Synthesis of Fused Diaziridine Derivatives from Cyclic Secondary Amines by Utilizing N -Bromosulfonamides as an Aminating Reagent

Article abstract of DOI:10.1055/a-1468-8275

The synthesis of a series of fused diaziridines, which are difficult to access by existing methods, was achieved by the reaction of cyclic secondary amines with p -toluenesulfonamide in the presence of N -bromosuccinimide (NBS) and a suitable base. This o

Full text of DOI:10.1055/a-1468-8275

SYNTHESIS
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2021, 53, A–I
special topic
A
Bond Activation – in Honor of Prof. Shinji
Y. Kiyosu et al.
Special Topic
Synthesis
Synthesis of Fused Diaziridine Derivatives from Cyclic Secondary
Amines by Utilizing N-Bromosulfonamides as an Aminating
Reagent
Yuuki Kiyosu
H
Br
or
N
SO2Ar
N SO2Ar
Shino Tanaka
SO2Ar
H
H
Na
N
Sota Okumura
N
N
NBS, base
cat. CF3CO2H
Kensuke Kiyokawa
Satoshi Minakata*
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1–3
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X
Department of Applied Chemistry, Graduate School of Engineering,
Osaka University, Yamadaoka 2-1, Suita, Osaka 565-0871, Japan
minakata@chem.eng.osaka-u.ac.jp
In memory of Prof. Dr. Kilian Muñiz (1970−2020)
Published as part of the Special Topic
Bond Activation – in Honor of Prof. Shinji Murai
Corresponding Author
Received: 12.03.2021
Accepted after revision: 29.03.2021
Published online: 29.03.2021
some examples of the synthesis of diaziridines A, a class of
fused diaziridines, by the reaction of cyclic imines with
chloramine or hydroxylamine-O-sulfonic acids, these meth-
ods suffer from limited substrate scope and low efficien-
cy.5a,6 This is mainly because of the instability of cyclic
imines, which exist in equilibrium between their mono-
mers and trimers,7 as well as a lack of suitable aminating
reagents.
DOI: 10.1055/a-1468-8275; Art ID: ss-2021-f0129-st
Abstract The synthesis of a series of fused diaziridines, which are dif-
ficult to access by existing methods, was achieved by the reaction of cy-
clic secondary amines with p-toluenesulfonamide in the presence of N-
bromosuccinimide (NBS) and a suitable base. This oxidation system en-
ables the efficient in situ formation of the key intermediates, which are
N-bromoamines (a precursor of cyclic imines) and N-bromosulfon-
amides. In addition, an alternative method using N-bromo-N-sodio-p-
toluenesulfonamide (bromamine-T) in the presence of a catalytic
amount of CF3CO2H for the synthesis of fused diaziridines is also report-
ed.
R3
R3
R1
R4
N
R4
H
N
N
N
R4
N
R3
LG
+
N
LG
R2
R1
R1
R2
H
R2
LG (leaving group) = halogen, OSO3H, OSO2R, OCOR
Key words cyclic secondary amines, cyclization, diaziridines, N-bro-
mosulfonamides, nitrogen-containing heterocyclic compounds
Synthetic approach for fused diaziridines
R
N
N
R
H
N
N
LG
+
Diaziridines, which contain two nitrogen atoms and one
carbon atom, are among the smallest known nitrogen-con-
taining heterocyclic compounds and exhibit some unique
chemical and biological properties.1 Owing to the strained
nature of the three-membered ring, diaziridines have
unique reactivity. For example, they readily open through
either C−N or N−N bond cleavage and are frequently used in
dipolar cycloaddition, ring expansion, and alkylation reac-
tions.2 In addition, they have many applications in the field
of medicinal and pharmaceutical chemistry.3 Because of
this, continual efforts have been devoted to the develop-
ment of new methods for the synthesis of this class of com-
pounds.4 The most general approach to accessing diaziri-
dines involves the reaction of imines with aminating re-
agents such as N-haloamines, hydroxylamine-O-sulfonic
acids, or hydroxylamine O-esters (Scheme 1).5 However, de-
spite the advances made in the synthesis of monocyclic di-
aziridines, methods that enable the formation of fused di-
aziridines continue to be scarce. Indeed, although there are
n
n
A
Scheme 1 A general approach to accessing diaziridines
Our group has been involved in investigations related to
oxidative amination reactions, with emphasis on the azirid-
ination of alkenes, by utilizing inexpensive and readily
available chloramine salts as aminating reagents that have
both a sufficient level of nucleophilicity and electrophilici-
ty.8 Based on these previous studies, we hypothesized that
the unique reactivity of haloamine salts might be used to
develop an efficient method for the synthesis of fused dia-
ziridines from cyclic imines. To investigate this hypothesis
further, the commercially available N-chloro-N-sodio-p-tol-
uenesulfonamide (chloramine-T) was initially chosen as an
aminating reagent for use in the diaziridination of 1-pyrro-
line (a mixture of monomers and trimers), but no reaction
was observed, probably as a result of insufficient nucleo-
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–I
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
Y. Kiyosu et al.
Special Topic
Synthesis
philicity of chloramine-T (Scheme 2). Changing the chlorine
atom on the nitrogen atom to a bromine atom was found to
enhance the nucleophilicity of the haloamine salt, resulting
in the formation of the desired diaziridine in high yield.
This promising result encouraged us to develop a more
practical process using cyclic secondary amines as sub-
strates and p-toluenesulfonamide as the aminating reagent,
in the presence of a bromine-based oxidant and a base,
which allows the preparation of unstable cyclic imines and
N-bromo-N-sodio-p-toluenesulfonamide (bromamine-T) to
be avoided.8b,9
Table 1 Survey of Oxidants and Basesa
Ts
oxidant (2 equiv)
base (2 equiv)
H
N
N
N
H
H
+
N
Ts
MeCN, r.t., 3 h
1a
2a (1 equiv)
3aa
Entry
Oxidant
Base
Yield (%)b
1
2
3
4
5
6
7d
NBS
NBS
NBS
DBHc
NCS
NIS
NaOH
Na2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
59
0
83
67
0
Ts
N
X
N
N
trimer
N
Ts
+
MeCN, r.t.
Na
0
(23:77)
X = Cl 0%
[O]
base
82%
X = Br
NBS
89
H
N
a Standard reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), oxidant (1
mmol), base (1 mmol), MeCN (5 mL), r.t., 3 h.
H
H
Br oxidant, base
+
N
Ts
b Determined by 1H NMR analysis of the crude product with 1,1,2,2-tetra-
chloroethane as an internal standard.
Scheme 2 Synthesis of a fused diaziridine from 1-pyrroline with
haloamine salts: Preliminary results and working hypothesis
c DBH (1 equiv) was used.
d 2a (1.2 equiv), NBS (2.4 equiv), and K2CO3 (2.4 equiv) were used.
We then conducted a survey of bromine-based oxidants
and bases for the reaction of pyrrolidine (1a) with p-tolue-
nesulfonamide (2a) in MeCN at room temperature (Table 1).
The use of N-bromosuccinimide (NBS) and NaOH gave the
desired diaziridine 3aa in moderate yield (entry 1). We then
evaluated several bases and were pleased to find that K2CO3
was effective in this diaziridination and afforded 3aa in 83%
yield, even though the use of Na2CO3 resulted in no desired
product formation (entries 2 and 3). When 1,3-dibromo-
5,5-dimethylhydantoin (DBH) was used (entry 4), 3aa was
also obtained but in a lower yield than that in the reaction
using NBS. Meanwhile, no reaction was observed when N-
chloro- and N-iodosuccinimide (NCS and NIS) were used
(entries 5 and 6). These results demonstrate that NBS to-
gether with K2CO3 is a suitable oxidation system for this di-
aziridination. Slightly increasing the amounts of reagents
used improved the yield of 3aa up to 89% (entry 7).
The reactivity of other amides as the aminating reagent
for this diaziridination was evaluated (Scheme 3). Instead of
2a, highly electron-deficient 2-nitrobenzenesulfonamide
(2b) was also applicable, affording the corresponding di-
aziridine in moderate yield. However, carbamates, such as
O-benzyl or O-tert-butyl carbamate (2c and 2d), which
have a higher nucleophilicity than sulfonamides,8d were not
effective. This is probably a result of the low conversion of
carbamates into the corresponding bromamine salts under
the reaction conditions used. These results demonstrate
that the use of 2a was optimal, that 2a can be readily con-
verted into the corresponding bromamine salt in situ, and
that it has sufficient nucleophilicity and electrophilicity to
react with a cyclic imine to form a fused diaziridine.
With the simple system using 2a and NBS/K2CO3 for the
preparation of diaziridines in hand, the scope of the amines
was investigated (Scheme 4). In addition to pyrrolidine (1a),
methyl pyrrolidine-2-carboxylate was found to be applica-
ble and underwent regioselective diaziridination to form
3ba in moderate yield. However, when 2-phenylpyrrolidine
was used as a substrate, imine 4 was formed instead of the
desired diaziridine product. The method was also success-
fully applied to the synthesis of tricyclic fused diaziridines
3ca and 3da. In addition, a series of six-membered nitro-
gen-containing heterocycles, including piperidines (3ea,
3fa), morpholine (3ga), and piperazines (3ha, 3ia, 3ja),
were also suitable substrates. Although piperidine and 1-
tosylpiperazine showed low reactivity, extensive screening
of bases and solvents revealed that the use of Cs2CO3 in 1,2-
dimethoxyethane (DME) was effective and provided 3ea
and 3ia, respectively. By using this system, it was possible
to prepare not only fused diaziridines but also monocyclic
diaziridines. Dibenzyl amine and di-n-butyl amine could be
transformed into the corresponding diaziridines 3ka and
3la, respectively, albeit in low yields. The site-selective for-
EWG
NBS (2.4 equiv)
K2CO3 (2.4 equiv)
H
N
N
H
H
N
+
N
EWG
MeCN, r.t., 5 h
1a
2 (1.2 equiv)
3
H
H
H
H
H
H
N
o-Ns
N
Cbz
N Boc
2b 51%
2c 18%
2d <5%
Scheme 3 Effect of the electron-withdrawing group on the nitrogen
atom
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–I

C
Y. Kiyosu et al.
Special Topic
Synthesis
mation of high yields of 3ma indicates that diaziridination
at an acidic C−H bond is preferred. Interestingly, when
DL-proline (1n) was used as a substrate, decarboxylative di-
aziridination proceeded and provided 3aa in good yield
(Scheme 5).10
Ts
NH
N
I2 (10 mol%)
Mg (10 equiv)
N
N
N
MeOH, r.t., 40 min
N
Boc
Boc
5 68%
3ha
Scheme 6 Removal of the tosyl group from a diaziridine product
NBS
K2CO3
H
amines
diaziridines
+
N
Ts
2a
MeCN, r.t.
H
1
3
We performed several experiments to gain additional
insights into the reaction mechanism (Scheme 7). First, to
determine whether a bromamine salt is generated under
the reaction conditions, 2a was mixed with an equimolar
amount of NBS and K2CO3 in MeCN at room temperature. In
the mixture, 2a was consumed within 15 min, and quanti-
tative formation of bromamine salt 6 was observed
(Scheme 7a).9 Treatment of 1a with NBS led to a downfield
shift in the signals corresponding to 1a and quantitative
formation of succinimide, which strongly indicates that the
N−H bromination of 1a occurred to provide an N-bromo-
pyrrolidine species (Scheme 7b). However, subsequent ad-
dition of K2CO3 to the mixture did not give the correspond-
ing cyclic imine. Meanwhile, the use of bromamine salt 6,
instead of K2CO3, resulted in the smooth conversion of N-
bromopyrrolidine to diaziridine 3aa, with no cyclic imine
observed (Scheme 7c). These results indicate that 6, and not
K2CO3, functions as a base to provide a cyclic imine, which
then rapidly reacts with the remaining 6 to form 3aa. When
the reaction was carried out either in the dark or under an
O2 atmosphere, it proceeded as efficiently as under the
standard conditions (under N2 in the presence of a fluores-
cent light), suggesting that the reaction does not involve a
radical process (Scheme 7d).
Ts
Ts
N
Ph
N
N
N
N
CO2Me
NHTs
4 39%
3aa 88%
3ba 44%
Ts
Ts
N
N
N
N
3ca 60%
3da 67%
(d.r. = 63:37)a
(d.r. = 83:17)a
Ts
Ts
Ts
N
N
N
N
N
N
O
3ea 50%
(Cs2CO3 in DME)
3ga 61%
CO2Et
3fa 60%
(d.r. = 51:49)a
Ts
Ts
Ts
N
N
N
N
N
N
N
N
N
Boc
Ts
o-Ns
3ha 45%
3ia 31%
(Cs2CO3 in DME)
3ja 87%
Ts
Ts
N
Ts
N
N
N
Ph
N
N
a)
Ph
nBu
Me
NBS (1 equiv)
K2CO3 (1 equiv)
F3C
H
H
Br
K
3ka 24%
(Cs2CO3 in DME)
3la 23%
3ma 83%
(Cs2CO3 in DME)
N
Ts
N
Ts
(Cs2CO3 in DME)
MeCN, r.t., 15 min
Scheme 4 Substrate scope of amines. Reagents and conditions: 1
(0.5 mmol), 2a (1–1.2 equiv), NBS (2–2.4 equiv), K2CO3 or Cs2CO3
(2–5 equiv), MeCN or DME (5 mL), r.t., 12 h. Yields are isolated yields.
a Determined by 1H NMR analysis of the crude product.
6 quant.
2a
b)
Br
NBS
(1 equiv)
K2CO3
(1 equiv)
N
N
1a
CD3CN
r.t., 5 min
r.t., 30 min
+
not formed
succinimide
Ts
NBS (2 equiv)
Cs2CO3 (5 equiv)
H
quant.
N
H
H
N
N
CO2H
c)
Ts
+
N
Ts
DME, r.t., 12 h
N
N
NBS
(1 equiv)
N
6 (1 equiv)
1n
2a (1 equiv)
3aa 72%
1a
CD3CN
r.t., 30 min
r.t., 5 min
Scheme 5 Decarboxylative diaziridine synthesis from DL-proline
3aa
not detected
d)
Ts
NBS (2.4 equiv)
K2CO3 (2.4 equiv)
H
N
N
N
H
H
The tosyl group of the fused diaziridine product could
be removed without the decomposition of the diaziridine
skeleton. Diaziridine 3ha was treated with magnesium in
the presence of a catalytic amount of iodine in MeOH to af-
ford N−H diaziridine 5 (Scheme 6),5e indicating that such
diaziridine derivatives can be further elaborated.
+
N
Ts
MeCN, r.t., 3 h
1a
2 (1.2 equiv)
3aa
in the dark 83%
conditions
under O2
90%
Scheme 7 Mechanistic investigations
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–I

D
Y. Kiyosu et al.
Special Topic
Synthesis
Based on the experimental results, a proposed reaction
pathway is shown in Scheme 8. The cyclic secondary amine
1 initially reacts smoothly with NBS, generating N-bro-
moamine 7. The bromamine salt 6, which is generated by
the reaction of 2a with NBS/K2CO3 in situ, then abstracts a
proton from 7 to give cyclic imine 8. Subsequent nucleo-
philic attack of 6 onto 8 affords aminal 10; the resulting N-
bromo-p-toluenesulfonamide (9) may serve as a Brønsted
acid to promote the addition. Finally, intramolecular cy-
clization of 10 leads to the formation of the diaziridine
product 3. The key to the success of this diaziridination is
the use of an NBS/base oxidation system that permits the
generation of sufficient amounts of bromamine salt 6 and
bromoamine 7, resulting in the smooth formation of the
fused diaziridine 3.
We then investigated the substrate scope for this acid-
catalyzed diaziridination (Scheme 10). The method was
successfully applied to the preparation of a series of cyclic
secondary amines including five-, six-, and seven-mem-
bered ring systems. Thiomorpholine was not a suitable sub-
strate in the NBS/base system (not shown in this report) but
could be used as a reactant in the acid-catalyzed diaziridi-
nation (3oa). Notably, product yields were generally higher
than those from the NBS/base oxidation system. Moreover,
not only bromamine-T but also bromamine-o-Ns and bro-
mamine-p-Ns could be used in this acid-catalyzed method,
affording 3ab and 3ae, respectively.12
Br
CF3CO2H (10 mol%)
amines
+
diaziridines
N
Ts
DME, r.t., 12 h
Na
Ts
1
(2 equiv)
3
NBS
Ts
N
Ts
N
K2CO3
N
TsNH2
Br
N
N
N
2a
N
Ts
Br
K
9
H
N
Br
K
Br
N
N
Ts
3aa 91%
3ca 82%
3da 84%
(d.r. = 77:23)a
H
N
(d.r. = >95:5)a
N
Ts
6
H
NBS
6
Ts
N
Ts
N
Ts
Ts
1,2
1,2
1,2
N
N
1
7
8
N
N
O
N
N
S
Br
K
base
Ts
N
H
N
Br
N
N
Ts
Ts
N
N
3ea 38%
Ts
3ga 79%
3ia 88%
3oa 62%
6
Ts
1,2
1,2
3
10
o-Ns
p-Ns
N
N
N
N
N
N
Scheme 8 Plausible mechanism
3ab 51%b
3ae 60%c
(X-ray)
3pa 71%
We assumed that in situ generated N-bromo-p-toluene-
sulfonamide (9) would function not only as a Brønsted acid
but also as a brominating reagent instead of NBS. To exam-
ine this possibility, the reaction of 1a with bromamine-T in
the presence of CF3CO2H, which enables the protonation of
bromamine-T to generate 9, was examined (Scheme 9).11
When 100 mol% of CF3CO2H was used, diaziridine 3aa was
formed in 32% yield. As compound 9 is regenerated during
the formation of the imine from 7 with bromamine-T, based
on the proposed reaction pathway described in Scheme 8, a
catalytic amount of CF3CO2H would be sufficient to allow
the diaziridination to proceed. In fact, addition of 10 mol%
of CF3CO2H is sufficient to promote the diaziridination, pro-
viding 3aa in 91% yield.
Scheme 10 Substrate scope for the acid-catalyzed method. Reagents
and conditions: 1 (0.5 mmol), NaNBrTs (2 equiv), CF3CO2H (10 mol%),
DME (5 mL), r.t., 12 h. a Determined by 1H NMR analysis of the crude
product. b Bromamine-o-Ns was used instead of bromamine-T.
c Bromamine-p-Ns was used instead of bromamine-T.
In conclusion, new and practical methods for the syn-
thesis of fused diaziridine derivatives from cyclic secondary
amines were developed. The NBS/base oxidation system
was successfully applied to the reaction of cyclic secondary
amines with p-toluenesulfonamide, in which N-bromo-
amines (and cyclic imines) and bromamine salts are effi-
ciently produced. In addition, a valid and reliable alterna-
tive method using bromamine-T as an aminating reagent in
the presence of a catalytic amount of CF3CO2H was also
achieved.
Ts
H
N
N
Br
N
CF3CO2H (x mol%)
DME, r.t., 12 h
N
Ts
+
Na
(2 equiv)
1a
3aa
CF3CO2H: 100 mol% 32%
50 mol% 46%
New compounds were characterized by 1H, 13C, and 19F NMR spectros-
copy, IR spectroscopy, MS, and HRMS. 1H, 13C, and 19F NMR spectra
were recorded on a JEOL JMTC-400/54/SS spectrometer (1H NMR, 400
MHz; 13C NMR, 100 MHz; 19F NMR, 377 MHz). 1H NMR chemical shifts
were determined relative to Me4Si (0.0 ppm) as an internal standard
in CDCl3 or residual undeuterated methanol (3.31 ppm) in CD3OD.
10 mol% 91%
Scheme 9 Reaction of pyrrolidine (1a) with bromamine-T in the pres-
ence of CF3CO2H
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–I

E
Y. Kiyosu et al.
Special Topic
Synthesis
13C NMR chemical shifts were determined relative to CDCl3 (77.0
ppm) and CD3OD (49.0 ppm). 19F NMR chemical shifts were deter-
mined relative to C6F6 (–164.9 ppm in CDCl3) as an external standard.
Infrared spectra were recorded on a SHIMADZU IRAffinity-1 FT-IR
spectrophotometer. Mass spectra were obtained on a SHIMADZU
GCMS-QP2010 mass spectrometer. High-resolution mass spectra
were obtained on JEOL JMS-700 (magnetic sector type mass spec-
trometer) and JEOL JMS-T100LP mass spectrometers. Melting points
were determined on a Stanford Research Systems MPA100 OptiMelt
Automated Melting Point System. The X-ray diffraction data of the
single crystal were collected on a two-dimensional X-ray detector
(PILATUS 200K/R) attached to a Rigaku XtaLAB PRO diffractometer by
using thin multi-layer mirror monochromated Cu-K radiation
( =1.54187 Å). All reactions were carried out under nitrogen. Prod-
ucts were purified by chromatography on silica gel BW-300 or Chro-
matorex NH (Fuji Silysia Chemical Ltd.). Analytical thin-layer chroma-
tography (TLC) was performed on pre-coated silica gel glass plates
(Merck silica gel 60 F254 and Fuji Silysia Chromatorex NH, 0.25 mm
thickness). Compounds were visualized under a UV lamp or by treat-
ment with an ethanolic solution of phosphomolybdic acid followed
by heating. Recycle gel permeation chromatography (GPC) was per-
formed with CHCl3 as the eluent.
13C NMR (CD3OD, 100 MHz):  = 142.3, 141.3, 129.7, 128.6, 21.3.
Anal. Calcd for C7H10BrKNO3.5S: C, 26.67; H, 3.20; N, 4.44. Found: C,
26.46; H, 2.93; N, 4.39.
Diaziridination with TsNH2 in the NBS/Base Oxidation System;
General Procedure GP1
A reaction flask containing a magnetic stirrer bar was charged with
TsNH2 (0.5 mmol), NBS (0.5 mmol), K2CO3 (0.5 mmol), and MeCN (5
mL). To the mixture, an amine (0.5 mmol) was added, and the mixture
was stirred at room temperature for 3 h on the benchtop. The reac-
tion was quenched by addition of aq. Na2S2O3 (1 M, 5 mL) and extract-
ed with EtOAc (3 × 10 mL). The collected organic layers were dried
over Na2SO4. The solution was concentrated under reduced pressure
to give the crude product, which was analyzed by 1H NMR spectrosco-
py with 1,1,2,2-tetrachloroethane as an internal standard. Purifica-
tion by flash column chromatography on silica gel (hexane/EtOAc) or
GPC (CHCl3, JAIGEL-2H) gave the product.
Diaziridination with Bromamine-T; General Procedure GP2
A reaction flask containing a magnetic stirrer bar was charged with
bromamine-T·3 H2O (1 mmol), 1,2-dimethoxyethane (5 mL), and
CF3CO2H (0.05 mmol). To the mixture, an amine (0.5 mmol) was add-
ed, and the mixture was stirred at room temperature for 12 h. The re-
action was quenched by addition of aq. Na2S2O3 (1 M, 10 mL) and ex-
tracted with CH2Cl2 (3 × 20 mL). The collected organic layers were
dried over Na2SO4. The solution was concentrated under reduced
Cyclic secondary amines methyl pyrrolidine-2-carboxylate hydro-
chloride (1b),13 2-phenylpyrrolidine,14 and 1-tosylpiperazine (1i),15
were prepared according to reported procedures. 1-Pyrroline was
prepared according to a reported procedure.7d N-Bromo-N-sodio-p-
toluenesulfonamide (bromamine-T), N-bromo-N-sodio-2-nitroben-
zenesulfonamide (bromamine-o-Ns), and N-bromo-N-sodio-4-nitro-
benzenesulfonamide (bromamine-p-Ns) were prepared according to
a reported procedure.8b,9 All other solvents and reagents were pur-
chased and used as obtained.
1
pressure to give the crude product, which was analyzed by H NMR
spectroscopy with 1,1,2,2-tetrachloroethane as an internal standard.
Purification by flash column chromatography on silica gel (hex-
ane/EtOAc) gave the product.
6-Tosyl-1,6-diazabicyclo[3.1.0]hexane (3aa)
GP1; white solid; yield: 105.7 mg (88%); mp 90.8–92.0 °C.
GP2; yield: 108.2 mg (91%).
1-((2-Nitrophenyl)sulfonyl)piperazine (1j)
According to the reported procedure,16 the reaction was carried out
by using piperazine (864.5 mg, 10.0 mmol), CH2Cl2 (60 mL), triethyl-
amine (1.66 g, 16.4 mmol), and 2-nitrobenzenesulfonylchloride (3.32
g, 15.0 mmol). Purification by washing with water (3 × 10 mL) to re-
move trimethylamine hydrochloride gave the product as a pale-
yellow solid (1.02 g, 38% yield); mp 142.2–143.2 °C.
TLC: Rf = 0.10 (hexane/EtOAc, 8:2).
IR (ATR): 3032, 2986, 2956, 2863, 1597, 1447, 1335, 1159, 1119, 1091,
1080, 980 cm–1
.
1H NMR (CDCl3, 400 MHz):  = 7.85 (d, J = 8.4 Hz, 2 H), 7.35 (d, J = 8.4
Hz, 2 H), 4.09 (d, J = 2.8 Hz, 1 H), 3.17–3.11 (m, 1 H), 2.81–2.73 (m, 1
H), 2.46 (s, 3 H), 2.41–2.35 (m, 1 H), 1.91–1.81 (m, 1 H), 1.61–1.55 (m,
2 H).
13C NMR (CDCl3, 100 MHz):  = 144.9, 133.0, 129.5, 129.0, 66.3, 54.2,
26.6, 21.7, 19.4.
IR (ATR): 3088, 2963, 2837, 1587, 1557, 1439, 1375, 1356, 1325, 1234,
1165, 1130, 1076, 1043, 947, 878, 853, 791, 764, 748, 733 cm–1
.
1H NMR (CDCl3, 400 MHz):  = 7.95 (d, J = 8.0 Hz, 1 H), 7.76–7.67 (m, 2
H), 7.46 (d, J = 8.0 Hz, 1 H), 3.26 (t, J = 5.6 Hz, 4 H), 2.93 (t, J = 5.6 Hz, 4
H).
13C NMR (CDCl3, 100 MHz):  = 148.3, 133.7, 131.4, 130.8, 130.6,
123.9, 46.7, 45.4.
HRMS (FAB+): m/z [M + H]+ calcd for C10H14N3O4S: 272.0705; found:
HRMS (CI): m/z [M + H]+ calcd for C11H15N2O2S: 239.0854; found:
239.0855.
272.0706.
Methyl 6-Tosyl-1,6-diazabicyclo[3.1.0]hexane-5-carboxylate (3ba)
GP1; yellow oil; yield: 65.1 mg (44%).
N-Bromo-N-potassio-p-toluenesulfonamide (6)
TLC: Rf = 0.15 (hexane/EtOAc, 1:1).
According to the reported procedure,8b,9 the reaction was carried out
by using chloramine-T·3 H2O (8.4 g, 29.9 mmol), H2O (150 ml), bro-
mine (1.93 mL, 37.5 mmol), and aq. KOH (5 M, 150 mL). Purification
by recrystallization from water gave the product as a pale-yellow sol-
id (2.24 g, 24% yield), which was determined by elemental analysis to
be TsNBrK·1.5 H2O.
IR (ATR): 2955, 1748, 1597, 1439, 1366, 1339, 1290, 1244, 1223, 1186,
1163, 1111, 1086, 1016, 976, 937, 910, 874, 820, 775, 735 cm–1
.
1H NMR (CDCl3, 400 MHz):  = 7.89 (d, J = 8.4 Hz, 2 H), 7.35 (d, J = 8.4
Hz, 2 H), 3.91 (s, 3 H), 3.09–2.99 (m, 2 H), 2.69–2.63 (m, 1 H), 2.46 (s, 3
H), 2.09–2.01 (m, 1 H), 1.72–1.66 (m, 2 H).
IR (ATR): 3441, 3375, 3248, 3034, 3022, 1645, 1597, 1493, 1393, 1373,
13C NMR (CDCl3, 100 MHz):  = 166.1, 145.1, 134.2, 129.5, 128.8, 77.2,
55.5, 53.2, 30.7, 21.7, 20.1.
1304, 1209, 1121, 1088, 1018, 947, 810, 706 cm–1
.
1H NMR (CD3OD, 400 MHz):  = 7.72 (d, J = 8.4 Hz, 1 H), 7.26 (d, J = 8.4
Hz, 1 H), 2.39 (s, 3 H).
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–I

F
Y. Kiyosu et al.
Special Topic
Synthesis
HRMS (FAB+): m/z [M + H]+ calcd for C13H17N2O4S: 297.0909; found:
297.0914.
IR (ATR): 2920, 2856, 1726, 1595, 1449, 1331, 1292, 1258, 1089, 986,
962, 910, 893, 841, 810, 785 cm–1
.
1H NMR (CDCl3, 400 MHz):  = 7.84 (d, J = 8.4 Hz, 2 H), 7.35 (d, J = 8.4
Hz, 2 H), 3.90 (s, 1 H), 2.97 (dd, J = 13.2, 8.4 Hz, 1 H) 2.71 (dd, J = 13.2,
11.2 Hz, 1 H) 2.46 (s, 3 H), 2.43–2.39 (m, 1 H), 2.22–2.17 (m, 1 H),
1.80–1.71 (m, 1 H), 1.70–1.62 (m, 1 H), 1.52–1.49 (m, 3 H), 1.25–0.96
(m, 3 H).
1-Tosyloctahydrocyclopenta[c]diazirino[1,3-a]pyrrole (3ca)
GP1; major isomer as a white solid; yield: 70.9 mg (51%); mp 113.5–
114.0 °C; minor isomer as a white solid; yield: 12.9 mg (9%); mp
91.5–92.0 °C.
13C NMR (CDCl3, 100 MHz):  = 144.8, 133.2, 129.5, 128.8, 69.8, 55.1,
37.2, 30.1, 25.0, 24.1, 22.5, 21.7, 20.9.
HRMS (FAB+): m/z [M + H]+ calcd for C15H21N2O2S: 293.1324; found:
293.1328.
GP2; major isomer; yield: 114.6 mg (82%).
Major isomer:
TLC: Rf = 0.38 (hexane/EtOAc, 7:3).
IR (ATR): 2945, 2936, 2926, 1595, 1331, 1294, 1172, 1152, 1117, 1090,
1011, 955, 853, 843, 810, 756cm–1
.
7-Tosyl-1,7-diazabicyclo[4.1.0]heptane (3ea)
GP1; yellow solid; yield: 63.3 mg (50%); mp 110.5–112.0 °C.
GP2; yield: 48.4 mg (38%).
1H NMR (CDCl3, 400 MHz):  = 7.84 (d, J = 8.4 Hz, 2 H), 7.35 (d, J = 8.4
Hz, 2 H), 4.01 (s, 1 H), 3.25 (dd, J =13.2, 8.0 Hz, 1 H), 3.06–3.00 (m, 1
H), 2.56–2.49 (m, 2 H), 2.46 (s, 3 H), 1.83–1.74 (m, 1 H), 1.66–1.54 (m,
4 H), 1.38–1.35 (m, 1 H).
TLC: Rf = 0.30 (hexane/EtOAc, 7:3).
13C NMR (CDCl3, 100 MHz):  = 144.9, 133.1, 129.5, 128.8, 71.3, 61.8,
46.1, 41.4, 31.4, 28.3, 25.0, 21.7.
IR (ATR): 2943, 2864, 1927, 1811, 1726, 1597, 1445, 1335, 1304, 1163,
1086, 970, 922, 812, 725 cm–1
.
HRMS (FAB+): m/z [M + H]+ calcd for C14H19N2O2S: 279.1167; found:
279.1167.
1H NMR (CDCl3, 400 MHz):  = 7.83 (d, J = 8.4 Hz, 2 H), 7.35 (d, J = 8.4
Hz, 2 H), 3.76 (d, J = 4.8 Hz, 1 H), 3.17–3.10 (m, 1 H), 2.94–2.88 (m, 1
H), 2.46 (s, 3 H), 2.24–2.17 (m, 1 H), 2.04–1.96 (m, 1 H), 1.55–1.46 (m,
2 H), 1.36–1.21 (m, 2 H).
13C NMR (CDCl3, 100 MHz):  = 144.8, 132.4, 129.4, 128.9, 58.4, 49.0,
21.9, 21.6, 19.5, 16.3.
Minor isomer:
TLC: Rf = 0.25 (hexane/EtOAc, 7:3).
IR (ATR): 2956, 2936, 2920, 2866, 1709, 1595, 1443, 1341, 1304, 1186,
1121, 1086, 1061, 993, 953, 862, 816, 785 cm–1
.
HRMS (FAB+): m/z [M + H]+ calcd for C12H17N2O2S: 253.1011; found:
253.1014.
1H NMR (CDCl3, 400 MHz):  = 7.83 (d, J = 8.4 Hz, 2 H), 7.35 (d, J = 8.4
Hz, 2 H), 4.04 (d, J = 4.0 Hz, 1 H), 3.19 (dd, J = 14.4, 8.8 Hz, 1 H), 2.96
(dd, J = 14.0, 2.4 Hz, 1 H), 2.92–2.86 (m, 1 H), 2.60–2.55 (m, 1 H), 2.46
(s, 3 H), 1.94–1.78 (m, 3 H), 1.72–1.67 (m, 1 H), 1.54–1.48 (m, 1 H),
1.40–1.34 (m, 1 H).
13C NMR (CDCl3, 100 MHz):  = 144.8, 133.1, 129.5, 128.8, 71.5, 60.6,
45.4, 45.2, 33.9, 28.5, 27.7, 21.7.
Ethyl 7-Tosyl-1,7-diazabicyclo[4.1.0]heptane-4-carboxylate (3fa)
GP1; major isomer as a yellow oil; yield: 48.2 mg (30%); minor isomer
as a yellow oil; yield: 49.1 mg (30%).
Major isomer:
HRMS (FAB+): m/z [M + H]+ calcd for C14H19N2O2S: 279.1167; found:
TLC: Rf = 0.30 (hexane/EtOAc, 1:1).
279.1166.
IR (ATR): 2982, 2967, 2938, 1726, 1713, 1597, 1445, 1381, 1331, 1306,
1256, 1184, 1159, 1090, 1030, 941, 908, 812, 727 cm–1
.
1H NMR (CDCl3, 400 MHz):  = 7.82 (d, J = 8.4 Hz, 2 H), 7.36 (d, J = 8.4
Hz, 2 H), 4.12 (q, J = 7.4 Hz, 2 H), 3.83 (d, J = 5.6 Hz, 1 H), 3.16–3.11 (m,
1 H), 3.03–2.95 (m, 1 H), 2.46 (s, 3 H), 2.45–2.40 (m, 1 H), 2.35–2.27
(m, 2 H), 1.77–1.57 (m, 1 H), 1.57–1.53 (m, 1 H), 1.24 (t, J = 7.4 Hz, 3
H).
13C NMR (CDCl3, 100 MHz):  = 173.4, 145.0, 132.3, 129.5, 128.9, 60.8,
57.3, 48.3, 34.5, 22.8, 21.7, 21.1, 14.1.
1-Tosyloctahydro-1H-diazirino[3,1-a]isoindole (3da)
GP1; major isomer as a white solid; yield: 62.6 mg (42%); mp 100.5–
111.5 °C; minor isomer as a white solid; yield: 36.6 mg (25%); mp
100.5–101.0 °C.
GP2; combined yield of stereoisomers: 122.6 mg (84%).
Major isomer:
TLC: Rf = 0.25 (hexane/EtOAc, 7:3).
HRMS (FAB+): m/z [M + H]+ calcd for C15H21N2O4S: 325.1222; found:
325.1221.
IR (ATR): 2945, 2920, 2857, 1597, 1439, 1339, 1321, 1240, 1207, 1186,
1159, 1086, 1020, 980, 907, 870, 837, 802, 752 cm–1
.
Minor isomer:
1H NMR (CDCl3, 400 MHz):  = 7.84 (d, J = 8.8 Hz, 2 H), 7.35 (d, J = 8.8
Hz, 2 H), 3.96 (d, J = 2.8 Hz, 1 H), 3.07 (dd, 13.6, 7.6 Hz, 1 H) 2.91 (d, J =
13.6 Hz, 1 H) 2.46 (s, 3 H), 2.45–2.42 (m, 1 H), 2.05–2.00 (m, 1 H),
1.93–1.89 (m, 1 H), 1.74–1.60 (m, 2 H), 1.57–1.45 (m, 2 H), 1.44–1.37
(m, 2 H), 1.11–1.06 (m, 1 H).
13C NMR (CDCl3, 100 MHz):  = 144.8, 133.3, 129.5, 128.7, 70.0, 61.1,
37.4, 33.0, 30.6, 24.5, 23.2, 21.7, 21.3.
TLC: Rf = 0.40 (hexane/EtOAc, 1:1).
IR (ATR): 2980, 2959, 2938, 1728, 1597, 1447, 1381, 1325, 1250, 1184,
1159, 1088, 1032, 1018, 970, 814, 789, 756 cm–1
.
1H NMR (CDCl3, 400 MHz):  = 7.82 (d, J = 8.0 Hz, 2 H), 7.36 (d, J = 8.0
Hz, 2 H), 4.12 (q, J = 7.2 Hz, 2 H), 3.86 (d, J = 3.6 Hz, 1 H), 3.37–3.31 (m,
1 H), 2.94–2.87 (m, 1 H), 2.61–2.45 (m, 2 H), 2.46 (s, 3 H), 2.18–2.11
(m, 1 H), 1.82–1.78 (m, 1 H), 1.50–1.40 (m, 1 H), 1.23 (t, J = 7.2 Hz, 3
H).
13C NMR (CDCl3, 100 MHz):  = 173.8, 145.1, 132.1, 129.5, 129.0, 60.8,
58.9, 47.9, 33.4, 24.9, 23.1, 21.6, 14.0.
HRMS (FAB+): m/z [M + H]+ calcd for C15H21N2O2S: 293.1324; found:
293.1323.
Minor isomer:
TLC: Rf = 0.38 (hexane/EtOAc, 7:3).
HRMS (FAB+): m/z [M + H]+ calcd for C15H21N2O4S: 325.1222; found:
325.1217.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–I

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Y. Kiyosu et al.
Special Topic
Synthesis
7-Tosyl-4-oxa-1,7-diazabicyclo[4.1.0]heptane (3ga)
GP1; white solid; yield: 78.4 mg (61%); mp 97.9–98.7 °C.
GP2; yield: 100.3 mg (79%).
1H NMR (CDCl3, 400 MHz):  = 7.98–7.94 (m, 1 H), 7.78–7.66 (m, 4 H),
7.64 (d, J = 8.0 Hz, 1 H), 7.35 (d, J = 8.0 Hz, 2 H), 3.96 (d, J = 2.8 Hz, 2 H),
3.89 (dd, J = 2.8, 2.8 Hz, 1 H), 3.30 (dd, J = 9.2, 4.4 Hz, 2 H), 3.24–3.17
(m, 1 H), 3.07 (dt, J = 14.0, 4.0 Hz, 1 H), 2.46 (s, 3 H).
13C NMR (CDCl3, 100 MHz):  = 148.1, 145.6, 134.0, 131.9, 131.5,
131.2, 130.9, 129.7, 129.1, 124.4, 55.9, 48.1, 40.6, 38.9, 21.7.
TLC: Rf = 0.30 (hexane/EtOAc, 7:3).
IR (ATR): 2971, 2945, 2902, 2859, 1959, 1438, 1465, 1381, 1336, 1301,
1262, 1159, 1126, 1087, 1056, 1005, 926, 862, 779, 705 cm–1
.
HRMS (FAB+): m/z [M + H]+ calcd for C17H19N4O6S2: 439.0746; found:
439.0748.
1H NMR (CDCl3, 400 MHz):  = 7.85 (d, J = 8.4 Hz, 2 H), 7.37 (d, J = 8.4
Hz, 2 H), 4.24 (d, J = 13.2 Hz, 1 H), 4.09 (dd, J = 13.2, 3.6 Hz, 1 H), 3.77
(d, J = 3.6 Hz, 1 H), 3.64–3.59 (m, 1 H), 3.35–3.29 (m, 1 H), 3.21–3.14
(m, 1 H), 2.96–2.90 (m, 1 H), 2.47 (s, 3 H).
13C NMR (CDCl3, 100 MHz):  = 145.3, 132.1, 129.6, 129.1, 62.1, 60.7,
55.6, 47.8, 21.7.
1-Benzyl-3-phenyl-2-tosyldiaziridine (3ka)
GP1; colorless oil; yield: 42.6 mg (24%).
1H NMR (CDCl3, 400 MHz):  = 7.71 (d, J = 8.0 Hz, 2 H), 7.53–7.50 (m, 2
H), 7.44–7.40 (m, 3 H), 7.16–7.12 (m, 3 H), 7.03 (t, J = 8.0 Hz, 2 H), 6.91
(d, J = 7.2 Hz, 2 H), 4.92 (s, 1 H), 3.35 (d, J = 13.2 Hz, 1 H), 3.28 (d, J =
13.2 Hz, 1 H), 2.41 (s, 3 H).
HRMS (CI): m/z [M + H]+ calcd for C11H15N2O3S: 255.0803; found:
255.0805.
13C NMR (CDCl3, 100 MHz):  = 144.9, 135.8, 131.8, 129.7, 129.34,
129.27, 129.15, 129.09, 129.06, 128.4, 128.1, 127.0, 63.3, 56.0, 21.7.
tert-Butyl 7-Tosyl-1,4,7-triazabicyclo[4.1.0]heptane-4-carboxylate
(3ha)
The analytical data for this compound were in excellent agreement
with the reported data.5e
GP1; white solid; yield: 80.2 mg (45%); mp 112.5–113.0 °C.
TLC: Rf = 0.25 (hexane/EtOAc, 7:3).
IR (ATR): 2976, 2968, 1693, 1597, 1412, 1391, 1364, 1331, 1292, 1184,
1-Butyl-3-propyl-2-tosyldiaziridine (3la)
GP1; yellow oil; yield: 35.1 mg (23%).
1159, 1112, 1090, 1007, 989, 897, 868, 833, 810, 772, 760 cm–1
.
1H NMR (CDCl3, 400 MHz):  (mixture of rotamers) = 7.84 (d, J = 8.4
Hz, 2 H), 7.37 (d, J = 8.4 Hz, 2 H), 4.04 (dd, J = 15.2, 15.2 Hz, 1 H), 3.87–
3.76 (m, 2 H), 3.30–3.26 (m, 2 H), 3.10–3.07 (m, 2 H), 2.47 (s, 3 H),
1.44 (s, 9 H).
13C NMR (CDCl3, 100 MHz):  (observable signals in the mixture of ro-
tamers) = 154.3, 145.3, 132.3, 132.0, 129.6, 128.9 80.5, 80.4, 57.2,
56.4, 48.0, 39.5, 38.2, 37.2, 36.2, 28.2, 21.7.
TLC: Rf = 0.30 (hexane/EtOAc, 9:1).
IR (ATR): 2959, 2932, 2874, 1597, 1495, 1458, 1402, 1335, 1257, 1119,
1090, 962, 876, 814, 760 cm–1
.
1H NMR (CDCl3, 400 MHz):  = 7.84 (d, J = 8.4 Hz, 2 H), 7.35 (d, J = 8.4
Hz, 2 H), 3.62 (dd, J = 7.2, 4.8 Hz, 1 H), 2.62–2.55 (m, 1 H), 2.46 (s, 3 H),
2.41–2.35 (m, 1 H), 1.75–1.58 (m, 2 H), 1.58–1.49 (m, 2 H), 1.27–1.10
(m, 4 H), 1.00 (t, J = 7.2 Hz, 3 H), 0.77 (t, J = 7.2 Hz, 3 H).
13C NMR (CDCl3, 100 MHz):  = 145.0, 132.4, 129.4, 128.4, 63.8, 51.8,
30.4, 27.2, 21.7, 20.2, 19.6, 13.8, 13.7.
HRMS (FAB+): m/z [M + H]+ calcd for C16H24N3O4S: 354.1488; found:
354.1491.
HRMS (FAB+): m/z [M + H]+ calcd for C15H25N2O2S: 297.1637; found:
297.1642.
4,7-Ditosyl-1,4,7-triazabicyclo[4.1.0]heptane (3ia)
GP1; white solid; yield: 63.0 mg (31%); mp 122.1–123.8 °C.
GP2; yield: 180.2 mg (88%).
1-Methyl-2-tosyl-3-(4-(trifluoromethyl)phenyl)diaziridine (3ma)
GP1; white solid; yield: 143.2 mg (83%); mp 82.5–83.5°C.
TLC: Rf = 0.38 (hexane/EtOAc, 1:1).
TLC: Rf = 0.18 (hexane/EtOAc, 7:3).
IR (ATR): 2952, 2859, 2362, 1922, 1596, 1493, 1457, 1345, 1306, 1214,
1183, 1163, 1111, 1088, 1019, 991, 974, 951, 736 cm–1
.
IR (ATR): 3078, 2980, 2932, 1620, 1595, 1452, 1422, 1337, 1263, 1161,
1H NMR (CDCl3, 400 MHz):  = 7.75 (d, J = 8.4 Hz, 2 H), 7.60 (d, J = 8.4
Hz, 2 H), 7.34–7.27 (m, 4 H), 3.87–3.77 (m, 2 H), 3.49 (d, J = 13.2 Hz, 1
H), 3.23–3.19 (m, 1 H), 3.13–3.08 (m, 1 H), 2.99 (dt, J = 14.0, 4.0 Hz, 1
H), 2.85–2.79 (m, 1 H), 2.50–2.40 (m, 6 H).
13C NMR (CDCl3, 100 MHz):  =145.5, 144.2, 132.6, 131.6, 129.9, 129.6,
129.1, 127.5, 55.8, 48.6, 40.9, 38.6, 21.7, 21.5.
1136, 1105, 1088, 1065, 1005, 876, 843, 802, 764 cm–1
.
1H NMR (CDCl3, 400 MHz):  = 7.92 (d, J = 8.4 Hz, 2 H), 7.66 (d, J = 7.6
Hz, 2 H), 7.57 (d, J = 7.6 Hz, 2 H), 7.40 (d, J = 8.4 Hz, 2 H), 4.76 (s, 1 H),
2.49 (s, 3 H), 2.17 (s, 3 H).
13C NMR (CDCl3, 100 MHz):  = 145.5, 133.1, 132.0, 131.7 (q, J = 32.1
Hz), 129.7, 129.4, 129.1, 125.4 (q, J = 3.3 Hz), 123.6 (q, J = 270.9 Hz),
63.1, 38.9, 21.7.
HRMS (CI): m/z [M + H]+ calcd for C18H22N3O4S2: 408.1052; found:
408.1057.
19F NMR (CDCl3, 377 MHz):  = −65.4.
HRMS (FAB+): m/z [M + H]+ calcd for C16H16F3N2O2S: 357.0885; found:
357.0886.
4-((2-Nitrophenyl)sulfonyl)-7-tosyl-1,4,7-triazabicyclo[4.1.0]hep-
tane (3ja)
GP1; white solid; yield: 192.8 mg (87%); mp 107.0–108.5 °C.
TLC: Rf = 0.30 (hexane/EtOAc, 1:1).
7-Tosyl-4-thia-1,7-diazabicyclo[4.1.0]heptane (3oa)
GP2; white solid; yield: 83.6 mg (62%); mp 78.3–79.9 °C.
TLC: Rf = 0.40 (hexane/EtOAc, 7:3)
IR (ATR): 2926, 1595, 1541, 1439, 1337, 1271, 1159, 1126, 1090, 1059,
955, 887, 853, 812, 777, 727 cm–1
.
IR (ATR): 2917, 2914, 2865, 1922, 1593, 1386, 1330, 1296, 1176, 1161,
1143, 1092, 1060, 988, 893, 758 cm–1
.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–I

H
Y. Kiyosu et al.
Special Topic
Synthesis
1H NMR (CDCl3, 400 MHz):  = 7.83 (d, J = 8.4 Hz, 2 H), 7.37 (d, J = 8.4
Hz, 2 H), 3.96 (dd, J = 6.0, 3.2 Hz, 1 H), 3.34–3.27 (m, 1 H), 3.23 (dd, J =
14.4, 3.2 Hz, 1 H), 3.12–3.04 (m, 2 H), 2.77–2.71 (m, 1 H), 2.47 (s, 3 H),
2.32–2.25 (m, 1 H).
13C NMR (CDCl3, 100 MHz):  = 145.3, 132.0, 129.6, 129.1, 55.8, 48.1,
21.9, 21.7, 21.3.
TLC: Rf = 0.50 (hexane/EtOAc, 2:8).
IR (ATR): 3240, 2859, 1622, 1595, 1576, 1493, 1444, 1331, 1290, 1184,
1155, 1086, 1059, 1024, 972, 924, 899, 858, 814, 774 cm–1
1H NMR (CDCl3, 400 MHz):  = 7.73 (d, J = 8.0 Hz, 2 H), 7.70 (d, J = 7.2
Hz, 2 H), 7.40 (t, J = 7.2 Hz, 1 H), 7.31 (d, J = 8.0 Hz, 2 H), 7.27 (d, J = 7.2
Hz, 2 H), 5.07 (br d, J = 8.8 Hz, 1 H), 4.96–4.89 (m, 1 H), 3.93–3.88 (m,
2 H), 2.46 (s, 3 H), 2.13–2.04 (m, 1 H), 1.67–1.59 (m, 1 H).
.
HRMS (CI): m/z [M + H]+ calcd for C11H15N2O2S2: 271.0575; found:
271.0574.
13C NMR (CDCl3, 100 MHz):  = 170.3, 143.8, 137.4, 131.7, 130.7,
129.8, 128.5, 128.2, 127.2, 59.5, 58.9, 31.5, 21.6.
HRMS (FAB+): m/z [M + H]+ calcd for C17H19N2O2S: 315.1167; found:
315.1174.
8-Tosyl-1,8-diazabicyclo[5.1.0]octane (3pa)
GP2; yellow oil; yield: 93.9 mg (71%).
TLC: Rf = 0.25 (hexane/EtOAc, 8:2).
tert-Butyl 1,4,7-Triazabicyclo[4.1.0]heptane-4-carboxylate (5)
IR (ATR): 2926, 2858, 1598, 1401, 1335, 1163, 1091, 1120, 1048, 1034,
934, 914, 866, 814, 732 cm–1
.
According to the reported procedure,5e the reaction was carried out
using tert-butyl-7-tosyl-1,4,7-triazabicyclo[4,1,0]heptane-4-carbox-
ylate (3ha) (70.0 mg, 0.20 mmol), I2 (5.2 mg, 0.02 mmol), Mg (50.2
mg, 2.1 mmol), and MeOH (3.0 mL). Purification by flash column
chromatography on silica gel (hexane/EtOAc, 7:3) gave the product as
a yellow solid (26.7 mg, 68%); mp 110.0–111.5 °C.
1H NMR (CDCl3, 400 MHz):  = 7.85 (d, J = 8.4 Hz, 2 H), 7.35 (d, J = 8.4
Hz, 2 H), 3.80 (dd, J = 9.2, 4.4 Hz, 1 H), 3.18 (dd, J = 12.4, 7.2 Hz, 1 H),
2.52 (t, J = 11.2 Hz, 1 H), 2.46 (s, 3 H), 2.29–2.22 (m, 1 H), 1.83–1.65
(m, 4 H), 1.59–1.45 (m, 2 H), 1.23–1.21 (m, 1 H).
13C NMR (CDCl3, 100 MHz):  =144.8, 133.2, 129.5, 128.8, 63.0, 54.1,
30.2, 27.0, 25.7, 24.6, 21.7.
IR (ATR): 3240, 2976, 2932, 2870, 1670, 1545, 1456, 1427, 1391, 1364,
1288, 1244, 1163, 1120, 1103, 1061, 995, 979, 858, 826, 773, 756 735
HRMS (CI): m/z [M + H]+ calcd for C13H19N2O2S: 267.1167; found:
267.1169.
cm–1
.
1H NMR of mixture of rotamers (CDCl3, 400 MHz):  = 4.00–3.89 (m, 1
H), 3.75–3.66 (m, 1 H), 3.45–3.33 (m, 2 H), 3.23–3.25 (m, 3 H), 2.05 (d,
J = 6.0 Hz, 1 H), 1.45 (s, 9 H).
Observable signals in the 13C NMR of a mixture of rotamers (CDCl3,
100 MHz):  = 154.9, 154.7, 79.8, 50.3, 49.7, 48.4, 48.0, 39.9, 39.0,
37.7, 36.2, 28.4.
6-((2-Nitrophenyl)sulfonyl)-1,6-diazabicyclo[3.1.0]hexane (3ab)
GP2; yellow oil; yield: 60.3 mg (51%).
TLC: Rf = 0.21 (hexane/EtOAc, 7:3).
IR (ATR): 3103, 3051, 2992, 2926, 2855, 1730, 1595, 1537, 1460, 1439,
1359, 1344, 1315, 1292, 1263, 1236, 1195, 1163, 1144, 1123, 1061,
HRMS (FAB+): m/z [M + H]+ calcd for C9H18N3O2: 200.1399; found:
200.1401.
1032, 964, 905, 873, 843, 773, 750, 732, 727, 700 cm–1
.
1H NMR (CDCl3, 400 MHz):  = 8.25–8.15 (m, 1 H), 7.84–7.75 (m, 3 H),
4.37 (d, J = 3.2 Hz, 1 H), 3.38 (ddd, J = 14.0, 7.6, 2.8 Hz, 1 H), 2.93–2.85
(m, 1 H), 2.48 (ddd, J = 14.8, 6.8, 1.6 Hz, 1 H), 1.98–1.89 (m, 1 H), 1.69–
1.55 (m, 2 H).
Conflict of Interest
The authors declare no conflict of interest.
13C NMR (CDCl3, 100 MHz):  = 148.9, 134.8, 132.3, 132.2, 132.0,
130.0, 124.4, 69.5, 54.8, 26.7, 19.1.
HRMS (CI): m/z [M + H]+ calcd for C10H12N3O4S: 270.0549; found:
270.0548.
Funding Information
This work was supported by Japan Society for the Promotion of Sci-
ence (JSPS) KAKENHI Grant Numbers JP19H02716 (S.M.) and
6-((4-Nitrophenyl)sulfonyl)-1,6-diazabicyclo[3.1.0]hexane (3ae)
GP2; yellow solid; yield: 80.1 mg (60%); mp 82.3–85.5 °C.
TLC: Rf = 0.23 (hexane/EtOAc, 7:3).
JP20K05511 (K.K.).JapanSocietyforth
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Supporting Information
IR (ATR): 3115, 3111, 2973, 2952, 2944, 2879, 2873, 1609, 1559, 1524,
1402, 1350, 1337, 1316, 1308, 1300, 1289, 1178, 1173, 1106, 1091,
Supporting information for this article is available online at
https://doi.org/10.1055/a-1468-8275. Su
1086, 1012, 969, 910, 877, 857, 851, 830, 780, 755, 740, 732 cm–1
.
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ortingInformatio
n
1H NMR (CDCl3, 400 MHz):  = 8.41 (d, J = 8.8 Hz, 2 H), 8.18 (d, J = 8.8
Hz, 2 H), 4.25 (d, J = 2.8 Hz, 1 H), 3.09 (ddd, J = 13.2, 7.2, 1.6 Hz, 1 H),
2.83–2.75 (m, 1 H), 2.43 (ddd, J = 14.8, 8.0, 1.6 Hz, 1 H), 1.98–1.88 (m,
1 H), 1.64–1.54 (m, 2 H).
References
13C NMR (CDCl3, 100 MHz):  = 150.8, 142.0, 130.3, 124.0, 67.3, 54.3,
26.6, 19.2.
HRMS (CI): m/z [M + H]+ calcd for C10H12N3O4S: 270.0549; found:
270.0549.
(1) (a) Schmitz, E. Adv. Heterocycl. Chem. 1979, 24, 63. (b) Schmitz,
E. Three-membered Rings with Two Heteroatoms and Fused-ring
Derivatives, In Comprehensive Heterocyclic Chemistry, Vol. 7;
Lwowski, W., Ed.; Pergamon Press: Oxford, 1984, 195. (c) Heine,
H. W. Diaziridines, 3H-Diazirines, Diaziridinones and Diaziridin-
imines, In The Chemistry of Heterocyclic Compounds Vol. 42:
Small Ring Heterocycles – Part 2; Hassner, A., Ed.; Wiley Inter-
science: New York, 1983.
4-Methyl-N-(5-phenyl-3,4-dihydro-2H-pyrrol-4-yl)benzenesul-
fonamide (4)
GP1; yellow solid; yield: 60.4 mg (39%); mp 146.5–147.3 °C.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–I

I
Y. Kiyosu et al.
Special Topic
Synthesis
(2) (a) Makhova, N. N.; Shevtsov, A. V.; Petukhova, V. Y. Russ. Chem.
Rev. 2011, 80, 1035. (b) Chuang-Yang, H.; Doyle, A. G. Chem. Rev.
2014, 114, 8153. (c) Zhu, Y.; Cornwall, R. C.; Du, H.; Zhao, B.; Shi,
Y. Acc. Chem. Res. 2014, 47, 3665. (d) Makhova, N. N.; Belen’kii, L.
I.; Gazieva, G. A.; Dalinger, I. L.; Konstantinova, L. S.; Kuznetsov,
V. V.; Kravchenko, A. N.; Krayushkin, M. M.; Rakitin, O. A.;
Starosotnikov, A. M.; Fershtat, L. L.; Shevelev, S. A.; Shirinian, V.
Z.; Yarovenko, V. N. Russ. Chem. Rev. 2020, 89, 55.
(3) (a) Dehn, D. L.; Winski, S. L.; Ross, D. Clin. Cancer Res. 2004, 10,
3147. (b) Sridar, C.; Kobayashi, Y.; Brevig, H.; Kent, U. M.;
Puppali, S. G.; Rimoldi, J. M.; Hollenberg, P. F. Drug Metab.
Dispos. 2006, 34, 1849. (c) Yan, C.; Kepa, J. K.; Siegel, D.;
Stratford, I. J.; Ross, D. Mol. Pharmacol. 2008, 74, 1657.
(d) Kamuf, M.; Trapp, O. Chirality 2011, 23, 113. (e) Masuda, Y.;
Aoyama, K.; Yoshida, M.; Kobayashi, K.; Ohshiro, T.; Tomoda, H.;
Doi, T. Chem. Pharm. Bull. 2016, 64, 754.
S. N.; Asfandiarov, N. L.; Khusnutdianova, L. R.; Kostyanovskii, R.
G. Izv. Akad. Nauk SSSR, Ser. Khim. 1986, 1824. (e) Shustov, G. V.;
Denisenko, S. N.; Kostyanovskii, R. G. Izv. Akad. Nauk SSSR, Ser.
Khim. 1986, 1831. (f) Allen, J. M.; Lambert, T. H. Tetrahedron
2014, 70, 4111.
(7) (a) Schöpt, C.; Komzak, A.; Braun, F.; Jacobi, E. Ann. Chem. 1947,
559, 1. (b) Nomura, Y.; Ogawa, K.; Takeuchi, Y.; Tomoda, S. Chem.
Lett. 1977, 6, 693. (c) Baker, J. D.; Heath, R. R.; Millar, J. G.
J. Chem. Ecol. 1992, 18, 1595. (d) Zhang, X.; Chingin, K.; Zhong,
D.; Liang, J.; Ouyang, Y.; Chen, H. Sci. Rep. 2017, 7, 7675.
(8) (a) Minakata, S. Acc. Chem. Res. 2009, 42, 1172. (b) Hayakawa, J.;
Kuzuhara, M.; Minakata, S. Org. Biomol. Chem. 2010, 8, 1424.
(c) Minakata, S.; Hayakawa, J. Chem. Commun. 2011, 47, 1905.
(d) Murakami, Y.; Takeda, Y.; Minakata, S. J. Org. Chem. 2011, 76,
6277. (e) Kiyokawa, K.; Kojima, T.; Hishikawa, Y.; Minakata, S.
Chem. Eur. J. 2015, 21, 15548.
(4) (a) Makhova, N. N.; Petukhova, V. Y.; Kuznetsov, V. V. ARKIVOC
2008, (i), 128. (b) Ravindra, S.; Jesin, C. P. I.; Shabashini, A.;
Nandi, G. C. Adv. Synth. Catal. 2021, 363, 1756.
(9) Nair, C. G. R.; Indrasenan, P. Talanta 1976, 23, 239.
(10) Konigsberg, N.; Stevenson, G.; Luck, J. M. J. Biol. Chem. 1960, 235,
1341.
(5) For selected examples, see: (a) Schmitz, E. Angew. Chem. 1959,
71, 127. (b) Abendroth, H. J.; Henrich, G. Angew. Chem. 1959, 71,
283. (c) Carroccia, L.; Fioravanti, S.; Pellacani, L.; Sadun, C.;
Tardella, P. A. Tetrahedron 2011, 67, 5375. (d) Carroccia, L.;
Delfini, M.; Fioravanti, S.; Pellacani, L.; Sciubba, F. J. Org. Chem.
2012, 77, 2069. (e) Lykke, L.; Halskov, K. S.; Carlsen, B. D.; Chen,
V. X.; Jørgensen, K. A. J. Am. Chem. Soc. 2013, 135, 4692.
(f) Beede, A. W.; Dohmeier, E. F.; Moura-Letts, G. Chem.
Commun. 2015, 51, 13511.
(6) For selected examples, see: (a) Nielsen, A. T.; Moore, D. W.;
Atkins, R. L.; Mallory, D.; DiPol, J.; LaBerge, J. M. J. Org. Chem.
1976, 41, 3221. (b) Shustov, G. V.; Denisenko, S. N.;
Kostyanovskii, R. G. Izv. Akad. Nauk SSSR, Ser. Khim. 1983, 1930.
(c) Denisenko, S. N.; Shustov, G. V.; Kostyanovskii, R. G. J. Chem.
Soc., Chem. Commun. 1983, 1275. (d) Shustov, G. V.; Denisenko,
(11) Treatment of bromamine-T with CF3CO2H provided N-bromo-p-
toluenesulfonamide (9), which was analyzed by 1H NMR spec-
troscopy and ESI-MS.
(12) CCDC 2067657 contains the supplementary crystallographic
data for this paper. The data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via DOI:
www.ccdc.cam.ac.uk/structures.
(13) Biancalana, L.; Bortoluzzi, M.; Ferretti, E.; Hayatifar, M.;
Marchetti, F.; Pampaloni, G.; Zacchini, S. RSC Adv. 2017, 7,
10158.
(14) Man, R.-J.; Tang, D.-J.; Lu, X.-Y.; Duan, Y.-T.; Tao, X.-X.; Yang, M.-R.;
Wang, L.-L.; Wang, B.-Z.; Xu, C.; Zhu, H.-L. Med. Chem. Commun.
2016, 7, 1759.
(15) Chen, W.; Ma, L.; Paul, A.; Seidel, D. Nat. Chem. 2018, 10, 165.
(16) Kaplanek, R.; Krchnaak, V. Tetrahedron Lett. 2013, 54, 2600.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–I