Iodine-catalyzed N-alkylation of tosylhydrazones with benzylic alcohols

Article abstract of DOI:10.1007/s13738-012-0205-1

A new and highly efficient method for the C-N bond formation using molecular iodine-catalyzed N-alkylation reaction of tosylhydrazones with benzylic/benzhydryl alcohols at room temperature in methylene chloride is described. A variety of tosylhydrazones r

Full text of DOI:10.1007/s13738-012-0205-1

J IRAN CHEM SOC (2013) 10:717–724
DOI 10.1007/s13738-012-0205-1
ORIGINAL PAPER
Iodine-catalyzed N-alkylation of tosylhydrazones
with benzylic alcohols
•
P. Theerthagiri A. Lalitha
Received: 24 September 2012 / Accepted: 30 November 2012 / Published online: 22 December 2012
Ó Iranian Chemical Society 2012
Abstract A new and highly efficient method for the C–N
bond formation using molecular iodine-catalyzed N-alkyl-
ation reaction of tosylhydrazones with benzylic/benzhydryl
alcohols at room temperature in methylene chloride is
described. A variety of tosylhydrazones reacted readily
with various substituted benzylic alcohols in presence of
20 mol % iodine under mild reaction conditions to produce
the corresponding biologically active N-alkylated com-
pounds in good to excellent yields.
antituberculosis, antitumoral, antiproliferative and anti-
malarial activities [8]. Biological activities of various
hydrazones are well reported in the literature. Generally,
this transformation is carried out using alkyl halides in the
presence of stoichiometric amount of base [9, 10]. But, the
use of alkyl halides is undesirable from an environmental
point of view, and it generates wasteful salts as by-prod-
ucts. Cahhi et al. [11] reported the N-alkylation of tosyl-
hydrazones using phase transfer catalyst. Among a variety
of approaches for the N-alkylation of tosylhydrazones,
alcohols are arguably one of the most ideal substrates that
are receiving more attention [12, 13]. In principle, C–N
bond formation by direct substitution of a hydroxyl group
is difficult because of its poor leaving group ability.
Therefore, hydroxyl groups usually require pre-activation
through transformation into good leaving groups such as
halides, carboxylates, and carbonates before treatment
with tosylhydrazones. However, such a process inevitably
produces salt waste, which would set limits for the
industrial application and for the scope of substrates.
Recently, DEAD/Ph3P (Mitsunobu reaction), as well as
acid catalyst systems such as B(C6F5)3 have been proved
to be successful for the N-alkylation of tosylhydrazones
using alcohols as electrophiles directly [1, 14, 15]. Despite
significant recent advances in this area, there remains
room for improvement, such as increase in catalyst sta-
bility, lowering reaction temperature and increase in yield
in the carbon–nitrogen single bond formation between
tosylhydrazones with an alcohol.
Keywords N-alkylation ꢀ Molecular iodine ꢀ
Tosylhydrazones ꢀ Benzylic alcohols
Introduction
The N-alkylation of tosylhydrazones represents one of the
most important C–N bond formation methodologies in
organic synthesis [1]. The N-alkylated hydrazones have
various applications in organic synthesis as useful syn-
thons [2–6] and hydrazones constitute an important class
of biologically active drug molecules [7] which have
attracted attention of medicinal chemists due to their
wide range of pharmacological properties. These com-
pounds are being synthesized as drugs by many
researchers to combat diseases with minimal toxicity and
maximal effects. A number of hydrazone derivatives have
been reported to exert notably antimicrobial, antihyper-
tensive, anticonvulsant, analgesic, anti-inflammatory,
To the best of our knowledge, there is only one report
on the N-alkylation of tosylhydrazones with alcohols in
the presence of acid catalyst [1], and there are no exam-
ples of the iodine-catalyzed N-alkylation of tosylhydra-
zones with alcohols. Therefore, development of a general,
efficient and readily available catalyst like molecular
P. Theerthagiri ꢀ A. Lalitha (&)
Department of Chemistry, Periyar University,
Salem 636 011, Tamil Nadu, India
e-mail: lalitha2531@yahoo.co.in
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J IRAN CHEM SOC (2013) 10:717–724
Ar1
N
R
General experimental procedure for iodine-catalyzed
N-alkylation of aldehyde tosylhydrazones using
benzylic alcohols
H
N
OH
I2 (20 mol%)
CH2 Cl2, rt
+
Ar
N
Ts
N
Ar1
R
Ar
Ts
2a
Ar1= aryl; R = alkyl, aryl
1a
3a
Ar = aryl
To a stirred solution of benzylic alcohol (1 mmol) in
dichloromethane (5 ml), tosylhydrazone (1.2 mmol) and
20 mol % iodine were added. The reaction mixture was
stirred at room temperature for appropriate time mentioned
in Table 2 and the reaction was monitored by TLC. After
the completion of the reaction, the mixture was quenched
with 10 % solution of sodium thiosulfite and separated
organic layer was washed with water, brine and then con-
centrated. The crude solid was washed with 10 % hexane
in ethyl acetate to give the corresponding N-alkylated
products.
Scheme 1 Molecular iodine-catalyzed N-alkylation of tosylhydra-
zones
iodine for this valuable but challenging transformation is
highly desirable.
In recent years, molecular iodine has received consid-
erable attention as an inexpensive, non-toxic, readily
available catalyst for various organic transformations due
to its moderate Lewis acidity and water tolerance [16–22].
Molecular iodine has been used to be a versatile catalyst for
alkylation of 1,3 dicarbonyl compounds and 4-hydroxy-
coumarines [23, 24], synthesis of bis(indolyl)methane [25],
Michael addition of indole and pyrrole to nitroolefins [26],
etc. More recently, iodine-catalyzed transformation of
molecules containing oxygen functional groups has been
reported in the literature [27]. As part of our ongoing
program on organic transformations [28, 29], herein we
describe a highly efficient method for the C–N bond for-
mation via molecular iodine-catalyzed N-alkylation reac-
tion of tosylhydrazones with benzylic as well as benzhydric
alcohols (Scheme 1).
Compounds 3d and 3p [1] were previously reported and
their structures were confirmed by comparison of their
spectroscopic data with the reported data. Characterization
data for some new compounds are given below.
Compound (3a)
Pale yellow solid. m.p.: 125–128 °C. IR (neat): m = 3,021,
1
2,938, 1,593, 1,167 cm-1. H NMR (400 MHz, CDCl3):
d = 8.13 (s, 1H, =CH–), 7.68–7.76 (dd, 2H, ArH),
7.59–7.57 (dd, J = 9.6 Hz, 2H, ArH), 7.35–7.40 (m, 5 H,
ArH), 7.22–7.30 (m, 5H, ArH) 5.67–5.72 (q, J = 7.2 Hz,
1H, CH), 2.40 (s, 3H, Ar–CH3), 1.48–1.49 (d, J = 6.8 Hz,
3H, –CH3) ppm. 13C NMR (100 MHz, CDCl3): 153.83,
143.86, 140.83, 135.77, 134.31, 130.49, 129.47, 128.65,
128.50, 128.12, 127.64, 127.40, 127.11, 58.70, 21.58,
16.92 ppm. LC–MS: m/z cacld for C22H22N2O2S 378.14;
found 379.2 (M?).
Experimental
General
Iodine was purchased from Spectra Chem. All other
chemicals were procured from S.D. Fine. Chem. Limited
and used as received. Reactions were monitored by thin
layer chromatography (TLC). TLC was performed on
Merck pre-coated aluminum sheets of 60 F-254 silica gel
plates with visualization by UV-light using ethyl acetate
and n-hexane as solvent system. Melting points were
Compound (3b)
Pale yellow oil. IR (neat): m = 3,024, 2,945, 1,596, 1,339,
1,162 cm-1
.
1H NMR (400 MHz, CDCl3): d = 8.11
(s, 1H, =CH–), 7.69–7.71 (dd, J = 8.4 Hz, 2H, ArH),
7.57–7.59 (dd, J = 9.2 Hz, 2H, ArH), 7.34–7.40 (m, 5 H,
ArH), 7.21–7.28 (m, 2H, ArH), 7.03–7.14 (m, 2H, ArH)
5.64–5. (q, J = 6.8 Hz, 1H, CH), 2.41 (s, 3H, Ar–CH3),
2.32 (s, 3H, Ar–CH3), 1.45–1.47 (d, J = 7.2 Hz, 3H,
–CH3) ppm. 13C NMR (100 MHz, CDCl3): 153.60, 143.77,
137.77, 137.05, 135.87, 134.36, 130.41, 129.42, 129.15,
128.61, 128.11, 127.61, 126.99, 58.44, 21.57, 21.03,
16.77 ppm. LC–MS: m/z cacld for C23H24N2O2S 392.16;
found 392.9 (M?).
}
determined in capillary tubes using Buchi Melting Point
B-545 apparatus. The IR spectra (neat) were recorded on a
Nicolet 6700 FT-IR spectrometry. 1H and 13C NMR
spectra were recorded in CDCl3 with Bruker 400 MHz
high-resolution NMR spectrometers. CDCl3 was used as
the solvent for the NMR spectral measurements and spectra
were recorded in parts per million with TMS as internal
standard. Multiplicities are abbreviated as follows: singlet
(s), doublet (d), triplet (t), multiplet (m) and broad (br). The
mass spectra were recorded on GC–MS-Agilent 5975 ser-
ies. Column chromatography was performed on silica gel
(230–400 mesh) supplied by Acme Chemical Co. (India)
for compound purification.
Compound (3c)
Light brown solid. m.p.: 110–113 °C. IR (neat): m =
3,060, 2,919, 1,686, 1,588, 1,338, 1,162 cm-1. H NMR
1
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719
Compound (3h)
(400 MHz, CDCl3): d = 8.25 (s, 1H, =CH–),
7.60–7.62(m, 4H, ArH), 7.37–7.42 (m, 3H, ArH),
7.30–7.32 (m, 2H, ArH), 7.21–7.27 (m, 4H, ArH),
5.54–5.59 (q, J = 7.2 Hz, 1H, CH), 2.41 (s, 3H, Ar–CH3),
1.27 (d, 3H, J = 7.2 Hz, Ar–CH3), 1.45–1.47 (d, J =
6.8 Hz, 3H, –CH3) ppm. 13C NMR (100 MHz, CDCl3):
1,156.15, 144.01, 139.38, 135.55, 134.06, 133.28, 130.83,
129.45, 128.73, 128.70, 128.49, 128.01, 127.82, 58.45,
21.56, 17.56 ppm. LC–MS: m/z cacld for C22H21N2O2S
412.9; found 413.2 (M?).
White solid. m.p.: 140–143 °C. IR (neat): m = 3,061,
2,982, 1,596, 1,380, 1,165 cm-1 1H NMR (400 MHz,
.
CDCl3): d = 8.25 (s, 1H, =CH–), 7.83–7.85 (dd,
J = 9.6 Hz, 1H, ArH), 7.78–7.80 (d, J = 8.4 Hz, 2H,
ArH), 7.21–7.31 (m, 7H, ArH), 7.12–7.14 (d, J = 8.0 Hz,
2H, ArH), 5.86–5.91(q, J = 7.2 Hz, 1H, CH), 2.41 (s, 3H,
Ar–CH3), 2.32 (s, 3H, Ar–CH3), 1.55–1.59 (d, J =
12.8 Hz, 3H, –CH3) ppm. 13C NMR (100 MHz, CDCl3):
144.05, 143.74, 137.17, 136.99, 135.80, 134.26, 132.16,
130.61, 129.63, 129.56, 129.36, 128.35, 128.20, 126.88,
126.80, 126.71, 57.61, 21.60, 21.04, 16.03 ppm. LC–MS:
m/z cacld for C23H23ClN2O2S 426.10; found 427.2
(M?).
Compound (3e)
Pale yellow solid. m.p.: 118–121 °C. IR (neat): m = 3,021,
1
2,940, 1,591, 1,339 cm-1. H NMR (400 MHz, CDCl3):
d = 8.14 (s, 1H, =CH–), 7.50–7.52 (dd, J = 8.4 Hz, 2H,
ArH), 7.41–7.44 (m, 2H, ArH), 7.21–7.32 (m, 7H, ArH),
7.14–7.16 (dd, J = 8.0 Hz, 2H, ArH) 7.08–7.10 (dd,
J = 8.0 Hz, 2H, ArH), 7.02–7.04 (dd, J = 8.0 Hz, 2H,
ArH), 6.86 (s, 1H, CH), 2.35 (s, 3H, Ar–CH3), 2.30 (s, 3H,
Ar–CH3) ppm. 13C NMR (100 MHz, CDCl3): 151.38,
143.70, 138.40, 137.18, 135.50, 135.15, 134.47, 130.14,
129.15, 129.09, 129.04, 128.90, 128.55, 128.19, 127.43,
127.37, 66.74, 21.52, 21.06 ppm. LC–MS: m/z cacld for
C28H26N2O2S 454.0; found 455.2 (M?).
Compound (3i)
Off white solid. m.p.: 121–123 °C. IR (neat): m = 3,024,
2,945, 1,596, 1,339, 1,162 cm-1 1H NMR (400 MHz,
.
CDCl3): d = 8.34 (s, 1H, =CH–), 7.82–7.84 (dd,
J = 9.6 Hz, 1H, ArH), 7.73–7.75 (d, J = 8.4 Hz, 2H,
ArH), 7.31–7.33 (m, 7H, ArH), 7.25–7.29 (m, 2H, ArH),
5.79–5.84 (q, J = 7.2 Hz, 1H, CH), 2.42 (s, 3H, Ar–CH3),
1.55–1.57 (d, J = 8.8 Hz, 3H, –CH3) ppm. 13C NMR
(100 MHz, CDCl3): 144.33, 144.31, 138.81, 135.48,
134.43, 133.41, 131.90, 130.94, 129.76, 129.63, 128.77,
128.34, 128.13, 126.96, 126.84, 57.55, 21.60, 16.69 ppm.
LC–MS: m/z cacld for C22H20Cl2N2O2S 446.06; found
447.2 (M?), 449.0 (M ? 2).
Compound (3f)
Pale yellow oil. IR (neat): m = 3,025, 2,939, 1,598, 1,337,
1,162 cm-1
.
1H NMR (400 MHz, CDCl3): d = 8.24
(s, 1H, =CH–), 7.44–7.51 (m, 5H, ArH), 7.31–7.36 (m, 4H,
ArH), 7.17–7.25 (m, 6H, ArH), 7.05–7.12 (m, 4H, ArH),
2.36 (s, 3H, Ar–CH3) ppm. 13C NMR (100 MHz, CDCl3):
152.11, 143.89, 137.63, 136.52, 135.34, 133.98, 131.27,
130.37, 129.51, 129.20, 129.04, 128.84, 128.64, 128.29,
128.09, 127.56, 126.51, 64.44, 21.54 ppm. LC–MS: m/z
cacld for C27H23ClN2O2S 474.12; found 475.2 (M?).
Compound (3j)
Brown solid. m.p.: 137–139 °C. IR (neat): m = 3,060,
2,941, 1,686, 1,588, 1,332, 1,161 cm-1
.
1H NMR
(400 MHz, CDCl3): d = 8.39 (s, 1H, =CH–), 7.61–7.64
(m, 3H, ArH), 7.73–7.75 (d, J = 8.4 Hz, 2H, ArH),
7.21–7.32 (m, 9H, ArH), 7.15–7.19 (m, 5H, ArH),
7.11(s,1H, CH), 2.38 (s, 3H, Ar–CH3) ppm. 13C NMR
(100 MHz, CDCl3): 144.16, 142.89, 137.89, 135.25,
134.20, 130.52, 130.08, 129.61, 129.37, 128.96, 128.40,
127.63, 127.44, 127.28, 126.85, 126.75, 66.46, 21.57 ppm.
LC–MS: m/z cacld for C27H23ClN2O2S 474.12; found
447.2 (M ? 2), 475.2 (M?).
Compound (3g)
White solid. m.p.: 133–136 °C. IR (neat): m = 3,059,
2,982, 1,597, 1,350, 1,166 cm-1 1H NMR (400 MHz,
.
CDCl3): d = 8.26 (s, 1H, =CH–), 7.84–7.86 (dd,
J = 9.2 Hz, 1H, ArH), 7.78–7.80 (dd, J = 8.0 Hz, 2H,
ArH), 7.42–7.44 (d, J = 7.6 Hz, 2H, ArH), 7.22–7.35
(m, 8H, ArH), 5.92–5.94 (q, J = 7.2 Hz, 1H, CH), 2.40
(s, 3H, Ar–CH3), 1.60–1.62 (d, J = 6.8 Hz, 3H, –CH3)
ppm. 13C NMR (100 MHz, CDCl3): 144.12, 143.86,
140.08, 135.69, 134.28, 132.10, 129.65, 129.59, 128.72,
128.22, 127.51, 126.90, 126.78, 57.80, 21.60, 16.13 ppm.
LC–MS: m/z cacld for C22H21ClN2O2S 412.10; found
413.2 (M?).
Compound (3k)
Pale yellow solid. m.p.: 111–113 °C. IR (neat): m = 3,032,
2,944, 1,682, 1,581, 1,336, 1,165 cm-1
.
1H NMR
(400 MHz, CDCl3): d = 8.36 (s, 1H, =CH–), 7.63.–7.66
(m, 3H, ArH), 7.26–7.28 (m, 4H, ArH), 7.19–7.24 (m, 8H,
ArH), 7.09–7.18 (m, 3H, ArH) 2.38 (s, 3H, Ar-CH3), 2.33
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(s, 3H, Ar–CH3) ppm. 13C NMR (100 MHz, CDCl3):
144.09, 142.73, 138.00, 137.35, 135.38, 134.75, 134.18,
132.19, 130.45, 129.59, 129.34, 129.07, 128.94, 128.85,
128.37, 127.52, 126.82, 126.76, 66.21, 21.57, 21.09 ppm.
LC–MS: m/z cacld for C28H25ClN2O2S 488.13; found
489.2 (M?).
Compound (3r)
Yellow oil. IR (neat): m = 3,032, 2,946, 1,594, 1,335,
1
1,160 cm-1. H NMR (400 MHz, CDCl3): d = 8.38–8.40
(dd, J = 8.4 Hz 2H, ArH), 7.89 (s, 1H, =CH–), 7.76–7.78
(dd, J = 8.0 Hz, 2H, ArH), 7.60–7.62 (dd, J = 8.8 Hz,
2H, ArH), 7.25–7.31 (m, 4H, ArH), 7.11–7.17 (m, 2H,
ArH), 5.87–5.93 (q, J = 7.2 Hz, 1H, CH), 2.43 (s, 3H, Ar–
CH3), 2.33 (s, 3H, Ar–CH3), 1.59–1.61 (d, J = 7.2 Hz, 3H,
–CH3) ppm. 13C NMR (100 MHz, CDCl3): 148.15, 144.50,
143.16, 140.63, 137.45, 136.71, 135.60, 130.49, 129.49,
128.02, 127.46, 126.56, 125.35, 124.31, 123.90, 58.03,
21.62, 21.04, 16.59 ppm. LC–MS: m/z cacld for
C23H23N3O4S 437.51; found 438.2 (M?).
Compound (3l)
Pale yellow oil. IR (neat): m = 3,026, 2,939, 1,598, 1,337,
1,162 cm-1
.
1H NMR (400 MHz, CDCl3): d = 8.37
(s, 1H, =CH–), 7.66.–7.68 (m, 3H, ArH), 7.27–7.29 (m, 4H,
ArH), 7.22–7.25 (m, 8H, ArH), 7.09–7.20 (m, 3H, ArH)
2.38 (s, 3H, Ar–CH3), 2.33 (s, 3H, Ar–CH3) ppm. 13C
NMR (100 MHz, CDCl3): 144.11, 142.83, 138.03, 137.35,
135.58, 134.85, 134.20, 132.21, 130.46, 129.55, 129.35,
129.08, 128.95, 128.86, 128.39, 127.55, 126.89, 126.78,
66.23, 21.59, 21.09 ppm. LC–MS: m/z cacld for
C27H22Cl2N2O2S 508.13; found 509.2 (M?).
Compound (3s)
Yellow oil. IR (neat): m = 3,026, 2,939, 1,597, 1,336,
1
1,160 cm-1. H NMR (400 MHz, CDCl3): d = 8.18–8.21
(dd, J = 8.8 Hz, 2H, ArH), 8.03 (s, 1H, =CH–), 7.66–7.72
(dd, J = 8.4 Hz, 2H, ArH), 7.64–7.66 (dd, J = 8.0 Hz,
2H, ArH), 7.26–7.33 (m, 7H, ArH), 5.81–5.83 (q, J =
7.2 Hz, 1H, CH), 2.43 (s, 3H, Ar–CH3), 1.58–1.60
(d, J = 7.2 Hz, 3H, –CH3) ppm. 13C NMR (100 MHz,
CDCl3): 148.37, 144.92, 144.76, 140.32, 138.59, 135.33,
133.64, 129.83, 128.89, 128.60, 127.91, 127.62, 126.80,
123.98, 69.75, 58.03, 25.30, 21.62, 17.26 ppm. LC–MS:
m/z cacld for C22H20 ClN3O4S 457.9; found 458.0 (M?),
459.2 (M ? 2).
Compound (3n)
Brown oil. IR (neat): m = 3,025, 2,937, 1,596, 1,333,
1,169 cm-1
.
1H NMR (400 MHz, CDCl3): d = 8.08
(s, 1H, =CH–), 7.67.–7.71 (m, 2H, ArH), 7.35–7.38 (m, 2H,
ArH), 7.18–7.29 (m, 5H, ArH), 7.08–7.14 (m, 2H,
ArH),6.90–6.93 (m, 1H, ArH), 5.68–5.70 (q, J = 7.2 Hz,
1H, CH), 5.29 (s, 3H, –CH3), 3.81 (s, 3H, Ar–OCH3), 2.39
(s, 3H, Ar–CH3) 1.47–149(s, J = 7.2 Hz, 3H, CH3) ppm.
13C NMR (100 MHz, CDCl3): 159.79, 152.79, 143.94,
140.75, 135.73, 129.66, 129.48, 129.31, 128.61, 128.53,
128.43, 128.14, 127.68, 127.57, 127.43, 127.07, 120.63,
116.71, 116.58, 116.45, 111.93, 58.62, 55.30, 53.47, 21.58,
16.89 ppm. LC–MS: m/z cacld for C23H24N2O3S 408.51;
found 409.2 (M?).
Compound (3t)
Yellow oil. IR (neat): m = 3,032, 2,938, 1,597, 1,334,
1
1,164 cm-1. H NMR (400 MHz, CDCl3): d = 8.12–8.36
Table 1 Optimizing the reaction conditions for the N-alkylation of
tosylhydrazone (1a) with 1-phenylethanol (2a) using iodine as cata-
lyst
Ar1
N
R
H
N
OH
I2 (20 mol%)
Compound (3o)
+
Ts
Ar
N
N
Ar1
R Solvents
Ar
Ts
Pale yellow oil. IR (neat): m = 3,032, 2,939, 1,598, 1,337,
1,162 cm-1. 1H NMR (400 MHz, CDCl3): d = 8.18(s, 1H,
=CH–), 7.67.–7.71 (m, 2H, ArH), 7.60–7.62 (d, J =
8.4 Hz, 1H, ArH), 7.25–7.31 (m, 3H, ArH), 7.13–7.22
(m, 7H, ArH), 6.94–6.96 (m, 1H, ArH), 5.56–5.58 (q, J =
7.2 Hz, 1H, CH), 3.83 (s, 3H, Ar–OCH3), 2.40 (s, 3H,
Ar–CH3) 1.43–145 (s, J = 6.8 Hz, 3H, CH3) ppm. 13C
NMR (100 MHz, CDCl3): 159.83, 155.14, 144.07, 139.34,
135.55, 135.47, 133.29, 129.75, 129.47, 128.82, 128.67,
128.52, 128.02, 120.78, 116.69, 112.22, 58.39, 55.33,
21.57, 17.52 ppm. LC–MS: m/z cacld for C23H23ClN2O3S
442.9; found 443.2 (M?).
Entry
Solvent
T (°C)
Time (h)
Yield (%)a
1
2
3
4
5
6
DMSO
THF
25
25
25
25
25
25
25
25
20
20
20
25
–
10
80
55
92
60
C2H4Cl2
CH3CN
CH2Cl2
CH3NO2
All reactions were performed with tosylhydrazone (1a; 1 mmol),
1-phenylethanol (2a; 1.2 mmol), and iodine (20 mol %) in the indi-
cated solvent
a
Isolated yield after washing with 10 % hexane in ethyl acetate
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Table 2 Iodine-catalyzed N-alkylations of aldehyde tosylhydrazones using benzylic alcohols
Ar1
R
OH
H
I2 (20 mol %)
CH2Cl2, rt
N
+
Ar
N
Ts
N
Ar1
R
Ar
N
Ts
Entry
1
Tosylhydrazone
Benzylic alcohol
Time (h)
18
Product
Yield (%)a
92
OH
Ts
N
N
Ph
Ts
N
C6H5
N
H
1a
3a
Ph
2a
Ts
N
Ph
OH
N
3b
4-MeC6H4
2b
2
3
18
20
88
80
1a
OH
Ts
N
Ph
N
1a
3c
2c
Cl
4-ClC6H4
OH
Ts
N
Ph
N
N
3d
4
5
18
20
83
78
1a
1a
Ph
Ts
Ph
N
2d
OH
Ph
3e
2e
Ph
4-MeC6H4
OH Cl
Ts
N
Ph
N
3f
2f
Ph
2-ClC6H4
6
7
20
90
1a
Ts
N
2-ClC6H4
Ts
N
2-ClC6H4
N
N
3g
H
1b
Ph
20
18
18
18
92
81
86
80
2a
2b
2c
2d
Ts
N
2-ClC6H4
N
N
N
8
9
3h
4-MeC6H4
1b
1b
1b
Ts
N
2-ClC6H4
3i
4-ClC6H4
Ts
N
2-ClC6H4
3j
Ph
Ph
10
Ts
N
2-ClC6H4
N
N
3k
Ph
4-MeC6H4
11
12
13
20
18
18
65
52
75
1b
1b
2e
2f
Ts
N
2-ClC6H4
3l
2-ClC6H4
Ph
Ts
Ts
N
3-OMeC6H4
3m
N
3-OMeC6H4
1c
N
N
H
Ph
2a
123

722
J IRAN CHEM SOC (2013) 10:717–724
Table 2 continued
Entry
Tosylhydrazone
Benzylic alcohol
Time (h)
20
Product
Yield (%)a
Ts
Ts
N
3-OMeC6H4
N
3n
4-MeC6H4
14
66
55
63
95
1c
1c
1c
2b
N
3-OMeC6H4
N
N
3o
4-ClC6H4
15
16
17
18
20
20
2c
2d
2a
Ts
N
3-OMeC6H4
3p
Ph
Ph
Ts
Ts
N
4-NO2C6H4
N
4-NO2C6H4
N
N
H
3q
1d
Ph
N
Ts
4-NO2C6H4
N
3r
4-MeC6H4
18
19
20
18
18
20
90
83
78
1d
1d
1d
2b
2c
2d
Ts
N
4-NO2C6H4
N
3s
4-ClC6H4
Ts
N
4-NO2C6H4
N
3t
Ph
Ph
All reactions were performed with tosylhyrdrazones (1 mmol), benzylic alcohols (1.2 mmol), and iodine (20 mol %) in dichloromethane
a
Isolated yield after washing with 10 % hexane in ethyl acetate
(dd, J = 8.4 Hz 2H, ArH), 8.0 (s, 1H, =CH–), 7.62–7.68
(dd, J = 8.0 Hz, 2H, ArH), 7.45–7.49 (dd, J = 8.4 Hz,
2H, ArH), 7.22–7.40 (m, 10H, ArH), 7.14–7.20 (m, 2H,
ArH), 7.10 (s, 1H, CH), 2.38 (s, 3H, Ar–CH3) ppm. 13C
NMR (100 MHz, CDCl3): 148.08, 144.63, 142.39, 142.23,
140.64, 137.69, 135.11, 133.19, 130.00, 129.60, 129.28,
129.06, 128.84, 128.68, 128.39, 127.86, 127.44, 127.39,
127.28, 127.07, 126.56, 126.45, 123.90, 80.03, 66.83,
21.61 ppm. LC–MS: m/z cacld for C27H23N3O4S 485.14;
found 486.2 (M?).
sulfonohyrazide with 1-phenylethanol in presence of
molecular iodine as Lewis acid catalyst. First we examined
the solvent suitability for this reaction and the results are
summarized in Table 1. The reaction in DMSO did not
proceed well and in THF afforded only 10 % of the product
with several unwanted side products. After substantial
experimentation with different solvents (C2H4Cl2 80 %
yield, CH3CN 55 % yield, CH3NO2 60 % yield), dichlo-
romethane (92 % yield) came out as a solvent of choice.
With this encouraging result, next we investigated the
amount of iodine required to catalyze the transformation.
To start with, we have used 10 mol % of iodine
which afforded the products in 45 % yield after 20 h.
Use of 15 mol % of iodine improved the yield to 75 %
with the reaction time almost same as that of 10 mol %.
On the other hand, using 20 mol % of iodine as catalyst,
the product yield was increased to 94 % in 20 h and
20 mol % of iodine has been used as catalyst for further
reactions.
Results and discussion
Initially, we attempted the N-alkylation of N-benzylidene-
4-methylbenzene sulfonohydrazide (1a) with 1-phenyleth-
anol (2a) in dichloromethane using 20 mol % of iodine as
catalyst and it was observed that the reaction went to
completion at room temperature within 20 h to give
product (3a) in 93 % yield (Scheme 1).
To check the versatility of iodine-catalyzed N-alkylation
reaction, we next investigated the reaction of tosylhydra-
zones of different aldehydes with a series of substituted
To obtain the optimized reaction conditions, we have
chosen the reaction of N-benzylidene-4-methyl benzene
123

J IRAN CHEM SOC (2013) 10:717–724
723
Ar1 Ar1
O
completely converted to the desired product when the
reaction was stirred at room temperature for 18–20 h.
A
I
2
Conclusions
OH
I2
Ar1
Ar1
-H+
1
H2O
B
Ar
In summary, we have successfully employed molecular
iodine as an efficient catalyst to promote N-alkylation of
tosylhydrazones using secondary benzylic alcohols,
affording the N-alkylated tosylhydrazone derivatives in
good to excellent yields. The notable advantages of this
method are broad scope, mild reaction conditions, opera-
tional simplicity, direct use of alcohols and the use of
inexpensive and non-toxic catalyst. This method is energy
saving, environmentally friendly, since water is the only
side product. In addition, due to the easy availability of the
starting materials and catalyst, this reaction may prove to
be very useful in organic synthesis. Further studies in this
area to explore the mechanism and synthetic applications
of this reaction are being carried out in our laboratory.
N
H
N
Ar
N
3
Ts
Ar
N
2
Ts
Fig. 1 Plausible mechanism for the iodine-catalyzed N-alkylation
benzylic alcohols under the optimized conditions. The
results are summarized in Table 2.
N-alkylations of N0-benzylidene-4-methylbenzenesulfo-
nohydrazide (1a) with benzylic alcohols (2a–2f) bearing
electron-donating and electron-withdrawing groups on
benzylic alcohols 2a–2f, proceeded smoothly to give the
corresponding N-alkylated products in moderate to good
yields (entries 7–12, Table 2). Similarly, N0-(4-methylb-
enzylidence)-4-methylbenzene sulfonohydrazide (1c) and
4-methyl-N0-(-4-nitrobenzlidene)benzenesulfonohydrazide
(1d) with benzylic alcohols 2a–2d also undergo N-alkyl-
ation with smooth conversion to give the desired products
in substantial yields (entries 13–16, Table 2). Next, the
reaction was extended to simple primary alcohols such as
benzyl alcohols as the substrates for N-alkylation of
tosylhydrazones under the same reaction conditions, where,
disappointingly, the corresponding N-alkylated products
were obtained in low yields (10–15 %).
Acknowledgments We would like to thank Dr. P. N. Arunachalam
for his encouragement and support.
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