Structural Revision of the Ring-Opened Product in the ZnCl 2-Catalyzed Reactions of 1-Benzyl-2-phenylaziridine with Thiols

Article abstract of DOI:10.1055/s-2003-44993

The reported β-amino sulfide structures for the products in the ZnCl₂-catalyzed ring-opening reactions of 1-benzyl-2-phenylaziridine with thiols should be revised to 2-amino-1-phenyl-ethyl sulfides from 2-amino-2-phenylethyl sulfides.

Full text of DOI:10.1055/s-2003-44993

3
62
LETTER
Structural Revision of the Ring-Opened Product in the ZnCl -Catalyzed
2
Reactions of 1-Benzyl-2-phenylaziridine with Thiols
Z
Y
nCl -Catalyzed R
u
eactions of
1
k
-Benzyl-2-p
i
henylaz
k
iridine
w
ith
o
Thiols Furuta, Takuya Kumamoto, Tsutomu Ishikawa*
2
Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi, Inage, Chiba 263-8522, Japan
Fax +81(43)2902910; E-mail: benti@p.chiba-u.ac.jp
Received 21 November 2003
benzylic (C3) position to give 2-amino-2-phenylethyl sul-
Abstract: The reported b-amino sulfide structures for the products
fides 4 when 1 was used as a substrate. However, our trials
for the ring-opening reaction of 1 with thiols under their
conditions resulted in the exclusive formation of isomeric
in the ZnCl -catalyzed ring-opening reactions of 1-benzyl-2-
2
phenylaziridine with thiols should be revised to 2-amino-1-phenyl-
ethyl sulfides from 2-amino-2-phenylethyl sulfides.
2
-amino-1-phenylethyl sulfides 5, contrary to the reported
Key words: structural revision, b-amino sulfide, ring-opening, 1-
benzyl-2-phenylaziridine, thiol, ZnCl2
results (Scheme 1). In this paper we present the structural
revision of the b-amino sulfides obtained in the ZnCl -cat-
alyzed ring-opening reaction of 1-benzyl-2-phenylaziri-
2
dine (1) with thiols.
Aziridines are very versatile synthetic intermediates for
3
the synthesis of biologically active N-containing com- According to the Hou’s conditions, we at first tried the
pounds. Their reactivity is dependent upon highly strained ring-opening reaction of 1 with 2-bromothiophenol in or-
three-member ring structures and thus, a nucleophilic der to prepare 2-benzylamino-2-phenylethyl 2-bromophe-
ring-opening reaction is one of major reaction paths.1 nyl sulfide (6) for our synthetic utility. Treatment of 1
During the course of our studies on aziridine chemistry2 with 2-bromothiophenol in the presence of a catalytic
we tried to prepare 2-substituted 1-phenylethylamines 2 amount of ZnCl in CH Cl at room temperature for 10
2
2
2
from 1-benzyl-2-phenylaziridine (1) by ring-opening minutes afforded a ring-opened product in 63% yield. At
reaction with organometallics including higher-ordered a glance, the ring-opened product could be assigned to be
1
organocupurates or halides as nucleophiles. However, the an intended product 6 by comparison of its H NMR data
ring-opened products that were obtained were only with those of the so-called Hou’s product, 2-benzylamino-
isomeric 2-phenylethylamines 3 resulting from the attack 2-phenylethyl phenyl sulfide (4: R = phenyl) [CH: d 4.40
H
of nucleophiles at the benzylic (C2) position.
(t, J = 7.3 Hz, 1 H), CH : d 3.10 (d, J = 7.3 Hz, 2 H),
2
H
3
PhCH
2
N: d 3.80 (s, 2 H)], obtained in the reaction using
H
In 2001, Hou et al. reported the effective cleavage of azir-
thiophenol as a nucleophile. The 2-bromothiophenol-de-
rived product showed signals assignable to the sequence
of PhC(NCH Ph)HCH SAr [CH: d 4.52 (t, J = 7.0 Hz, 1
idines including 1 with various thiols in the presence of
ZnCl , in which thiols exclusively attacked at the non-
2
2
2
H
H) and d 52.1; CH : d 3.11, 3.15 (dd, J = 12.4, 7.0 Hz,
Nu
H
N
C
2
H
PhCH2-N
H
each 1 H,) and d 53.7] in 6, in addition to N-benzyl me-
Nu
C
Ph
Ph
CH2Ph
thylene group [d 3.78, 3.82 (d, J = 13.5 Hz, each 1 H) and
H
2
3
d 53.3] and an aromatic quaternary carbon (d 136.1)
C
C
1
13
bonded to sulfur function in the H- and C NMR spectra.
However, possibility of the alternative sequence of
nucleophile (Nu)
CH2Ph
PhC(SAr)HCH NCH Ph in an isomeric 2-benzylamino-
2
2
2
N
1-phenylethyl 2-bromophenyl sulfide (7) could not be ex-
Ph
3
cluded by the above NMR data.
1
Thus, we applied 2 D NMR techniques for the structural
determination of the ring-opened product. The HMBC ex-
periments showed diagnostic cross peaks between the me-
ZnCl2
RSH
Hou's
result
our
result
at C3
H
at C2
RS
thine proton (d 4.52) and the sulfur-substituted aromatic
H
H
quaternary carbon (d 136.1) and between the N-benzyl
PhCH2-N
C
N
methylene protons (d 3.78 and 3.82) and the methylene
SR
H
Ph
CH2Ph
Ph
carbon (d 53.7) derived from the aziridine ring. How-
C
5
4
ever, it was difficult to explain the presence of the former
sequence of PhC(NCH Ph)HCH SAr in the molecule be-
Scheme 1 Nucleophilic ring-opening reaction of 1-benzyl-2-
phenylaziridine (1)
2
2
cause these cross peaks must be coming from unusual
four-bond connection. Instead, the latter sequence of
PhC(SAr)HCH NCH Ph can be reasonably deduced be-
SYNLETT 2004, No. 2, pp 0362–0364
Advanced online publication: 16.12.2003
DOI: 10.1055/s-2003-44993; Art ID: U25103ST.pdf
0
2.
0
2.
2
0
0
4
2
2
cause of the commonly acceptable three-bond connection,
©
Georg Thieme Verlag Stuttgart · New York

LETTER
ZnCl -Catalyzed Reactions of 1-Benzyl-2-phenylaziridine with Thiols
363
2
as shown Figure 1. Therefore, the product in the ZnCl2- benzylamino-2-phenyethyl sulfide like 4, a non-benzylic
catalyzed ring-opening reaction of 1-benzyl-2-phenyl- position (C3) attacked product, or 2-benzylamino-1-phe-
aziridine (1) with 2-bromothiophenol should be 2-benzyl- nylethyl sulfide like 5, a benzylic position (C2) attacked
amino-1-phenyethyl 2-bromophenyl sulfide (7), but not 2- one. Treatment of 8a with Raney Ni in EtOH under reflux
benzylamino-2-phenylethyl 2-bromophenyl sulfide (6) as afforded the known N-benzyl-N-(2-phenylethyl)amine
3
4
expected from the Hou’s paper.
(9) in 33% yield as the sole reduction product. These
facts indicated that the starting sulfide should be 2-benzyl-
amino-1-phenylethyl phenyl sulfide resulting from the at-
tack on the benzylic (C2) position of the 2-phenylaziridine
1 (Scheme 2).
Br
136.1
C
3
3
.78
.82
H
H
S
4.52
H
H
4.52
H
H
N
In conclusion, we have demonstrated the exclusive attack
at the benzylic (C2) position of 1-benzyl-2-phenylaziri-
N
?
Br
?
C
3.7
5
S
C
C
H
H
H H
dine (1) with thiols in the ZnCl -catalyzed ring-opening
2
5
3.7
136.1
H
H
3.78
3.82
reaction, in which 2-benzylamino-1-phenylethyl sulfides
7
3
were formed, contrary to the Hou’s report. Recently Yu-
6
5
din et al. studied the tris(pentafluorophenyl)borane-cayt-
Figure 1 Selected H-C correlations in the HMBC experiments in
the ring-opened product of 1 with 2-bromothiophenol
alyzed ring-opening reaction of aziridines with nitrogen
or sulfur nucleophiles and reported the exclusive produc-
tion of the so-called Hou’s product, 2-benzylamino-2-
These situations made us re-examine Hou’s experiments phenyl phenyl sulfide, when 1 was treated with thiophe-
using the same nucleophiles used by them. The ZnCl2- nol. The same structure that was given in Hou’s report
catalyzed ring-opening reactions of 1 using thiophenol, was also given as the reaction product in their case be-
4
-methylthiophenol, and phenylmethylthiol were carried cause of identical spectral data. However, as mentioned
out under the reported conditions and smooth reaction was above, the structure of the ring-opened product obtained
5
observed in each case, to afford the product 8 in good by Yudin et al. should be revised from 2-benzylamino-2-
yields, the spectral data of which were identical with those phenylethyl phenyl sulfide to 2-benzylamino-1-phenyl-
3
in the literature (see Scheme 2). Thus, the general effi- ethyl phenyl sulfide.
ciency of the ZnCl -catalyzed ring-opening reaction of
2
1
-benzyl-2-phenylaziridine (1) with thiols was confirmed,
IR spectra were recorded on a JASCO FT/IR-300E spectrophoto-
meter. H- (400 MHz) and C NMR (100 MHz) spectra were
but the correct structure of the product remained unclear.
1
13
recorded in CDCl on a JEOL JNM-LA400, and TMS (0.00 ppm)
3
and the middle resonance of CDCl (77.0 ppm) were used as an
3
CH2Ph
N
internal standard, respectively. EIMS were recorded on JEOL
JMS-GCMATE. FABMS were recorded on JEOL JMS-HX110
with m-nitrobenzyl alcohol as a matrix. Reactions were monitored
by TLC on Kieselgel 60 F254 (Merck, 5715). Raney Ni in water was
purchased from Aldrich Co. Ltd. Column chromatography was
performed on silica gel (Fuji Silysia, FL100D).
Ph
RSH
1
ZnCl2
The ZnCl -Catalyzed Ring-Opened Reaction of 1-Benzyl-2-
2
RS
H
N
phenylaziridine (1) with Thiols
According to the reported method, a thiol was added to a mixture
3
Ph
CH2Ph
of 1 and ZnCl (0.05 mol equiv) in anhyd CH Cl and the resulting
2
2
2
8
8
8
a: R=Ph (89%)
b: R=Tol (81%)
c: R=CH2Ph (78%)
mixture was stirred at r.t. under Ar. After addition of Et O the
2
mixture was partitioned with sat. NH Cl and 1% aq KOH, and H O.
4
2
The organic solution was dried over MgSO and evaporated. The
4
residual oil was purified by column chromatography (hexane–
EtOAc, 10:1) to give a ring-opened product 8.
Raney Ni
on 8a
33%
H
N
With 2-Bromophenylthiol: N-Benzyl-N-[2-(2-bromophenyl-
thio)-2-phenylethyl)amine (7)
Ph
CH2Ph
p-Bromothiophenol (45 mg, 0.24 mM), 1 (50 mg, 0.24 mM), and
ZnCl (3 mg, 0.019 mM) in anhyd CH Cl (0.3 mL) were treated for
9
2
2
2
1
0 min to give a colorless oil (60 mg, 63%). IR (neat): 3325 (NH)
Scheme 2 The ZnCl -promoted ring-opening reactions of 1-benzyl-
–1 1
2
cm . H NMR: d = 3.11, 3.15 (dd, J = 12.4, 7.0 Hz, each 1 H, C -
H ), 3.78, 3.82 (d, J = 13.5 Hz, each 1 H, NCH Ph), 4.52 (t, J = 7.0
Hz, 1 H, C -H), 7.00 (ddd, J = 7.9, 7.3, 1.6 Hz, 1 H, ArH), 7.10 (td,
1
2
-phenylaziridine (1) with thiols followed by reductive desulfurizati-
2
2
on of the thiophenol-derived sulfide 8a with Raney Ni
2
J = 7.9, 1.5 Hz, 1 H, ArH), 7.18 (dd, J = 7.9, 1.5 Hz, 1 H, ArH),
1
3
7
.21–7.36 (m, 10 H, ArH), 7.52 (dd, J = 7.9, 1.5 Hz, 1 H, ArH). C
Next, we tried the chemical conversion of the product 8a
NMR: d = 52.1, 53.3, 53.7, 126.0, 127.0, 127.7, 127.8, 128.0, 128.4,
28.7, 131.9, 132.0, 133.0, 136.1, 139.6, 139.8. FABMS: m/z = 400,
(
R = Ph) obtained in the reaction using thiophenol to a
1
3
known phenylethylamine derivative in order to unambig-
uously determine whether the ring-opened product was 2-
+
98 [MH ].
Synlett 2004, No. 2, 362–364 © Thieme Stuttgart · New York

3
64
Y. Furuta et al.
LETTER
With Thiophenol: N-Benzyl-N-(2-phenyl-2-phenylthio-
ethyl)amine (8a)
Thiophenol (0.09 mL, 0.86 mM), 1 (181 mg, 0.86 mM), and ZnCl2
N-Benzyl-N-phenylethylamine (9)
After the water in 50% slurry of Raney Ni in water was replaced by
EtOH, a mixture of the sulfide (50 mg, 0.16 mmol) and the Raney
Ni (0.4 mL in EtOH) in EtOH (1.2 mL) was refluxed for 10 h. After
dilution with CH Cl (ca 3 mL) the mixture was filtered through
(
6 mg, 0.047 mM) in anhyd CH Cl (3 mL) were treated for 15 min
2 2
–
1
to give a colorless oil (246 mg, 89%). IR (neat): 3337 (NH) cm .
2
2
1
H NMR: d = 3.09 (d, J = 7.3 Hz, 2 H, C -H ), 3.79 (s, 2 H,
Celite pad and the filtrate was evaporated. Purification of the resi-
1
2
NCH Ph), 4.37 (t, J = 7.3 Hz, 1 H, C -H), 7.18–7.33 (m, 15 H, ArH).
FABMS: m/z = 320 [MH ].
due by preparative TLC (CHCl –MeOH, 20:1) gave 9 as a colorless
2
2
3
+
–1 1
oil (11 mg, 33%). IR (neat): 3321 (NH) cm . H NMR: d = 2.82–
2
.93 (m, 4 H, NCH CH Ph), 3.80 (s, 2 H, NCH Ph), 7.19–7.33 (m,
2
2
2
+
With 4-Methylthiophenol: N-Benzyl-N-[2-phenyl-2-(4-
10 H, ArH). EIMS: m/z (%) = 211 (0.2) [M ], 120 (42), 91 (100).
methylphenylthio)ethyl]amine (8b)
4
-Methylthiophenol (41 mg, 0.33 mM), 1 (70 mg, 0.33 mM), and
Acknowledgment
ZnCl (3 mg, 0.019 mM) in anhyd CH Cl (5 mL) were treated for
2
2
2
1
h to give a colorless oil (89 mg, 81%). IR (neat): 3324 (NH)
This work was supported by a Grant-in-Aid for Scientific Research
–
1 1
cm . H NMR: d = 2.29 (s, 3 H, PhMe), 3.07 (d, J = 7.3 Hz, 2 H,
C -H ), 3.77 (s, 2 H, NCH Ph), 4.30 (t, J = 7.3 Hz, 1 H, C -H), 7.00
(14370717) from the Ministry of Education, Culture, Sports,
1
2
2
2
Science and Technology, Japan.
(
(
d, J = 7.9 Hz, 2 H, ArH), 7.14 (d, J = 8.1 Hz, 2 H, ArH), 7.20–7.31
m, 10 H, ArH). FABMS: m/z = 334 [MH ].
+
References
With Phenylmethylthiol: N-Benzyl-N-[2-phenyl-2-(phenyl-
methylthio)ethyl]amine (8c)
(1) Recent examples, see: (a) Kang, S. H.; Kim, M.; Ryu, D. H.
Synlett 2003, 1149. (b) Nishikawa, T.; Kajii, S.; Wada, K.;
Ishikawa, M.; Isobe, M. Synthesis 2002, 1658. (c) Bhanu
Prasad, B. A.; Sanghi, R.; Singh, V. K. Tetrahedron 2002,
58, 7355.
(2) Hada, K.; Watanabe, T.; Isobe, T.; Ishikawa, T. J. Am.
Chem. Soc. 2001, 123, 7705.
(3) Wu, J.; Hou, X.-L.; Dai, L.-X. J. Chem. Soc., Perkin Trans.
Phenylmethylthiol (32 mg, 0.26 mM), 1 (51 mg, 0.24 mM), and
ZnCl (2 mg, 0.015 mM) in anhyd CH Cl (0.7 mL) were treated for
2
2
2
2
h to give a colorless oil (62 mg, 78%). IR (neat): 3315 (NH)
–
1 1
cm . H NMR: d = 2.97 (d, J = 7.3 Hz, 2 H, C -H ), 3.46, 3.57 (d,
J = 13.4 Hz, each 1 H, SCH Ph), 3.69 (s, 2 H, NCH Ph), 3.90 (t,
1
2
2
2
J = 7.3 Hz, 1 H, C -H), 7.20–7.36 (m, 15 H, ArH). FABMS: m/z =
2
+
3
34 [MH ].
1
2001, 1314.
4) Salvatore, R. N.; Nagle, A. S.; Jung, K. W. J. Org. Chem.
002, 67, 674.
5) Watson, I. D. G.; Yudin, A. K. J. Org. Chem. 2003, 68, 5160.
(
(
2
Synlett 2004, No. 2, 362–364 © Thieme Stuttgart · New York