solvents were obtained from commercial
sources. Solvents were purified according to standard procedures.
1H, 13C, and 19F spectra were recorded using Bruker 400 MHz
instrument. All 1H and 13C NMR spectra were referenced
internally to solvent signals and 19F NMR spectra, to ,,-
trifluorotoluene (0.05% in CDCl3;  = -63.73). High resolution
mass spectra (HRMS) were recorded with micro TOF-QII mass
spectrometer. Elemental analyses was carried out with a
VarioMICRO CHNS analyzer (IIT-Bhubaneswar). Single-crystal
X-ray diffraction data were collected at 296 K using, Mo-Kα
radiation (0.71073 Å). Crystallographic data for the palladacycle-
1 and compound 49 and details of X-ray diffraction experiments
and crystal structure refinements are given in Table S1. SADABS
absorption corrections were applied in both cases. The structures
were solved and refined with SHELX suite of programs. All non-
hydrogen atoms were refined with anisotropic displacement
2.5 Procedure for N-alkylation of sulfanilamide using aryl
alcohols
An oven dried Schlenk tube was charged with LiOH (1.5 mmol),
pre-catalyst (1.5 x 10-2 mmol), P(2-Fur)3 (3 x 10-2 mmol) and
activated 4 Å MS (100 mg). The tube was connected to a vacuum
line under argon and purged three times. To the reaction mixture,
sulfanilamide (3.0 mmol) and aryl alcohol (6.0 mmol) were
added. The Schlenk tube was closed with PTFE stopper and the
reaction mixture was stirred at 120 C for 24 h. At the end of the
reaction time, the reaction mixture was cooled to room
temperature, diluted with methanol (5 mL), and the tube was
washed with methanol three more times (3x 2 mL). The methanol
solution was concentrated under vacuum and the crude was

3
ACCEPTED MANUSCRIPT
subjected to flash column chromatography on silica gel using
ethyl acetate and n-hexane mixtures to afford the N-alkylated
product.
(100 MHz, CDCl3): δ = 180.6, 159.6, 146.6, 137.8, 134.6,
132.3, 131.7, 131.2, 130.1, 129.5, 129.1, 128.9, 128.8, 128.4,
128.0, 127.9, 127.9, 127.8, 125.1, 124.1, 122.2, 101.4, 24.3 ppm.
19F NMR (376 MHz, CDCl3):  = -60.2 ppm. HRMS (ESI):
calcd. for C46H31F6N4O2Pd2 {[M-OAc]+} : 998.0535, found :
998.0497. Elemental analysis calcd (%) for C48H36F6N4O4Pd2: C
54.41, H 3.42, N 5.29; found: C 54.30, H 3.29, N 5.22. IR
(KBr): (cm-1) = 3055 (m), 1593 (s), 1576 (s), 1505 (m), 1419
(m), 1316 (s), 1140 (s), 765 (s), 697 (m).
2.6 Procedure for gram scale reaction for N-benzylation of
aniline using benzyl alcohol
3. Results and discussion
A similar protocol as mentioned for N-alkylation of amines using
benzyl alcohol was used. The quantities involved are as follows:
Amine (1.0 g, 10.7 mmol), alcohol (12.8 mmol), LiOH (5.3
mmol), palladacycle (1.1 x 10-7mmol, 0.001 mol %), P(2-Fur)3
(2.2 x 10-7mmol, 0.002 mol %) and activated 4 Å MS (300 mg).
3.1 Synthesis and characterization of palladacycle
The palladium pre-catalyst (palladacycle (1)) was synthesized in
two steps from commercially available starting materials
according to literature reported method.8d,e The formation of the
o
The reaction mixture was stirred at 130 C for 48 h. Yield =1.75
g (89%).
pre-catalyst was confirmed by standard techniques like H, 13C
1
&19F NMR spectroscopy, HRMS and elemental analysis as well
as single crystal X-ray analysis (Figure 1, Table S1). It is
noteworthy to mention that the palladacycle (1) reported in this
study shows C-H bond activation on the 3-phenyl of the pyrazole
and not on the N-phenyl of the pyrazole as observed in our
previous studies.8d,11
2.7 Synthesis of 3, 5-diphenyl-1-(2-(trifluoromethyl) phenyl)-1H-
pyrazole10
1,3-Diphenylpropane-1,3-dione (2.54 g, 11.30 mmol) and (2-
(trifluoromethyl)phenyl) hydrazine (2.00 g, 11.30 mmol) were
taken in 100 mL round bottom flask. Then 15 mL of methanol
and 15 mL of acetic acid were added to the flask and the reaction
mixture was refluxed for 12 h. To the reaction mixture, saturated
sodium carbonate solution was added and the compound was
extracted using dichloromethane. The solvent was removed under
vacuum and the residue was purified by column chromatography
(n-hexane-ethyl acetate as eluent) to afford the product, 3,5-
diphenyl-1-(2-(trifluoromethyl)
phenyl)-1H-pyrazole.Yield:
o 1
3.14g (8.6 mmol, 76%). m.p: 109-110 C. H NMR (400 MHz,
CDCl3): δ = 7.92 (d, J = 8 Hz, ArH, 2H), 7.82 (t, J = 4 Hz, ArH,
1H), 7.55 (t, J = 4 Hz, ArH, 2H), 7.44 (t, J = 8 Hz, ArH, 2H),
7.35 (t, J = 8 Hz, ArH, 2H), 7.28-7.24 (m, ArH, 5H), 6.89 (s,
4Pz-H, 1H) ppm.13C NMR (100 MHz, CDCl3): δ = 152.2, 146.3,
138.3, 133.0, 132.6, 130.7, 129.9, 129.3, 128.8, 128.6, 128.4,
128.3, 128.2, 128.0, 128.0, 127.9, 127.9, 127.8, 126.1, 104.3
ppm. 19F NMR (376 MHz, CDCl3): δ = -60.81 (s) ppm. HRMS
(ESI): calcd. for C22H15F3N2 ([M+H]+) : 365.1260, found :
365.1273. Elemental analysis calcd (%) for C22H15F3N2 : C 72.52,
H 4.15, N 7.69; found: C 72.60, H 4.22, N 7.58. ; found: . IR
(KBr) :  (cm-1) = 3064 (m), 1501 (m), 1485 (m), 1465 (m), 1315
(s), 1154 (m), 1137 (s), 1113 (m), 761 (s), 596 (s).
Fig. 1. (left) Chemdraw representation of palladacyle (1) (right)
Molecular structure of palladacycle (1) used in this study
(hydrogen atoms are omitted for clarity).
3.2 Optimization and study of catalyst efficiency towards N-
alkylation of aniline with benzyl alcohol
Initially, we studied the reaction of benzyl alcohol with aniline as
a model reaction using different bases/solvents, 4 Å molecular
sieves for 24 h by using 0.2 mol % of pre-catalyst and 0.4 mol %
of PPh3(1:1 ratio metal to ligand) as a ligand at 120 C. After
screening various solvents and bases, we found that LiOH (50
mol%) was the best choice under solvent free conditions (Table
1). The use of carbine as a ligand resulted a low yield of only 19
%. When we lowered the temperature from 120 C to 100 C
using PPh3 as a ligand the yield got reduced from 91 % to 26 %.
2.8 Cyclopalladation of 3, 5-diphenyl-1-(2-(trifluoromethyl)
phenyl)-1H-pyrazole
Palladium acetate (1.23 g, 5.50 mmol) and 3, 5-diphenyl-1-(2-
(trifluoromethyl) phenyl)-1H-pyrazole (2.00 g, 5.50 mmol) were
suspended in glacial acetic acid (20 mL) and the mixture was
heated in an oil bath (100 °C, 2 h). The reaction mixture (in hot
condition) was filtered through celite to remove palladium black
and the solution was concentrated. The residue was re-dissolved
in dichloromethane, layered with n-hexane and stored at 5 °C for
24 h and filtered through celite (1cm height) and silica gel (100-
200 mesh, 1cm height) to remove remaining palladium black
traces. The solvents were removed under vacuum and the yellow
product was recrystallized from a mixture of dichloromethane
To determine the best suited phosphine for a particular reaction,
in many instances it is necessary to rely on a trial and error type
screening process.12 Keeping this in mind we examined the effect
of different phosphines at 100 C. The combination of the pre-
catalyst with P(2-Fur)3 gave an almost quantitative yield (98 %)
of the N-alkylated product. Next, the amount of P(2-Fur)3 loading
with respect to pre-catalyst was evaluated. It was found that 2:1
ratio of the P(2-Fur)3 to pre-catalyst is optimum to get maximum
yield of the desired product (see table 2, entries 8,9,10 and 11). In
the absence of P(2-Fur)3, the combination of the pre-catalyst with
the base gave a low yield of 12 % (Table 2, entry 14). Under
similar conditions, in the absence of the pre-catalyst no product
formation was observed (Table 2, entry 13), however palladium
o
and n-hexane. Yield : 2.57 g (4.8 mmol, 88%). mp: 218-219 C
(decompose). 1H NMR (400 MHz, CDCl3): δ = 7.75 (d, J =8 Hz,
ArH, 2H), 7.50 (t, J = 8 Hz, ArH, 2H), 7.41 (t, J = 8 Hz, ArH,
2H), 7.28-7.21 (m, ArH, 6H), 7.17-7.15 (m, ArH, 2H), 7.04 ((t, J
= 8 Hz, ArH, 2H), 6.95 (d, J =8 Hz, ArH, 6H), 6.88-6.82 (m,
ArH, 4H), 6.30 (s, 4Pz-H, 2H), 1.42 (s, OAc) ppm. 13C NMR
precursors such as Pd(OAc)2 PdCl2 or Pd2(dba)3 gave lower
,

4
Tetrahedron
ACCEPTED MANUSCRIPT
yields of 26 %, 46% and 37% respectively (Table 2, entry 16,
17 & 18). It is noteworthy that the N-phenyl ring of pyrazole
ligand with electron withdrawing group (-CF3) gave high yields
of the N-alkylated product. However, our previously reported
palladacycle8d did not yield any product under the reaction
conditions mentioned above. The observed results are consistent
with pyrazole-based palladacycles reported by Grigg and co-
workers, where fluorinated pyrazoles show superior activity for
the Heck reaction. We believe that fluorination on pyrazoles
plays a very important role for the observed catalytic activity of
our palladacycle reported in this study over the non-fluorinated
pyrazole.
Yieldb
(%)
Phosphine/
Entry Phosphine
X
T (oC)
palladacycle
1
PPh3
0.4
2
120
91
2
PPh3
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.2
0.6
0.1
0.4
0.4
-
2
2
2
2
2
2
2
1
3
0.5
2
-
110
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
54
3
PPh3
26
Table 1.Optimization of N-alkylation of aniline with benzyl
alcohol using palladacyclea
4
P(2-Tol)3
P(Bn)(Ph)2
P(Cy)3
19
5
24
6
6
7
P(tBu)3
Trace
98
8
P(2-Fur)3
P(2-Fur)3
P(2-Fur)3
P(2-Fur)3
P(2-Fur)3
P(2-Fur)3
-
Yieldb (%)
9
91
Entry
Base
Solvent
10
11
12
13
14
15
16
17
18
64
1
2
3
LiOH
LiOH
LiOH
Benzene
Toluene
o-Xylene
Trace
19
81
28c
0d
27
4
LiOH
TBB
76
-
12e
56f
26g
46h
37i
5
LiOH
-
-
-
-
-
-
-
-
-
91
P(2-Fur)3
P(2-Fur)3
P(2-Fur)3
P(2-Fur)3
0.4
0.4
0.4
0.4
2
-
6
LiOH.H2O
KOtBu
Cs2CO3
K3PO4
KOH
82
7
76
-
8
Trace
Trace
Trace
Trace
90
-
9
aReaction condition: aniline (3 mmol), benzyl alcohol (3.2 mmol), LiOH
(1.5 mmol), bIsolated yield after column chromatography, cLiOH was not
10
11
12c
13d
d
e
f
used, Palladacycle was not used, P(2-Fur)3 was not used, Molecular sieves
were not used, gInstead of precatalyst 1, 0.4 mol% Pd(OAc)2 was used,
hInstead of precatalyst 1, 0.4 mol% PdCl2 was used, Instead of precatalyst 1,
NaOH
LiOH
i
0.2 mol% Pd2(dba)3 was used
LiOH
73
aReaction condition: aniline (3.0 mmol), benzyl alcohol (3.6 mmol), LiOH
(1.5 mmol), precatalyst (6.0 x 10-3 mmol), PPh3 (12.0 x 10-3 mmol), TBB
The efficiency of the catalyst for the N-alkylation of aniline using
benzyl alcohol as an alkylating agent was studied by gradually
decreasing the pre-catalyst loading from 0.2 mol% to 0.001
mol% and by increasing the temperature from 100 C to 130 C
(Table 3). With 0.01 mol % of pre-catalyst at 100 C, 93 % (TON
= 4600) of the N-alkylated product was observed. When the
catalyst loading was lowered to 0.001 mol %, the pre-catalyst
exhibited higher turnover number (43000) at 130 C, which is
among the highest TON’s (Table 3, entry 11) reported for any
homogeneous Pd-based catalytic system till date for N-alkylation
of amines using aniline and benzyl alcohol.
b
c
=tert-butyl benzene. Isolated yield after column chromatography. 50 mol%
LiOH was used, d25 mol% LiOH was used
Table 2. Palladacycle catalysed N-alkylation of aniline using
benzyl alcohol: Screening of phosphinesa
3.3 Substrate scope of the reaction for N-alkylation of various
amines using primary and secondary alcohols
With these optimized conditions, we examined the substrate
scope of the reaction using various substituted anilines,
secondary amines and heterocyclic amines with benzyl alcohol at
100 C using 0.2 mol % of pre-catalyst (Table 4). As presented in
Table 4, most of the amines underwent the coupling reactions
with benzyl alcohol to yield the desired product in good to
excellent yields. Aromatic amines such as aniline, o,p-methoxy
aniline, o,m,p-methyl aniline, o,p-fluoroaniline and benzylamine

5
ACCEPTED MANUSCRIPT
were alkylated to give the corresponding N-benzyl amines in
isolated yields of 74 to 98 % (Table 4, compounds 1-9). Cyclic
secondary amines were also readily alkylated to the
corresponding tertiary amines in good yields (Table 4,
compounds 11 and 12). Aromatic primary alcohols such as p-
methyl benzyl alcohol, p-methoxy benzyl alcohol were also used
as alkylating agents (Table 4, compounds 14, 15). Sterically
hindered o-methyl benzyl alcohol, o-methoxy benzyl alcohol and
2-biphenyl methanol were also efficiently utilized as alkylating
agents at 120 C (Table 4, compounds 15, 16 and 17). o-
Toluidine was also successfully alkylated with 3,4-
methylenedioxy benzyl alcohol (Table 4, compound 18).
However, 4-chloroaniline and 4-bromoaniline were failed to give
the desired products.
Table 4. N-Alkylation of various amines using benzyl
alcohola
0.2 mol % palladacycle
0.4 mol % P(2-Fur)3
H
R2
N
N
OH
R1
R2
+
R
LiOH, 100 oC / 24 h
4Å MS, Solvent free
The least reactive and more challenging alcohols such as
aliphatic alcohols and secondary alcohols were also tested for N-
alkylation using our pre-catalyst (Table 5). The reaction between
aliphatic alcohols such as 1-octanol, 1-hexanol, n-butanol with p-
methoxy aniline or aniline provided the corresponding N-
alkylated product in good isolated yield of more than 72 %
(Table 5, compounds 19, 20, 21 and 22). The reactions of benzyl
alcohol with p-trifluoromethylaniline and 2-phenylethanol with
p-methoxyaniline progressed well to give the corresponding
secondary amines in 76 % and 72 % isolated yields respectively
(Table 5, compounds 31 & 23). To our delight, a good yield of
N-alkylated morpholine was achieved with 2-phenylethanol as an
alkylating reagent (Table 5, compound 32). When we applied
this approach to the more challenging secondary alcohols such as
1-phenylpropanol, 1-phenylethanol,1-(3-methylphenyl)ethanol,
1-(4-methylphenyl)-1-propanol, 2-hexanol, 2-decanol, 1-phenyl
2-propanol and cylohexanol at 120 C (or) 130 C, they were
successfully alkylated to the corresponding amines (Table 5,
compounds 25-30, 33-35).
H
N
H
N
NH
3, 86 %
1b, 98 %
74c
2, 90 %
73c
%
%
O
H
N
N
H
NH
O
6, 74 %
5b, 96 %
78c
4, 93 %
%
F
H
N
N
H
N
H
9b, 94 %
F
8, 93 %
7, 86 %
N
N
H
N
O
12, 79 %
11, 86 %
10, 91 %
Table 3. A study of catalyst efficiency for N-alkylation of
aniline using benzyl alcohola
H
O
H
N
H
N
N
O
O
O
13, 90 %
15, 54 %
91d
14, 95 %
%
H
O
NH
N
NH
O
F
17, 93d
%
16, 68 %
95d
18, 70d
%
%
Entry
Y
Time (h)
Yieldb (%) TONc
T (C )
aReaction condition: amine (3 mmol), benzyl alcohol (3.6 mmol), LiOH (1.5
1
2
3
0.2
100
100
100
24
24
24
98
91
85
245
453
845
b
mmol), palladacycle (6 X 10-3 mmol), P(2-Fur)3 (12 X 10-3 mmol), Average
isolated yields of two runs, cIn tert-butylbenzene (concentration = 1M),
dReactions were performed at 120 C.
0.1
0.05
4
0.025
100
24
81
1621
5
6
7
0.1
110
110
110
24
24
24
96
92
87
482
0.05
0.025
917
1734
8
0.01
110
110
120
130
24
48
48
48
83
93
61
89
4142
9
0.01
4643
10d
11d
0.001
0.001
30013
43358
aReaction condition: aniline (5.3 mmol), benzyl alcohol (6.4 mmol), LiOH
(2.65 mmol), bIsolated yield after column chromatography, cTurn Over
d
Number (TON) based on the isolated product, Gram scale: aniline (10.7
mmol), benzyl alcohol (12.8 mmol), LiOH (5.3 mmol); average isolated
yield of two runs.

6
Tetrahedron
ACCEPTED MANUSCRIPT
regioselective N-alkylation of 2-amino benzothiazoles with
benzylic alcohols. Compared to the solvent free condition, the
use of representative reactions using non-polar solvent (tert-
butylbenzene) gave relatively low yields for the N-alkylation of
amines (Table 4, compounds 1, 2, 5; Table 5, compounds 22, 35;
Table 6, compound 37).
Table 5. N-Alkylation of various amines using primary and
secondary alcoholsa
Table 6. N-Alkylation of amines using aryl (hetero) amines
and aryl (hetero) alcoholsa
0.5 mol% palladacycle
1 mol % P(2-Fur)3
H
R2
N
R3
NH2
N
R1
H
N
R
R1
OH
0.2 mol % palladacycle 1
0.4 mol % P(2-Fur)3
R
R3
+
R1
R2
R1
R4
OH
LiOH, 120-130 oC / 24-48h
4Å MS, Solvent free
R4
LiOH, 100-120 oC / 24 h
4Å MS, Solvent free
N
R2
OH
R
N
S
NH
NH
NH
NH2
NH
S
O
O
O
20, 89b
%
19, 78b
%
21, 73b
%
H
H
N
N
N
H
N
H
NH
NH
N
N
N
N
O
36, 84 %
38, 97 %
37, 96 %
22, 81b
49d
%
%
23, 72b
%
24, 68b
%
89c
%
H
N
S
S
N
NH
NH
NH
NH
N
NH
N
39, 93 %
O
40, 72 %
41, 78 %
O
27, 77b
%
26, 84b
%
25, 86b
%
H
N
O
H
N
H
N
N
NH
NH
NH
N
O
42b, 92 %
44b, 72 %
43b, 77 %
30, 75c
%
29, 76c
%
28, 70b
%
a
Reaction condition: amine (3.0 mmol), benzyl alcohol (6.0 mmol), LiOH
(1.5 mmol), palladacycle (6 x 10-3 mmol), P(2-Fur)3 (12 x 10-3 mmol),
Reactions were performed using 0.5 mol% palladacycle 1, 1 mol% P(2-Fur)3
and at 120 C, cIn tert-butylbenzene (concentration = 1M)
b
NH
N
NH
O
CF3
33, 81c
%
32, 74c
%
31, 76c
%
3.4 Regioselective N-alkylation of sulfanilamide using benzyl
alcohols
NH
NH
O
35, 81c
36d
%
%
34, 85c
%
Inspired by the regioselective N-alkylation of sulfanilamides
using alcohols reported by Feng Li and co-workers14a,14b we
attempted N-alkylation of sulfanilamide using alcohols. To our
delight our pre-catalyst successfully alkylated sulfanilamide,
regioselectively, at moderate temperatures (Table 7, compounds
45 – 49). As representative examples, single crystals of product
49, were grown and analysed using X-ray crystallography to
confirm the regioselectivity (Figure 2). Benzyl alcohol having
electron withdrawing group such as -CF3 gave the N-alkylated
product in 64% yield. Furthermore, benzyl alcohol bearing
electron donating group such as methyl and methoxy gave the
desired products 46 and 47 in 71% and 64% yield respectively.
aReaction condition: amine (3.0 mmol), alcohol (6.0 mmol), LiOH (1.5
mmol), palladacycle (1.5 x 10-2mmol), P(2-Fur)3 (3.0 x 10-2 mmol),
b
Reactions were performed at 120 C for 24 h, c Reactions were performed at
o
130 C for 48 h, dIn tert-butylbenzene (concentration = 1M)
Heteroaromatic amines, such as 4-aminopyridine, 2-
aminopyridine and 2-aminopyramidine, were also efficiently
alkylated under these conditions to give the products 36, 37, and
38 in 84 %, 96 % and 97 % yields respectively (Table 6). 2-
Aminopyridine was successfully alkylated with 1-decanol and
gave quantitative yield of the corresponding product (Table 6,
compound 42). Heteroaromatic aryl alcohols such as 2-
pyridinemethanol, 3-pyridinemethanol and furfuryl alcohol were
also efficiently utilized as alkylating reagents at moderate
temperatures (Table 6, compounds 39, 43 and 44). Interestingly,
2-amino benzothiazole (Table 6, compounds 40 and 41)
selectively alkylated at the primary amine position with benzyl
alcohol and 1-naphthyl methanol.13 As reported in the literature
the regioselective N-alkylation of 2-amino benzothiazole is a
challenging task, here we show that our pre-catalyst has the
potential to prepare 2-(N-alkyamine)benzothiazoles via
Fig. 2. Molecular structure of product 49 with thermal
ellipsoids at the 50% probability level

7
ACCEPTED MANUSCRIPT
Notably, our palladacycle has been shown to be an active
regioselective catalyst for the monoalkylation of sulfanilamide.
Table 7. Regioselective N-Alkylation of sulfanilamide using
aryl alcohols a
O
O
0.5 mol% palladacycle 1
1 mol % P(2-Fur)3
O
O
S
S
NH2
N
R
R
O
OH
H
LiOH, 120 oC / 24 h
4 Å MS, Solvent free
H2N
H2N
O
O
O
S
S
N
N
H
H
H2N
H2N
45, 69%
46, 71 %
O
O
O
O
S
S
N
N
H
H
H2N
CF3
H2N
O
O
48, 64 %
47, 64 %
O
S
O
O
N
H
H2N
49, 72 %
Scheme 4: Proposed catalytic pathway for N-alkylation of
amines using alcohols
aReaction condition: sulfanilamide (3.0 mmol), aryl alcohol (6.0 mmol),
LiOH (1.5 mmol), palladacycle (1.5 x 10-2 mmol), P(2-Fur)3 (3.0 x 10-2 mmol)
Acknowledgements
3.5 Synthesis of piribedil by using our palladacycle
KV thanks the Department of Science and Technology (DST)
(SR/S1/IC-58/2012 and SR/S2/RJN-49/2011), New Delhi and
Department of Atomic Energy (DAE) for financial support. RM,
VM, KD thank CSIR, New Delhi for research fellowship. We
thank Prof. V. R. Pedireddi-IIT Bhubaneswar, for the X-ray
analysis of product 49. We thank Prof. Victor Snieckus for
insightful discussion. We also thank the reviewers for their useful
suggestions.
Furthermore, we established the synthetic utility of our
palladacyle in the synthesis of piribedil,3d which is clinically used
for the treatment of Parkinson’s disease. To our delight the
reaction of 1-(pyrimidin-2-yl)piperazine with piperonyl alcohol
in the presence of 0.5 mol % of palladacycle afforded 76 %
isolated yield (Scheme 3).
O
0.5 mol % palladacycle
1 mol% P(2-Fur)3
N
O
O
N
N
N
References and notes
+
OH
N
N
NH
LiOH, MS (4 Å)
120 oC, 24 h
Solvent free
O
N
50, 76 %
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1
analysed using H NMR (Figure S1). The formation of aldehyde
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8
Tetrahedron
ACCEPTED MANUSCRIPT
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Supplementary Material
Supplementary material associated with this article can be found
in the online version.