Synthesis of C-Unsubstituted 1,2-Diazetidines and Their Ring-Opening Reactions via Selective N-N Bond Cleavage

Article abstract of DOI:10.1021/acs.joc.8b01223

C-Unsubstituted 1,2-diazetidines, a rarely studied type of four-membered heterocyclic compounds, were synthesized through an operationally simple intermolecular vicinal disubstitution reaction. 1,2-Diazetidine derivatives bearing various N-arylsulfonyl groups were readily accessed and studied by experimental and computed Raman spectra. The ring-opening reaction of the diazetidine was explored and resulted in the identification of a selective N-N bond cleavage with thiols as nucleophiles, which stereoselectively produced a new class of N-sulfenylimine derivatives with C-aminomethyl groups.

Full text of DOI:10.1021/acs.joc.8b01223

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Note
Synthesis of C-unsubstituted 1,2-Diazetidines and their
Ring-opening Reactions via Selective N#N Bond Cleavage
Hetti Handi Chaminda Lakmal, Joanna Xiuzhu Xu, Xue Xu, Bassem Ahmed, Christopher Fong, David
J. Szalda, Keith Ramig, Andrzej Sygula, Charles Edwin Webster, Dongmao Zhang, and Xin Cui
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01223 • Publication Date (Web): 13 Jun 2018
Downloaded from http://pubs.acs.org on June 13, 2018
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The Journal of Organic Chemistry
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Synthesis of C-unsubstituted 1,2-Diazetidines and their Ring-opening
Reactions via Selective N─N Bond Cleavage
Hetti Handi Chaminda Lakmal,† Joanna Xiuzhu Xu,† Xue Xu,† Bassem Ahmed,‡ Christopher Fong,‡
David J. Szalda,‡ Keith Ramig,‡ Andrzej Sygula,† Charles Edwin Webster,† Dongmao Zhang,† Xin
Cui*,†
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† Department of Chemistry, Mississippi State University, Mississippi State, Mississippi 39762, United States
‡ Department of Natural Sciences, Baruch College of the City University of New York, 17 Lexington Avenue, New York,
New York 10010, United States
Supporting Information Placeholder
ABSTRACT: C-unsubstituted 1,2-diazetidines, a rarely studied type of four-membered heterocyclic compounds, were synthesized
through an operationally simple intermolecular vicinal disubstitution reaction. 1,2-Diazetidine derivatives bearing various N-aryl-
sulfonyl groups were readily accessed and studied by experimental and computed Raman spectra. Ring-opening reaction of the diaz-
etidine was explored and resulted in the identification of a selective N‒N bond cleavage with thiols as nucleophiles, which stereose-
lectively produced a new class of N-sulfenylimine derivatives with C-aminomethyl groups.
Among small-ring heterocyclic compounds, 1,2-diazetidine
represents one of the most structurally unique classes as the
four-membered skeleton contains three types of bonds, C‒C, C‒
N, and N‒N.1 This diversity of the bond types, together with the
ring strain, would potentially enable rich synthetic applications.
Their structural relationship with β-lactams and 1,2-diazet-
idinones also makes them biologically and pharmacologically
attractive.1-2 However, none of these promising directions has
been extensively explored due to the largely underdeveloped
synthetic approaches toward these compounds. Among the lim-
ited synthetic strategies, [2+2] cycloaddition of alkenes and azo
compounds serves as a classical method, which was often used
to construct 1,2-diazetidine derivatives with relatively hindered
C-substituents in variable yields (Scheme 1, A).3 Recently, in-
tramolecular ring-closing reactions have been proven success-
ful for accessing several types of 1,2-diazetidine derivatives, ei-
ther based on intramolecular addition reactions to allenes,4 or
intramolecular substitution reactions (Scheme 1, A).5 While the
parent 1,2-diazetidine continues to be unknown, simple 1,2-di-
azetidines with unsubstituted C3 and C4 were rarely reported.
Their synthesis has not been known by using the previous meth-
ods for making the C-substituted derivatives.5c
Scheme 1. Synthetic Pathways for Constructing 1,2-Diazet-
idines
available 2-hydroxyethyl-hydrazine is largely diminished by
the tedious trisulfonylation and iodination step for constructing
the precursors. In contrast, a more practical access to C-unsub-
stituted 1,2-disulfonyl-1,2-diazetidines would be an intermolec-
ular vicinal disubstitution reaction with dihaloethane and hydra-
zines (Scheme 1, B).6 Identification of suitable and general con-
ditions for this intermolecular process will offer a more direct
and operationally simple pathway.
The sole effective synthesis of these simple diazetidines has
been demonstrated by Shipman and coworkers’ intramolecular
ring closure reaction involving an iodide as a “soft” leaving
group, affording 1,2-diazetidines with N-electron-withdrawing
groups (Scheme 1, B).5c While the ring closure step is produc-
tive, the effectiveness of the entire synthesis from commercially
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Scheme 2. Ring-opening Reactions of 1,2-Diazetidines.
Initial effort was focused on identifying optimal conditions
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for the intermolecular dialkylation reactions (Table 1). 1,2-Di-
tosylhydrazine (1a) and 1,2-dibromoethane were used as reac-
tants with conditions similar to Shipman’s intramolecular cy-
clization.5c Even at elevated temperature, no desired dialkyla-
tion product was observed with cesium carbonate as the base in
polar solvents, such as acetonitrile and DMF (entries 1 and 2).
The employment of 1,2-diiodoethane, which contains the much
“softer” leaving group, was not successful for the intermolecu-
lar process (entry 3). Complete bis-deprotonation of the hydra-
zine with 2.2 equivalents of NaH in DMF followed by immedi-
ate introduction of 1,2-dibromoethane at 0 oC resulted in the ob-
servation of the desired 1,2-diazetidine 2a albeit in very low
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o
yield (entry 4). Lowering the temperature to -10 C increased
Herein we report a practical synthesis of simple 1,2-disul-
fonyl-1,2-diazetidines via an intermolecular dialkylation pro-
cess with 1,2-disulfonylhydrazines and 1,2-dibromoethane. Ar-
ylsulfonyl groups with various electronic and steric properties
can be tolerated in the cyclization, which is scalable to 50-gram
level without column chromatography needed for purification.
the yield to 22%, presumably because of the prolonged life-time
of the dianionic intermediate resulting from the deprotonation
(entry 5).6 However, further decreasing the temperature resulted
in poor conversion and caused a large amount of precipitate dur-
ing the reaction (entry 6). The starting hydrazine could be
mostly recovered after quenching the reaction, which suggests
the disodium salt of the ditosylhydrazine may be more stabi-
lized under lower temperature. Nevertheless, its solubility is too
low even in DMF and thus largely slowed down the reaction.
Meanwhile, 1,2-diiodoethane gave dark solution with a compli-
cated system without major product observed (entry 7). Unfor-
tunately, when 1,2-diphenylsulfonylhydrazine (1b) was em-
ployed, no suitable temperature could be found to allow both
the stabilization of the dianion intermediate and a proper solu-
bility (entry 8). The challenge was then addressed by forming
the corresponding dilithium diamide intermediate by using n-
butyl lithium as the base.
Although these four-membered heterocycles would presum-
ably have diverse synthetic applications based on ring-opening
reactions,3g, 5b, 7 their known transformations were mainly re-
ported to occur on the side chain of the ring.5a, 5b The C-unsub-
stituted 1,2-diazetidines would serve as ideal model compounds
for exploring the transformations on the ring (Scheme 2).
Among different modes of ring-opening reactions, N‒N bond
cleavage is highly attractive as it splits the hydrazine unit into
two nitrogen-containing functional groups. To this end, how-
ever, only hydrogenation has previously been disclosed
(Scheme 2).7 As an application, we report the first nucleophile-
initiated N‒N bond cleavage reaction of the 1,2-diazetidines.
By treatment with different thiols, facile ring-opening followed
by elimination reactions of the 1,2-diazetidines were demon-
strated at room temperature in a stereoselective manner, provid-
ing a new approach to N-sulfenylimine derivatives, a useful
class of sulfur analogs of oximes with a N‒S bond (Scheme 2).8
Table 2. Direct Synthesis of Simple 1,2-Disulfonyl-1,2-diaz-
etidinesa
Table 1. Intermolecular Dialkylation of 1,2-Disulfonylhy-
drazinea
a Carried out with 1 (1 mmol), 1,2-dihaloethane (1.2 mmol), and base (2.2
mmol) in 4 mL anhydrous solvent. Entries 4 – 13 were carried out under N2
atmosphere. b Isolated yields.
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a Carried out under N2 atmosphere with 1 (1 mmol), 1,2-dibromoethane (1.2
experimental and computational Raman spectra suggests that
the C3 and C4 in 1,2-diazetidines 2a have substantially more
sp2 characteristics than the carbons in cyclobutane (Fig. 1 and
the supporting information). Two bands, calculated at 3027 and
3043 cm-1 were attributed to the C‒H stretching of the meth-
ylene fragment of the 1,2-diazetidine ring. Apparently, they ap-
pear above the expected frequencies of methylene Csp3-H bond
stretching, which, by the rule of thumb, should appear below
2930 cm-1.10 Interestingly, the Raman shifts of the methylene
C‒H stretching in cyclobutane derivatives appear below 3000
cm-1.11 The contrast may indicate the higher degree of sp2 char-
acter of C3 and C4 carbon atoms in the diazetidine ring of 2a.
Moreover, the C3 and C4 methylene groups in 2a exhibit much
higher torsional strain (H‒C3‒C4‒H torsional angle is 2.6°)
than that between two neighboring methylene groups in cyclo-
butane. Both x-ray analysis and computational model revealed
that the four-membered ring in 1,2-dizedidine 2a is almost pla-
nar with a dihedral angle of only 2.6°, while cyclobutanes, in-
cluding 1,2-disubstituted cyclobutanes, are generally puckered
with a 25-30° dihedral angles.12
mmol), and nBuLi (2.2 mmol) in 4 mL anhydrous DMF. Isolated yields are
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shown. 2a was synthesized by using 50 grams of 1,2-ditosylhydrazine.
While similar performance was shown at -10 oC (entries 9 and
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10), few precipitate was observed in both cases at -20 C and
the desired 1,2-diazetidine 2a and 2b were produced in 71% and
40%, respectively (entries 11 and 13). Again, 1,2-diiodoethane,
with a softer leaving group, was ineffective for this intermolec-
ular cyclization.9
With the optimized conditions, C-unsubstituted 1,2-diazet-
idines bearing different arylsulfonyl groups were synthesized to
enrich the number of this less known type of compounds. It was
shown that the vicinal dilithiation process worked well for var-
ious disulfonylhydrazines with different electronic and steric
properties (Table 2). Remarkably, synthesis of 1,2-ditosyl-1,2-
diazetidine (2a, DTD) was carried out at 50-gram scale with an
even higher yield. The white crystalline product, which was pu-
rified by only washing with ethanol, is thermally stable at its
melting point 213 oC. The structure of 2a was further confirmed
by X-ray analysis on the single crystal. With the simple proce-
dures, 1,2-diazetidine 2b, as well as 2c containing electron-do-
nating MeO- groups, were synthesized in 40% and 73% yield,
respectively. Electron-withdrawing groups, such as CF3, could
be well tolerated in the cyclization process (2d). To our delight,
cyano groups, which are sensitive to nucleophiles, could be in-
corporated into the 1,2-diazetidine product in 23% yield (2e),
although the nitro group could not be tolerated under the same
conditions (2f). Moreover, sterically encumbered 1,2-bis(2-me-
sitylenesulfonyl)hydrazine (1g) did not completely disable
the disubstitution reactions and afforded 1,2-diazetidine 2g
in 10% yield. Other aryl functionality, as exemplified by a 2-
naphthalenesulfonyl group, was shown to produce the cor-
responding 1,2-diazetidine in good yield (2h). Lastly, un-
symmetrical hydrazine 1i was employed and proven to
form 1-tosyl-2-(4-(trifluoromethyl)phenylsulfonyl)-1,2-di-
azetidine (2i) in 40% yield, indicating the feasibility of the
intermolecular dialkylation for constructing unsymmetrical
1,2-diazetidines. While disulfonylhydrazines were success-
fully employed, the current method has not been shown ef-
fective for hydrazine with two carbonyl groups.
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Table 3. Thiolate-initiated Ring-opening N─N Bond Cleav-
age of 1,2-Ditosyl-1,2-diazetidine (DTD)
With three types of bonds in the ring, selective bond-breaking
events of the C-unsubstituted 1,2-diazetidines would be inter-
esting for exploration. Initial results indicated a new and simple
approach for N‑sulfenylimines, which is based on a selective
N‒N bond cleavage process with thiols as nucleophiles (Table
3). At room temperature, DTD was explored as the ring-open-
ing substrate with thiophenyl (3a) as the nucleophile. While
K2CO3 and triethylamine were not productive (entries 1 and 2),
DBU in THF was able to convert DTD into C-aminomethyl-
N‑sulfenylimines 4a in 78% yield and 4:1 E/Z ratio (entry 3).
The same reaction was carried out in DMF and resulted in com-
parable yield and increased E/Z ratio to 10:1 (entry 4). As illus-
trated in the proposed mechanism, DBU presumably played two
major roles, including the deprotonation of the thiol for the nu-
cleophilic N‒N bond cleavage affording intermediate A, as well
as promoting the subsequent elimination process of intermedi-
ate B.
Figure 1. The experimental and computed Raman spectra of 2a
(Left). The vector representation of the Raman peaks associated
with methylene C‒H stretching (indicated by the arrows) in 2a
(Right). Assignment of other peaks are shown in the supporting in-
formation.
The selective N‒N cleavage-based ring opening process was
effective for various thiols, producing C-aminomethyl-N‑sul-
fenylimines 4 stereoselectively (Table 4). Thiophenyls with
strong electron-withdrawing and -donating groups were suc-
cessfully transformed into N‑sulfenylimines 4b and 4c in excel-
lent yield and good E/Z ratio, respectively. Sterically hindered
The practical synthesis of the C-unsubstituted 1,2-diazet-
idines 2 offers a unique opportunity for comparing and con-
trasting the structure and property of this four-membered heter-
ocycle and the homocycle in cyclobutane. Investigation by both
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thiols, such as 2,4-dimethylphenylthiol (3d), were demon-
or KMnO4 or in iodine chamber. Silica-gel flash column chro-
matography was performed on SiliCycle Inc. 40-63 μm silica
gel.
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strated to be highly favorable reagents, affording almost quan-
titative yield with a 5.0:1 E/Z ratio. Furthermore, the ring-open-
ing process works equally well for aliphatic thiols, as indicated
by bulky tert-butylthiol (3e) and linear dodecane-1-thiol (3f),
forming N‑sulfenylimines 4e and 4f in comparably good yields
and stereoselectivity.
Materials: Unless otherwise indicated, starting catalysts and
materials were obtained from Sigma Aldrich, Oakwood, Strem,
or Acros Co. Ltd. Moreover, commercially available reagents
were used without additional purification.
Table 4. Ring-opening N─N Bond Cleavage for the Synthe-
ses of N‑Sulfenylimines a
Instrumentation: All NMR spectra were run at 500 MHz or
300 MHz in CDCl3 or d-DMSO solution. 1H NMR spectra were
internally referenced to TMS. 13C NMR spectra were internally
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referenced to the residual solvent signal. Data for H NMR are
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reported as follows: chemical shift (δ ppm), multiplicity (s =
singlet, d = doublet, t = triplet, q = quartet, m= multiplet, br =
broad), coupling constants (J) were reported in Hz. High reso-
lution mass spectra (HRMS) were recorded on Bruker MicrO-
TOF-QII mass instrument (ESI). Melting points of the solid
compounds were determined on DgiMelt melting point appa-
ratus. The Raman spectrum was acquired using Horiba LabRam
HR Raman microscope system equipped with a 632.8 nm HeNe
laser. The Raman shifts were calibration used a neon lamp. The
uncertainty in the experimental Raman shift is below 0.5 cm-1.
A crystal of compound 2a were mounted on the end of glass
fibers and the X-Ray data was collected with a Bruker Kappa
Apex II diffactometer.
Computational modeling: To understand the nature of the Ra-
man vibrational spectroscopy, a density functional theory
(DFT)13 study was carried out using Gaussian 09.14 The gas-
phase geometries were optimized using the B3LYP functional
(the B3 exchange functional15 and LYP correlation func-
tional16). For all computations, basis set 1 was utilized (BS1 is
defined as LanL2DZ(D,P)+ECP17 for S and 6-31G(d')18 basis
sets were used for all other atoms; the 6-31G(d') basis sets have
the d polarization functions taken from the 6-311G(d)19 basis
sets rather than the default value of 0.820 for all other atoms).
Default self-consistent field convergence criteria (10-8) were
used for all computations. Raman intensities were computed us-
ing analytical derivatives,21 default pruned grids for energies
(75, 302), and default pruned coarse grids for gradients and
Hessians (35, 110). The computationally-derived Raman spectra
were simulated with an in-house Fortran program by convoluting
the computed vibrational energies and computed intensities with a
Lorentzian line shape and a broadening of 2 cm-1.22 The computed
Raman shifts were scaled by 0.96. Such an adjustment is a com-
monly accepted practice in aligning DFT-calculated spectra
with experimental data.23
a Carried out under N2 atmosphere with 2a (1 mmol), thiol (1.5 mmol), and
DBU (1.5 mmol) in 1.5 mL anhydrous DMF. Isolated yields are shown. E/Z
ratio was determined by 1H NMR study of the mixture of the stereoisomers.
In summary, a operationally simple and direct synthesis of
1,2-disulfonyl-1,2-diazetidine derivatives has been developed
via an intermolecular dialkylation reaction of readily available
N, N’-disulfonylhydrazine and 1,2-dibromoethane. The easy ac-
cess to C-unsubstituted 1,2-diazetidines, even at a 50-gram
scale, would encourage the physical study and chemical appli-
cation of this structurally unique and rarely known class of mol-
ecules. Among different types of bonds in the ring, selective N‒
N bond cleavage of the resulting 1,2-diazetidines was shown
and enabled a new pathway for a stereoselective access to C-
aminomethyl-N‑sulfenylimines. The facile synthesis, together
with the attractive structural features, of these highly strained
four-membered heterocycles would encourage the further ex-
ploration of their synthetic applications either with other nucle-
ophiles or in catalytic fashions.
General Procedure for the preparation of 1,2-ditosyl-1,2-di-
azetidine (2a, DTD) Tosyl chloride (174 mmol) was added to
tosylhydrdazine (139 mmol) in dichloromethane (242 mL) in an
ice bath. Pyridine (14.1mL) was added dropwise in a tempera-
0
ture range of 0-10 C. TLC analysis was done to monitor the
reaction. A mixture of water (250mL) and hexane (250 mL) was
added to the solution and stirred vigorously for 30 minutes. The
solution was then suction filtered and washed with a 1:1 ratio
of acetone and water (100ml). The crystals were then added to
acetone (320 mL) and boiled at 80 0C. Water (150 mL) was
added while stirring, and the solution was placed in an ice bath
for an hour. The solution was then suction filtered and washed
with a small amount of cold diethyl ether. The white solid ob-
tained was used directly in the next step. Other disulfonylhydra-
zides were synthesized using the same known methods.
EXPERIMENTAL SECTION
General Considerations:
Experimental: All reactions were set up under argon atmos-
phere, utilizing glassware that was flame-dried and cooled un-
der vacuum. All non-aqueous manipulations were using stand-
ard Schlenk techniques. Reactions were monitored using thin-
layer chromatography (TLC) on Silica Gel plates. Visualization
of the developed plates was performed under UV light (254 nm)
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Under nitrogen atmosphere, n-butyl lithium (2.5M in hexanes,
yield was 46 %. 1H NMR (500 MHz, DMSO) δ 8.21 (d, J = 8.4
Hz, 4H), 8.17 (d, J = 8.4 Hz, 4H), 3.73 (s, 4H). 13C NMR (125
MHz, DMSO) δ 135.6, 134.4 (q, J = 32.4 Hz), 131.0, 126.8 (d,
J = 3.7 Hz), 123.4 (q, J = 260.0 Hz), 48.6. HRMS (ESI) Calcd
for C16H12F6N2O4S2K [M+K]: 512.9774, found 512.9771. Melt-
ing point was not measured due to degradation of the compound
at 195.0 oC.
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0.88 mL, 2.2 mmol) solution was added drop wise to a solution
of 1,2-ditosylhydrazine (1 mmol) in anhydrous dimethylforma-
mide (4 mL) at -200C via gas tight syringe, and stirred for 15
minutes. 1,2-Dibromoethane (1.2 mmol) was then added drop-
wise to the solution at -20 0C over 10 minutes. The solution was
then stirred overnight at -20 0C. This solution was then allowed
to warm to room temperature. The reaction mixture was then
added to 20 mL of dilute ammonium chloride solution in a
beaker. After thorough precipitation, the solid was then suction
filtered, washed with water (10 mL), and then washed with eth-
anol (5 mL). Then the solid were washed with dichloromethane
(10mL) into a clean filter flask, and the filtrate was collected as
a yellow solution. Ethanol (10 mL) was then added to the solu-
tion and the solution was evaporated at low vacuum to only re-
move the dichloromethane. The white precipitate formed in the
remaining ethanol was then suction filtered and washed with
ethanol (2 x 5 mL). 1,2-Ditosyl-1,2-diazetidine (DTD) was pro-
duced in 71 % yield. Starting from 1,2-ditosylhydrazine (0.15
mol, 51 g), a large scale reaction with the same procedure led
to 78% yield. Detailed X-ray data of the crystal of 2a is shown
1,2-bis(4-cyanophenylsulfonyl)-1,2-diazetidine (2e) Synthe-
sis of 1,2-bis((4-cyanophenyl)sulfonyl)-1,2-diazetidine was
followed general procedure and percentage yield of reaction be-
tween 4-cyano-N-((4cyanophenyl)sulfonyl)benzenesulfonohy-
drazide and 1,2-dibromoethane was 23 %. 1H NMR (500 MHz,
DMSO-d6) δ 8.26 (d, J = 8.0 Hz, 4H), 8.15 (d, J = 8.0 Hz, 4H),
3.74 (s, 4H). 13C NMR (125 MHz, DMSO-d6) δ 135.6, 133.6
130.6, 117.5, 117.4, 48.6. HRMS (ESI) Calcd for
C16H12N4O4S2K [M+K]: 426.9931, found 426.9931. Melting
point was not measured due to degradation of the compound at
195.0 oC.
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1,2-bis(mesitylsulfonyl)-1,2-diazetidine (2g) Synthesis of 1,2-
bis(mesitylsulfonyl)-1,2-diazetidine was followed general pro-
cedure and percentage yield of reaction between N’-((3,4-di-
methoxyphenyl)sulfonyl)-3,4-dimethoxybenzenesulfonohy-
drazide and 1,2-dibromoethane was 10 %. 1H NMR (500 MHz,
CDCl3) δ 6.65 (s, 4H), 4.52 (s, 4H), 2.45 (s, 12H), 2.24 (s, 6H).
13C NMR (125 MHz, CDCl3) δ 143.7, 141.8, 131.8, 128.3, 48.3,
23.2, 21.2. HRMS (ESI) Calcd for C20H26N2O4S2K [M+K]:
461.0965, found 461.0962. Melting point: 212.9 oC - 213.4 oC
1
in the supporting information. H NMR (500 MHz, CDCl3) δ
7.93 (d, J = 8.3 Hz, 4H), 7.44 (d, J = 8.1 Hz, 4H), 3.69 (s, 4H),
2.51 (s, 6H). 13C NMR (126 MHz, CDCl3) δ 145.7, 130.3,
129.7, 129.3, 47.8, 21.8. HRMS (ESI) [M+Na] Calcd for
C16H18N2O4S2Na: 389.0600, found 389.0600. Melting point:
213.0 oC - 214.0 oC.
1,2-bis(phennylsulfonyl)-1,2-diazetidine (2b) Synthesis of
1,2-bis(phennylsulfonyl)-1,2-diazetidine was followed general
procedure and percentage yield of reaction between N’-
(phenylsulfonyl)benzenesolfonohydrazide and 1,2-dibromoeth-
ane was 40 %. 1H NMR (500 MHz, CDCl3) δ 8.04 (d, J = 8.0
Hz, 4H), 7.76 (t, J = 7.4 Hz, 2H), 7.64 (t, J = 7.6 Hz, 4H), 3.68
(s, 4H). 13C NMR (125 MHz, CDCl3) δ 134.1, 131.7, 129.9,
128.7, 47.4. HRMS (ESI) Calcd for C14H15N2O4S2 [M+H]:
339.0467, found 339.0466. Melting point: 169.3 oC - 170.8 oC.
1,2-bis(naphthalene-2-ylsulfonyl)-1,2-diazetidine (2h) Syn-
thesis of 1,2-bis(naphthalene-2-ylsulfonyl)-1,2-diazetidine was
followed general procedure and percentage yield of reaction be-
tween N’-(naphthalen-2-ylsulfonyl)naphthalen-2-ylsolfonohy-
drazide and 1,2-dibromoethane was 62 %. 1H NMR (500 MHz,
CDCl3) δ 8.58 (s, 2H), 8.02 (br, 4H), 8.03 (d, J = 8.0 Hz, 2H),
7.95 (d, J = 8.0 Hz, 2H), 7.74 – 7.69 (m, 2H), 7.68 – 7.64 (m,
2H), 3.76 (s, 4H). 13C NMR (125 MHz, CDCl3) δ 135.7, 132.3,
131.9, 129.7, 129.6, 129.4, 129.2, 128.0, 127.8, 124.7, 47.9.
HRMS (ESI) Calcd for C22H18N2O4S2Na [M+Na]: 461.0600,
found 461.0600. Melting point: 196.8 oC - 197.4 oC.
1,2-bis((3,4-dimethoxphenyl)sulfonyl)-1,2-diazetidine (2c)
Synthesis of 1,2-bis((3,4-dimethoxphenyl)sulfonyl)-1,2-diazet-
idine was followed general procedure and percentage yield of
reaction between N’-((3,4-dimethoxyphenyl)sulfonyl)-3,4-di-
methoxybenzenesulfonohydrazide and 1,2-dibromoethane was
73 %. 1H NMR (300 MHz, CDCl3) δ 7.63 (dd, J = 8.5, 1.8 Hz,
2H), 7.48 (d, J = 1.7 Hz, 2H), 7.03 (d, J = 8.5 Hz, 2H), 3.99 (s,
6H), 3.97 (s, 6H), 3.71 (s, 4H). 13C NMR (125 MHz, CDCl3) δ
154.0, 148.9, 124.3, 123.4, 112.5, 110.3, 56.3, 56.2, 47.7.
HRMS (ESI) Calcd for C18H22N2O8S2Na [M+Na]: 481.0709,
found 481.0709. Melting point: 198.2 oC - 198.9 oC
1-tosyl-2-(((4-trifluoromethyl)phenyl)sulfonyl)-1,2- diazet-
idine (2i) Synthesis of 1,2-bis((3,4-dimethoxphenyl)sulfonyl)-
1,2-diazetidine was followed general procedure and percentage
yield of reaction between 4-methyl-N-((4-trifluoromethyl)phe-
nyl)sulfonyl)benzenesulfonohydrazide and 1,2-dibromoethane
was 40 %. 1H NMR (500 MHz, CDCl3) δ 8.17 (d, J = 8.2 Hz,
2H), 7.91 (d, J = 8.2 Hz, 2H), 7.89 (d, J = 8.2 Hz, 2H), 7.43 (d,
J = 8.2 Hz, 2H), 3.72 (s, 4H), 2.50 (s, 3H). 13C NMR (125
MHz, CDCl3) δ 146.0, 136.0 (q, J = 33.2 Hz), 130.8, 130.3,
129.9, 128.9, 126.2 (q, J = 3.6 Hz), 122.2 (q, J = 271.2 Hz),
47.8, 21.8. HRMS (ESI) Calcd for C16H15F3N2O4S2Na [M+Na]:
443.0317, found 443.0318. Melting point: 211.3 oC - 212.8 oC.
1,2-bis((4-(trifluoromethyl)phenyl)sulfonyl)-1,2-diazetidine
(2d) Synthesis of 1,2-bis((4-(trifluoromethyl)phenyl)sulfonyl)-
1,2-diazetidine was followed general procedure with some
modification.
4-(trifluromethyl)-N’-((4-trifluromethyl)phe-
General procedure for synthesis of N-(2-((phenyl-
thio)imino)ethyl)-4-methylbenzenesulfonamide (4a) 1,2-
dithosyl-1,2-diazetidine (DTD, 2a) (0.1 mmol) was added to the
Schlenk tube and vacuum was applied to remove air from the
tube. Schenk tube was filled with nitrogen gas and thiophenol
(0.15 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)
(0.15 mmol) and dimethylformamide (0.5 mL) were added to
the Schlenk tube and closed properly with Teflon cap. Reaction
mixture was stirred at room temperature for 12 hours. Water (3
mL) and dichloromethane (DCM) (1 mL) were added to the re-
action mixture and shake well. DCM layer was separated and
solvent was removed under reduced pressure. 4-Methyl-N-(2-
nyl)sulfonyl)benzenesulfonohydrazide was added to the round
bottom flask and purge with nitrogen gas. DMF was added to
the mixture and followed by 1,2-dibromoethane was added and
mixed until dissolved. Round bottom flask was place in cooling
bath at -20 oC and treated with n-BuLi and reaction mixture was
stirred for 12h. Round bottom flask was remove from the cool-
ing bath and warm up room temperature. Ammonium chloride
solution was added to the mixture and extracted with ethyl ace-
tate for three times. Ethyl acetate was evaporated under reduced
pressure and got yellow color residue. Residue was washed with
ethanol and got white color residue as product and percentage
ACS Paragon Plus Environment

The Journal of Organic Chemistry
((phenylthio)imino)ethyl)benzenesulfonamide 4a was isolated
Page 6 of 7
N-(2-((dodecylthio)imino)ethyl)-4-methylbenzenesulfona-
mide (4f) Synthesis of N-(2-((dodecylthio)imino)ethyl)-4-
methylbenzenesulfonamide was followed general procedure
and percentage yield of reaction between 1-dodecanethiol and
1,2-ditosyl-1,2-diazetidine was 92 %. E/Z: 10:1. 1H NMR (500
MHz, CDCl3) δ 8.11 (s, 1H), 7.83 (d, J = 7.8 Hz, 2H), 7.32 (d,
J = 7.9 Hz, 2H), 7.09 (t, J = 6.1 Hz, 1H), 3.16 (d, J = 6.1 Hz,
2H), 2.44 (s, 3H), 2.16 (t, J = 7.2 Hz, 2H), 1.46-1.20 (m, 20H),
0.90 (t, J = 6.7 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 147.1,
144.2, 135.1, 129.7, 128.0, 32.6, 31.9, 30.7, 29.7, 29.6, 29.6,
29.6, 29.4, 29.3, 29.1, 28.7, 22.7, 21.6, 14.1. HRMS (ESI) Calcd
for C21H36N2O2S2Na [M+Na]: 435.2110, found 435.2111. Melt-
ing point: 77.8 oC - 79.5 oC.
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5
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7
8
by column chromatography with 1:1 hexane and ethyl acetate
mixture in 76% yield. E/Z ratio was determined by the 1H NMR
to be 10:1. 1H NMR (500 MHz, CDCl3) δ 7.90 (s, 1H), 7.73 (d,
J = 8.1 Hz, 2H), 7.29 – 7.24 (m, 2H), 7.23 – 7.21 (m, 3H), 7.17-
7.16 (m, 2H), 7.10 (t, J = 5.9 Hz, 1H), 3.61 (d, J = 5.9 Hz, 2H),
2.43 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 146.7, 144.2,
135.1, 134.1, 129.7, 129.6, 128.9, 127.8, 126.5, 35.0, 21.6.
HRMS (ESI) Calcd for C15H16N2O2S2Na [M+Na]: 343.0545,
found 343.0541. Melting point: 141.3 oC - 142.9 oC.
9
N-(2-(((4-(trifluoromethyl)phenyl)thio)imino)ethyl)-4-
methylbenzenesulfonamide (4b) Synthesis of 4-methyl-N-(2-
(((4-(trifluoromethyl)phenyl)thio)imino)ethyl)benzenesulfona-
mide was followed general procedure and percentage yield of
reaction between 4-trifluoromethylbenzenethiol and 1,2-dito-
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ASSOCIATED CONTENT
Supporting Information
1
syl-1,2-diazetidine was 94 %. E/Z: 6.8:1. H NMR (500 MHz,
CDCl3) δ 7.85 (br, 1H), 7.77 (d, J = 8.0 Hz, 2H), 7.30 (m, 4H),
7.22 (d, J = 8.1 Hz, 2H), 7.09 (t, J = 5.8 Hz, 1H), 3.71 (d, J =
5.8 Hz, 2H), 2.44 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 145.4,
132.1, 129.9, 129.6, 128.1, 127.5, 125.7(q, J = 3.7 Hz), 124.0
(q, J = 271.0 Hz), 33.7, 21.6. HRMS (ESI) Calcd for
C16H16F3N2O2S2 [M+H]: 389.0599, found 389.0594. Melting
point: 141.3 oC - 142.5 oC.
The Supporting Information is available free of charge on the ACS
Publications website.
Experimental procedures, additional experimental data, and com-
pounds characterization data (PDF)
Crystallographic data (excluding structure factors) for the structure
in this paper has been deposited with the Cambridge Crystallo-
graphic Data Centre as supplementary publication no. CCDC
1832697. Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK,
(fax: +44-(0)1223-336033 or e-mail:deposit@ccdc.cam.ac.uk).
N-(2-(((4-methoxyphenyl)thio)imino)ethyl)-4-methylben-
zenesulfonamide (4c) Synthesis of N-(2-(((4-methoxy-
phenyl)thio)imino)ethyl)-4-methylbenzenesulfonamide
was
followed general procedure and percentage yield of reaction be-
tween 4-methoxybenzenethiol and 1,2-ditosyl-1,2-diazetidine
was 93 %. E/Z: 3.5:1. 1H NMR (500 MHz, CDCl3) δ 8.01 (br,
1H), 7.71 (d, J = 8.3 Hz, 2H), 7.26 (d, J = 8.1 Hz, 2H), 7.21 (d,
J = 8.8 Hz, 2H), 7.11 (t, J = 5.9 Hz, 1H), 6.71 (d, J = 8.7 Hz,
2H), 3.77 (s, 3H), 3.49 (d, J = 5.9 Hz, 2H), 2.43 (s, 3H). 13C
NMR (125 MHz, CDCl3) δ 159.4, 147.3, 144.2, 135.2, 135.1,
129.7, 127.8, 124.0, 114.6, 55.3, 37.0, 21.6. HRMS (ESI) Calcd
for C16H18N2O3S2K [M+K]: 389.0390, found 389.0390. Melting
point: 133.7 oC – 134.8 oC.
AUTHOR INFORMATION
Corresponding Author
* E-mail: xcui@chemistry.msstate.edu.
Author Contributions
The manuscript was written through contributions of all authors.
All authors have given approval to the final version of the manu-
script.
N-(2-(((2,4-dimethylphenyl)thio)imino)ethyl)-4-methylben-
zenesulfonamide (4d) Synthesis of N-(2-(((2,4-dime-
thylphenyl)thio)imino)ethyl)-4-methylbenzenesulfonamide
was followed general procedure and percentage yield of reac-
tion between 2,4-dimethylbenzenethiol and 1,2-ditosyl-1,2-di-
azetidine was 99 %. E/Z: 5.0:1. 1H NMR (500 MHz, CDCl3) δ
8.02 (s, 1H), 7.74 (d, J = 8.3 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H),
7.12 – 7.04 (m, 2H), 6.92 (s, 1H), 6.80 – 6.70 (m, 1H), 3.53 (d,
J = 5.9 Hz, 2H), 2.44 (s, 3H), 2.26 (s, 3H), 2.25 (s, 3H). 13C
NMR (125 MHz, CDCl3) δ 147.1, 144.1, 138.5, 136.7, 135.3,
131.2, 130.2, 129.6, 127.9, 127.2, 34.9, 21.6, 20.9, 20.3. HRMS
(ESI) Calcd for C17H21N2O2S2 [M+H]: 349.1039, found
349.1036. Melting point: 91.7 oC - 93.1 oC.
ACKNOWLEDGMENT
We are grateful for financial support from the Mississippi State
University Office of Research and Economic Development, De-
partment of Chemistry, and the National Science Foundation (OIA-
1539035). Computations were performed at the Mississippi State
University High Performance Computing Collaboratory (HPC2)
and the Mississippi Center for Supercomputing Research. We also
acknowledge the Weissman School of Arts and Sciences at Baruch
College at the City University of New York (CUNY), and Dr. E.
Fujita of Brookhaven National Laboratory for the use of the Bruker
Kappa Apex II diffractometer for X-ray data collection.
REFERENCES
N-(2-((tert-butylthio)imino)ethyl)-4-methylbenzenesulfona-
mide (4e) Synthesis of N-(2-((tert-butylthio)imino)ethyl)-4-
methylbenzenesulfonamide was followed general procedure
and percentage yield of reaction between tert-butylthiol and
1,2-ditosyl-1,2-diazetidine was 47 %. E/Z: 7.5:1. 1H NMR (500
MHz, CDCl3) δ 7.92 (s, 1H), 7.81 (d, J = 8.2 Hz, 2H), 7.30 (d,
J = 8.0 Hz, 2H), 7.09 (t, J = 6.0 Hz, 1H), 3.28 (d, J = 6.0 Hz,
2H), 2.43 (s, 3H), 1.18 (s, 9H). 13C NMR (125 MHz, CDCl3) δ
149.0, 144.3, 135.3, 129.7, 128.0, 43.3, 3.0, 30.7, 21.6. HRMS
(ESI) Calcd for C13H20N2O2S2Na [M+Na]: 323.0858, found
323.0855. Melting point: 115.8 oC - 117.8 oC.
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