A convenient access to 3-(trihalomethyl)-3-phenyl-3,4-dihydro-2H-1,4- benzoxazines/thiazines and chlorinated 3-phenyl-2,3-dihydro-1,5-benzoxazepines/ thiazepines by an aziridination-selective-ring-opening sequence

Article abstract of DOI:10.1055/s-2006-958938

Aziridine ring opening with N-C(1) bond breaking in 1,1-dichloro-1a-phenyl- 1a,2-dihydro-1H-azirino[2,1-c][1,4]benzoxazine and -benzothiazine proceeds under the action of hydrohalo acid to give 3-trihalomethyl derivatives of 1,4-benzoxazine and thiazine.

Full text of DOI:10.1055/s-2006-958938

PAPER
225
A Convenient Access to 3-(Trihalomethyl)-3-phenyl-3,4-dihydro-2H-1,4-benz-
oxazines/thiazines and Chlorinated 3-Phenyl-2,3-dihydro-1,5-benzoxazepines/
thiazepines by an Aziridination–Selective-Ring-Opening Sequence
S
elective RingO
k
pening of
A
a
z
iridines terina Yu. Shinkevich, Mikhail S. Novikov, Alexander F. Khlebnikov*
Department of Chemistry, St. Petersburg State University, Universitetskii pr. 26, 198504 St. Petersburg, Petrodvorets, Russian Federation
Fax +7(812)4286939; E-mail: Alexander.Khlebnikov@pobox.spbu.ru
Received 4 September 2006
X
Abstract: Aziridine ring opening with N–C(1) bond breaking in
Nu
1,1-dichloro-1a-phenyl-1a,2-dihydro-1H-azirino[2,1-c][1,4]benz-
Y
Z
oxazine and -benzothiazine proceeds under the action of hydrohalo
acid to give 3-trihalomethyl derivatives of 1,4-benzoxazine and thi-
azine. When the same compounds react with boron trifluoride ether-
ate, the ring expansion with N–C(1a) bond breaking takes place
with formation of 3,4-dichloro-3-phenyl-2,3-dihydro-1,5-benzox-
azepine and -1,5-benzothiazepine. These are convenient precursors
for the synthesis of 4-substituted 1,5-benzoxazepine and 1,5-ben-
zothiazepine derivatives via reaction with nucleophiles.
NH
Nu
functionalized
n-membered
heterocycle
X
Y
:CXY
Z
Z
N
N
X
n-membered
heterocycle
Z
Key words: fused haloaziridines, O,N-heterocycles, S,N-heterocy-
cles, ring expansion, dihalocarbenes, acid catalysis
N
Y
functionalized
(n+1)-membered
heterocycle
Derivatives of 1,4-benzoxazine,1,2 1,4-benzothiazine,3
1,5-benzoxazepine4 and 1,5- benzothiazepine4,5 have been
reported to exhibit a wide range of biological activity and
this has stimulated the search for new effective methods
for their synthesis. The main synthetic strategies used in
the preparation of these heterocyclic systems include cy-
clization reactions which form heterocycles and the intro-
duction or modification of substituents in heterocyclic and
benzene rings.1,6,7
Scheme 1
containing two heteroatoms, transformations of 1,1-di-
halogeno-1a,2,3,4-tetrahydro-1H-azirino[2,1-e][1,6]benz-
oxazocines and -thiazocines were investigated.11
Unlike azirinoisoquinolines, aziridine ring transforma-
tions into these azirino-fused eight-membered O,N- or
S,N-heterocycles involve opening of the three-membered
ring and contraction of the medium-sized ring via transan-
nular reactions of endocyclic O or S atoms11 to afford de-
rivatives of functionalized 1,4-benzox(thi)azines or 1,3-
benzox(thi)azoles.
A synthetic sequence consisting of cycloaddition of
dichlorocarbene to a heterocycle with a C=N double bond
leading to formation of a gem-dihaloaziridine fused with
the heterocycle, which then undergoes subsequent ring
enlargement, is a potentially simple and efficient ap-
proach to homologation and functionalization of nitroge-
nated heterocycles (Scheme 1). Utility of this approach
takes advantage of the availability of starting materials,
efficiency of carbenic methods of preparation of dihalo-
aziridines and the high reactivity of halogenated aziri-
dines.8
In this work, ring transformations in azirinobenzoxazine 3
and azirinobenzothiazine 4 were examined to evaluate the
influence of ring size on the reactivity of the three-mem-
bered ring in azirino-fused n-membered O,N- or S,N-het-
erocycles and the possibilities of using transformations
according to Scheme 1 for functionalization and homolo-
gation of 2H-benzo-1,4-benzoxazine and 2H-1,4-ben-
zothiazine.
However, the potential of this scheme has still not been in-
vestigated enough. The aziridine ring in 1,1-dichloro-
1,3,4,8b-tetrahydroazirino[2,1-a]isoquinolines, which are
the products of cycloaddition of dichlorocarbene to 3,4-
dihydroisoquinolines, could be opened by any C–N bond
according to Scheme 1, providing routes to derivatives of
benzazepine and tetrahydoisoquinoline-1-carboxylic ac-
id.9,10 Among the heterocyclic systems of such types
Azirinobenzoxazine 3 and azirinobenzothiazine 4 were
synthesized via cycloaddition of dichlorocarbene (gener-
ated by alkaline hydrolysis of chloroform or thermocata-
lytic decomposition of sodium trichloroacetate) to the
C=N double bond of 3-phenyl-2H-1,4-benzoxazine (1)
and 3-phenyl-2H-1,4-benzothiazine (2), respectively
(Scheme 2). Alkaline hydrolysis of chloroform in the
presence of compound 2 gave only tarry products. All the
newly obtained compounds were fully characterized us-
ing standard spectral and analytical methods.
SYNTHESIS 2007, No. 2, pp 0225–0230
x
x
.
x
x
.2
0
0
7
Advanced online publication: 14.12.2006
DOI: 10.1055/s-2006-958938; Art ID: P10606SS
© Georg Thieme Verlag Stuttgart · New York

226
E. Yu. Shinkevich et al.
PAPER
O
Z
Z
HX, H2O
MeOH
:CCl2
5a or 5b
Ph
3
Ph
Cl
N
H
N
CO2Me
N
Ph
Cl
6
1, Z = O
2, Z = S
3, Z = O
4, Z = S
MeOH
5a,b
6
Scheme 2
Scheme 4
Unexpectedly, attempts to synthesize the corresponding
chlorofluoro derivatives using reactions of chlorofluoro-
carbene (generated by alkaline hydrolysis of dichlorofluo-
romethane or thermocatalytic decomposition of sodium
dichlorofluoroacetate) were unsuccessful, although corre-
sponding cycloadducts were obtained under the same con-
ditions from eight-membered rings with a C=N double
bond.11 Compounds 1 and 2 were unreactive in the pres-
ence of chlorofluorocarbene and recovered completely
unchanged.
In the presence of hydrogen chloride in anhydrous meth-
anol, a faster and more selective reaction of azirinobenz-
oxazine 3 is observed. Thus, heating aziridine 3 in 5%
solution of HCl in methanol for 0.5 hour gave trichloride
5a in 76% yield. The trichloride 7a was obtained from
azirinobenzothiazine 4 in 81% yield under the same con-
ditions (Scheme 5).
S
HCl
Ph
4
MeOH
N
H
We found that the opening of the aziridine ring in 3 in the
presence of nucleophilic halogenide ions proceeds with
conservation of the benzoxazine ring. 3-(Trichlorometh-
yl)- and 3-(bromodichloromethyl)-3-phenyl-3,4-dihydro-
2H-1,4-benzoxazines 5a,b were obtained on heating com-
pound 3 in hydrohalo acids (HCl, HBr) (Scheme 3). Un-
der these conditions the aziridine ring opening with N–
C(1) bond breaking occurs probably through a mechanism
of nucleophilic substitution of the ‘ammonium group’ of
the protonated aziridine. Trichloride 5a can be trans-
formed quantitatively back into aziridine 3 via reaction
with base (Scheme 3). This type of transformation was
earlier realized for acyclic 2,2,2-trichloroethylamines.12,13
CCl3
7a
Scheme 5
On heating azirinobenzothiazine 4 in concentrated hydro-
bromic acid, the 3-bromodichloromethyl derivative of
benzoxazine 7b was obtained as the main product. How-
ever, in contrast to the reaction of azirinobenzoxazine 3
under the same conditions, the product of ring enlarge-
ment, the 1,5-benzothiazepine 8 was also formed here in
5% yield (Scheme 6). This finding prompted us to look
for reaction conditions for the transformation of aziri-
no[c][1,4]benzoxazine and benzothiazine systems into
derivatives of 1,5-benzoxazepine and benzothiazepine.
O
O
N
HX
Ph
Ph
Cl
N
H
S
S
CCl2X
Br
HBr
4
Ph
Cl
Ph
5a X = Cl 63%
5b X = Br 62%
N
H
3
N
H
CCl2Br
O
8
5%
7b 45%
NH2CH2CH2NH2
reflux
Scheme 6
5a
3
95%
We investigated the chemical behavior of compounds 3
and 4 without addition of active nucleophiles, and under
these conditions we succeeded in the ring expansion with
breaking of N–C(1a) bond. Thus, reaction of the
azirinobenzoxazine 3 with trifluoroacetic acid at room
temperature proceeds with formation of 1,5-benzoxazepi-
none 9. When compound 3 was treated with boron trifluo-
ride etherate at room temperature the imidoyl chloride 10
was isolated as the sole product in 77% yield (Scheme 7).
Scheme 3
Heating compound 3 in methanol with addition of hydro-
halo acids afforded a mixture of 5 and 6 (Scheme 4). The
ratio trihalide 5/ester 6 depends on the added acid. Reflux-
ing a solution of azirinobenzoxazine 3 in methanol in the
presence of hydrofluoric acid gave 18% of compound 5a
and 34% of compound 6. Under similar conditions, addi-
tion of aqueous hydrochloric or hydrobromic acid gave
compounds 5a or 5b and 6 (43% of 5a and 8% of 6; 46%
of 5b and 14% of 6, respectively). It was also found that
compounds 5a,b react on prolonged heating with methan-
ol to form ester 6.
Similarly, the azirinobenzothiazine 4 with boron trifluo-
ride etherate at room temperature gave the imidoyl chlo-
ride 11. This imidoyl chloride hydrolyzed more easily
under purification on silica gel, than the oxazepine deriv-
ative 10, forming 1,5-benzothiazepinone 12. Thus, after
chromatography on silica gel, 28% of compound 11 and
Synthesis 2007, No. 2, 225–230 © Thieme Stuttgart · New York

PAPER
Selective Ring Opening of Aziridines
227
O
In conclusion, we have developed a simple and efficient
approach for the synthesis of 3-(trihalomethyl)-3-phenyl-
3,4-dihydro-2H-1,4-benzoxazines (thiazines) and chlori-
nated 3-phenyl-2,3-dihydro-1,5-benzoxazepines (thiaz-
Cl
CF3CO2H
Ph
3
3
N
H
O
epines) via
a
synthetic sequence consisting of
9
66%
cycloaddition of dichlorocarbene to the C=N double bond
of 2H-benzo-1,4-benzoxazine and 2H-1,4-benzothiazine,
leading to the formation of the gem-dihaloazirino-fused
heterocycle, and subsequent selective C–N bond break-
ing.
O
Cl
Ph
BF3⋅Et2O
N
Cl
10 77%
Scheme 7
Melting points were determined on a Boetius melting point appara-
tus; uncorrected values are given. The IR spectra were recorded on
1
a Carl Zeiss UR-20 instrument. H (300 MHz) and 13C (75 MHz)
44% of compound 12 were isolated whereas chromatog-
raphy on alumina gave 83% of compound 11 and 13% of
compound 12 (Scheme 8).
NMR were measured with a Bruker DPX 300 spectrometer using
CDCl3 as the solvent, and are reported in ppm relative to the solvent
peak of CDCl3 (d = 7.26 for H NMR and d = 77.0 for the central
1
resonance in 13C NMR). Mass spectral data were collected on MX-
1303 and Finnigan MAT 95 LCQ instruments. The elemental com-
positions were determined on an HP-185B CHN analyzer. The
progress of reactions was monitored by TLC using Silufol UV-254
plates. Silica gel Merck 60 was used for column chromatography.
All solvents were purified according to standard procedures. Benz-
oxazine 1 and benzothiazine 2 were prepared according published
procedures.14,15
S
S
Cl
Cl
BF3⋅Et2O
4
Ph
Ph
N
H
N
O
Cl
11 83%
12 13%
Scheme 8
1,1-Dichloro-1a-phenyl-1a,2-dihydro-1H-azireno[2,1-c][1,4]-
benzoxazine (3)
The compounds 10 and 11 contain two chlorine atoms
which could potentially be used for their modification via
reactions with nucleophiles. We succeeded, however, in
reacting only at the imidoyl chloride part of these mole-
cules. According to simple PM3 computations, com-
pounds 10 and 11 were unable to undergo SN2 reactions
due to steric reasons. When compounds 10 and 11 were
heated with sodium methoxide in methanol, they were
smoothly transformed into the corresponding methoxy
derivatives 13 and 14, respectively. Chloride 11 also re-
acts with morpholine to give amidine 15 in good yield
(Scheme 9).
Method a: Powdered KOH (2.1 g, 37.5 mmol) was added to a solu-
tion of 3-phenyl-2H-1,4-benzoxazine (1; 1 g, 4.785 mmol) and ben-
zyltriethylammonium chloride (0.1 g, 0.44 mmol) in CHCl3 (10
mL) under vigorous stirring, keeping the temperature of the mixture
at 21–23 °C (water bath). The mixture was stirred at this tempera-
ture for 3 h and then filtered through a layer of Al2O3 (1 cm). After
removal of the solvent on a rotary evaporator (bath temperature £
30 °C) and crystallization of the residue from Et2O–hexane, com-
pound 3 (0.75 g, 54%) was obtained as white crystals; mp 83–84 °C.
1H NMR (CDCl3): d = 4.36 and 4.76 (d, J = 11.7 Hz, 2 H, OCH2),
6.99–7.18 (m, 3 H), 7.43–7.53 (m, 6 H).
13C NMR (CDCl3): d = 50.9 (CPh), 66.4 (OCH2), 82.7 (CCl2),
117.6, 122.4, 125.8, 126.1, 127.3, 128.59, 128.62, 129.0, 136.9,
147.8.
O
Cl
MeONa
Anal. Calcd for C15H11Cl2NO: C, 61.66; H, 3.80; N, 4.79. Found: C,
61.57; H, 3.94; N, 4.72.
10
Ph
MeOH
N
O
Method b: A mixture of compound 5a (0.16 g, 0.487 mmol) and an-
hyd 1,2-diaminoethane (2 mL) was refluxed for 0.25 h. After cool-
ing, H2O (10 mL) was added, the precipitated crystals were filtered,
dried, and after crystallization from Et2O–hexane, compound 3
(0.135 g, 95%) was obtained as white crystals; mp 83–84 °C.
13 (65%)
S
Cl
MeONa
11
Ph
MeOH
N
O
1,1-Dichloro-1a-phenyl-1a,2-dihydro-1H-azireno[2,1-c][1,4]-
benzothiazine (4)
14 (59%)
Powdered sodium trichloroacetate (7 g, 37.7 mmol) was added in
small portions with stirring to a mixture of the benzothiazine 2 (2 g,
8.89 mmol), and benzyltriethylammonium chloride (0.20 g, 0.879
mmol) in refluxing CHCl3 (60 mL) over 3 h. After completion of the
reaction, the mixture was filtered and the solvent distilled off on a
rotary evaporator. The residue was chromatographed on a basic
Al2O3 column using EtOAc–hexane as eluent to give compound 4
(0.70 g, 26%) as a white solid; mp 97–99 °C (hexane–Et2O).
H
N
S
Cl
O
Ph
11
N
N
15 (71%)
O
Scheme 9
1H NMR (CDCl3): d = 3.09 and 3.43 (d, J = 13.1 Hz, 2 H, SCH2),
7.11–7.16 (m, 1 H), 7.30–7.51 (m, 8 H).
Synthesis 2007, No. 2, 225–230 © Thieme Stuttgart · New York

228
E. Yu. Shinkevich et al.
PAPER
13C NMR (CDCl3): d = 30.3 (SCH2), 55.6 (CPh), 81.9 (CCl2), 124.1,
124.2, 124.3, 127.0, 128.0, 128.4, 128.5, 129.5, 137.9, 138.0.
the above-mentioned work-up, compounds 5a (48 mg, 43%) and 6
(7 mg, 8%) were isolated.
Anal. Calcd for C15H11Cl2NS: C, 58.45; H, 3.60; N, 4.54. Found: C,
58.38; H, 3.99; N, 4.57.
Method d: A mixture of compound 3 (300 mg, 1.03 mmol), concd
HBr (1.4 g) and MeOH (10 mL) was refluxed for 2 h. By following
the above-mentioned work-up, compounds 5b (171 mg, 46%) and
6 (38 mg, 14%) were isolated.
3-Phenyl-3-(trichloromethyl)-3,4-dihydro-2H-1,4-benzoxazine
(5a)
Method e: A solution of compound 5a (0.05 g, 0.152 mmol) in
MeOH (1.5 mL) was refluxed for 14 h (66% conversion). By fol-
lowing the above-mentioned work-up, compound 6 (13 mg, 48%)
was isolated.
Method a: A mixture of compound 3 (57 mg, 0.196 mmol) and
concd HCl (1 mL) was heated at 90 °C for 5.5 h. After cooling, the
mixture was made alkaline with aq sat. Na2CO3 (pH 8), extracted
with Et2O (3 × 10 mL) and the combined Et2O layers were dried
(Na2SO4). After removal of the solvent and crystallization of the
residue from Et2O–CH2Cl2, compound 5a (40 mg, 63%) was ob-
tained as a white solid; mp 115–116 °C.
Method f: A solution of compound 5b (0.03 g, 0.081 mmol) in
MeOH (1.5 mL) was refluxed for 8 h (80% conversion). By follow-
ing the above-mentioned work-up, compound 6 (16 mg, 92%) was
isolated.
Method b: A mixture of compound 3 (0.301 g, 1.03 mmol) and 5%
aq solution of HCl in anhyd MeOH (10 mL) was refluxed for 0.5 h.
The solvent was removed under vacuum, and purification of the res-
idue was performed by chromatography on silica gel using EtOAc–
hexane as eluent to give 5a (0.253 g, 76%) as a white solid.
6
White solid; mp 81–82 °C (hexane–Et2O).
IR (CCl4): 3390 (NH), 1745 cm–1 (C=O).
1H NMR (CDCl3): d = 3.83 (s, 3 H, OCH3), 4.17 and 4.66 (d, J = 11
Hz, 2 H, OCH2), 4.78 (s, 1 H, NH), 6.69–6.90 (m, 4 H), 7.52–7.58
(m, 5 H).
13C NMR (CDCl3): d = 53.0 (OCH3), 62.4 (CPh), 70.4 (OCH2),
115.9, 116.8, 119.5, 122.0, 125.7, 128.6, 131.9, 137.5, 143.0, 172.2
(C=O).
IR (CCl4): 3410 (NH) cm–1.
1H NMR (CDCl3): d = 4.72 and 5.16 (d, J = 10.9 Hz, 2 H, OCH2),
5.13 (br s, 1 H, NH), 6.70–6.91 (m, 4 H), 7.40–7.42 (m, 3 H), 7.74–
7.76 (m, 2 H).
13C NMR (CDCl3): d = 67.6 (CPh), 68.3 (OCH2), 103.6 (CCl3),
115.5, 116.7, 119.5, 122.2, 127.9, 128.7, 129.5, 131.0, 135.2, 142.9.
MS (EI, 70 eV): m/z (%) = 329 (2.4), 327 (3, [M]+), 220 (6), 210
(100), 182 (11), 180 (6), 165 (8), 132 (11), 117 (13).
MS (EI, 70 eV): m/z (%) = 269 (13, [M]+), 211 (16), 210 (100,
[M – CO2Me]+), 182 (10), 180 (4).
Anal. Calcd for C16H15NO3: C, 71.36; H, 5.63; N, 5.20. Found: C,
71.38; H, 5.71; N 5.39.
Anal. Calcd for C15H12Cl3NO: C, 54.82; H, 3.69; N, 4.26. Found: C,
54.76; H, 3.69; N, 4.18.
3-Phenyl-3-(trichloromethyl)-3,4-dihydro-2H-1,4-benzothia-
zine (7a)
3-[Bromo(dichloro)methyl]-3-phenyl-3,4-dihydro-2H-1,4-
benzoxazine (5b)
A similar procedure starting from compound 3 (57 mg, 0.196
mmol) and concd HBr (1 mL) afforded the compound 5b (45 mg,
62%) as a white solid; mp 113 °C (CH2Cl2–Et2O).
A solution of compound 4 (0.202 g, 0.649 mmol) and a 5% solution
of HCl in anhyd MeOH (10 mL) was refluxed for 2 h. The solvent
was removed under vacuum, and the residue was purified by chro-
matography on silica gel using EtOAc–hexane as eluent. Com-
pound 7a (0.183 g, 81%) was obtained as a white solid; mp 132–134
°C (CH2Cl2–Et2O).
IR (CCl4): 3410 (NH) cm–1.
1H NMR (CDCl3): d = 4.39 and 5.00 (d, J = 11 Hz, 2 H, OCH2), 5.08
(br s, 1 H, NH), 6.61–6.90 (m, 4 H), 7.26–7.40 (m, 3 H), 7.69–7.75
(m, 2 H).
13C NMR (CDCl3): d = 67.4 (CPh), 68.7 (OCH2), 101.7 (CCl2Br),
115.5, 116.7, 119.5, 122.2, 127.9, 128.7, 129.8, 131.1, 135.0, 142.9.
IR (CHCl3): 3420 cm–1 (NH).
1H NMR (CDCl3): d = 3.72 and 3.87 (d, J = 13.1 Hz, 2 H, SCH2),
5.19 (br s, 1 H, NH), 6.71–6.74 (m, 1 H), 6.82–6.85 (m, 1 H), 7.01–
7.07 (m, 2 H), 7.39–7.41 (m, 3 H), 7.69–7.74 (m, 2 H).
MS (EI, 70 eV): m/z (%) = 373 (1), 371 (1, [M]+), 227 (2), 220 (4),
212 (16), 210 (100, [M – CCl2Br]+), 208 (2), 182 (4), 132 (5), 117
(5), 103 (8), 91 (8), 77 (10), 65 (4).
13C NMR (CDCl3): d = 31.8 (SCH2), 70.9 (CPh), 106.3 (CCl3),
115.9, 116.1, 119.0, 126.4, 127.6, 127.8, 128.6, 129.7, 137.5, 140.1.
Anal. Calcd for C15H11Cl3NS: C, 52.27; H, 3.51; N, 4.06. Found: C,
52.18; H, 3.60; N, 3.96.
Anal. Calcd for C15H12BrCl2NO: C, 48.29; H, 3.25; N, 3.75. Found:
C, 48.73; H, 3.45; N, 3.59.
3-[Bromo(dichloro)methyl]-3-phenyl-3,4-dihydro-2H-1,4-ben-
zothiazine (7b) and 3-Bromo-3-phenyl-2,3-dihydro-1,5-benzo-
thiazepin-4(5H)-one (8)
A mixture of compound 4 (0.381 g, 1.23 mmol) and concd HBr (3
mL) was heated at 90 °C for 12 h (79% conversion). The solvent
was removed under vacuum and the residue was treated with aq sat.
Na2CO3 (2 mL), and extracted with CH2Cl2 (3 × 40 mL). The resi-
due obtained on removal of solvent was chromatographed on silica
gel using EtOAc–hexane as eluent to give compounds 7b (0.170 g,
45%) and 8 (0.020 g, 5%).
Methyl 3-Phenyl-3,4-dihydro-2H-1,4-benzoxazine-3-carboxyl-
ate (6)
Method a: A solution of compound 3 (0.05 g, 0.172 mmol) in
MeOH (2 mL) was refluxed for 17.5 h (92% conversion). The sol-
vent was removed under vacuum and the residue treated with aq sat.
Na2CO3 (2 mL), extracted with Et2O (3 × 10 mL) and chromato-
graphed on silica gel using EtOAc–hexane as eluent to give com-
pounds 5a (13 mg, 31%) and 6 (18 mg, 34%).
Method b: A mixture of compound 3 (1 g, 3.44 mmol), 80% HF (6
mL) and MeOH (30 mL) was refluxed for 3 h. By following the
above-mentioned work-up, compounds 5a (0.211 g, 18%) and 6
(0.312 g, 34%) were isolated.
7b
White solid; mp 155–157 °C (CH2Cl2–Et2O).
IR (CHCl3): 3420 cm–1 (NH).
Method c: A mixture of compound 3 (100 mg, 0.344 mmol), concd
HCl (0.5 mL) and MeOH (3 mL) was refluxed for 6 h. By following
Synthesis 2007, No. 2, 225–230 © Thieme Stuttgart · New York

PAPER
Selective Ring Opening of Aziridines
229
1H NMR (CDCl3): d = 3.73 and 3.89 (d, J = 13.1 Hz, 2 H, SCH2),
5.21 (br s, 1 H, NH), 6.69–6.74 (m, 1 H), 6.83–6.86 (m, 1 H), 7.01–
7.09 (m, 2 H), 7.38–7.41 (m, 3 H), 7.70–7.73 (m, 2 H).
13C NMR (CDCl3): d = 32.2 (SCH2), 70.9 (CPh), 92.0 (CCl2Br),
115.9, 116.1, 119.0, 126.4, 127.5, 127.8, 128.6, 129.9, 137.2, 140.2.
220 (50), 210 (14), 207 (10), 155 (18), 153 (57), 140 (23), 138 (75),
103 (59), 88 (11), 86 (64), 84 (100), 77 (24), 47 (14).
HRMS: m/z calcd for C15H11Cl2NO: 291.0218; found: 291.0218.
3,4-Dichloro-3-phenyl-2,3-dihydro-1,5-benzothiazepine (11)
and 3-Chloro-3-phenyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-
one (12)
Anal. Calcd for C15H12BrCl2NS: C, 46.30; H, 3.11; N, 3.60. Found:
C, 46.40; H, 3.18; N, 3.49.
BF3·OEt2 (0.400 g, 2.82 mmol) was added dropwise to a stirred so-
lution of the compound 4 (0.145 g, 0.471 mmol) in anhyd CH2Cl2
(10 mL) and the mixture was kept at r.t. overnight. The solvent was
removed under vacuum and purification of the residue was per-
formed by chromatography on silica gel using EtOAc–hexane as
eluent. Compounds 11 (0.041 mg, 28%) and 12 (0.060 mg, 44%)
were isolated. The yield of dichlorobenzothiazepine 11 was in-
creased (83%) and that of its hydrolysis product 12 decreased (13%)
when alumina was used instead of silica gel for chromatography.
8
White solid; mp 183–184 °C (CH2Cl2–hexane).
IR (CHCl3): 1690 (C=O), 3390 cm–1 (NH).
1H NMR (CDCl3): d = 3.90 and 4.28 (d, J = 10.2 Hz, 1 H, CH),
6.72–6.85 (m, 1 H), 6.92–7.45 (m, 7 H), 7.57–7.68 (m, 2 H), 8.86
(br s, 1 H, NH).
13C NMR (CDCl3): d = 36.8 (SCH2), 56.1 (CBrPh), 116.6, 119.2,
124.1, 127.0, 127.5, 128.0, 128.56, 128.62, 135.2, 135.6, 166.7
(C=O).
MS (EI): m/z (%) = 336 (4), 335 (34, [M + 2]+), 333 (35, [M]+), 242
(6), 241 (17), 240 (100, [M – CH2Br]+), 212 (27), 152 (45), 103
(92), 77 (37).
11
White solid; mp 94–96 °C (hexane).
IR (CHCl3): 1620 cm–1 (C=N).
1H NMR (CDCl3): d = 4.12 and 4.31 (d, J = 11.6 Hz, 2 H, SCH2),
7.15–7.23 (m, 2 H), 7.29–7.39 (m, 5 H), 7.64–7.67 (m, 2 H).
13C NMR (CDCl3): d = 47.9 (SCH2), 56.4 (CClPh), 122.7, 126.4,
127.2, 127.5, 127.6, 128.3, 128.5, 128.9, 136.5, 140.1, 151.2 (C=N).
Anal. Calcd for C15H12BrNOS·0.25C6H14: C, 55.70; H, 3.94; N,
4.39. Found: C, 55.62; H, 4.27; N, 4.03.
3-Chloro-3-phenyl-2,3-dihydro-1,5-benzoxazepin-4(5H)-one
(9)
Anal. Calcd for C15H11Cl2NS: C, 58.45; H, 3.60; N, 4.54. Found: C,
58.47; H, 3.85; N, 4.58.
A mixture of compound 3 (0.13 g, 0.445 mmol) and 95% trifluoro-
acetic acid (2 mL) was kept overnight at 20 °C. Trifluoroacetic acid
was removed under vacuum and purification of the residue was per-
formed by chromatography on silica gel using EtOAc–hexane as
eluent. Compound 9 (0.080 g, 66%) was obtained as a white solid;
mp 153–155 °C (Et2O).
12
White solid; mp 195–197 °C (Et2O).
IR (CHCl3): 1680 (C=O), 3400 cm–1 (NH).
1H NMR (CDCl3): d = 4.06 and 4.41 (d, J = 11.6 Hz, 2 H, SCH2),
6.79–6.82 (m, 1 H), 6.96–7.13 (m, 2 H), 7.25–7.40 (m, 4 H), 7.61–
7.64 (m, 2 H), 9.28 (br s, 1 H, NH).
IR (CHCl3): 1680 (C=O), 3380 cm–1 (NH).
1H NMR (CDCl3): d = 4.48 and 4.70 (d, J = 13.1 Hz, 2 H, OCH2),
6.99–7.02 (m, 3 H), 7.10–7.12 (m, 1 H), 7.38–7.44 (m, 3 H), 7.64–
7.66 (m, 2 H), 9.87 (br s, 1 H, NH).
13C NMR (CDCl3): d = 48.7 (SCH2), 56.7 (CClPh), 116.8, 118.9,
124.0, 127.5, 127.9, 128.5, 128.6, 135.0, 135.6, 167.2 (C=O).
Anal. Calcd for C15H12ClNOS: C, 62.17; H, 4.17; N, 4.83. Found:
C, 62.00; H, 4.34; N, 4.79.
13C NMR (CDCl3): d = 72.4 (CClPh), 74.8 (OCH2), 120.7, 121.1,
124.0, 124.9, 127.1, 128.6, 129.0, 137.36, 137.39, 148.3, 171.1
(C=O).
MS (EI, 70 eV): m/z (%) = 275 (26, [M + 2]+), 273 (83, [M]+), 224
(48), 210 (12), 138 (25), 126 (100), 120 (25), 103 (90), 77 (28), 52
(19).
3-Chloro-4-methoxy-3-phenyl-2,3-dihydro-1,5-benzoxazepine
(13)
A solution of chloride 10 (0.55 g, 1.884 mmol) in MeOH (5 mL)
was added to a solution of MeONa [prepared from Na (0.201 g) and
MeOH (5 mL)] and the mixture was refluxed for 0.5 h. The solvent
was removed in vacuum and the residue was partitioned between
H2O (20 mL) and EtOAc (30 mL). The organic layer was washed
with H2O (20 mL), brine (20 mL) and dried (Na2SO4). Purification
of the residue obtained on removal of the solvent was performed by
chromatography on silica gel using EtOAc–hexane as eluent. Com-
pound 13 (0.350 g, 65%) was obtained as a pale yellow oil.
Anal. Calcd for C15H12ClNO2: C, 65.82; H, 4.42; N, 5.12. Found: C,
65.89; H, 4.59; N, 5.03.
3,4-Dichloro-3-phenyl-2,3-dihydro-1,5-benzoxazepine (10)
BF3·OEt2 (1.38 g, 9.72 mmol) was added dropwise to a stirred solu-
tion of compound 3 (0.71 g, 2.44 mmol) in anhyd CH2Cl2 (10 mL)
and the mixture was kept overnight at r.t.. The solvent was removed
under vacuum and the residue was purified by chromatography on
silica gel using EtOAc–hexane as eluent. Compound 10 (0.551 g,
77%) was obtained as a pale yellow oil.
IR (CHCl3): 1670 cm–1 (C=N).
1H NMR (CDCl3): d = 3.91 (s, 3 H, OCH3), 4.33 and 4.43 (d,
J = 12.7 Hz, 2 H, OCH2), 6.97–7.00 (m, 1 H), 7.11–7.14 (m, 2 H),
7.40–7.53 (m, 6 H).
IR (CHCl3): 1670 cm–1 (C=N).
1H NMR (CDCl3): d = 4.38 and 4.48 (d, J = 12.9 Hz, 2 H, OCH2),
7.02–7.05 (m, 1 H), 7.17–7.30 (m, 2 H), 7.43–7.47 (m, 3 H), 7.58–
7.62 (m, 3 H).
13C NMR (CDCl3): d = 76.8 (CClPh), 78.0 (OCH2), 120.2, 124.3,
126.9, 128.7, 129.2, 130.2, 132.1, 133.7, 136.7, 150.2, 153.5 (C=N).
13C NMR (CDCl3): d = 54.0 (OCH3), 71.4 (CClPh), 77.3 (OCH2),
119.8, 123.9, 126.7, 126.8, 128.5, 128.7, 131.5, 132.3, 138.1, 153.4,
157.2 (C=N).
MS (EI, 70 eV): m/z (%) = 289 (32, [M + 2]+), 287 (100, [M]+), 252
(18), 238 (71), 220 (16), 149 (97), 134 (34), 103 (75), 77 (39), 51
(15).
MS (EI, 70 eV): m/z (%) = 293 (34, [M + 2]+), 291 (53, [M]+), 258
(6, [M – Cl + 2]+), 256 (19, [M – Cl]+), 244 (6), 242 (21), 221 (15),
HRMS: m/z calcd for C16H14ClNO2: 287.0713; found: 287.0713.
Synthesis 2007, No. 2, 225–230 © Thieme Stuttgart · New York

230
E. Yu. Shinkevich et al.
PAPER
3-Chloro-4-methoxy-3-phenyl-2,3-dihydro-1,5-benzo-
thiazepine (14)
Acknowledgment
We gratefully acknowledge the Russian Foundation for Basic
Research (project no. 05-03-33257) and the Russian Foundation for
Basic Research – The Government of Flanders ‘Bilateral Scientific
Cooperation’ program (project no. 05-03-34811) for support of this
research.
Chloride 11 (0.12 g, 0.390 mmol) was added to a solution of
MeONa [prepared from sodium (0.10 g) and MeOH (7 mL)] and the
mixture was refluxed for 4 h. The solvent was removed under vac-
uum and the residue was partitioned between H2O (10 mL) and
CH2Cl2 (40 mL). The organic layer was washed with brine (10 mL)
and dried (Na2SO4). The solvent was removed and the residue was
purified by chromatography on silica gel using EtOAc–hexane as
eluent. Compound 14 (0.071 g, 59%) was obtained as a white solid;
mp 81–82 °C (hexane).
References
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IR (CHCl3): 1640 cm–1 (C=N).
1H NMR (CDCl3): d = 4.08 (s, 3 H, OCH3), 4.04 and 4.30 (d,
J = 11.6 Hz, 2 H, SCH2), 6.98–7.03 (m, 1 H), 7.10–7.32 (m, 6 H),
7.52–7.55 (m, 2 H).
13C NMR (CDCl3): d = 48.0 (SCH2), 53.0 (CClPh), 54.6 (OCH3),
121.4, 124.9, 125.5, 126.6, 126.9, 127.2, 128.26, 128.29, 136.8,
141.1, 159.3 (C=N).
Anal. Calcd for C16H14ClNOS: C, 63.25; H, 4.64; N, 4.61. Found:
C, 63.32; H, 4.60; N, 4.68.
4-(3-Chloro-3-phenyl-2,3-dihydro-1,5-benzothiazepin-4-
yl)morpholine (15)
A mixture of chloride 11 (0.085 g, 0.276 mmol) and morpholine
(distilled from NaOH) was refluxed for 0.5 h. The excess of mor-
pholine was removed under vacuum and the residue was partitioned
between H2O (10 mL) and EtOAc (30 mL). The organic layer was
washed with H2O (10 mL) and brine (10 mL), and dried (Na2SO4).
Purification of the residue obtained after removal of the solvent was
performed by chromatography on silica gel using EtOAc–hexane as
eluent to give 15 (0.071 g, 71%) as a white solid; mp 154–156 °C
(Et2O).
1H NMR (CDCl3): d = 3.19–3.33 (m, 4 H), 3.48–3.51 (m, 4 H), 3.79
and 4.08 (d, J = 12.3 Hz, 2 H, SCH2), 6.96–7.02 (m, 1 H), 7.21–7.25
(m, 2 H), 7.37–7.50 (m, 4 H), 7.67–7.70 (m, 2 H).
13C NMR (CDCl3): d = 44.2 (SCH2), 47.0 (CClPh), 49.2 (CH2N),
66.2 (OCH2), 120.3, 123.1, 125.3, 127.0, 128.3, 128.4, 128.6, 137.4,
141.8, 154.7 (C=N).
Anal. Calcd for C19H19ClN2OS: C, 63.59; H, 5.34; N, 7.81. Found:
C, 63.40; H, 5.48; N, 7.66.
Synthesis 2007, No. 2, 225–230 © Thieme Stuttgart · New York