Transformations of 3-aryl-2-chloro-2-imidoylaziridines: Novel entries to 4-chloro-2,5-diaryl-1H-imidazoles and 2-chloro-2-acylaziridines

Article abstract of DOI:10.1016/j.tet.2010.11.082

The reactivity of stereochemically defined 3-aryl-2-chloro-2- imidoylaziridines, an unexplored class of substituted aziridines, was investigated under various reaction conditions. 2-Chloro-2-imidoylaziridines underwent a novel thermal rearrangement by reflux in acetonitrile via C-C bond cleavage to 4-chloro-2,5-diarylimidazoles in high yield. Alternatively, a novel efficient entry toward 2-aroyl-2-chloroaziridines was based on the chemoselective hydrolysis of 2-chloro-2-imidoylaziridines with hydrochloric acid in aqueous tetrahydrofuran.

Full text of DOI:10.1016/j.tet.2010.11.082

Tetrahedron 67 (2011) 1258e1265
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Transformations of 3-aryl-2-chloro-2-imidoylaziridines: novel entries
to 4-chloro-2,5-diaryl-1H-imidazoles and 2-chloro-2-acylaziridines
y
*
Filip Colpaert, Sven Mangelinckx , Nicola Giubellina, Norbert De Kimpe
Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
The reactivity of stereochemically defined 3-aryl-2-chloro-2-imidoylaziridines, an unexplored class of
substituted aziridines, was investigated under various reaction conditions. 2-Chloro-2-imidoylaziridines
underwent a novel thermal rearrangement by reflux in acetonitrile via CeC bond cleavage to 4-chloro-
2,5-diarylimidazoles in high yield. Alternatively, a novel efficient entry toward 2-aroyl-2-chloroaziridines
was based on the chemoselective hydrolysis of 2-chloro-2-imidoylaziridines with hydrochloric acid in
aqueous tetrahydrofuran.
Received 8 November 2010
Accepted 24 November 2010
Available online 1 December 2010
Keywords:
Aziridines
Imidazoles
Ó 2010 Elsevier Ltd. All rights reserved.
Azomethine ylides
Rearrangement
Ring opening
1. Introduction
aziridines via reaction of aziridines 3 with sodium cyanoborohy-
dride in the presence of acetic acid.4
Functionalized aziridines are versatile building blocks in the
synthesis of acyclic nitrogen-containing compounds and azahe-
terocycles via cleavage of the CeN or CeC bond and via elaboration
of functionalized substituents.1 As such, a strong interest among
experimental and theoretical chemists exists to obtain a better
understanding of the reactivity of aziridines, which depends
strongly on the substitution pattern of the aziridines and the re-
action conditions.2 The further development of aziridine-mediated
synthesis of heavily functionalized compounds relies, of course, on
the availability of stereochemically defined highly substituted
aziridines and the ability to control their further transformations in
the desired way. The synthesis of cis-3-aryl-2-chloro-2-imidoyla-
ziridines 3aec and the unreported aziridines 3def, representing
interesting and novel examples of stable 2-chloroaziridines,3 was
described via aza-Darzens type reaction of 3,3-dichloro-1-azaallylic
anions 1 and N-sulfonylaldimines 2 (Scheme 1).4 The aziridines 3
belong to a class of aziridines 4 or 5 bearing an imidoyl or carbonyl
functionality at the 2-position leading to an interesting substitution
pattern, which opens up a whole range of further possible trans-
formations (Scheme 2). Nucleophilic addition (path a) across the
imino group in aziridines 4 (Y¼NR0) is possible as previously
demonstrated by the stereoselective synthesis of 2-(aminomethyl)
SO2Ph
H
N
1) 1 equiv
R2
R
SO2Ph
N
Li
R
N
N
2
Cl
Cl
- 40 °C -> rt, 6-16 h
(47-95%)
2) 1.2-1.3 equiv 2 N KOH
THF-H2O (1:1)
20-37 °C, 6-24 h
Cl
R1
R1
R2
1
3a (R = i-Pr, R1 = R2 = H, 99%)
3b (R = i-Pr, R1 = Cl, R2 = H, 89%)
3c (R = i-Pr, R1 = H, R2 = Cl, 99%)
3d (R = i-Pr, R1 = H, R2 = Me, 96%)
3e (R = i-Pr, R1 = R2 = Me, 96%)
3f (R = c-Hex, R1 = H, R2 = Me, 75%)
Scheme 1.
The thermal formation of azomethine ylides 7 (path b) can be
envisioned due to the presence of the inductively electron-with-
drawing 2-imidoyl and 2-chloro substituents, which stabilize the
carbanionic center, and the 3-aryl group, which stabilizes the
benzylic cationic center in azomethine ylides 7. Subsequent 1,5-
dipolar electrocyclization of the generated azomethine ylides 7
would lead to the formation of 1H-imidazoles 9 (Y¼NR0). 1H-Im-
idazoles are a very important class of heterocycles due to their
known biological activity and diverse medical uses, explaining that
the synthesis of substituted 1H-imidazoles has received significant
* Corresponding author. Tel.: þ32 9 264 59 51; fax: þ32 9 264 62 21; e-mail
address: norbert.dekimpe@UGent.be (N. De Kimpe).
y
Postdoctoral Fellow of the Research FoundationdFlanders (FWO), Belgium.
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.11.082

F. Colpaert et al. / Tetrahedron 67 (2011) 1258e1265
1259
R
N
R1
R2
Y
Nu
HY
R1
Y
R1
R2
R3
R1
R2
Y
R3
- HR
N
R
R3
N
R2 R3
6
N
Path b:
R
Path a:
C=Y
addition
7
8
9
Nu-H
R1
R2
Y
C-C bond
cleavage
R
N
Y
R3
C-C bond
cleavage
N
R1
R2 R3
Path c:
13
- HR
4 (Y = NR')
5 (Y = O)
Y
Y
R1
R2
Y
N
R1
N
N
R1
R3
R2
R2
R3
R3
C-N bond
10
11
12
cleavage
Scheme 2.
attention.5,6 1H-Imidazoles are nonpeptide angiotensin II receptor
antagonists for the treatment of hypertension,7 as well as inhibitors
of p38 MAP kinase, implicated with the release of the pro-in-
product in 88% yield (Scheme 3). 1H NMR and 13C NMR spectral data
did not show any aliphatic signals except for the aliphatic substituent
at nitrogen. As previously highlighted, either the formation of
a pyrazole 15 or an imidazole 14a can be justified by thermal rear-
rangement of 2-imidoylaziridines. The obtained reaction product
definitely represented a tetrasubstituted diazole derivative, as con-
firmed by spectroscopic and combustion elemental analysis. Further,
comparison of the literature data of substituted 1H-imidazoles and
1H-pyrazoles were useful during the structure elucidation.
flammatory cytokine TNF-a 8
. Naturally occurring imidazoles in-
clude the amino acid histidine, and purines, important bases in
nucleic acids. 2,5-Diarylimidazoles are responsible of the modula-
tion of the NPY5 receptor, involved in regulating the food intake
and body weight, and several derivatives have anorexic effects in
rodents, especially when an electron-withdrawing group was in-
troduced at the aromatic ring at carbon-5.9
The investigation of the thermal rearrangement of 2-imidoy-
laziridines 4 to imidazole derivatives 9 lacks a comprehensive
SO2Ph
N
N
N
CH3CN
Δ, 7 h
N
N
study.10 The thermal ring transformation of
a-imidoylaziridines
or
N
into pyrroles has been described previously.11 The limited reports
on the rearrangement of 2-imidoylaziridines are probably due to
the difficulty to access these functionalized strained heterocycles.
In fact, the synthesis of ketimines derived from 2-acylaziridines
cannot be performed at high temperature, i.e., in hot toluene or
benzene, because intramolecular rearrangement to oxazole de-
rivatives is in competition with the imine condensation.12 Few
examples of thermal reactions of 2-aroylaziridines were described.
The synthesis of 2,5-diaryloxazole derivatives (R1¼R3¼aryl) from
the thermally induced rearrangement of aroylaziridines 5 (Y¼O)
was reported.12,13
Cl
Cl
(88%)
Cl
3a
14a
Scheme 3.
15
At first, analyses of the 13C NMR data of some imidazole de-
rivatives5,23 showed that for imidazoles related to the present
compound 14a only carbon-2 is subjected to a low field shift, as can
be easily predicted as a result of its position in between two ni-
trogen atoms. The presence of a resonance signal at 146.5 ppm in
the 13C NMR spectrum of our compound 14a (or 15) gave a first
indication of an imidazole ring.
To establish the structure of the reaction product of the thermal
rearrangement of aziridine 3a as a 1H-imidazole 14a (or a 1H-
pyrazole 15), without any reasonable doubt, an authentic sample of
1-isopropyl-4-chloro-1H-imidazole 14a or 1-isopropyl-4-chloro-
1H-pyrazole 15 was needed. At the moment that the structural
attribution of the unknown diazole was not performed yet, it was
decided to start with a new synthesis of 4-chloro-3,5-diphenyl-1-
isopropyl-1H-pyrazole 15. First attempts directed at the N-alkyl-
ation of the commercially available 3,5-diphenyl-1H-pyrazole 16
afforded 1-isopropyl-1H-pyrazole 18 in low yields (Scheme 4).
Reaction of pyrazole 16 with 2-bromopropane 17 in the presence of
potassium tert-butoxide in tetrahydrofuran under reflux resulted in
poor yield of the desired N-isopropyl-1H-pyrazole 18 (25%), along
with starting material. The use of allyl bromide 19 as an electrophile
in tetrahydrofuran at 50 ꢀC for 3 days in the presence of 2 equiv of
2 N sodium hydroxide gave N-allylpyrazole 20 and starting product
16 (ratio 1/1) (Scheme 4), confirming the reluctant behavior of the
pyrazole 16 toward N-alkylation.
2H-Azirines are important building blocks in heterocyclic syn-
thesis,14 and they were found in some natural products, e.g., azir-
inomycin.15 N-(Benzenesulfonyl)aziridines 4 (R¼SO2Ph) are prone
to elimination of benzenesulfinate when treated with base (path c)
and thus, 2H-azirines 10 can be obtained in this way.16 One of the
possible ways of constructing 1H-pyrazoles 12 involves the thermal
rearrangement of 2-imidoyl-2H-azirines 10 (Y¼NR0) via nitrene
intermediates 11.17e19 1H-Pyrazoles were found to be active as anti-
hypertensives,7 in the cure of gout,20 as well as anti-inflammatory
agents21 and herbicides.22 In contrast, the photochemical rear-
rangement 2-imidoyl-2H-azirines 10 has led to 1H-imidazoles 9.17,19
Therefore an evaluation of the reactivity of 3-aryl-2-chloro-2-
imidoylaziridines 3 is of significant synthetic and mechanistic in-
terest and will fill up important gaps in heterocyclic chemistry.
2. Results and discussion
In an initial experiment, 2-chloro-2-imidoylaziridine 3a was
heated under reflux in acetonitrile for 7 h resulting in a complete
rearrangement to a diazaaromatic compound as the only reaction

1260
F. Colpaert et al. / Tetrahedron 67 (2011) 1258e1265
2 equiv KOt-Bu
4 equiv
2 equiv 2 N NaOH
4 equiv
19
Br
H
N
Br
17
N
N
N
N
N
THF, Δ
3 days
THF, 50 °C
3 days
18 (25%, crude)
16
Scheme 4.
20 (45%)
AlthoughchlorinationofN-alkylated1H-pyrazole18 shouldafford
the 4-chloro-3,5-diphenylpyrazole 15 useful for structural elucida-
tion, this N-alkylation strategy of pyrazole 16 was not continued be-
cause of the poor results. However, a different strategy for the
synthesis of 4-chloro-3,5-diphenylpyrazole 15 was applied. Knowing
that 3,5-diphenyl-1H-pyrazoles were synthesized via the condensa-
tion of arylhydrazones and dibenzoylmethane,24 also the reaction
of N-isopropylhydrazine and dibenzoylmethane would give the
desired N-isopropyl-1H-pyrazole 18 (Scheme 5). An independent
synthesis of N-isopropylhydrazine 21 started with hydrazine and
2-bromopropane 17 followed by distillation to yield N-iso-
propylhydrazine 21 as a 24% w/w solution in water. Therefore,
distilled N-isopropylhydrazine was condensed with dibenzoyl-
methane 22 in ethanol under reflux for 24 h to afford crystalline
N-isopropylpyrazole 18 in 84% yield (Scheme 5). The resulting
N-isopropylpyrazole 18 was chlorinated at the 4-position with
are in agreement with previously reported spectra of related im-
idazoles.5,23 Finally, 1H-pyrazole derivatives showed to be unstable
under hv, i.e., the conversion of substituted pyrazoles into imida-
zoles via 2-imidoyl-2H-azirine intermediates.30 This fact contrasts
with the chemical behavior of compound 14a, which is a stable
compound, i.e., by photochemical irradiation or simply upon
heating. Compound 14a was stable in daylight in tetrahydrofuran
and CDCl3 solutions, as well as on heating, e.g., in acetic acid or
tetrahydrofuran for 3 days at reflux.
In conclusion, spectroscopic data, in particular 13C NMR, as
compared to the spectra of synthesized 4-chloro-3,5-diphenylpyr-
azole 15, along with its chemical behavior, ascertained the identi-
fication of the compound from the thermal rearrangement of
2-imidoylaziridine 3a as 4-chloro-2,5-diphenyl-1H-imidazole 14a.
The previously described route to 4-chloroimidazole 14a was
evaluated during the synthesis of some derivatives by varying the
2.2 equiv NH2NH2
Br
20 mol% NaOH
H2O, 80 °C, 14 h
(100%)
17
i-PrNHNH2
21
5 equiv
O
O
1.5 equiv NCS
N
N
N
N
H2O, EtOH, Δ, 24 h
CCl4, Δ, 13 h
Cl
22
18 (84%)
Scheme 5.
15 (80%)
N-chlorosuccinimide in carbon tetrachloride at reflux overnight, as
previously performed with 3,5-diphenylisoxazole analogues,25 to
give 4-chloropyrazole 15 in 80% yield.
aromatic substituents and the N-substituent. Thus, 2-chloroazir-
idines 3bef were converted to 4-chloroimidazoles in acetonitrile
at reflux for 7e16 h in generally good yields (Scheme 6). Impor-
tantly, 4-chloroimidazole 14b was obtained on leaving the azir-
idine 3b in chloroform for 24 h at room temperature, albeit in lower
yield (47%). Finally, 1H-imidazole 14a was also obtained in lower
yields when imidoylaziridine 3a was refluxed in mixtures of
1-Alkyl-4-chloropyrazoles are interesting compounds for bio-
logical screening, as some 1,5-diarylpyrazoles were found active as
anti-inflammatory agents, e.g., in the cure of arthritis.21,26 Previously,
4-bromo- and 4-fluoro-1H-pyrazoles were generated by condensa-
tion of 2-bromo- or 2-fluoro-1,3-propanediones and phenyl-
hydrazines.27,28 A drawback of the latter procedurewas the formation
of mixtures of isomers when unsymmetrical propane-1,3-dione
derivatives were used.
After spectroscopic characterization of the 4-chloro-1H-pyr-
azole 15, it was clear that the latter synthesized 4-chloro-1H-pyr-
azole had different spectroscopic features than the former
unknown compound 14a. The 13C NMR data of the 4-chloropyr-
azole 15 were in agreement with a previously synthesized 1-alkyl-
4-chloropyrazole.29 Looking into the details of the NMR spectra it
was clear that the 1H NMR spectra of 4-chloropyrazole 15 and
compound 14a were quite alike, while their 13C NMR spectra
revealed more differences. In the 13C NMR spectrum of pyrazole 15
a shielded signal appeared at 106.1 ppm (tetramethylsilane as ref-
erence), attributed to the C-4 of the pyrazole ring, while the C-3 and
C-5 were found at lower field, 146.1 and 140.2 ppm, respectively. In
contrast, in the 13C NMR spectrum of compound 14a no shielded
resonance signal around 105 ppm is present, and its 13C NMR data
R
SO2Ph
N
R
N
N :
Δ
R1
CH3CN, 7-16 h
Cl
N
R2
R1
Cl
SO2Ph
23
R2
3a-c
R
N
R
N
R1
R2
R1
R2
N
N
Cl
SO2Ph
Cl
14a (R = i-Pr, R1 = R2 = H, 88%)
14b (R = i-Pr, R1 = Cl, R2 = H, 89%)
14c (R = i-Pr, R1 = H, R2 = Cl, 84%)
14d (R = i-Pr, R1 = H, R2 = Me, 92%)
14e (R = i-Pr, R1 = R2 = Me, 95%)
14f (R = c-Hex, R1 = H, R2 = Me, 76%)
24
Scheme 6.

F. Colpaert et al. / Tetrahedron 67 (2011) 1258e1265
1261
methanolꢁtetrahydrofuran (1/1) (40e70%) along with mixtures of
unidentified reaction products. The structures of 4-chloro-
imidazole derivatives 14bef (vide infra) were confirmed as their
spectroscopic data were in analogy with data of 4-chloro-2,5-
diphenyl-1H-imidazole 14a.
During the course of our investigation on the thermal rear-
rangement, it was found that 2-chloroaziridine 3a led to mixtures of
4-chloroimidazole 14a and 4-methoxyimidazole 25 when 3a was
treated with sodium borohydride in methanol or 2 N sodium
methoxide in methanol under reflux (Scheme 7). The methoxy
substituent at position 4 of the imidazole ring 25 is not generated by
a direct substitution from the 4-chloroimidazole 14a, because a
direct conversion of 14a into 25 with sodium methoxide in methanol
under reflux did not give 4-methoxyimidazole 25. Therefore, the
methoxylation resulted from a substitution of the aziridine 3 rather
than from the 4-chloro-1H-imidazole 14a. A reasonable mechanism
for the synthesis of 4-methoxyimidazole 25 involved the displace-
3a to the desired 2H-azirine 29 could not be achieved, even when
TMEDA (N,N,N0,N0-tetramethylethylenediamine), or HMPA (hexa-
methylphosphor(V) amide), was used as co-solvent,16 as complex
reaction mixtures were obtained instead (Scheme 9). At present,
some 2-acyl-2-halo-2H-azirines have been synthesized.32 There-
fore our efforts moved toward the synthesis of 2-aroyl-2-chloro-
2H-azirines from 2-chloro-2-imidoylaziridines 3. An additional
hydrolysis step was required to synthesize 2-aroyl-2-chloro-2H-
azirines. The latter chemoselective hydrolysis of ketimines 3 was
simply accomplished by 1.5 equiv of 2 N hydrochloric acid in tet-
rahydrofuranꢁwater (1/1) at room temperature, giving (1-benze-
nesulfonyl-2-chloro-3-arylaziridin-2-yl)(aryl)methanones 30aee
in 68e99% yield (Scheme 9).
Unfortunately, also the attempted elimination reactions per-
formed from 30a with 1.1 equiv of LDA in tetrahydrofuran, with and
without TMEDA, at low temperature (ꢁ100 ꢀC) were not successful
to give 2-chloroazirine 31.
1 equiv NaBH4
MeOH, 6 h, Δ
SO2Ph
N
N
H
N
N
+
or
Cl
N
N
2.5 equiv 2 N NaOMe
MeOH, 72 h, Δ
Cl
14a (2-10%)
MeO
25 (12-20%)
3a
X
5 equiv. 2 N NaOMe
MeOH, Δ, 48 h
Scheme 7.
ment of the chloride ion by addition of sodium methoxide or
methanol, which gave 2-methoxyaziridine 26 (Scheme 8). Although
not proven, the substitution reaction of 3a probably occurs via
stereoselective addition of methoxide or methanol to afford the in-
termediate 26 with a trans relationship of the phenyl and methoxy
substituents.3
SO2Ph
N
SO2Ph
N
1.5 equiv 2 N HCl
N
O
THF/H2O (2:1)
rt, 4 - 8 h
Cl
Cl
R1
R1
3a-f
R2
R2
30a (R1 = R2 = H, 99%)
30b (R1 = Cl, R2 = H, 93%)
30c (R1 = H, R2 = Cl, 74%)
SO2Ph
N
SO2Ph
N
MeOM
N
(M = H, Na)
MeO
30d (R1 = H, R2 = Me, 73% from 3d, 85% from 3f)
30e (R1 = R2 = Me, 68%)
- MCl
Cl
N
X (1+.11e.0queiqvuLivDTAM(oErDnA-BourLHi)M, PA)
1.1 equiv LDA (or n-BuLi, or
NaHMDS, or LiHMDS)
3a
26
THF, -100 °C
(+ 1.0 equiv TMEDA or HMPA)
Y
N
X
N :
THF, -100 °C
N
(For R1 = R2 = H)
N
Cl
R1
R2
N
N
N
MeO
MeO
SO2Ph
29 (Y = i-PrN)
31 (Y = O)
MeO
25 (12-20%)
SO2Ph
28
27
Scheme 9.
Scheme 8.
The aziridine 26 underwent ring opening to dipolar intermediate
27 followed by intramolecular ring closure to give imidazoline 28,
which afterlossof benzenesulfinate afforded 4-methoxyimidazole 25.
After having evaluated the thermal behavior of aziridines 3,
some efforts were directed toward the generation of 2-chloro-
2H-azirines 29 through the use of strong bases (lithium diiso-
propylamide, butyl lithium, sodium, and lithium hexamethyldi-
silazide).16,31 2-Halo-2H-azirines are a class of not well studied
azaheterocycles with a unique reactivity due to the presence of
the highly strained unsaturated three-membered ring and the
halogen substituent.32
3. Conclusion
As conclusion, the reactivity of a new class of stereochemically
defined densely functionalized cis-3-aryl-2-chloro-2-imidoyl-1-
(phenylsulfonyl)aziridines was evaluated. The thermal rearrange-
ment of the 2-chloro-2-imidoylaziridines via cleavage of the CeC
bond gave unreported 4-chloro-2,5-diarylimidazoles upon reflux in
acetonitrile. Novel chlorinated 2-aroylaziridines were generated in
good yields (68e99%) via selective acid hydrolysis of the imidoyl
functionality of the aziridines. Neither the 2-imidoylaziridines nor
the 2-aroylaziridines gave the corresponding 2H-azirine derivatives
when treated with strong bases to induce elimination of the
N-substituent.
Despite all efforts and a range of reaction conditions in-
vestigated, the elimination of benzenesulfinic acid from aziridine

1262
F. Colpaert et al. / Tetrahedron 67 (2011) 1258e1265
4. Experimental
300 MHz):
d
¼1.13 (d, 3H, J¼6.1 Hz, CH3), 1.28 (d, 3H, J¼6.1 Hz, CH3),
2.29 (s, 3H, CH3), 3.65 (sept, 1H, J¼6.1 Hz, CHN]), 4.86 (s, 1H, CHp-
Tol), 6.97 (d, 2H, J¼8.3 Hz, CHarom.), 7.05 (d, 2H, J¼8.3 Hz, CHarom.),
7.41e7.62 (m, 8H, CHarom.), 7.99e8.04 (m, 2H, CHarom.); 13C NMR
4.1. General
Flame-dried glassware was used for all non-aqueous reactions.
Commercially available solvents and reagents were purchased from
common chemical suppliers and used without further purification,
unless stated otherwise. Tetrahydrofuran was distilled from sodium
and sodium benzophenone ketyl. Dichloromethane was distilled
over calcium hydride. Petroleum ether and chloroform were dried
and purified by washing with concentrated sulfuric acid and dis-
tilled. Methanol was dried with magnesium and distilled. Hexa-
methylphosphor(V) amide (HMPA) was dried over CaH2 and
distilled, then stored over molecular sieves. Flash chromatography
was carried out using a glass column filled with silica gel (Acros,
particle size 0.035e0.070 mm, pore diameter ca. 6 nm). TLC was
(CDCl3, 75 MHz):
d
¼21.2, 22.9, 23.4, 51.0, 53.5, 73.4, 127.5, 127.6,
128.05, 128.11, 128.4, 128.6, 128.8, 129.0, 133.5, 134.8, 138.3, 140.0,
159.6; IR (ATR):
n
¼1637 (C]N), 1344 and 1166 (S]O); MS (ESþ): m/
z (%)¼453/455 (MHþ, 29), 298/300 (100). Mp¼46.3e46.9 ꢀC. Yield
96%, brown crystals. Anal. Calcd for C25H25ClN2O2S: C, 66.28; H,
5.56; N, 6.18. Found: C, 66.03; H, 5.75; N, 6.01.
4.2.1.2. N-{(1E)-1-[cis-1-Benzenesulfonyl-2-chloro-3-p-tolylazir-
idin-2-yl](p-tolyl)methylidene}isopropylamine 3e. 1H NMR (CDCl3,
300 MHz):
d
¼1.12 (d, 3H, J¼6.1 Hz, CH3), 1.28 (d, 3H, J¼6.1 Hz, CH3),
2.29 (s, 3H, CH3), 2.42 (s, 3H, CH3), 3.68 (sept, 1H, J¼6.1 Hz, CHN]),
4.85 (s, 1H, CHp-Tol), 6.98 (d, 2H, J¼7.7 Hz, CHarom.), 7.05 (d, 2H,
J¼8.3 Hz, CHarom.), 7.28 (d, 2H, J¼7.7 Hz, CHarom.), 7.39 (d, 2H,
J¼7.7 Hz, CHarom.), 7.47e7.62 (m, 3H, CHarom.), 8.01 (d, 2H, J¼7.2 Hz,
performed on glass-backed silica plates (Merck Kieselgel 60 F254
,
precoated 0.25 mm), which were developed using standard visu-
alization techniques or agents: UV fluorescence (254 nm and
CHarom.); 13C NMR (CDCl3, 75 MHz):
d¼21.2, 21.4, 23.0, 23.4, 51.0,
366 nm), coloring with iodine vapor, permanganate solution/
D
or
53.4, 73.6, 127.5, 127.6, 128.0, 128.6, 128.8, 129.0, 131.8, 133.4, 138.3,
50% aqueous sulfuric acid/ . The purity of the synthesized com-
D
139.0, 140.1, 159.6; IR (ATR):
n
¼1636 (C]N), 1344 and 1166 (S]O);
pounds or reaction mixtures was monitored by gas chromatogra-
phy, using a Hewlett-Packard 6890 GC Plus coupled with a FID
Detector equipped with a CIS-4-PTV (Programmed Temperature
Vaporization) Injector (Gerstel), and EC5 capillary column (fused
MS (ESþ): m/z (%)¼467/469 (MHþ, 100). Mp¼59.2e59.6 ꢀC. Yield
96%, yellow crystals. Anal. Calcd for C26H27ClN2O2S: C, 66.87; H,
5.83; N, 6.00. Found: C, 66.54; H, 5.99; N, 6.09.
silica, AT-1, film thickness 0.25
carrier gas, FID, H2 gas) and Agilent 6890 Series gas chromatograph
(fused silica, AT-5, film thickness 0.25 m, length 30 m, i.d. 0.25 mm,
m
m, length 30 m, i.d. 0.25 mm, N2 as
4.2.1.3. N-{(1E)-1-[cis-1-Benzenesulfonyl-2-chloro-3-p-tolylazir-
idin-2-yl](phenyl)methylidene}cyclohexylamine 3f. 1H NMR (CDCl3,
m
300 MHz):
d
¼1.03e1.90 (m, 10H, 5ꢂCH2), 2.29 (s, 3H, CH3),
He as carrier gas, FID, H2 gas). 1H NMR (300 MHz) and 13C NMR
(75 MHz) spectra were run with a Jeol Eclipse FT 300 NMR spec-
trometer at room temperature unless otherwise specified. Peak
assignments were performed with the aid of DEPT, 2D-HETCOR and
2D-COSY NMR techniques when required. The compounds were
diluted in deuterated chloroform, quoted in parts per million (ppm)
3.31e3.40 (m, 1H, CHN]), 4.91 (s, 1H, CHp-Tol), 6.97 (d, 2H,
J¼8.3 Hz, CHarom.), 7.05 (d, 2H, J¼8.3 Hz, CHarom.), 7.42e7.63 (m, 8H,
CHarom.), 7.99e8.04 (m, 2H, CHarom.); 13C NMR (CDCl3, 75 MHz):
d
¼21.2, 24.0, 24.1, 25.7, 32.7, 33.3, 51.0, 61.5, 73.6, 127.5, 128.0, 128.1,
128.3, 128.6, 128.8, 129.0, 133.4, 134.8, 138.3, 140.1, 159.6; IR (ATR):
n
¼1637 (C]N), 1345 and 1166 (S]O); MS (ESþ): m/z (%)¼493/495
and referenced to tetramethylsilane (TMS,
d
¼0) or the appropriate
(MHþ, 100). Mp¼72.1e72.3 ꢀC. Yield 75%, yellow crystals. Anal.
Calcd for C28H29ClN2O2S: C, 68.21; H, 5.93; N, 5.68. Found: C, 67.95;
H, 6.12; N, 5.51.
residual solvent peak. Infrared spectra were obtained from a Per-
kineElmer Spectrum One FT-IR spectrometer. For liquid samples,
the spectra were recorded by preparing a thin film of compound
between sodium chloride plates. Solid compounds were mixed with
potassium bromide and pressed at high pressure until a transparent
disc was obtained. IR spectra were also obtained from samples in
neat form with an ATR (Attenuated Total Reflectance) accessory.
Only selected absorbances (vmax/cmꢁ1) are reported. LCeMS was
performed with Agilent 1100 Series VL (ES, 4000V) equipment or
Agilent 1100 Series SL (ES, 4000V) equipment, performing electron-
spray ionization at 4 kV (positive mode) or 3.5 kV (negative mode)
and fragmentation at 70 eV, with only molecular ions ([MH]þ), and
major peaks being reported with intensities quoted as percentage of
the base peak, using either an LCeMS coupling or a direct inlet
system. GCeMS was performed with Hewlett-Packard 6890 GC Plus
coupled with a FID Detector equipped with a CIS-4-PTV (Pro-
grammed Temperature Vaporization) Injector (Gerstel), and HP5-
4.2.2. Synthesis of 2,5-diaryl-1H-imidazoles 14. Procedure A: a so-
lution of 2-chloro-2-imidoylaziridine 3 (2 mmol) in 10 mL of aceto-
nitrile was heated under reflux for 7e16 h (the reactionwas followed
up via TLC). After usual workup (diethyl etherdaqueous extraction),
1H-imidazole 14 was isolated in pure form after recrystallization
from methanol.
Procedure B: aziridine 3 (1 mmol) was dissolved in CHCl3 (2 mL)
and stirred at room temperature for 24e48 h. After workup by water
and CHCl3 extraction, evaporation of the solvent gave a nearly pure
crude sample, that was recrystallized from methanol.
4.2.2.1. 1-Isopropyl-4-chloro-2,5-diphenyl-1H-imidazole 14a. 1H
NMR (CDCl3, 300 MHz):
1H, J¼6.7 Hz, CHN), 7.39e7.50 (m, 8H, CHarom.), 7.55e7.57 (m, 2H,
CHarom.); 13C NMR (CDCl3, 75 MHz):
¼23.4, 50.4, 127.6, 128.5, 128.6,
129.1, 129.3, 129.9, 131.3, 131.7, 146.5; IR (KBr):
d¼1.26 (d, 6H, J¼6.7 Hz, 2ꢂCH3), 4.51 (sept,
MS capillary column (fused silica, AT-1, film thickness 0.25
mm,
d
length 30 m, i.d. 0.25 mm, He as carrier gas), ionization EI at 70 eV.
Melting points of crystalline compounds were measured with
n¼1688 (C]N), 1606,
1482, 1448; MS (EI): m/z (%)¼296/298 (Mþ, 75), 254/256 (100), 227/
229 (20), 192 (10), 150 (10), 124 (8), 104 (6), 89 (18), 77 (5). Mp
(MeOH)¼103.8e105.0 ꢀC. Yield 88%, white crystals. Anal. Calcd for
C18H17ClN2:C, 72.84;H, 5.77; N, 9.44. Found:C, 72.72; H, 5.65;N, 9.49.
€
a Buchi 540 apparatus and were not corrected. The elemental
analysis of new compounds was performed with an Anca-NT Sys-
tem Elemental Analyzer.
4.2. Synthetic procedures
4.2.2.2. 1-Isopropyl-4-chloro-5-(4-chlorophenyl)-2-phenyl-1H-
imidazole 14b. 1H NMR (CDCl3, 300 MHz):
d
¼1.25 (d, 6H, J¼6.9 Hz,
4.2.1. Synthesis of 2-imidoylaziridines 3. Aziridines 3 were prepared
2ꢂCH3), 4.51 (sept, 1H, J¼6.9 Hz, CHN), 7.39e7.48 (m, 2H, CHarom.),
according to the method described previously.4
7.38e7.41 (m, 5H, CHarom.), 7.51e7.60 (m, 2H, CHarom.); 13C NMR
(CDCl3, 75 MHz):
d
¼23.3, 50.4, 128.1, 128.4, 128.5, 128.8, 129.4, 129.7,
4.2.1.1. N-{(1E)-1-[cis-1-Benzenesulfonyl-2-chloro-3-p-tolylazir-
130.0, 132.9, 135.3, 146.8; IR (KBr):
n
¼1687 (C]N), 1601, 1481, 1446;
idin-2-yl](phenyl)methylidene}isopropylamine 3d. 1H NMR (CDCl3,
MS (EI): m/z (%)¼330/332/334 (Mþ, 50), 288/290/292 (100), 226/

F. Colpaert et al. / Tetrahedron 67 (2011) 1258e1265
1263
228 (14), 207 (5), 150/152 (6), 89 (10), 43 (5). Mp (MeOH)¼
CHarom.); 13C NMR (CDCl3, 75 MHz):
d
¼23.0, 50.2, 102.9, 125.6, 127.3,
120.7e122.5 ꢀC. Yield 89%, white crystals. Anal. Calcd for
C18H16Cl2N2: C, 65.27; H, 4.87; N, 8.46. Found: C, 65.19; H, 4.62; N,
8.40.
128.4, 128.5, 128.7, 129.0, 131.2, 134.0,þ143.9, 150.2; IR (KBr):
n
¼1606,
1482, 1460; MS (ESþ): m/z¼263 (MH ). Mp (MeOH)¼57.6e58.9 ꢀC.
Yield 84%, colorless crystals. Anal. Calcd for C18H18N2: C, 82.41; H,
6.92; N, 10.68. Found: C, 82.23; H, 6.98; N, 10.73.
4.2.2.3. 1-Isopropyl-4-chloro-2-(4-chlorophenyl)-5-phenyl-1H-
imidazole 14c. 1H NMR (CDCl3, 300 MHz):
d
¼1.23 (d, 6H, J¼6.9 Hz,
2ꢂCH3), 4.47 (sept, 1H, J¼6.9 Hz, CHN), 7.40e7.56 (m, 9H, CHarom.);
13C NMR (CDCl3, 75 MHz):
¼23.4, 50.5, 128.6, 128.8, 129.2, 129.7,
131.1, 131.7, 135.6, 145.3; IR (KBr):
4.2.5. Synthesis of 4-chloropyrazole 15. To pyrazole 18 (0.26 g,
1.0 mmol) in carbon tetrachloride (5 mL) was added N-chlor-
osuccinimide (0.20 g,1.5 mmol). After 13 h under reflux the reaction
was cooled to room temperature, the precipitate was filtered and
rinsed with carbon tetrachloride. After removal of the solvent in
vacuo, the crude 4-chloropyrazole 15 together with 7% unreacted
pyrazole 18 was obtained. Further purification by flash chroma-
tography gave pure pyrazole 15 (0.24 g) as a yellow oil (80% yield).
d
n
¼1662 (C]N), 1485, 1450; MS
(EI): m/z (%)¼330/332/334 (Mþ, 51), 288/286/284 (100), 226/228
(14), 123 (6), 89 (9), 43 (5). Mp (MeOH)¼146.1e147.4 ꢀC. Yield 84%,
white crystals. Anal. Calcd for C18H16Cl2N2: C, 65.27; H, 4.87; N,
8.46. Found: C, 65.12; H, 4.67; N, 8.39.
4.2.2.4. 1-Isopropyl-4-chloro-5-phenyl-2-p-tolyl-1H-imidazole
4.2.5.1. 1-Isopropyl-4-chloro-3,5-diphenyl-1H-pyrazole
14d. 1H NMR (CDCl3, 300 MHz):
d
¼1.24 (d, 6H, J¼6.6 Hz, 2ꢂCH3),
15. Spectral data obtained from the 93/7 mixture of 4-chloropyr-
2.42 (s, 3H, CH3), 4.51 (sept, 1H, J¼7.0 Hz, CHN), 7.27 (d, 2H,
azole 15 and pyrazole 18. 1H NMR (CDCl3, 300 MHz):
d
¼1.48 (d, 6H,
J¼7.7 Hz, CHarom.), 7.41e7.50 (m, 7H, CHarom.); 13C NMR (CDCl3,
J¼6.6 Hz, 2ꢂCH3), 4.45 (sept, 1H, J¼6.6 Hz, CHN), 7.34e7.56 (m, 8H,
75 MHz):
d
¼21.4, 23.3, 50.3, 127.4, 128.2, 128.4, 129.0, 129.1, 129.6,
CHarom.), 7.95e7.99 (m, 2H, CHarom.); 13C NMR (CDCl3, 75 MHz):
129.9,131.6,139.2,1þ46.6; IR (ATR):
n
¼1731,1482,1443; MS (ESþ): m/
d
¼22.7, 51.2, 106.1, 127.4, 127.8, 128.3, 128.5, 128.8, 129.1, 129.9,
z (%)¼311/313 (MH , 100). Mp¼143.9e144.3 ꢀC. Yield 92%, yellow
crystals. Anal. Calcd for C19H19ClN2: C, 73.42; H, 6.16; N, 9.01. Found:
C, 73.31; H, 6.45; N, 8.87.
132.4, 140.2, 146.1; IR (KBr):
n
¼1773, 1700, 1605, 1483, 1456; MS
(EI): m/z (%)¼296/298 (Mþ, 79), 281/283 (63), 254/256 (100), 225
(8), 189 (24), 104 (12), 77 (10). Yield 80%. Anal. Calcd for C18H17ClN2:
C, 72.84; H, 5.77; N, 9.44. Found: C, 72.65; H, 5.81; N, 9.47.
4.2.2.5. 1-Isopropyl-4-chloro-2,5-di-p-tolyl-1H-imidazole 14e. 1H
NMR (CDCl3, 300 MHz):
d
¼1.25 (d, 6H, J¼6.6 Hz, 2ꢂCH3), 2.42 (s, 3H,
4.2.6. Synthesis of 2,5-diphenyl-4-methoxy-1H-imidazole 25. Pro-
cedure A: to aziridine 3a (1.0 mmol, 0.44 g) in methanol (5 mL) was
added 2 N sodium methoxide in methanol (2.5 mmol, 1.25 mL).
After 72 h under reflux the reaction mixture was neutralized with
aqueous ammonium chloride, then the solvent was partially
evaporated under vacuo. The residue was washed with water
(20 mL) and extracted with diethyl ether (3ꢂ20 mL), then washed
with brine. After drying the combined organic phases over mag-
nesium sulfate, filtration and removal of the solvent in vacuo,
a crude yellow oil was obtained. Chromatographic purification over
silica gel (petroleum ethereethyl acetate 9/1, Rf¼0.30) gave crys-
talline imidazole 25 (0.06 g, 20% yield) and imidazole 14a (0.03 g,
10%).
Procedure B: to a solution of aziridine 3a (1 mmol, 0.44 g) in
5 mL of methanol at 0 ꢀC, NaBH4 (1.0 mmol, 38 mg) was added
portionwise. The mixture was allowed to reach room temperature
in 10 min, then refluxed for 6 h. Workup started with pouring the
reaction mixture into an ice cooled solution of water (10 mL), and
extraction with dichloromethane (3ꢂ60 mL). After drying of the
combined extracts with magnesium sulfate and evaporation of the
solvent in vacuo, the crude reaction mixture was purified by flash
chromatography.
CH3), 2.44 (s, 3H, CH3), 4.50 (sept, 1H, J¼6.9 Hz, CHN), 7.24e7.34 (m,
6H, CHarom.), 7.43e7.48 (m, 2H, CHarom.); 13C NMR (CDCl3, 75 MHz):
d
¼21.39, 21.44, 23.2, 50.2, 126.8, 127.4, 128.3, 128.4, 129.1, 129.2,
129.6,131.5,138.9,139.2,146.4; IRþ(ATR):
n¼1682 (C]N),1498,1454;
MS (ESþ): m/z (%)¼325/327 (MH , 100). Mp¼132.8e133.1 ꢀC. Yield
95%, light brown crystals. Anal. Calcd for C20H21ClN2: C, 73.95; H,
6.52; N, 8.62. Found: C, 73.80; H, 6.69; N, 8.41.
4.2.2.6. 1-Cyclohexyl-4-chloro-5-phenyl-2-p-tolyl-1H-imidazole
14f. 1H NMR (CDCl3, 300 MHz):
d¼0.67e1.14 (m, 3H, CH2, and CHH),
1.41e1.85 (m, 7H, 3ꢂCH2, and CHH), 2.42 (s, 3H, CH3), 3.98e4.08 (m,
1H, CHN), 7.26 (d, 2H, J¼7.7 Hz, CHarom.), 7.39e7.49 (m, 7H, CHarom.);
13C NMR (CDCl3, 75 MHz):
d
¼21.4, 24.9, 26.0, 33.5, 59.1, 127.6, 128.2,
128.3, 128.9, 129.1, 129.6, 130.0, 131.7, 139.1, 146.7; IR (ATR):
n¼1684
(C]N), 1485, 1442; MS (ESþ): m/z (%)¼351/353 (MHþ, 100).
Mp¼149.3e149.5 ꢀC. Yield 76%, yellow crystals. Anal. Calcd for
C22H23ClN2: C, 75.31; H, 6.61; N, 7.98. Found: C, 75.02; H, 6.84; N, 7.91.
4.2.3. Synthesis of N-isopropylhydrazine 21. To hydrazine (64% in
water) (5.0 g, 0.1 mol) was added 2-bromopropane (0.04 mol, 4.88 g)
followed by aqueous 2 N sodium hydroxide (10 mL, 0.02 mol). The
reaction mixture was heated under reflux for 14 h, then distilled to
give N-isopropylhydrazine 21 as a 24% w/w solution in water in
quantitative yield (bp 103.0 ꢀC/1 atm).
4.2.7. 1-Isopropyl-4-methoxy-2,5-diphenyl-1H-imidazole 25. 1H NMR
(CDCl3, 300 MHz):
OCH3), 4.48 (sept, 1H, J¼7.0 Hz, CHN), 7.38e7.45 (m, 8H, CHarom.),
7.55e7.57 (m, 2H, CHarom.); 13C NMR (CDCl3, 75 MHz):
¼23.5, 23.8,
d¼1.26 (d, 6H, J¼7.0 Hz, 2ꢂCH3), 3.90 (s, 3H,
4.2.4. Synthesis of 1-isopropyl-1H-pyrazole 18. To dibenzoylme-
thane 22 (0.44 g, 2.0 mmol) in ethanol (10 mL) was added aqueous
isopropylhydrazine 21 (24% w/w; 3.0 g, 10 mmol). After 24 h under
reflux, 40 mL of water was added to the reaction mixture followed
by extraction with diethyl ether (3ꢂ40 mL), and washing of the
combined organic layers with brine. After drying the combined
organic phases over magnesium sulfate, filtration, and removal of
the solvent in vacuo, a crude yellow oil was isolated. After addition
of methanol, pyrazole 18 (0.44 g) was isolated as colorless crystals
(84% yield).
d
49.7, 56.9, 112.4, 127.9, 128.4, 128.5, 128.8, 130.0, 130.9, 131.6, 132.4,
142.1, 153.0; IR (KBr):
n
¼1688 (C]N),1609,1368; MS (ESþ): m/z¼293
(MHþ). Mp¼109.5e110.3 ꢀC (flash chromatography, petroleum
ethereethyl acetate 9/1, Rf¼0.30). Yield 20%, white crystals. Anal.
Calcd for C19H20N2O: C, 78.05; H, 6.89; N, 9.58. Found: C, 77.91; H,
6.94; N, 9.50.
4.2.8. Synthesis of cis-(3-aryl-2-chloroaziridin-2-yl)(aryl)meth-
anones 30. A solution of 2-chloro-2-imidoylaziridines 3 (2 mmol)
in tetrahydrofuran (20 mL) was added to an equal amount of water
(20 mL) and 2 N hydrochloric acid in water (3 mmol, 1.5 mL). After
stirring at room temperature (4e8 h) the reaction was neutralized
with 2 N aqueous sodium hydroxide and extracted with diethyl
4.2.4.1. 1-Isopropyl-3,5-diphenyl-1H-pyrazole 18. 1H NMR (CDCl3,
300 MHz):
d
¼1.51 (d, 6H, J¼6.6 Hz, 2ꢂCH3), 4.55 (sept, 1H, J¼6.6 Hz,
CHN), 6.52 (s,1H, 4-CH), 7.29e7.46 (m, 8H, CHarom.), 7.85e7.88 (m, 2H,

1264
F. Colpaert et al. / Tetrahedron 67 (2011) 1258e1265
ether, then washed with water and brine. After drying (MgSO4) and
evaporation of solvents in vacuo, a crude solid material was iso-
lated. Recrystallization from methanol gave pure aziridines 30.
Supplementary data
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2010.11.082.
4.2.8.1. cis-[2-Chloro-1-(phenylsulfonyl)-3-phenylaziridin-2-yl]
(phenyl)methanone 30a. 1H NMR (CDCl3, 300 MHz):
d
¼4.74 (s, 1H,
References and notes
CHPh), 7.32e7.34 (m, 4H, CH), 7.47e7.53 (m, 4H, CH), 7.60e7.65 (m,
2H, CH), 7.92e7.95 (m, 2H, CH), 8.13e8.16 (m, 2H, CH); 13C NMR
1. (a) Lu, P. Tetrahedron 2010, 66, 2549; (b) Abbaspour Tehrani, K.; De Kimpe, N.
Curr. Org. Chem. 2009, 13, 854; (c) Padwa, A. In Comprehensive Heterocyclic
Chemistry III; Katritzky, A. R., Ramsden, C. A., Scriven, E. F. V., Taylor, R. J. K., Eds.;
Elsevier: Oxford, 2008; Vol. 1, pp 1e104; (d) Aziridines and Epoxides in Organic
Synthesis; Yudin, A. K., Ed.; Wiley-VCH: Weinheim, 2006; (e) Hu, X. E. Tetra-
hedron 2004, 60, 2701; (f) McCoull, W.; Davis, F. A. Synthesis 2000, 1347; (g)
Tanner, D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599.
2. For some selected publications on the influence of the aziridine substitution
pattern on CeN and CeC bond cleavage, see: (a) Paasche, A.; Arnone, M.; Fink,
R. F.; Schirmeister, T.; Engels, B. J. Org. Chem. 2009, 74, 5244; (b) Banks, H. D.
J. Org. Chem. 2010, 75, 2510; (c) Dauban, P.; Malik, G. Angew. Chem., Int. Ed. 2009,
48, 9026; (d) Gaebert, C.; Mattay, J. Tetrahedron 1997, 53, 14297.
(CDCl3, 75 MHz):
d
¼49.1, 70.2, 127.9, 128.3, 128.5, 128.6, 129.2,
129.3, 130.4, 130.8, 132.7, 134.4, 134.5, 137.9, 185.8; IR (KBr):
n
¼1692
(C]O); MS (ESþ): m/z¼398 (MHþ, 46), 256 (20), 105 (100). Mp
(MeOH)¼102.1e103.0 ꢀC. Yield 99%, white crystals. Anal. Calcd for
C21H16ClNO3S: C, 63.39; H, 4.05; N, 3.52. Found: C, 63.21; H, 4.16;
N, 3.60.
4.2.8.2. cis-[2-Chloro-1-(phenylsulfonyl)-3-phenylaziridin-2-yl]
(4-chlorophenyl)methanone 30b. 1H NMR (CDCl3, 300 MHz):
d¼4.74
3. Singh, G. S.; D’hooghe, M.; De Kimpe, N. Chem. Rev. 2007, 107, 2080.
4. Giubellina, N.; Mangelinckx, S.; Tornroos, K. W.; De Kimpe, N. J. Org. Chem.
2006, 71, 5881.
€
(s, 1H, CHPh), 7.32e7.34 (m, 4H, CH), 7.47e7.53 (m, 4H, CH),
7.60e7.65 (m, 2H, CH), 7.92e7.95 (m, 2H, CH), 8.13e8.16 (m, 2H,
5. (a) Grimmett, M. R. In Science of Synthesis; Neier, R., Ed.; Houben-Weyl: New
York, NY, 2002; Vol. 12, p 325; (b) Grimmett, M. R. In Science of Synthesis; Neier,
R., Ed.; Houben-Weyl: New York, NY, 2002; Vol. 12, p 529; (c) Grimmett, M. R.
In Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Ed.; Pergamon:
Oxford, 1984; Vol. 5, p 345.
6. (a) Laufer, S.; Wagner, G.; Kotschenreuther, D. Angew. Chem., Int. Ed. 2002, 41,
2290; (b) Kang, U. G.; Shechter, H. J. Am. Chem. Soc. 1978, 100, 651; (c) Zhang, C.;
Sarshar, S.; Moran, E. J.; Krane, S.; Rodarte, J. C.; Benbatoul, K. D.; Dixon, R.;
Mjalli, A. M. M. Bioorg. Med. Chem. 2000, 10, 2603; (d) Zhong, Y.-L.; Lee, J.;
Reamer, R.; Askin, D. Org. Lett. 2004, 6, 929.
7. (a) Carini, D. J.; Duncia, J. V.; Aldrich, P. E.; Chiu, A. T.; Johnson, A. L.; Pierce, M.
E.; Price, W. A.; Santella, J. B.; Wells, G. J.; Wexler, R. R.; Wong, P. C.; Yoo, S.-E.;
Timmermans, P. B. M. J. Med. Chem. 1991, 34, 2525; (b) Griffiths, G. J.; Hauck, M.
B.; Imwinkelried, R.; Kohr, J.; Roten, C. A.; Stucky, G. C. J. Org. Chem. 1999, 64,
8084 and references therein.
CH); 13C NMR (CDCl3, 75 MHz):
d
¼49.3, 70.0, 127.8, 128.3, 128.5,
129.0, 129.1, 129.2, 129.5, 130.2, 132.3, 134.6, 137.7, 141.1, 184.7; IR
(KBr):
n
¼1687 (C]O); MS (ESþ): m/z¼432/434/436 (MHþ, 45), 139/
141 (100). Mp (Et2O)¼182.1e182.5 ꢀC. Yield 93%, white crystals.
Anal. Calcd for C21H15Cl2NO3S: C, 58.34; H, 3.50; N, 3.24. Found: C,
58.18; H, 3.61; N, 3.40.
4.2.8.3. cis-[2-Chloro-1-(phenylsulfonyl)-3-(4-chlorophenyl)azir-
idin-2-yl](phenyl)methanone 30c. 1H NMR (CDCl3, 300 MHz):
d
¼4.69 (s, 1H, CHAr), 7.24e7.35 (m, 4H, CHarom.), 7.48e7.58 (m, 4H,
CHarom.), 7.62e7.69 (m, 2H, CHarom.), 7.91e7.94 (m, 2H, CHarom.),
8.12e8.16 (m, 2H, CHarom.); 13C NMR (CDCl3, 75 MHz):
¼48.4, 70.1,
8. Sisko, J.; Kassick, A. J.; Mellinger, M.; Filan, J. J.; Allen, A.; Olsen, M. A. J. Org.
Chem. 2000, 65, 1516.
d
128.3, 128.6, 128.8, 129.0, 129.2, 129.4, 130.8, 132.6, 134.55, 134.61,
9. Elliot, R. L.; Olivier, R. M.; LaFlamme, J. A.; Gillaspy, M. L.; Hammond, M.; Hank,
R. F.; Maurer, T. S.; Baker, D. L.; DaSilva-Jardin, P. A.; Stevenson, R. W.; Christine,
M. M.; Cassella, J. V. Bioorg. Med. Chem. Lett. 2003, 13, 3593.
10. For an isolated example of the oxidative thermal rearrangement of related
aziridinoimidazoline compounds to imidazoledicarboxylic esters, see: Meth-
Cohn, O.; Williams, N. J. R.; MacKinnon, A.; Howard, J. A. K. Tetrahedron 1998,
54, 9837.
135.2,137.7,185.5; IR (KBr):
n
¼1696 (C]O); MS (ESþ): m/z¼432/434/
436 (MHþ, 40), 290/292 (22), 105 (100). Mp (Et2O)¼132.5e133.6 ꢀC.
Yield 74%, white crystals. Anal. Calcd for C21H15Cl2NO3S: C, 58.34; H,
3.50; N, 3.24. Found: C, 58.20; H, 3.41; N, 3.32.
11. (a) De Kimpe, N.; Sulmon, P.; Schamp, N. Bull. Soc. Chim. Belg. 1986, 95, 567; (b)
Wartski, L. Bull. Soc. Chim. Fr. 1975, 1663; (c) Gelas-Mialhe, Y.; Hierle, R.;
4.2.8.4. cis-[2-Chloro-1-(phenylsulfonyl)-3-p-tolylaziridin-2-yl]
(phenyl)methanone 30d. 1H NMR (CDCl3, 300 MHz):
d¼2.34 (s, 3H,
ꢀ
Vessiere, R. J. Heterocycl. Chem. 1974, 11, 347.
CH3), 4.69 (s, 1H, CHp-Tol), 7.13e7.23 (m, 4H, CHarom.), 7.47e7.67 (m,
6H, CHarom.), 7.93e7.96 (m, 2H, CHarom.), 8.13e8.16 (m, 2H, CHarom.);
12. (a) Padwa, A. E.; Eisenhardt, W. J. Chem. Soc., Chem. Commun. 1968, 380; (b)
Lown, J. W.; Moser, J. P. J. Chem. Soc., Chem. Commun. 1970, 247; (c) Prosyanik, A.
V.; Belov, P. N.; Markov, V. I. Khim. Geterotsikl. Soedin. 1984, 1688; Chem. Abstr.
1985, 102, 113352.
13. (a) Padwa, A.; Eisenhardt, W. J. Am. Chem. Soc. 1968, 90, 2442; (b) Beletskii, E. V.;
Kuznetsov, M. A. Russ. J. Org. Chem. 2009, 45, 1229.
14. (a) Palacios, F.; Ochoa de Retana, A. M.; Martinez de Marigorta, E.; de los Santos, J.
M. Eur. J. Org. Chem. 2001, 2401; (b) Padwa, A. Adv. Heterocycl. Chem. 2010, 99, 1.
15. (a) Padwa, A.; Woolhouse, A. D. In Comprehensive Heterocyclic Chemistry; Ka-
tritzky, A. R., Rees, C. W., Eds.; Pergamon: Oxford, 1984; Vol. 7, p 47; (b) Nair, V.
In Heterocyclic Compounds; Hassner, A., Ed.; John Wiley: New York, NY, 1983;
Vol. 42; Part I, p 215.
16. Luisi, R.; Capriati, V.; Florio, S.; Ranaldo, R. Tetrahedron Lett. 2003, 44, 2677.
17. (a) Padwa, A.; Smolanoff, J.; Tremper, A. J. Am. Chem. Soc. 1975, 97, 4682;
(b) Isomura, K.; Tanaka, T.; Tagiuguchi, H. Chem. Lett. 1977, 397.
18. (a) Padwa, A.; Thomas, S. Tetrahedron Lett. 2004, 45, 5991; (b) Padwa, A.;
Stengel, T. Arkivoc 2005, 21.
13C NMR (CDCl3, 75 MHz):
d
¼21.2, 49.1, 70.1, 127.2, 127.6, 128.1,
128.4, 129.1, 129.2, 130.7, 132.6, 134.2, 134.4, 137.8, 139.0, 185.7; IR
(ATR):
n
¼1687 (C]O); MS (ESþ): m/z¼429/431 (MþNHþ4 , 100), 411/
413 (MHþ, 26). Mp (MeOH)¼119.0e119.3 ꢀC. Yield 73% from 3d, 85%
from 3f, yellow crystals. Anal. Calcd for C22H18ClNO3S: C, 64.15; H,
4.40; N, 3.40. Found: C, 63.82; H, 4.56; N, 3.57.
4.2.8.5. cis-[2-Chloro-1-(phenylsulfonyl)-3-p-tolylaziridin-2-yl]
(p-tolyl)methanone 30e. 1H NMR (CDCl3, 300 MHz):
d
¼2.33 (s, 3H,
CH3), 2.44 (s, 3H, CH3), 4.66 (s, 1H, CHp-Tol), 7.14 (d, 2H, J¼8.3 Hz,
CHarom.), 7.19 (d, 2H, J¼8.3 Hz, CHarom.), 7.30 (d, 2H, J¼8.3 Hz,
CHarom.), 7.48e7.53 (m, 2H, CHarom.), 7.60e7.65 (m,1H, CHarom.), 7.94
(d, 2H, J¼7.2 Hz, CHarom.), 8.06 (d, 2H, J¼8.3 Hz, CHarom.); 13C NMR
19. Padwa, A.; Smolanoff, J.; Tremper, A. J. Org. Chem. 1976, 41, 543.
20. Jelley, M. J.; Wortmann, R. Biodrugs 2000, 14, 99.
21. Talley, J.J.; Rogier, D.J.; Penning, T.D.; Yu, S.S. PCT Int. Appl. WO 9515318, 1995;
Chem. Abstr. 1995, 123, 313952.
(CDCl3, 75 MHz):
d
¼21.3, 21.9, 49.1, 70.2, 127.3, 127.6, 128.2, 129.1,
129.2, 130.1, 130.9, 134.2, 137.9, 139.0, 145.6, 185.3; IR (ATR):
n
¼1688
22. (a) Kimura, F. Jpn. Pestic. Inf. 1984, 45, 24; Chem. Abstr. 1985, 102, 199466; (b)
Konotsune, T.; Kawakubo, K.; Honma, T. Jpn. Kokai Tokkyo Koho JP 55033454,
1980; Chem. Abstr. 1980, 93, 63616.
(C]O); MS (ESþ): m/z¼443/445 (MþNHþ4 ,100), 426/428 (MHþ, 22).
Mp (MeOH)¼145.1e145.3 ꢀC. Yield 68%, yellow crystals. Anal. Calcd
for C23H20ClNO3S: C, 64.86; H, 4.73; N, 3.29. Found: C, 64.74; H,
4.96; N, 3.04.
€
23. Bleicher, K. H.; Gerber, F.; Wuthrich, Y.; Alanine, A.; Capretta, A. Tetrahedron
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24. (a) Texier-Boullet, F.; Hamelin, J. Synthesis 1986, 409; (b) Talley, J.J.; Rogier, D.J.,
Jr.; Penning, T.D.; Yu, S.S. PCT Int. Appl., WO9515318, 1995; Chem. Abstr. 1995,
123, 313952; (c) Sreekumar, R.; Padmakumar, R. Synth. Commun. 1998, 28, 1661;
(d) Balalaie, S.; Sharifi, A.; Ahangarian, B. Indian J. Heterocycl. Chem. 2000, 10,
149; Chem. Abstr. 2001, 134, 280766; (e) Singer, R. A.; Caron, S.; McDermott, R.
E.; Arpin, P.; Do, N. M. Synthesis 2003, 1727.
25. Day, R. A.; Blake, J. A.; Stephens, C. E. Synthesis 2003, 1586.
26. Singh, S. K.; Vobbalareddy, S.; Shivaramakrishna, S.; Krishnamraju, A.; Rajjak, S.
A.; Casturi, S. R.; Akhila, V.; Rao, Y. K. Bioorg. Med. Chem. Lett. 2004, 14, 1688.
Acknowledgements
The authors are indebted to Ghent University (BOF-GOA) and
the Research FoundationdFlanders (FWO-Vlaanderen) for financial
support of this research.

F. Colpaert et al. / Tetrahedron 67 (2011) 1258e1265
1265
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