Convenient synthesis of structurally novel 1,3-disubstituted azetidine derivatives

Article abstract of DOI:10.1080/00397910801982340

A convenient synthesis of structurally novel 1,3-disubstituted azetidine derivatives is described. The approach involves condensation of an azetidine building block with sulfonylated carbamic acid methyl ester, subsequently followed by quenching the imidoyl chloride with amines. Different derivatives were prepared by substituting benzhydrol as well as benzenesulfonamide as part of the core structure. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910801982340

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Convenient Synthesis of Structurally Novel
1,3‐Disubstituted Azetidine Derivatives
Rajendra K. Kharul a , Amitgiri Goswami a , Archana Gite a , Atul K. Godha a
, Mukul Jain a & Pankaj R. Patel a
a Zydus Research Center , Ahmedabad, Gujarat, India
Published online: 09 May 2008.
To cite this article: Rajendra K. Kharul , Amitgiri Goswami , Archana Gite , Atul K. Godha , Mukul Jain &
Pankaj R. Patel (2008) Convenient Synthesis of Structurally Novel 1,3‐Disubstituted Azetidine Derivatives ,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
38:11, 1703-1717, DOI: 10.1080/00397910801982340
To link to this article: http://dx.doi.org/10.1080/00397910801982340
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Synthetic Communicationsw, 38: 1703–1717, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910801982340
Convenient Synthesis of Structurally Novel
1,3-Disubstituted Azetidine Derivatives
Rajendra K. Kharul, Amitgiri Goswami, Archana Gite,
Atul K. Godha, Mukul Jain, and Pankaj R. Patel
Zydus Research Center, Ahmedabad, Gujarat, India
Abstract: A convenient synthesis of structurally novel 1,3-disubstituted azetidine
derivatives is described. The approach involves condensation of an azetidine
building block with sulfonylated carbamic acid methyl ester, subsequently followed
by quenching the imidoyl chloride with amines. Different derivatives were prepared
by substituting benzhydrol as well as benzenesulfonamide as part of the core structure.
Keywords: Amination, azetidine, benzhydrol, imidoyl chloride
INTRODUCTION
Azetidine derivatives are biologically important. Recently, azetidine deriva-
tives have been reported to treat CB1 receptor–mediated disorders
including obesity.[1] Azetidine caboxamides have also been proposed for
use in the treatment of anxiety and epilepsy[2] and for neuroprotection.[3]
3-Aryloxy and 3-arylthio azetidinecarboxamides have been reported to
possess anticonvulsant and anti-epileptic activity.[4]
In continuation of our efforts to develop biologically active azetidine
derivatives, the present communication describes synthesis of various
N-[(3-benzhydryl-azetidin-1-yl)-alkylamino-methylene]-benzenesulfonamide
Received August 30, 2007
ZRC Communication No. 182
Address correspondence to Rajendra K. Kharul, Zydus Research Center, Sarkhej
Bavla N. H. 8A, Moraiya, Ahmedabad, 382210, Gujarat, India. E-mail:
rajendrakharul@zyduscadila.com
1703

1704
R. K. Kharul et al.
derivatives by amination of its corresponding imidoyl chloride derivatives
with aminoalkanes in dichloromethane at room temperature.
The various azetidine derivatives were synthesized via the general route
depicted in Scheme 1. Thus, benzhydrols (2) were condensed with 1-benzhy-
dryl-azetidin-3-ol[5] by using p-Toluenesulfonic acid (p-TSA) in refluxing
toluene to furnish substituted benzhydrylamines (4). The various benzhydrols
needed for the condensation reaction were prepared either by Grignard
reaction between corresponding benzaldehyde and the Grignard reagent,
aryl magnesium bromide, or by reducing the corresponding ketone.
The benzhydrylamine (4) was regioselectively deprotected with 1-chlor-
oethylchloroformate[6] to yield hydrochloride salt followed by treatment with
a base to furnish azetidine (5). Azetidine (5) was converted into its carbamoyl
chloride by treating it with phosgene, and then the resulting carbamoyl
chloride was reacted with substituted benzenesulfonamide to give sulfona-
mide (6). Sulfonamide (6) was treated with PCl5 to furnish imidoyl
chloride[7] followed by its quenching either with methylamine solution
(40% methanolic solution) or with cyclohexyl amine to yield the amine.
The amine was converted into its hydrochloride salt (1) by treating the
amine with ethereal HCl. The yields for the conversion from azetidines (5)
to (6) were low. Hence, sulfonamides (6) were synthesized according to
Scheme 2. Thus, azetidine (5) was coupled with sulfonylated carbamic acid
methyl ester of general formula (8) to furnish corresponding benezenesulfona-
mide derivative (6) in improved yields up to 60%. The carbamic acid methyl
esters (8) were obtained by condensing the corresponding arylsulfonamide
and methyl chloroformate in acetonitrile and using triethyl amine as a base
at room temperature for 15 h. The various azetidine derivatives synthesized
are listed in Table 1.
Scheme 1. Reagents and conditions: a) p-TSA, toluene, 110–115 8C, 2 h, 65–70%;
b) i, 1-chloroethylchloroformate, CH2Cl2, 20–25 8C, 16 h; ii, NaOH (1M), 25 8C, 75–
80%; c) i, COCl2, CH2Cl2, Et3N, 0 8C; ii, R4C6H4SO2NH2, Et3N, CH2Cl2, 25 8C, 15 h,
25%; d) PCl5, PhCl, 130–135 8C, 1 h; e); R5NH2, CH2Cl2, 0 8C, 10 min; ii, ethereal
HCl, 0 8C, 50%.

Novel 1,3-Disubstituted Azetidine Derivatives
1705
Scheme 2. Reagents and conditions: a) R4C6H4SO2NHCOOMe (8), toluene, reflux,
2 h, 60%.
It is noteworthy to mention that the high reactivity of the intermediate
imidoyl chloride (7) enables their quick conversion with wide range of
amines, which makes this route particularly amenable to combinatorial
chemistry purposes. It is further interesting to note that azetidine derivative
(1) contains the guanidine moiety, which can further be functionalized. The
guanidine moiety can be modified into chiral bases by the introduction of
chirality into the molecule, which has been well documented in the literature.[8]
Table 1. Various azetidine derivatives synthesized
Compound
R1
R2
R3
R4
R5
1a
1b
1c
1d
1e
1f
40-Cl
40-Cl
40-Cl
H
2-Cl
2-CF3
4-Cl
2-Cl
4-Cl
4-F
H
H
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Me
Me
Me
Me
Me
Me
Me
H
4-Cl
H
H
H
H
1g
1h
H
4-CF3
4-Cl
H
H
H
1i
1j
H
H
H
2-Cl
H
3-Cl
H
Cl
Me
Me
Me
1k
1l
H
H
2-Cl
H
3-Cl
H
Cl
CF3
1m
H
H
H
CF3

1706
R. K. Kharul et al.
In conclusion, we have synthesized various novel azetidine-based analogs
in good yield. The synthesis features condensation of azetidine building block
(5) with sulfonylated carbamic acid methyl ester (8) subsequently followed by
quenching of the imidoyl chloride with amines. The current synthesis
provided the flexibility of varying the first and third positions of the
azetidine. The biological activity of these compounds will be published in a
more specific journal in due course.
EXPERIMENTAL SECTION
General Methods
1H NMR was recorded on the NMR spectrometer M-300 (300 MHz) in CDCl3
or DMSO-d6 solvent. Chemical shifts were reported as parts per million
downfield from an internal tetramethylsilane standard (d ¼ 0.00 for 1H
NMR). Mass spectra were recorded on a Perkin-Elmer Sciex API 3000. IR
spectra were recorded on a FT-IR 8300 Shimadzu in KBr pellets or CHCl3
or CCl4 as solvent. Target compounds were analyzed for purity by analytical
high pressure liquid chromatography (HPLC) at lmax 220 nm using column
ODS C-18, 150 mm ꢀ 4.6 mm ꢀ 4 m on an Agilent 100 series. Melting
points were taken on a scientific melting-point apparatus and are uncorrected.
Thin-layer chromatography (TLC) was performed by using 25 DC-Alufolien
20 ꢀ 20 cm Kieselgel 60 F254 Merck plates.
Glassware was oven or flame dried prior to use. Reactions were
performed under an argon or nitrogen inert atmosphere whenever needed.
Crude products were purified by flash chromatography using 100- to 200-
mesh silica gel, 230- to 400-mesh silica gel, or neutral aluminum oxide.
General Procedure for Preparation of Benzhydrol (2)
Method A: By Reduction of Benzophenone using Sodium Borohydride
Diphenylmethanol (2h)
Sodium borohydride (4.157 g, 109.89 mmol, 2 equiv.) was added in
portions to a stirred solution of benzophenone (10 g, 54.94 mmol, 1 equiv.)
in methanol (60 mL) at 0–5 8C. The resulting mixture was warmed to room
temperature and stirred for 1 h. Excess of sodium borohydride was then
quenched with acetone and methanol was removed in vacuo. The residue
was diluted with ethyl acetate (400 mL). The organic phase was washed
with water (2 ꢀ 100 mL) and brine (100 mL), dried over sodium sulfate,
filtered, and concentrated in vacuo to yield diphenyl methanol (9.1 g,
1
49.45 mmol, 90%). H NMR (CDCl3, 300 MHz) d 5.79 (m, 1H), 7.2–7.3
(m, 8H). ESI-MS: 206.9 (M þ Na)þ, mp: 65–67 8C.

Novel 1,3-Disubstituted Azetidine Derivatives
1707
(4-Chlorophenyl)-(2-chloro-phenyl)-methanol (2a)
Yield: 99%. 1H NMR (CDCl3, 300 MHz) d 6.20–6.20 (m, 1H),
7.23–7.36 (m, 7H), 7.54–7.57 (m, 1H). ESI-MS: 236 (M-OH)þ.
Bis-(4-chlorophenyl)-methanol (2c)
1
Yield: 100%. H NMR (CDCl3, 300 MHz) d 5.79 (m, 1H), 7.2–7.3
(m, 8H). ESI-MS: 236 (M-OH)þ, mp: 100–102 8C.
Method B: By Grignard Reaction of Arylbromides with Substituted
Benzaldehydes
A one-fifth portion of arylbromide (2 equiv.) solution in dry tetrahydrofuran
was added in one portion to the stirring mixture of magnesium metal
(3 equiv.) in dry tetrahydrofuran at room temperature. It was supplied with
external heat to initiate generation of the Grignard reagent. Once the
formation of Grignard reagent was initiated, the remaining portion of aryl
bromide solution was added dropwise using the pressure equalizer funnel in
such a way that continuous reflux should be maintained. After ca. 4 h, this
solution was transferred via cannula to a solution of substituted benzaldehyde
(1 equiv.) in dry tetrahydrofuran at 0–5 8C. The resulting mixture was allowed
to warm to room temperature and stirred for 18 h (overnight), then diluted
with diethyl ether and acidified to pH ꢀ 3–5 slowly at 0–5 8C (in an ice
bath) using 1N HCl solution. The organic phase was washed with water
(2 ꢀ 100 mL) and brine (100 mL), dried over sodium sulfate, filtered
through Celitew, and concentrated in vacuo to furnish the crude product.
The crude material was purified by flash chromatography on silica gel.
(4-Chlorophenyl)-(2-trifluoromethyl-phenyl)-methanol (2b)
1
Yield: 90%. H NMR (CDCl3, 300 MHz) d 2.42–2.43 (m, 1H), 6.26–
6.27 (m, 1H), 7.22–7.29 (m, 4H), 7.37–7.42 (m, 1H), 7.54–7.58 (m, 2H),
7.67 (d, 1H, J ¼ 7.8 Hz). ESI-MS: 261.0 (M-OH)þ.
(4-Chlorophenyl)-(2,4-dichloro-phenyl)-methanol (2d)
Yield: 70%. 1H NMR (CDCl3, 300 MHz) d 2.33 (d, 1H, J ¼ 3.6 Hz), 6.16
(d, 1H, J ¼ 3.6 Hz), 7.27–7.36 (m, 6H), 7.57 (d, 2H, J ¼ 8.4 Hz). ESI-MS:
235 (M-OH)þ.
4-Chloro-phenyl)-phenyl-methanol (2e)
1
Yield: 64%. H NMR (CDCl3, 300 MHz) d 5.79 (m, 1H), 7.25–7.36
(m, 9H). ESI-MS 217.1 (M)2.
(4-Fluoro-phenyl)-phenyl-methanol (2f)
1
Yield: 68%. H NMR (CDCl3, 300 MHz) d 5.81 (s, 1H), 6.97–7.04
(m, 2H), 7.24–7.35 (m, 7H). ESI-MS: 203.1 (M þ H)þ.

1708
R. K. Kharul et al.
Phenyl-(4-trifluoromethyl-phenyl)-methanol (2g)
Yield: 47%. 1H NMR (CDCl3, 300 MHz) d 5.79 (d, 1H, J ¼ 3.9 Hz), 6.10
(d, 1H, J ¼ 3.9 Hz), 7.18–7.39 (m, 5H), 7.58 (d, 2H, J ¼ 8.9 Hz), 7.65 (d, 2H,
J ¼ 8.4 Hz). ESI-MS: 260.7 (M þ NH4)þ.
(2,3)-Dichloro-phenyl)-phenyl-methanol (2i)
1
Yield: 63%. H NMR (CDCl3, 300 MHz) d 2.33 (d, 1H, J ¼ 3.78 Hz),
6.22 (d, 1H, J ¼ 3.69 Hz), 7.27–7.42 (m, 6H), 7.61 (m, 1H). ESI-MS:
235.0 (M-OH)þ.
Preparation of Benzhydrylamine (4)
1-Benzhydryl-(3)-[(4-chloro-phenyl)-(2-chloro-phenyl)-methoxy]-
azetidine (4a)
A mixture of (2a) (2 g, 7.9 mmol), p-toluenesulfonic acid (2.71 g,
15.8 mmol), and 1-benzhydryl-3-azetidinol (3) in toluene (20 mL) was
heated at reflux by using a Dean–Stark apparatus for 1 h. The reaction
mixture was cooled to room temperature, diluted with ethyl acetate
(20 mL), washed with
a saturated solution of sodium bicarbonate
(1 ꢀ 20 mL) and saturated brine solution (1 ꢀ 20 mL), dried over sodium
sulfate, and concentrated in vacuo. The crude product was purified by flash
chromatography on silica gel to afford the title compound as a colorless oil
(2.56 g, 70%). 1H NMR (CDCl3, 300 MHz) d 2.90–2.96 (m, 2H),
3.40–3.46 (m, 2H), 4.11–4.21 (m, 1H), 4.33 (s, 1H), 5.72 (s, 1H),
7.14–7.50 (m, 18H). ESI-MS: 474 (M)þ.
1-Benzhydryl-(3)-[(4-chloro-phenyl)-(2-trifluoromethyl-phenyl)-
methoxy]-azetidine (4b)
1
Yield: 65%. H NMR (CDCl3, 300 MHz) d 2.86 (t, 1H, J ¼ 7.7 Hz), 2.96
(t, 1H, J ¼ 6.7 Hz), 3.31–3.36 (m, 1H), 3.47–3.50 (m, 1H), 4.18 (m, 1H),
4.32 (s, 1H), 5.71 (s, 1H), 7.17–7.27 (m, 8H), 7.33–7.40 (m, 6H), 7.49–
7.57 (m, 2H), 7.60–7.64 (m, 2H). ESI-MS: 508 (M þ H)þ.
1-Benzhydryl-(3)-[bis-(4-chloro-phenyl)-methoxy]-azetidine (4c)
Yield: 65%. 1H NMR (CDCl3, 300 MHz) d 2.91 (s, 2H), 3.40 (s, 2H),
4.15–4.19 (m, 1H), 4.33 (s, 1H), 5.22 (s, 1H), 7.17–7.37 (m, 18H).
ESI-MS: 474 (M)þ.

Novel 1,3-Disubstituted Azetidine Derivatives
1709
1-Benzhydryl-(3)-[(2,4-dichloro-phenyl)-phenyl-methoxy]-azetidine (4d)
1
Yield: 70%. H NMR (CDCl3, 300 MHz) d 2.89–2.97 (m, 2H), 3.42–3.46
(m, 2H), 4.17–4.21 (m, 1H), 5.67 (s, 1H), 7.16–7.19 (m, 2H), 7.22–7.25
(m, 5H), 7.27–7.31 (m, 5H), 7.31–7.37 (m, 5H), 7.46 (d, 1H, J ¼ 8.4 Hz).
ESI-MS: 474.2 (M)þ.
1-Benzhydryl-(3)-[(4-chloro-phenyl)-phenyl-methoxy]-azetidine (4e)
1
Yield: 68%. H NMR (CDCl3, 300 MHz) d 2.89–2.95 (m, 2H), 3.36–3.44
(m, 2H), 4.15–4.21 (m, 1H), 4.33 (s, 1H), 5.25 (s, 1H), 7.16–7.28
(m, 15H), 7.34–7.37 (m, 4H). ESI-MS: 440.2 (M þ H)þ.
1-Benzhydryl-(3)-[(4-fluoro-phenyl)-phenyl-methoxy]-azetidine (4f)
1
Yield: 70%. H NMR (CDCl3, 300 MHz) d 2.89–2.94 (m, 2H), 3.38–3.42
(m, 2H), 4.17–4.21 (q, 1H, J ¼ 8.15 Hz), 4.34 (s, 1H), 5.26 (s, 1H), 6.94–
6.99 (m, 2H), 7.18–7.22 (m, 2H), 7.25–7.36 (m, 15H). ESI-MS: 424.2
(M þ H)þ.
1-Benzhydryl-(3)-[phenyl-(4-trifluoromethyl-phenyl)-methoxy]-
azetidine (4g)
1
Yield: 65%. H NMR (CDCl3, 300 MHz) d 2.92–2.95 (m, 2H), 3.40–3.44
(m, 2H), 4.20–4.25 (m, 1H), 4.34 (s, 1H), 5.32 (s, 1H), 7.10–7.37
(m, 15H), 7.45 (d, 2H, J ¼ 8.1 Hz), 7.58 (d, 2H, J ¼ 8.4 Hz). ESI-MS: 474
(M þ H)þ.
1-Benzhydryl-(3)-benzhydryloxy-azetidine (4h)
1
Yield: 68%. H NMR (CDCl3, 300 MHz) d 2.91–2.96 (m, 2H), 3.38–3.43
(m, 2H), 4.19–4.29 (m, 1H), 4.34 (s, 1H), 5.28 (s, 1H), 7.12–7.36
(m, 20H). ESI-MS: 406 (M)þ.
1-Benzhydryl-(3)-[(2,3)-dichloro-phenyl)-phenyl-methoxy]-azetidine (4i)
1
Yield: 68%. H NMR (CDCl3, 300 MHz) d 2.89–2.97 (m, 2H), 3.42–3.47
(m, 2H), 4.17–4.21 (m, 1H), 4.33 (s, 1H), 5.74 (s, 1H), 7.16–7.22 (m, 4H),
7.22–7.25 (m, 3H), 7.27–7.31 (m, 5H), 7.31–7.37 (m, 5H), 7.47 (m, 1H).
ESI-MS: 474 (M)þ.

1710
R. K. Kharul et al.
General Procedure for Preparation of Azetidine (5)
(3)-[(4-Chloro-phenyl)-(2-chloro-phenyl)-methoxy]-azetidine (5a)
1-Chloroethyl chloroformate (1.88 g, 13.18 mmol, 2.5 equiv.) was added
to a stirred solution of (4a) (2.5 g, 5.27 mmol, 1 equiv.) in dichloromethane
(25 mL) dropwise at 0 8C. The reaction mixture was stirred at room tempera-
ture for 20 h. Then the reaction mixture was concentrated in vacuo to yield a
thick residue. The residue was dissolved in methanol (25 mL) and stirred at
room temperature for 2 h. The reaction mixture was concentrated in vacuo
and diluted with n-hexane (5 mL), diisopropyl ether (40 mL), and methanol
(5 mL) [1:8:1], to obtain the hydrochloride salt of 3-[(4-chloro-phenyl)-(2-
chloro-phenyl)-methoxy]-azetidine. The hydrochloride salt was converted to
the corresponding free base by partitioning between dichloromethane and
0.5N sodium hydroxide solution to afford title compound (5a) as colorless
1
oil (1.6 g, crude). H NMR (CDCl3, 300 MHz) d 3.97–4.05 (m, 2H), 4.06–
4.17 (m, 2H), 5.27 (s, 1H), 5.91 (s, 1H), 7.21–7.61 (m, 8H). ESI-MS: 307.9
(M)þ.
(3)-[(4-Chloro-phenyl)-(2-trifluoromethyl-phenyl)-methoxy]-azetidine (5b)
1
Yield: 85%. H NMR (CDCl3, 300 MHz) d 3.73–3.78 (m, 1H), 3.84–4.00
(m, 3H), 4.35–4.39 (m, 1H), 5.83 (s, 1H), 7.3 (d, 2H, J ¼ 8.4 Hz), 7.42
(d, 2H, J ¼ 8.4 Hz), 7.55–7.6 (m, 1H), 7.69–7.78 (m, 3H), 8.83 (m, 2H).
ESI-MS: 342 (M þ H)þ, mp: 123–125 8C.
(3)-[Bis-(4-chloro-phenyl)-methoxy]-azetidine (5c)
1
Yield 80%. H NMR (CDCl3, 300 MHz) d 3.58–3.61 (m, 3H), 4.03–4.09
(m, 1H), 4.15–4.19 (m, 1H), 4.36–4.42 (m, 1H), 7.20–7.38 (m, 8H). ESI-
MS: 308 (M)þ, mp: 127–129 8C.
(3)-[(2,4-Dichloro-phenyl)-phenyl-methoxy]-azetidine (5d)
1
Yield 84%. H NMR (CDCl3, 300 MHz) d 3.70–3.77 (m, 1H), 3.9–3.92
(m, 2H), 4.08–4.10 (m, 1H), 4.37–4.35 (m, 1H), 5.79 (s, 1H), 7.28–7.39
(m, 5H), 7.50–7.53 (m, 1H), 7.61–7.65 (m, 2H), 8.64–8.81 (m, 2H). ESI-
MS: 308 (M)þ.
(3)-[(4-Chloro-phenyl)-phenyl-methoxy]-azetidine (5e)
1H NMR (CD3OD, 300 MHz) d 3.28–3.33 (m, 2H), 3.94–4.14 (m, 2H), 5.26
(s, 1H), 5.53 (s, 1H), 7.20–7.29 (m, 5H), 7.31–7.41 (m, 4H). ESI-MS: 274.0
(M)þ.

Novel 1,3-Disubstituted Azetidine Derivatives
1711
(3)-[(4-Fluoro-phenyl)-phenyl-methoxy]-azetidine (5f)
1H NMR (CDCl3, 300 MHz) d 3.81–3.82 (m, 2H), 3.94–3.95 (m, 2H), 4.37
(m, 1H), 5.59 (s, 1H), 7.14–7.18 (m, 2H), 7.27–7.40 (m, 7H), 9.1 (m, 2H).
ESI-MS: 258.1 (M þ H)þ.
(3)-[Phenyl-(4-trifluoromethyl-phenyl)-methoxy]-azetidine (5g)
1H NMR (CDCl3, 300 MHz) d 3.85–3.88 (m, 2H), 4.04–4.08 (m, 2H), 4.57
(s, 1H), 5.37 (s, 1H), 7.24–7.43 (m, 7H), 7.58 (d, 2H, J ¼ 7.6 Hz), 9.59
(m, 2H). ESI-MS: 308.1 (M þ H)þ.
(3)-Benzhydryloxy-azetidine (5h)
1H-NMR (CD3OD, 300 mHz) d 3.28–3.33 (m, 2H), 3.95–4.11 (m, 2H), 5.27
(s, 1H), 5.52 (s, 1H), 7.21–7.41 (m, 10H). ESI-MS: 240.1 (M)þ.
(3)-[(2,3)-Dichloro-phenyl)-phenyl-methoxy]-azetidine (5i)
1H NMR (DMSO-d6, 300 MHz) d 3.7–3.77 (m, 1H), 3.9–3.92 (m, 2H), 4.08–
4.10 (m, 1H), 4.3–4.35 (m, 1H), 5.75 (s, 1H), 7.22–7.39 (m, 6H), 7.50–7.53
(m, 1H), 7.62–7.64 (d, 1H, J ¼ 8.2 Hz), 8.67–8.81 (m, 2H). ESI-MS: 308
(M)þ.
General Procedure for Preparation of Sulphonamides (6)
Method A: Using Phosgene Solution
4-Chloro-N-f(3)-[(4-chloro-phenyl)-(2-chloro-phenyl)-methoxy]-
azetidine-1-carbonylg-benzenesulfonamide (6a)
To a stirred solution of (5a) (2.7 g, 7.46 mmol, 1 equiv.) in dry dichloro-
methane (25 mL), phosgene (1.84 g, 18.66 mmol, 2.5 equiv.) (20% solution in
toluene) was added dropwise at 0 8C, followed by addition of triethylamine
(2.26 g, 22.40 mmol, 3 equiv.). The reaction mixture was stirred at room
temperature for 30 min. Then the reaction mixture was concentrated in
vacuo, and thus 3-[(4-chloro-phenyl)-(2-chloro-phenyl)-methoxy]-azetidine-
1-carbonyl chloride was obtained as a thick oil. To a stirred solution
of
3-[(4-chloro-phenyl)-(2-chloro-phenyl)-methoxy]-azetidine-1-carbonyl
chloride in dry dichloromethane (27 mL), 4-chlorobenzenesulfonamide
(1.4 g, 7.46 mmol, 1 equiv.) and triethylamine (3.77 g, 37.33 mmol, 3
equiv.) were added and stirred at room temperature for 18 h. The reaction
mixture was diluted with dichloromethane (20 mL). The organic phase was
washed with water (1 ꢀ 20 mL), diluted HCl solution (1 ꢀ 20 mL), water
again (2 ꢀ 20 mL), and saturated brine (1 ꢀ 20 mL): dried over sodium

1712
R. K. Kharul et al.
sulfate; filtered; and concentrated in vacuo. The crude material was purified by
flash chromatography on silica gel to afford the title compound (6a) as
colorless oil. Yield: 15%. 1H NMR (CDCl3, 300 MHz) d 3.85–3.93
(m, 2H), 4.02–4.09 (m, 2H), 4.34–4.38 (m, 1H), 5.75 (s, 1H), 7.21–7.35
(m, 7H), 7.43–7.50 (m, 3H), 7.98 (d, 2H, J ¼ 8.7 Hz). ESI-MS: 524.5
(M)þ, mp: 75–78 8C.
Method B: Using Methyl Carbamate (8)
Azetidine (5) (7.34 mmol, 1 equiv.) was mixed with 4-chlorobenzenesulfona-
mide methyl carbamate (8) (6.61 mmol, 0.9 equiv.) in toluene (50 mL) and
then refluxed for 1 h. The progress of the reaction was monitored by thin-
layer chromatography (TLC). After completion of the reaction, the reaction
mixture was cooled to room temperature and diluted with ethyl acetate
(75 mL). The organic layer washed with saturated bicarbonate solution
(2 ꢀ 20 mL), water (2 ꢀ 20 mL), and saturated ammonium chloride
solution (1 ꢀ 20 mL). The organic layer was dried over anhydrous sodium
sulphate, filtered, and concentrated in vacuo to furnish the crude compound.
The crude material was purified by column chromatography to furnish the
pure compound.
4-Chloro-N-f(3)-[(4-chloro-phenyl)-(2-trifluoromethyl-phenyl)-
methoxy]-azetidine-1-carbonylg-benzenesulfonamide (6b)
1H NMR (CDCl3, 300 MHz) d 3.73–3.80 (m, 1H), 3.93–3.99 (m, 2H),
4.08–4.13 (m, 1H), 4.29–4.35 (m, 1H), 5.73 (s, 1H), 7.11 (s, 1H), 7.20–7.4
(m, 4H), 7.42–7.49 (m, 3H), 7.50–7.54 (m, 2H), 7.67 (d, 1H, J ¼ 7.7 Hz),
7.97 (d, 2H, J ¼ 8.7 Hz). ESI-MS: 557 (M)2.
N-f(3)-[Bis-(4-chloro-phenyl)-methoxy]-azetidine-1-carbonylg-4-chlor-
obenzenesulfo namide (6c).
1H NMR (CDCl3, 300 MHz) d 3.84–3.89 (m, 2H), 4.00–4.06 (m, 2H),
4.32 (s, 1H), 5.24 (s, 1H), 7.27–7.19 (m, 4H), 7.26–7.30 (m, 4H), 7.5
(d, 2H, J ¼ 8.7 Hz), 7.97 (d, 2H, J ¼ 8.6 Hz). ESI-MS: 525 (M)2. Mp:
201–203 8C.
4-Chloro-N-f(3)-[(2,4-dichloro-phenyl)-phenyl-methoxy]-azetidine-1-
carbonyl]-benzenesulfonamide (6d)
1H NMR (CDCl3, 300 MHz) d 3.78–3.81 (m, 1H), 3.91–4.00 (m, 2H),
4.08–4.13 (m, 1H), 4.30–4.32 (m, 1H), 5.68 (s, 1H), 7.26–7.34 (m, 8H),
7.45–7.50 (m, 3H), 7.95 (d, 1H, J ¼ 9.45 Hz). ESI-MS: 524.8 (M)þ.
4-Chloro-N-f(3)-[(4-chloro-phenyl)-phenyl-methoxy]-azetidine-1-
carbonylg-benzenesulfonamide (6e)
1H NMR (CDCl3, 300 MHz) d 3.81–4.08 (m, 4H), 4.32–4.33 (m, 1H),
5.31 (s, 1H), 7.20–7.35 (m, 9H), 7.48 (d, 2H, J ¼ 8.5 Hz), 7.97 (d, 2H,
J ¼ 8.6 Hz). ESI-MS: 491.1 (M)þ.

Novel 1,3-Disubstituted Azetidine Derivatives
1713
4-Chloro-N-f(3)-[(4-fluoro-phenyl)-phenyl-methoxy]-azetidine-1-
carbonylg-benzenesulfonamide (6f)
1H NMR (CDCl3, 300 MHz) d 3.86–4.06 (m, 4H), 4.32–4.37 (m, 1H),
5.28 (s, 1H), 6.97–7.06 (m, 2H), 7.23–7.33 (m, 7H), 7.47 (d, 2H,
J ¼ 8.6 Hz), 7.97 (d, 2H, J ¼ 8.6 Hz). ESI-MS: 575 (M þ H)þ.
4-Chloro-N-f(3)-[phenyl-(4-trifluoromethyl-phenyl)-methoxy]-
azetidine-1-carbonylg-benzenesulfonamide (6g)
The crude material was carried forward without purification.
N-((3)-Benzhydryloxy-azetidine-1-carbonyl)-4-chloro-benzenesulfona-
mide (6h)
1H NMR (CDCl3, 300 MHz) d 3.90–3.96 (m, 2H), 3.97–4.29 (m, 2H),
4.29–4.31 (m, 1H), 5.30 (s, 1H), 7.27–7.29 (m, 10H), 7.46 (d, 2H,
J ¼ 8.5 Hz), 7.95 (d, 2H, J ¼ 8.5 Hz). ESI-MS: 455.1 (M)2.
N-((3)-Benzhydryloxy-azetidine-1-carbonyl)-4-chloro-benzenesulfona-
mide (6i)
1H NMR (CDCl3, 300 MHz) d 3.78–3.81 (m, 1H), 3.91–4.00 (m, 2H),
4.08–4.13 (m, 1H), 4.34–4.37 (m, 1H), 5.74 (s, 1H), 7.22–7.32 (m, 6H),
7.44–7.42 (m, 1H), 7.46–7.49 (m, 3H), 7.96 (d, 2H, J ¼ 8.7 Hz). ESI-MS:
525 (M)þ. Mp: 89–90 8C.
N-((3)-Benzhydryloxy-azetidine-1-carbonyl)-4-trifluoromethyl-benze-
nesulfonamide (6j)
1H NMR (CDCl3, 300 MHz) d 3.82–3.93 (m, 3H), 3.96–4.04 (m, 1H),
5.30 (s, 1H), 7.29–7.32 (m, 10H), 7.76 (d, 2H, J ¼ 8.1 Hz), 8.17 (d, 2H,
J ¼ 8.1 Hz).
Procedure for Preparation of Hydrochloride Salt (1)
4-Chloro-N-(f(3)-[(2-chloro-phenyl)-(4-chloro-phenyl)-methoxy]-
azetidin-1-ylg-methylamino-methylenebenzene sulfonamide HCl salt (1a)
Phosphorus pentachloride (0.22 g, 1.04 mmol, 1.1 equiv.) was added to a stirred
solution of (6a) (0.5 g, 0.96 mmol, 1 equiv.) in chlorobenzene (5 mL) at room
temperature. It was refluxed for 30 min, allowed to cool to room temperature
and concentrated in vacuo. The residual imidoyl chloride was then redissolved
in dichloromethane (10 mL) and quenched with 40% aqueous methylamine
solution. The reaction mixture was then stirred at room temperature for
30 min. The reaction mixture was then diluted with dichloromethane
(10 mL), washed with water (2 ꢀ 10 mL) and saturated brine solution
(1 ꢀ 10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo.
The crude material was purified by flash chromatography on neutral

1714
R. K. Kharul et al.
aluminum oxide as a stationary phase and ethyl acetate and n-hexane as mobile
phase to afford free amine (0.4 g). The free amine (0.4 g) was converted to its
corresponding hydrochloride salt in diethyl ether using ethereal HCl to afford
1
the title compound (1a) (0.4 g, 78%) as a white solid. H NMR (CDCl3,
300 MHz) d 2.87 (s, 3H), 4.09 (s, 2H), 4.25–4.34 (m, 3H), 5.77 (s, 1H),
7.17–7.41 (m, 9H), 7.46 (d, 1H, J ¼ 7.3 Hz), 7.78 (d, 2H, J ¼ 8.2 Hz).
ESI-MS ¼ 538.5 [M]þ, mp: 86–88 8C, HPLC purity: 95.58%.
4-Chloro-N-(f(3)-[(4-chloro-phenyl)-(2-trifluoromethyl-phenyl)-
methoxy]-azetidin-1-ylg-methylamino-methylene)-
benzenesulfonamide HCl salt (1b)
Yield: 35%. 1H NMR (CDCl3, 300 MHz) d 2.60 (d, 3H, J ¼ 4.5 Hz), 3.87–3.9
(m, 1H), 4.02–4.06 (m, 1H), 4.20–4.29 (m, 3H), 5.75 (s, 1H), 7.01 (m, 1H),
7.28 (d, 2H, J ¼ 8.5 Hz), 7.41 (d, 2H, J ¼ 8.5 Hz), 7.51–7.58 (m, 3H), 7.71–
7.76 (m, 5H). ESI-MS ¼ 572.1 [M]þ, mp: 104–106 8C, HPLC purity:
96.58%.
N-(f(3)-[Bis-(4-chloro-phenyl)-methoxy]-azetidin-1-ylg-methylamino-
methylene)-4-chloro-benzenesulfonamide HCl salt (1c)
Yield: 32%. 1H NMR (CDCl3, 300 MHz) d 2.79 (s, 3H), 4.08 (s, 2H), 4.22–
4.32 (m, 3H), 5.27 (s, 1H), 7.18–7.32 (m, 8H), 7.39 (d, 2H, J ¼ 8.1 Hz), 7.78
(d, 2H, J ¼ 8.1 Hz). ESI-MS ¼ 538.1 [M]þ, mp: 146–148 8C, HPLC purity:
98.22%.
4-Chloro-N-(f(3)-[(2,4-dichloro-phenyl)-phenyl-methoxy]-azetidin-
1-ylg-methylamino-methylene)- benzenesulfonamide HCl salt (1d)
1
Yield: 25%. H NMR (DMSO-d6, 300 MHz) d 2.60 (3H, d, J ¼ 4.6 Hz),
3.88–3.91 (1H, m), 4.00–4.03 (1H, m), 4.15–4.20 (1H, m), 4.26–4.31 (2H,
m), 5.73 (1H, s), 7.01 (1H, m), 7.29–7.37 (5H, m), 7.47–7.54 (3H, m),
7.59–7.65 (2H, m), 7.72–7.75 (2H, m). ESI-MS ¼ 538.0 [M]þ, mp:
68–70 8C, HPLC purity: 94.93%.
4-Chloro-N-(f(3)-[(4-chloro-phenyl)-phenyl-methoxy]-azetidin-1-ylg-
methylamino-methylene)-benzene Sulfonamide HCl Salt (1e)
Yield: 35%. 1H NMR (CDCl3, 300 MHz) d: 2.71 (3H, s), 3.96–4.02 (2H, m),
4.19–4.29 (3H, m), 5.54 (1H, s), 6.99 (1H, s), 7.24–7.34 (5H, m), 7.37–7.41
(4H, m), 7.53 (2H, d, J ¼ 8.1 Hz), 7.74 (2H, d, J ¼ 8.2 Hz). ESI-MS ¼ 504
[M]þ, mp: 126–128 8C, HPLC purity: 97.77%.

Novel 1,3-Disubstituted Azetidine Derivatives
1715
4-Chloro-N-(f(3)-[(4-fluoro-phenyl)-phenyl-methoxy]-azetidin-1-ylg-
methylamino-methylene)-benzenesulfonamide HCl Salt (1f)
Yield: 20%. 1H NMR (CDCl3, 300 MHz) d 2.71 (3H, s), 3.96–4.02 (2H, m),
4.19–4.29 (3H, m), 5.54 (1H, s), 6.99 (1H, s), 7.24–7.34 (5H, m), 7.37–7.41
(4H, m), 7.53 (2H, d, J ¼ 8.1 Hz), 7.74 (2H, d, J ¼ 8.2 Hz). ESI-MS ¼ 504
[M]þ, mp: 126–128 8C, HPLC purity: 97.77%.
4-Chloro-N-(f(3)-[(4-fluoro-phenyl)-phenyl-methoxy]-azetidin-1-ylg-
methylamino-methylene)-benzenesulfonamide HCl Salt (1g)
1
Yield: 40%. H NMR (DMSO-d6, 300 MHz) d 2.61 (3H, d, J ¼ 4.4 Hz),
3.94–3.97 (2H, m), 4.22–4.29 (3H, m), 5.66 (1H, s), 7.01 (1H, m), 7.35 –
7.39 (4H, m), 7.51–7.59 (4H, m), 7.69–7.76 (4H, m). ESI-MS ¼ 538 [M]þ,
mp: 89–90 8C, HPLC purity: 98.23%.
4-Chloro-N-(f(3)-[(4-chloro-phenyl)-phenyl-methoxy]-azetidin-1-ylg-
cyclohexylamino-methylene)-benzene Sulfonamide HCl Salt (1h)
1
Yield: 33%. H NMR (CDCl3, 300 MHz) d 1.05–1.09 (6H, m), 1.47–1.56
(4H, m), 3.36 (1H, q, J ¼ 6.9 Hz, 13.9 Hz), 3.97–3.98 (2H, m), 4.19–4.31
(3H, m), 5.55 (1H, s), 6.87 (1H, d, J ¼ 8.2 Hz), 7.25–7.41 (9H, m), 7.53
(2H, d, J ¼ 8.3 Hz), 7.69 (2H, d, J ¼ 8.3 Hz). ESI-MS ¼ 572 [M]þ, mp:
106–108 8C, HPLC purity: 96.13%.
N-[((3)-Benzhydryloxy-azetidin-1-yl)-methylamino-methylene]-
benzenesulfonamide Hydrochloride Salt (1i)
Yield 25%. 1H NMR (DMSO-d6, 300 MHz) d 2.62 (3H, d, J ¼ 4.5 Hz), 3.95–
3.99 (2H, m), 4.20–4.30 (3H, m), 5.51 (1H, s), 6.98 (1H,s), 7.24–7.34 (10H,
m), 7.45–7.50 (3H, m), 7.72–7.75 (2H, m). ESI-MS ¼ 436 [M þ H]þ, mp:
65–67 8C, HPLC purity: 92.69%.
4-Chloro-N-(cyclohexylamino-f(3)-[(2,(3)-dichloro-phenyl)-phenyl-
methoxy]-azetidin-1-ylg-methylene)-benzenesulfonamide HCl Salt. (1j)
Yield 50%. 1H NMR (DMSO-d6, 300 MHz) d 1.06–1.08 (6H, m), 1.54–1.56
(4H, m), 3.20 (1H, m), 3.89–3.92 (1H, m), 4.02–4.05 (1H, m), 4.16–4.22
(1H, m), 4.27–4.36 (2H, m), 5.79 (1H, s), 6.77 (1H, d, J ¼ 7.92 Hz), 7.29–
7.33 (5H, m), 7.45 (1H, t, J ¼ 7.9 Hz), 7.52 (2H, d, J ¼ 8.4 Hz), 7.60–7.70
(4H, m). ESI-MS ¼ 606 [M]þ, mp: 115–116 8C, HPLC purity: 94.12%.

1716
R. K. Kharul et al.
4-Chloro-N-(f(3)-[(2,(3)-dichloro-phenyl)-phenyl-methoxy]-azetidin-1-
ylg-methylamino-methylene)-benzenesulfonamide HCl Salt (1k)
1
Yield 40%. H NMR (DMSO-d6, 300 MHz) d: 2.60 (3H, d, J ¼ 4.5 Hz),
3.88–3.93 (1H, m), 4.02–4.05 (1H, m), 4.16–4.21 (1H, m), 4.26–4.35 (2H,
m), 5.79 (1H, s), 7.01 (1H, m), 7.29–7.37 (5H, m), 7.44 (1H, t,
J ¼ 7.8 Hz), 7.51–7.54 (2H, m), 7.59–7.65 (2H, m), 7.72–7.75 (2H, m).
ESI-MS ¼ 538 [M]þ, mp: 93–95 8C, HPLC purity: 95.99%.
N-[((3)-Benzhydryloxy-azetidin-1-yl)-cyclohexylamino-methylene]-4-
trifluoromethyl-benzenesulfonamide HCl Salt (1l)
Yield 40%. 1H NMR (DMSO-d6, 300 MHz) d 1.00–1.10 (5H, m), 1.48–1.51
(5H, m), 3.15 (1H, s), 3.96–4.00 (2H, dd, J ¼ 3.3 Hz, 9.91 Hz), 4.22–4.33
(3H, m), 5.52 (1H, s), 6.85 (1H, d, J ¼ 8.2 Hz), 7.23 – 7.35 (10H, m),
7.83–7.91 (4H, m). ESI-MS ¼ 571 [M þ H]þ, mp: 97–98 8C, HPLC
purity: 94.03%.
N-[((3)-Benzhydryloxy-azetidin-1-yl)-methylamino-methylene]-4-
trifluoromethyl-benzenesulfonamide HCl Salt (1m)
Yield 15%. 1H NMR (DMSO-d6, 300 MHz) d 2.61 (3H, d, J ¼ 4.5 Hz), 3.97–
4.00 (2H, dd, J ¼2.9 Hz, 9.5 Hz), 4.21–4.31 (3H, m), 5.52 (1H, s), 7.06 (1H,
m), 7.23–7.34 (10H, m), 7.85 (2H, d, J ¼ 8.33 Hz), 7.96 (2H, d, J ¼ 8.25 Hz).
ESI-MS ¼ 504 [M þ H]þ, mp: 119–120 8C, HPLC purity ¼ 97.67%.
ACKNOWLEDGMENT
We thank the management of Zydus Group for encouragement and our
analytical department for support.
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