Synthesis and characterization of N-arylsulfonylazetidines

Article abstract of DOI:10.1002/jhet.5570450449

(Chemical Equation Presented) A convenient method for the synthesis of N-arylsulfonyl azetidines using N-(3-bromopropyl)-arylsulfonamide with cesium carbonate and potassium iodide in DMF is reported. The reaction conditions are optimized and seven N-aryls

Full text of DOI:10.1002/jhet.5570450449

Jul-Aug 2008
1229
Synthesis and Characterization of N-Arylsulfonylazetidines
Songde Tan, Yiwen Chen, Ralph A. Zingaro* and Joseph H. Reibenspies
Department of Chemistry, Texas A&M University, College Station, TX 77843-3255, USA
Received July 16, 2007
CsCO3, KI
RO2SHN
Br
RO2SN
DMF
A convenient method for the synthesis of N-arylsulfonyl azetidines using N-(3-bromopropyl)-
arylsulfonamide with cesium carbonate and potassium iodide in DMF is reported. The reaction conditions
are optimized and seven N-arylsulfonyl azetidines have been synthesized in good yield using this method.
The structures of compounds 2a and 2e were determined by X-ray crystallography.
J. Heterocyclic Chem., 45, 1229 (2008).
INTRODUCTION
to deprotonate 3-halopropylaryl sulfonamide to form
N-arylsulfonyl azetidines. However, it is notable that
when a weaker base such as potassium carbonate or
stronger base such as sodium hydroxide is used, the
reaction is unsuccessful. And with these substrates, which
bear alkyl substituents on sulfonamine, the reaction is also
unsuccessful. Secondly, the solvent plays an important
role in the reaction yield. Because the deprotonation of
the sulfonamine is the key step during the reaction, polar
solvents favor the reaction. The solubility of cesium
carbonate is greater in polar solvents than in nonpolar
solvents. It was found that in the dehydrohalogenation of
N-(3-bromopropyl)-4-methylbenzenesulfonamide the
reaction yield can reach about 80% when the DMF is used
Azetidines are valuable compounds in pharmaceutical
research [1-4]. However, azetidines represent one of the
more difficult group of amines to synthesize because of
the unfavorable enthalpy of activation in four-membered
ring formation [5]. The development of effective methods
for the synthesis of azetidines has posed a challenge for
more than one hundred years since azetidines were first
prepared in low yield in 1888 by treatment of 3-bromo-
propylamine with a base [6].
Several methods have been utilized to synthesize
N-arylsulfonylazetidines and include alkylation of a
primary amine with the bis-triflate of a 1,3-propane-
diol species [7], methylene transfer from dimethyl-
oxosulphonium methylide to azetidines [8], cycliza-
tion of ditoslyloxypropanes with sulfonamines [9],
cyclization of N-[ꢀ-(phenylseleno)propyl]sulfon-
amines [10], and cyclization of 3-chloropropyl
sulfonamines [11]. Strong bases such as sodium metal
or sodium hydroxide have been used, but these lead to
competing elimination reactions and dimerization to
bisazacyclooctane sulfonamides and these reactions
are always run in ethanol at reflux temperature.
Scheme 1. Synthesis of compounds 2a-g.
CsCO3, KI
RO2SN
yield (%)
82.4
RO2SHN
Br
DMF
1a R=
1b R=
1c R=
2a R=
2b R=
2c R=
81.3
80.5
Recently, while investigating the synthesis of resorcin-
[4]arene derivates, a convenient method for the synthesis
of N-arylsulfonyl azetidines was discovered. Herein, are
described the syntheses of N-arylsulfonylazetidines by the
reaction between N-(3-bromopropyl)aryl sulfonamide and
cesium carbonate and potassium iodide in DMF.
Cl
Cl
1d R=
2d R=
2e R=
80.2
79.3
Cl
Cl
RESULTS AND DISCUSSION
1e R=
N
N
During optimization of the reaction conditions, it was
found that there are three key factors involved in this
reaction: base, solvent and the nature of the leaving
group. Vaughan, et al. [11] reported that in the dehydro-
halogenation of 3-chloropropylsulfonamines, deproto-
nation of the sulfonamine is necessary. Recently, we
found that cesium carbonate is a sufficiently strong base
1f R=
1g R=
78.4
77.9
2f R=
2g R=
S
S
Br
SO2N
SO2NH

1230
S. Tan, Y. Chen, R. A. Zingaro and J. H. Reibenspies
Vol 45
as the solvent. However, only about a 10% yield was
obtained when the solvent is dichloromethane or benzene.
Thirdly, the leaving group plays an important role in the
reaction. Potassium iodide converts N-(3-bromopropyl)-
arylsulfonamide to the more reactive N-(3-iodopropyl)-
arylsulfonamide. It was found that the reaction is
unsuccessful without potassium iodide.
The structures of compounds 2a and 2e were
determined utilizing X-ray crystallography. Compound 2a
or 2e was obtained in the form of air-stable, colorless
crystals by slow evaporation from a solution of 2a or 2e in
methanol. The perspective view of compound 2a is shown
in Figure 1.
The perspective view of compound 2e is shown in
Figure 2. Examination of the crystal structure of 2e shows
that its structure is very similar to that of 2a.
CONCLUSION
We report a convenient method for the synthesis of N-
arylsulfonyl azetidines using N-(3-bromopropyl)aryl-
sulfonamide with cesium carbonate and potassium iodide
in DMF. Seven N-arylsulfonyl azetidines have been
synthesized in good yield using this method. The
structures of compounds 2a and 2e have been determined
by X-ray crystallography.
Examination of the crystal structure of 2a shows that
the angle between the plane of the four-membered ring
and the plane of benzene is close to 90°. The angles
within the four-membered ring are close to 90° with
C(11)-N(1)-C(13) slightly larger [90.66(10)] than the
others. The average value of the endocyclic N-C bonds
[1.505(18)] and C-C bonds [1.539(2)] are in agreement
with the value obtained in 1-(diphenylmethyl)azetidin-3-
ol [12].
EXPERIMENTAL
General. N-(3-Bromopropyl)arylsulfonamides
1
were
prepared according to literature methods [13]. All melting points
were taken on a Buchi-Tottoli capillary apparatus and are
uncorrected; H and 13C NMR spectra were measured in CDCl3
(TMS as internal reference), unless otherwise specified, at 300
MHz and 75 MHz, using a Varian 300 MHz NMR spectrometer.
1
Figure 1. Molecular structure of 2a.
The mass spectral measurements were obtained using a Kratos
MS80 mass spectrometer. Column chromatography was
performed on Merck silica gel 230-400 mesh ASTM.
Microanalyses were in agreement with theoretical values (0.4%).
Elemental analyses were performed by the Galbraith
Laboratories, Knoxville, Tenn.
General method for synthesis of 2. To a stirred suspension
of 1 (0.001 mol) in DMF (10 mL), cesium carbonate (0.001 mol)
and potassium iodide (0.001 mol) were added. The resulting
mixture was stirred at room temperature overnight. The solvent
was removed in vacuo and the residue was purified by silica gel
column chromatography, eluted with dichloromethane, to afford
the desired product 2.
1-(Toluene-4-sulfonyl)-azetidine (2a), this compound was
obtained in the form of white crystals by recrystallization from
methanol in 82.4% yield. m.p. 119-121° (reported 120° [14]). 1H
NMR (CDCl3) ꢀ (ppm): 2.07 (m, 2H, CH2), 2.47 (s, 3H, CH3),
Figure 2. Molecular structure of 2e.

Jul-Aug 2008
Synthesis and Characterization of N-Arylsulfonylazetidines
1231
Table 1
Crystal data and Structure Refinement of Compound 2a and 2e
2a
2e
Empirical formula
C10H12NO2S
210.27
110(2)
C15H18N2O2S
290.37
Formula weight
Temperature (K)
Wavelength (Å)
Crystal system
Space group
Unit cell dimensions
a (Å)
110(2)
0.71073
0.71073
Monoclinic
P2(1)/n
Orthorhombic
Pnma
7.4237(7)
9.7647(10)
13.5192(14)
90
11.5918(7)
10.0015(6)
12.6481(8)
90
109.0880(10)
90
b (Å)
c (Å)
ꢁ (°)
ꢂ (°)
90
90
ꢃ (°)
Volume (Å3)
Z
980.01(17)
4
1.425
1385.74(15)
4
D
calc (Mg/m3)
1.392
Absorption coefficient (mm-1)
0.302
444
0.237
616
F(000)
Crystal size (mm3)
Theta range for data collection (°)
Index ranges
0.20 x 0.17 x 0.05
4.17 to 24.98
-8<=h<=8
-11<=k<=11
-13<=l<=16
6496
0.30 x 0.20 x 0.20
4.08 to 28.13
-15<=h<=15
-13<=k<=13
-16<=l<=16
13657
Reflections collected
Independent reflections
Refinement method
865 [R(int) = 0.0305]
Full-matrix least-squares on F
865 / 0 / 73
1.067
3422 [R(int) = 0.0198]
Full-matrix least-squares on F
3422 / 0 / 183
1.053
2
2
Data / restraints / parameters
2
Goodness-of-fit on F
Final R indices [I>2sigma(I)]
R1 = 0.0499
wR2 = 0.1222
R1 = 0.0536,
wR2 = 0.1290
0.874 and -0.322
R1 = 0.0448
wR2 = 0.1134
R1 = 0.0480
wR2 = 0.1173
0.558 and -0.375
R indices (all data)
Largest diff. peak and hole (e.Å-3)
3.77 (t, 4H, CH2), 7.27-7.37 (dd, J = 0.9, 4.8 Hz, 4H, ArH), 13C
NMR (CDCl3) ꢀ (ppm): 15.25, 21.58, 50.83, 128.40, 129.70,
143.92. MS (ESI) (CHCl3): 212 [M+H]+. Anal. Calcd. for
C10H13NO2S: C, 56.85; H, 6.20; N, 6.63; O, 15.15; S, 15.18.
Found: C, 56.48; H, 6.31; N, 6.30; O, 14.21; S, 13.92.
ArH), 8.01-8.04 (m, H, ArH), 13C NMR (CDCl3) ꢀ (ppm): 14.93,
51.06, 126.84, 131.26, 131.95, 132.61, 133.60, 136.01. MS
(ESI) (CHCl3): 232 [M+H]+. Anal. Calcd. for C9H10ClNO2S: C,
46.65; H, 4.35; Cl, 15.30; N, 6.05; O, 13.81; S, 13.84. Found: C,
46.35; H, 4.18; Cl, 15.58; N, 6.14; O, 14.50; S, 13.25.
1-[5-(Dimethyl-amine)-naphthalenyl-1-sulfony]-azetidine
(2e), this compound was obtained in the form of white crystals
by recrystallization from methanol in 79.3% yield, m.p. 77-79°.
1H NMR (CDCl3) ꢀ (ppm): 2.11 (m, 2H, CH2), 2.87 (s, 6H,
CH3), 3.90 (t, 4H, CH2), 7.16-7.19 (dd, J = 0.9, 7.8 Hz, 1H,
ArH), 7.24-7.57 (m, 2H, ArH), 8.21-8.23 (dd, J = 0.9, 7.2 Hz,
1H, ArH), 8.38-8.41 (dd, J =0.9, 8.7 Hz, 1H, ArH), 8.54-8.57
(m, 1H, ArH). 13C NMR (CDCl3) ꢀ (ppm): 15.04, 45.44, 50.21,
115.20, 120.03, 123.19, 128.04, 130.53, 130.83. MS (ESI)
(CHCl3): 291 [M+H]+. Anal. Calcd. for C15H18N2O2S: C, 62.04;
H, 6.25; N, 9.65; O, 11.02; S, 11.04. Found: C, 61.72; H, 6.30;
N, 9.24; O, 10.18; S, 11.05.
1-Benzenesulfonyl-azetidine (2b), this compound was
1
obtained as a liquid in 81.3% yield. H NMR (CDCl3) ꢀ (ppm):
2.06 (m, 2H, CH2), 3.77 (t, 4H, CH2), 7.56-7.66 (m, 3H, ArH),
7.82-7.86 (m, 2H, ArH), 13C NMR (CDCl3) ꢀ (ppm): 15.20,
50.87, 128.23, 129.04, 133.05. MS (ESI) (CHCl3): 198 [M+H]+.
Anal. Calcd. for C9H11NO2S: C, 54.80; H, 5.62; N, 7.10; O,
16.22; S, 16.26. Found: C, 54.44; H, 5.74; N, 7.40; O, 16.60; S,
15.82.
1-(4-Chlorobenzenesulfonyl)-azetidine (2c), this compound
was obtained in the form of white crystals by recrystallization
from methanol in 80.5% yield. m.p. 116-118°. 1H NMR (CDCl3)
ꢀ (ppm): 2.11 (m, 2H, CH2), 3.80 (t, 4H, CH2), 7.55-7.59 (m,
2H, ArH), 7.77-7.82 (m, 2H, ArH), 13C NMR (CDCl3) ꢀ (ppm):
15.26, 50.97, 129.42, 129.69. MS (ESI) (CHCl3): 232 [M+H]+.
Anal. Calcd. for C9H10ClNO2S: C, 46.65; H, 4.35; Cl, 15.30; N,
6.05; O, 13.81; S, 13.84. Found: C, 46.41; H, 4.23; Cl, 15.60; N,
6.21; O, 14.02; S, 13.54.
1-(Thiophene-2-sulfonyl)-azetidine (2f), this compound
was obtained in the form of white crystals by recrystallization
from methanol in 78.4% yield, m.p. 66-68°. 1H NMR (CDCl3) ꢀ
(ppm): 2.09 (m, 2H, CH2), 3.84 (t, 4H, CH2), 7.21-7.24 (m, H,
ArH), 7.62-7.64 (m, H, ArH), 7.70-7.72 (m, H, ArH), 13C NMR
(CDCl3) ꢀ (ppm): 14.99, 51.29, 127.77, 132.65, 133.41. MS
(ESI) (CHCl3): 204 [M+H]+. Anal. Calcd. for C7H9NO2S2: C,
1-(2-Chlorobenzenesulfonyl)-azetidine (2d), this compound
1
was obtained as a liquid in 80.2% yield. H NMR (CDCl3) ꢀ
(ppm): 2.21 (m, 2H, CH2), 4.04 (t, 4H, CH2), 7.56-7.62 (m, 3H,

1232
S. Tan, Y. Chen, R. A. Zingaro and J. H. Reibenspies
Vol 45
REFERENCES AND NOTES
41.36; H, 4.46; N, 6.89; O, 15.74; S, 31.55. Found: C, 41.16; H,
4.51; N, 6.82; O, 15.87; S, 31.64.
1,3-Bis[sulfonyl-azetidine]-benzene (2g), this compound
was obtained in the form of white crystals by recrystallization
from methanol in 77.9% yield, m.p. 179-181°. 1H NMR (CDCl3)
ꢀ (ppm): 2.15 (m, 4H, CH2), 3.86 (t, 8H, CH2), 7.80-7.85 (m, H,
ArH), 8.10-8.13(m, 2H, ArH) 8.30-8.31 (m, H, ArH), 13C NMR
(CDCl3) ꢀ (ppm): 15.27, 51.17, 127.62, 130.14, 132.23, 136.86.
MS (ESI) (CHCl3): 317 [M+H]+. Anal. Calcd. for C12H16N2O4S2:
C, 45.55; H, 5.10; N, 8.85; O, 20.23; S, 20.27. Found: C, 45.32;
H, 5.18; N, 8.24; O, 20.41; S, 20.85.
X-ray crystallography. Crystallographic measurements were
carried out on a Siemens P4 diffractometer using graphite-
monochromated Mo-Kꢀ radiation (ꢁ = 0.71073 Å) and a 12 kW
rotating generator. The data were collected at 110 K. The
structures were solved and refined using the programs SHELXS-
97 (Sheldrick, 1997) and SHELXL (Sheldrick, 1997). The
program X-Seed (Barbour, 1999) was used as an interface to the
SHELX programs.
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Acknowledgements. This work was supported by a grant
from the Robert A. Welch Foundation, Houston, Texas (A-
0084).