Syntheses of 1,4-benzothiazepines and 1,4-benzoxazepines via cyclizations of 1-[2-arylthio(oxy)ethyl]-5-benzotriazolyl-2-pyrrolidinones and 3-benzotriazolyl-2-[2-arylthio(oxy)ethyl]-1-isoindolinones

Article abstract of DOI:10.1021/jo010179b

1-[2-Arylthio(oxy)ethyl]-5-benzotriazolyl-2-pyrrolidinones 6a-e, 12 and 3-benzotriazolyl-2-[2-arylthio(oxy)ethyl]-1-isoindolinones 9a-f, 14 are readily available from reactions of benzotriazole (4), 2-(arylsulfanyl)ethylamines 3, or 2-phenoxyethylamine (11) with 2,5-dimethoxy-2,5-dihydrofuran (5) or 2-formylbenzoic acid (8). Lewis acid mediated cyclizations of 6 and 9 produced novel 1,4-benzothiazepines 7a-e and 10a-f, respectively. Cyclizations of 12 and 14 gave 1,4-benzoxazepines 13 and 15, respectively.

Full text of DOI:10.1021/jo010179b

5590
J . Org. Chem. 2001, 66, 5590-5594
Syn th eses of 1,4-Ben zoth ia zep in es a n d 1,4-Ben zoxa zep in es via
Cycliza tion s of
1-[2-Ar ylth io(oxy)eth yl]-5-ben zotr ia zolyl-2-p yr r olid in on es a n d
3-Ben zotr ia zolyl-2-[2-a r ylth io(oxy)eth yl]-1-isoin d olin on es
Alan R. Katritzky,* Yong-J iang Xu, Hai-Ying He, and Shamal Mehta
Center for Heterocyclic Chemistry, Department of Chemistry, University of Florida,
Gainesville, Florida 32611-7200
katritzky@chem.ufl.edu.
Received February 15, 2001
1-[2-Arylthio(oxy)ethyl]-5-benzotriazolyl-2-pyrrolidinones 6a -e, 12 and 3-benzotriazolyl-2-[2-aryl-
thio(oxy)ethyl]-1-isoindolinones 9a -f, 14 are readily available from reactions of benzotriazole (4),
2-(arylsulfanyl)ethylamines 3, or 2-phenoxyethylamine (11) with 2,5-dimethoxy-2,5-dihydrofuran
(5) or 2-formylbenzoic acid (8). Lewis acid mediated cyclizations of 6 and 9 produced novel 1,4-
benzothiazepines 7a -e and 10a -f, respectively. Cyclizations of 12 and 14 gave 1,4-benzoxazepines
13 and 15, respectively.
In tr od u ction
acid to form aminophthalides, followed by cyclization to
the corresponding 1,4-benzoxazepines in 18-70% yields;11
(ii) rearrangement of methyl 2-(8-methoxy-2,3-dihydro-
1,4-benzoxazepin-5-yl)benzoate using Bischler-Napier-
alski conditions;12 and (iii) scandium or copper triflate
catalyzed acylaminoalkylation of R-methoxyisoindolones
with the formation of 1,4-benzoxazepines in moderate
yields.13
Several methods have previously been reported for the
preparation of benzothiazepines14 and their condensed
analogues.9 However, the tricyclic ring system of com-
pounds 7 is recorded in just a single paper: starting from
the corresponding N-(bromoethyl)pyrrolidinone, 1,5,6,-
11b-tetrahydropyrrolo[1,2-d][1,4]benzothiazepin-3(2H)-
one (7a ) and 10-methoxy-1,5,6,11b-tetrahydro-pyrrolo-
[1,2-d][1,4]benzoxazepin-3(2H)-one were obtained in 44%
and 10% overall yields, respectively.15 There is no report
of the synthesis of 6,7-dihydroisoindolo[2,1-d][1,4]ben-
zothiazepin-9(13bH)-ones 10. Versatile alternative routes
to 7, 10, 13, and 15 are desirable. We now report herein
an efficient approach to the syntheses of related 1,4-
benzothiazepines and 1,4-benzoxazepines using the ben-
zotriazole methodology.
Seven-membered ring systems containing two hetero-
atoms, e.g., benzothiazepines (N and S) and benzox-
azepines (N and O), are of considerable interest. Ben-
zothiazepines are active constituents of a series of new
potent bradykinin agonists.1 Some of these compounds
have also shown activity as endogenous natriuretic
factors,2 enzyme inhibitors,3 HIV-1 integrase inhibitors,4
antitumor antibiotics,5 muscle relaxants, anticonvul-
sants,6 sedatives, hypnotics,7 and antipsychotics.8 Cam-
piani and co-workers developed a series of novel and
selective calcium entry blockers based on pyrroloben-
zothiazepines.9 Benzoxazepines also show some pharma-
cological properties, e.g., antipsychotic,8b and central
nervous system activity.10
Known syntheses of benzoxazepines include (i) con-
densations of 2-aryloxyethylamines with 2-formylbenzoic
(1) Amblard, M.; Daffix, I.; Bedos, P.; Berge´, G.; Pruneau, D.; Paquet,
J .-L.; Luccarini, J .-M.; Be´lichard, P.; Dodey, P.; Martinez, J . J . Med.
Chem. 1999, 42, 4185.
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Med. Chem. 1996, 39, 1196.
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J . Med. Chem. 1996, 39, 3539.
(4) Neamati, N.; Turpin, J . A.; Winslow, H. E.; Christensen, J . L.;
Williamson, K.; Orr, A.; Rice, W. G.; Pommier, Y.; Garofalo, A.; Brizzi,
A.; Campiani, G.; Fiorini, I.; Nacci, V. J . Med. Chem. 1999, 42, 3334.
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28, 213.
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64, 5122.
(7) Toshiyuki, H.; Takuhiro, I.; Hisao, Y. J apan 7,272,107, 1970;
Chem. Abstr. 1972, 77, 140187f.
Resu lts a n d Discu ssion
Syn th eses of 1,5,6,11b-Tetr a h yd r op yr r olo[1,2-d ]-
[1,4]ben zoth ia zep in -3(2H)-on es 7a -e. Treatment of
substituted thiophenols 1a -f with 2-chloroethylamine
hydrochloride (2) and excess potassium carbonate in
(8) (a) Campiani, G.; Nacci, V.; Bechelli, S.; Ciani, S. M.; Garofalo,
A.; Fiorini, I.; Wikstro¨m, H.; de Boer, P.; Liao, Y.; Tepper, P. G.;
Cagnotto, A.; Mennini, T. J . Med. Chem. 1998, 41, 3763. (b) Liao, Y.;
Venhuis, B. J .; Rodenhuis, N.; Timmerman, W.; Wikstro¨m, H.; Meier,
E.; Bartoszyk, G. D.; Bo¨ttcher, H.; Seyfried, C. A.; Sundell, S. J . Med.
Chem. 1999, 42, 2235.
(9) Campiani, G.; Fiorini, I.; De Filippis, M. P.; Ciani, S. M.;
Garofalo, A.; Nacci, V.; Giorgi, G.; Sega, A.; Botta, M.; Chiarini, A.;
Budriesi, R.; Bruni, G.; Romeo, M. R.; Manzoni, C.; Mennini, T. J . Med.
Chem. 1996, 39, 2922.
(11) (a) Pecher, J .; Waefelaer, A.; Poultier, P. Bull. Soc. Chim. Belg.
1977, 86, 1003. (b) Pecher, J .; Waefelaer, A. Bull. Soc. Chim. Belg.
1978, 87, 911.
(12) Heaney, H.; Shuhaibar, K. F. Tetrahedron Lett. 1994, 35, 2751.
(13) El Gihani, M. T.; Heaney, H.; Shuhaibar, K. F. Synlett 1996,
871.
(14) Nefzi, A.; Ong, N. A.; Giulianotti, M. A.; Ostresh, J . M.;
Houghten, R. A. Tetrahedron Lett. 1999, 40, 4939. (b) Schwarz, M. K.;
Tumelty, D.; Gallop, M. A. J . Org. Chem. 1999, 64, 2219. (c) Yamada,
S.; Mori, Y.; Morimatsu, K.; Ishizu, Y.; Ozaki, Y.; Yoshioka, R.;
Nakatani, T.; Seko, H. J . Org. Chem. 1996, 61, 8586.
(15) Kraus, G. A.; Yue, S. J . Org. Chem. 1983, 48, 2936.
(10) (a) Toshiyuki, H.; Takuhiro, I.; Hisao, Y. G.O. 2,014,223, 1969;
Chem. Abstr. 1970, 73, 120697h. (b) Standridge, R. T. U.S. 4,125,538,
1978; Chem. Abstr. 1979, 90, 72246r.
10.1021/jo010179b CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/18/2001

1,4-Benzothiazepines and 1,4-Benzoxazepines
J . Org. Chem., Vol. 66, No. 16, 2001 5591
Sch em e 1a
Sch em e 2
isomers for the subsequent reactions. Crude 6a -e were
stirred for 48 h at room temperature with 4 equiv of TiCl4
to give 1,5,6,11b-tetrahydropyrrolo[1,2-d][1,4]benzo-
thiazepin-3(2H)-ones 7a -e in 67-96% yields (Scheme 1,
Table 1). Compounds 6 and 7 were characterized by their
1H and 13C NMR spectra and by microanalysis. After
cyclization, the H(5) signal in compounds 6 (shown as a
doublet of doublets at 6.52-6.57 ppm) is shifted upfield
to 5.19-5.77 ppm H(11b) in 7 (as a doublet of doublets
or a multiplet). The correct numbers of quaternary
carbons determined by APT spectra for 7a -e further
confirmed the cyclization of 6.
Syn th eses of 6,7-Dih ydr oisoin dolo[2,1-d][1,4]ben zo-
th ia zep in -9(13bH)-on es 10a -f. Reactions of 2-(aryl-
sulfanyl)ethylamines 3a-f, benzotriazole (4), and 2-formyl-
benzoic acid (8) were carried out in refluxing toluene with
p-toluenesulfonic acid as a catalyst, using a Dean-Stark
apparatus to remove the water formed. After 24 h, the
corresponding 3-(1H-1,2,3-benzotriazol-1-yl)-2-[2-(aryl-
sulfanyl)ethyl]-1-isoindolinones 9a -f were obtained in
81-92% yields. Compounds 9 were stirred for 48 h at
room temperature with 2 equiv of TiCl4 to give 6,7-
dihydroisoindolo[2,1-d][1,4]benzothiazepin-9(13bH)-
ones 10a -f in 78-96% yields (Scheme 1, Table 1). For
10c and 10f, pure products were obtained after washing
with 2 M NaOH without the need for column chroma-
tography. The proton NMR spectra show that H(3) in
9a -f always appears as a singlet at 7.46-7.52 ppm,
overlapping with aromatic hydrogens. After TiCl4-medi-
ated cyclization, this proton is shifted upfield to 6.16-
6.80 ppm as a well-defined singlet [H(13b) in 10a -f].
Syn th esis of 1,5,6,11b-Tetr a h yd r op yr r olo[1,2-d ]-
[1,4]ben zoxa zep in -3(2H)-on e (13) a n d 6,7-Dih yd r o-
isoin d olo[2,1-d ][1,4]ben zoxa zep in -9(13bH)-on e (15).
1,5,6,11b-Tetrahydropyrrolo[1,2-d][1,4]benzoxazepin-3(2H)-
one (13) and 6,7-dihydroisoindolo[2,1-d][1,4]benz-
oxazepin-9(13bH)-one (15) were synthesized in 72% and
89% yields, respectively, via a similar procedure to that
described above using 2-phenoxyethylamine (11) instead
of compounds 3 as the starting material (Scheme 2). In
the case of 15, the pure product was obtained directly
after washing benzotriazole away with 2 M NaOH
without additional purification by column chromatogra-
phy.
a
For designation of substitutents R1, R2, and R3 in series a -f,
see Table 1.
Ta ble 1. P r ep a r a tion of Com p ou n d s 3, 6, 7, 9, a n d 10
substitutents
R2
isolated yields
entry
R1
R3
3
6a
7b
9a
10c
a
b
c
d
e
f
H
CH3
H
H
H
Cl
CH3
H
H
H
H
68
62
72
63
71
74
58
54
56
47
61
d
81
80
67
84
96
d
84
86
92
81
84
82
86
91
94
96
78
81
H
2-naphthyl
H
CH3
CH3
a
b
Isolated yields based on 3. Isolated yields based on 6.
c Isolated yields based on 9. The reactions have not been done.
d
methylene chloride gave 2-(arylsulfanyl)ethylamines 3a-f
in 62-74% yields (Scheme 1, Table 1).
The crude amines 3a -e were reacted with benzotria-
zole (4) and 2,5-dimethoxy-2,5-dihydrofuran (5) in acetic
acid to afford the corresponding 5-benzotriazolyl-1-[2-
(arylsulfanyl)ethyl]-2-pyrrolidinones 6a -e in moderate
yields. Crude 6a -e were obtained as mixtures of Bt1
(benzotriazol-1-yl) and Bt2 (benzotriazol-2-yl) isomers in
which the Bt1 isomers predominated. We reported the
1H and 13C NMR data of the major Bt1 isomers, and the
ratio of Bt1 and Bt2 isomers as determined by H NMR
spectroscopy.
1
According to our previous work,16 both Bt1 and Bt2 are
good leaving groups in the presence of a Lewis acid. Also,
removal of the benzotriazolyl groups from Bt1 and Bt2
isomers results in the same iminium cation. Therefore,
compounds 6a -e were used as mixtures of the two
(16) (a) Katritzky, A. R.; Lan, X.; Yang, J . Z.; Denisko, O. V. Chem.
Rev. 1998, 98, 409. (b) Katritzky, A. R.; Qiu, G.-F.; He, H.-Y.; Yang,
B.-Z. J . Org. Chem. 2000, 65, 3683. (c) Katritzky, A. R.; Mehta, S.;
He, H.-Y. J . Org. Chem. 2001, 66, 148.

5592 J . Org. Chem., Vol. 66, No. 16, 2001
Katritzky et al.
Gen er a l P r oced u r e for th e P r ep a r a tion of 5-Ben zo-
tr ia zolyl-1-[2-(a r ylsu lfa n yl)eth yl]-2-p yr r olid in on es 6a -
e. 2,5-Dimethoxy-2,5-dihydrofuran (5, 0.57 g, 4.4 mmol), a
crude 2-(arylsulfanyl)-1-ethanamine 3a -e (4 mmol), and ben-
zotriazole (0.96 g, 8 mmol) were dissolved in acetic acid (30
mL). The solution was stirred at 60-75 °C for 48 h. After the
mixture cooled, 2 M NaOH was added. The mixture was then
extracted three times with methylene chloride, and the organic
fractions were dried over Na2SO4 and evaporated under
reduced pressure. The black residue was purified by column
chromatography (hexanes/EtOAc ) 1/1) to give compounds
6a -e as yellow to brown oils.
Sch em e 3
5-Ben zot r ia zolyl-1-[2-(p h en ylt h io)et h yl]-2-p yr r olid i-
n on e (6a ): mixture of Bt1 and Bt2 isomers in 8/1 ratio; yellow
oil; yield, 58%; 1H NMR δ 8.10 (d, J ) 7.9 Hz, 1H), 7.46-7.38
(m, 2H), 7.30-7.21 (m, 6H), 6.56 (dd, J ) 7.6, 2.3 Hz, 1H),
3.79-3.70 (m, 1H), 3.24-3.14 (m, 1H), 2.97-2.81 (m, 3H),
2.64-2.50 (m, 2H), 2.45-2.36 (m, 1H); 13C NMR δ 175.2, 146.8,
135.2, 131.9, 129.6, 129.4, 128.8, 126.9, 125.0, 121.0, 109.3,
73.6, 41.0, 31.2, 29.7, 25.9. Anal. Calcd for C18H18N4OS: C,
63.88; H, 5.36; Found: C, 63.81; H, 5.65.
Gen er a l P r oced u r e for th e P r ep a r a tion of 1,5,6,11b-
Te t r a h yd r op yr r olo[1,2-d ][1,4]b e n zot h ia ze p in -3(2H )-
on es 7a -e. To a solution of a 5-benzotriazolyl-1-[2-(arylsul-
fanyl)ethyl]-2-pyrrolidinones 6a -e (2 mmol) in dry CH2Cl2 (20
mL) was added TiCl4 (8 mmol, 4.7 mL, 1.71 M in CH2Cl2), and
the mixture was stirred for 48 h. Then the solution was washed
with 2 M NaOH and brine, the organic fractions were dried
over Na2SO4, and the solvent was removed in vacuo. The
residue was purified by column chromatography (hexanes/
EtOAc ) 1/1-1/2) to give 7a -e.
The reaction mechanism proposed for the formation of
6a -e and 12 is similar to that discussed in our previous
report.17 The formation of compounds 9a -f and 14 may
involve the nucleophilic attack of 2-(arylsulfanyl)ethyl-
amines 3 or 2-phenoxyethylamine (11) at the aldehyde
carbonyl group, which is the most electrophilic center in
2-formylbenzoic acid (8), to form R-carbinolamines 16,
which then eliminate 1 equiv of H2O and are converted
into 2-iminomethylbenzoic acids 17.11a,18 Next a benzo-
triazole molecule attacks the double bond of these imines
17 to afford the intermediates 18, which undergo dehy-
drative cyclization to generate 9 or 14 in the presence of
an acid (Scheme 3). With the help of a Lewis acid,
compounds 9 or 14 formed eliminate the benzotriazole
anion to give transient iminium cations 19, which finally
cyclize with the loss of one proton to furnish products
10a -f or 15.
1,5,6,11b-Tetr ah ydr opyr r olo[1,2-d][1,4]ben zoth iazepin -
3(2H)-on e (7a ):13 brown oil; yield, 81%; 1H NMR δ 7.59 (d, J
) 7.6 Hz, 1H), 7.37-7.32 (m, 2H), 7.27-7.21 (m, 1H), 5.15 (dd,
J ) 7.0, 2.9 Hz, 1H), 4.27 (dt, J ) 14.0, 4.1 Hz, 1H), 3.35 (ddd,
J ) 13.7, 10.2, 3.5 Hz, 1H), 2.95 (dt, J ) 13.7, 4.1 Hz, 1H),
2.79 (ddd, J ) 14.0, 10.2, 4.1 Hz, 1H), 2.65-2.37 (m, 4H); 13
C
NMR δ 174.3, 142.0, 135.0, 134.9, 128.6, 128.2, 126.5, 61.6,
42.5, 32.8, 30.5, 25.7.
8-Me t h y l-1,5,6,11b -t e t r a h y d r o p y r r o lo [1,2-d ][1,4]-
ben zoth ia zep in -3(2H)-on e (7b): pale yellow prisms (from
CH2Cl2); mp 112-113 °C; yield, 80%; 1H NMR δ 7.22-7.17
(m, 3H), 5.23-5.19 (m, 1H), 4.18-4.12 (m, 1H), 3.41-3.32 (m,
1H), 2.96-2.89 (m, 1H), 2.74-2.35 (m, 5H), 2.50 (s, 3H); 13C
NMR δ 174.2, 142.2, 141.8, 134.8, 129.8, 127.8, 124.1, 61.5,
42.0, 32.5, 30.6, 26.0, 22.0. Anal. Calcd for C13H15NOS: C,
66.92; H, 6.48; N, 6.00. Found: C, 66.89; H, 6.34; N, 6.17.
10-Ch lor o-1,5,6,11b -t e t r a h yd r op yr r olo[1,2-d ][1,4]-
ben zoth ia zep in -3(2H)-on e (7c): black oil; yield, 67%; 1H
NMR δ 7.51 (d, J ) 8.2 Hz, 1H), 7.29 (s, 1H), 7.26-7.20 (m,
1H), 5.09 (dd, J ) 7.0, 3.8 Hz, 1H), 4.27 (dt, J ) 14.0, 4.1 Hz,
1H), 3.33 (ddd, J ) 13.7, 10.2, 3.5 Hz, 1H), 2.93 (dt, J ) 13.7,
3.8 Hz, 1H), 2.77 (ddd, J ) 14.0, 10.2, 4.1 Hz, 1H), 2.63-2.38
(m, 4H); 13C NMR δ 174.2, 143.7, 136.0, 134.5, 133.4, 128.1,
In summary, we have developed efficient and versatile
methods for the syntheses of 1,5,6,11b-tetrahydropyrrolo-
[1,2-d][1,4]benzothiazepin-3(2H)-ones 7a -e, 6,7-dihy-
droisoindolo[2,1-d][1,4]benzothiazepin-9(13bH)-ones 10a-
f, 1,5,6,11b-tetrahydropyrrolo[1,2-d][1,4]benzoxazepin-
3(2H)-one (13), and 6,7-dihydroisoindolo[2,1-d][1,4]benzox-
azepin-9(13bH)-one (15) from easily available starting
materials.
Exp er im en ta l Section
THF was distilled from sodium/benzophenone prior to use.
Melting points were determined using a Bristoline hot-stage
microscope and are uncorrected. 1H NMR and 13C NMR spectra
(300 and 75 MHz, respectively) were recorded on a Gemini
300 NMR spectrometer in CDCl3 (with TMS for 1H and
chloroform-d for 13C as the internal reference). Elemental
analyses were performed on a Carlo Erba-1106 instrument.
HRMS were measured on an AEI-30 mass spectrometer.
Column chromatography was performed on silica gel. All of
the reactions were carried out under N2.
Gen er a l P r oced u r e for th e P r ep a r a tion of 2-(Ar ylsu l-
fa n yl)eth yla m in es 3a -f. A substituted thiophenol (1, 10
mmol), 2-chloroethylamine hydrochloride (2, 1.51 g, 13 mmol),
and potassium carbonate (4.15 g, 30 mmol) were stirred in
methylene chloride (40 mL) at room temperature for 48 h.
Then the solution was washed with water and dried over Na2-
SO4. After removal of the solvent, crude 2-(arylsulfanyl)-
ethylamines 3a -f were obtained and used directly for the
subsequent reactions (Scheme 1, Table 1).
126.8, 61.3, 42.5, 32.8, 30.2, 25.6; HRMS calcd for C12H13
-
ClNOS 254.0406 (M + 1), found 254.0405; GC purity (after
column) 95%.
10-Me t h yl-1,5,6,11b -t e t r a h yd r op yr r olo[1,2-d ][1,4]-
1
ben zoth ia zep in -3(2H)-on e (7d ): brown oil; yield, 84%; H
NMR δ 7.46 (d, J ) 7.6 Hz, 1H), 7.11 (s, 1H), 7.05 (d, J ) 7.6
Hz, 1H), 5.12-5.09 (m, 1H), 4.24 (dt, J ) 14.0, 4.4 Hz, 1H),
3.32 (ddd, J ) 14.0, 9.2, 3.8 Hz, 1H), 2.91 (dt, J ) 13.4, 4.0
Hz, 1H), 2.77 (ddd, J ) 14.0, 9.9, 4.1 Hz, 1H), 2.64-2.40 (m,
4H), 2.37 (s, 3H); 13C NMR δ 174.4, 141.8, 138.7, 134.9, 131.2,
128.9, 127.5, 61.9, 42.4, 32.9, 30.7, 25.9, 21.4; HRMS calcd for
C
13H16NOS 234.0953 (M + 1), found 234.0952; GC purity (after
column) 97%.
1,2,10,11-Tetr a h yd r on a p h th o[1,2-f]p yr r olo[1,2-d ][1,4]-
th ia zep in -12(9cH)-on e (7e): brown prisms (from CH2Cl2/
Et2O); mp 122-123 °C; yield, 96%; 1H NMR δ 7.94 (d, J ) 8.2
Hz, 1H), 7.85 (d, J ) 8.2 Hz, 1H), 7.67 (d, J ) 8.4 Hz, 1H),
7.58-7.48 (m, 3H), 5.77 (t, J ) 7.0 Hz, 1H), 4.37-4.28 (m, 1H),
3.28-3.04 (m, 3H), 2.75-2.66 (m, 1H), 2.60-2.55 (m, 2H),
2.29-2.22 (m, 1H); 13C NMR δ 175.4, 137.3, 133.6, 133.0, 131.4,
130.0, 129.0, 128.0, 126.9, 126.0, 122.6, 62.1, 39.2, 33.8, 30.3,
(17) Katritzky, A. R.; Mehta, S.; He, H.-Y., Cui, X.-L. J . Org. Chem.
2000, 65, 4364.
(18) Walker, G. N.; Kempton, R. J . J . Org. Chem. 1971, 36, 1413.

1,4-Benzothiazepines and 1,4-Benzoxazepines
J . Org. Chem., Vol. 66, No. 16, 2001 5593
29.0. Anal. Calcd for C16H15NOS: C, 71.34; H, 5.61; N, 5.20.
Found: C, 71.02; H, 5.79; N, 5.23.
(d, J ) 8.2 Hz, 1H), 7.48 (d, J ) 7.8 Hz, 1H), 7.08 (d, J ) 7.6
Hz, 1H), 6.72 (s, 1H), 6.21 (s, 1H), 4.06-3.90 (m, 2H), 3.17-
3.10 (m, 1H), 3.07-2.98 (m, 1H), 2.23 (s, 3H); 13C NMR δ 168.7,
143.3, 138.9, 138.7, 134.0, 132.7, 132.3, 131.5, 129.5, 128.6,
128.2, 124.2, 124.1, 63.6, 42.5, 32.6, 21.2. Anal. Calcd for
Gen er a l P r oced u r e for th e P r ep a r a tion of 3-(1H-1,2,3-
Ben zot r ia zol-1-yl)-2-[2-(a r ylsu lfa n yl)et h yl]-1-isoin d oli-
n on es 9a -f. 2-Formylbenzoic acid (8, 2.65 g, 18 mmol), a
2-(arylsulfanyl)-1-ethanamine 3a -f (18 mmol), benzotriazole
(4, 2.38 g, 20 mmol), and p-toluenesulfonic acid monohydrate
(0.36 g, 2 mmol) were dissolved in toluene (50 mL) and heated
under reflux using a Dean Stark apparatus. After 24 h, the
reaction mixture was cooled. The solvent was evaporated, and
CH2Cl2 was added to dissolve the residue. Then the solution
was washed with 2 M NaOH three times. The organic phase
was washed with brine and dried over anhydrous Na2SO4.
After removal of solvent in vacuo, the residue was purified by
column chromatography (hexanes/EtOAc ) 6/1-3/1) to give
9a -f.
C
17H15NOS: C, 72.57; H, 5.37; N, 4.98. Found: C, 72.19; H,
5.64; N, 4.90.
8,9-Dih yd r on a p h t h o[1′,2′:6,7][1,4]t h ia ze p in o[5,4-a ]-
isoin d ol-11(15bH)-on e (10e): colorless plates (from CH2Cl2/
hexanes); mp 230 °C (decomposed); yield, 78%; 1H NMR δ 8.39
(d, J ) 8.5 Hz, 1H), 7.95 (d, J ) 7.6 Hz, 1H), 7.92 (d, J ) 8.5
Hz, 1H), 7.73 (d, J ) 8.5 Hz, 1H), 7.69 (d, J ) 8.6 Hz, 1H),
7.60 (t, J ) 7.3 Hz, 1H), 7.49 (d, J ) 8.4 Hz, 1H), 7.44 (d, J )
7.3 Hz, 1H), 7.35 (t, J ) 7.3 Hz, 1H), 7.18 (d, J ) 7.6 Hz, 1H),
6.80 (s, 1H), 4.55-4.48 (m, 1H), 3.45-3.20 (m, 3H); 13C NMR
δ 169.6, 144.3, 134.3, 134.0, 132.3, 132.2, 131.7, 129.3, 128.9,
128.8, 128.5, 127.3, 126.4, 125.7, 123.7, 123.2, 122.5, 63.6, 39.1,
31.7. Anal. Calcd for C20H15NOS: C, 75.68; H, 4.76; N, 4.41.
Found: C, 75.62; H, 4.80; N, 4.37.
3-(1H -1,2,3-Ben zot r ia zol-1-yl)-2-[2-(p h en ylsu lfa n yl)-
eth yl]-1-isoin d olin on e (9a ): yellow needles (from CH2Cl2/
1
Et2O); mp 100-101 °C; yield, 84%; H NMR δ 8.06-8.01 (m,
2H), 7.65 (t, J ) 7.3 Hz, 1H), 7.56 (t, J ) 7.8 Hz, 1H), 7.52 (s,
1H), 7.37-7.16 (m, 7H), 7.08 (t, J ) 7.0 Hz, 1H), 6.45 (d, J )
8.2 Hz, 1H), 3.95-3.86 (m, 1H), 3.23-3.10 (m, 2H), 2.94-2.85
(m, 1H); 13C NMR δ 166.8, 146.6, 138.7, 134.2, 132.7, 131.2,
130.5, 130.2, 128.8, 128.6, 127.9, 126.0, 124.3, 123.7, 123.2,
120.0, 109.6, 72.6, 39.5, 30.9. Anal. Calcd for C22H18N4OS: C,
68.37; H, 4.69; N, 14.50. Found: C, 68.05; H, 4.72; N, 14.49.
Gen er a l P r oced u r e for th e Syn th esis of 6,7-Dih y-
dr oisoin dolo[2,1-d][1,4]ben zoth iazepin -9(13bH)-on es 10a-
f. To a solution of 9a -f (1.5 mmol) in CH2Cl2 (15 mL) was
added TiCl4 (3.0 mmol, 1.7 mL, 1.71 M in CH2Cl2), and the
reaction mixture was stirred at room temperature for 48 h.
The yellow solution was quenched with water and washed
twice with 2 M NaOH and brine. The organic phase was dried
over Na2SO4, and the solvent was removed in vacuo. The
residue was purified by column chromatography (hexanes/
EtOAc ) 3/1) to give the product 10a ,b,e. In case of 10c,d ,f,
solids, formed after evaporation, were pure enough for NMR
analysis. These substances were additionally recrystallized for
microanalysis purposes.
1,4-Dim et h yl-6,7-d ih yd r oisoin d olo[2,1-d ][1,4]b en zo-
th ia zep in -9(13bH)-on e (10f): colorless plates (from CH2Cl2/
1
hexanes); mp 179-180 °C; yield, 81%; H NMR δ 7.94-7.91
(m, 1H), 7.49-7.43 (m, 2H), 7.21-7.12 (m, 3H), 6.16 (s, 1H),
4.46-4.39 (m, 1H), 3.36-3.10 (m, 2H), 2.98-2.92 (m, 1H), 2.64
(s, 3H), 2.38 (s, 3H); 13C NMR δ 170.1, 144.4, 141.4, 137.0,
134.5, 132.6, 131.6, 131.6, 131.3, 130.2, 128.1, 123.5, 122.1,
64.1, 39.2, 31.2, 21.7, 21.3. Anal. Calcd for C18H17NOS: C,
73.19; H, 5.80; N, 4.74. Found: C, 73.14; H, 5.62; N, 4.74.
P r oced u r e for th e P r ep a r a tion of 5-(1H-1,2,3-Ben zo-
tr ia zol-1-yl)-1-(2-p h en oxyeth yl)-2-p yr r olid in on e (12) a n d
1,5,6,11b -Tet r a h yd r op yr r olo[1,2-d ][1,4]b en zoxa zep in -
3(2H)-on e (13). 2,5-Dimethoxy-2,5-dihydrofuran (5, 0.72 g, 5.5
mmol), 2-phenoxyethylamine (11, 0.55 g, 4 mmol), and ben-
zotriazole (4, 1.19 g, 10 mmol) were dissolved in acetic acid
(30 mL). The mixture was kept at 60-75 °C for 72 h. The same
workup procedure as for the preparation of 6 afforded 12 as
brown oil.
To a solution of compound 12 (0.41 g, 2 mmol) in CH2Cl2
(20 mL) was added TiCl4 (8 mmol, 4.7 mL, 1.71 M), and the
reaction mixture was stirred for 72 h at room temperature.
Then the mixture was washed with 2 M NaOH and brine. The
organic fractions were dried over Na2SO4. The solvent was
removed in vacuo. Then the residue obtained was purified by
column chromatography (hexanes/EtOAc ) 1/1-1/2) to give
13.
6,7-Dih ydr oisoin dolo[2,1-d][1,4]ben zoth iazepin -9(13bH)-
on e (10a ): colorless plates (from CH2Cl2/hexanes); mp 147-
1
148 °C; yield, 86%, H NMR δ 7.93 (d, J ) 7.2 Hz, 1H), 7.67-
7.61 (m, 2H), 7.56 (t, J ) 7.3 Hz, 1H), 7.46 (d, J ) 7.5 Hz,
1H), 7.30-7.17 (m, 2H), 6.92 (d, J ) 7.5 Hz, 1H), 6.21 (s, 1H),
4.15-3.88 (m, 2H), 3.20-2.95 (m, 2H); 13C NMR δ 168.7, 143.3,
139.1, 136.0, 134.0, 132.7, 131.4, 128.7, 128.6, 128.5, 127.4,
124.3, 124.1, 63.5, 42.6, 32.6. Anal. Calcd for C16H13NOS: C,
71.88; H, 4.90; N, 5.24. Found: C, 71.76; H, 4.89; N, 5.20.
4-M e t h y l-6,7-d i h y d r o i s o i n d o lo [2,1-d ][1,4]b e n z o -
th ia zep in -9(13bH)-on e (10b): brown prisms (from CH2Cl2);
5-(1H-1,2,3-Ben zotr iazol-1-yl)-1-(2-ph en oxyeth yl)-2-pyr -
1
r olid in on e (12): brown oil; yield, 50%; H NMR δ 8.10 (d, J
) 8.5 Hz, 1H), 7.57-7.49 (m, 2H), 7.41 (t, J ) 7.9 Hz, 1H),
7.30-7.25 (m, 2H), 6.99-6.94 (t, J ) 7.3 Hz, 1H), 6.83-6.78
(m, 3H), 4.16-4.07 (m, 1H), 4.00-3.90 (m, 2H), 3.08-2.96 (m,
2H), 2.87-2.74 (m, 1H), 2.69-2.60 (m, 1H), 2.54-2.46 (m, 1H);
13C NMR δ 174.7, 157.9, 146.1, 131.9, 129.4, 128.1, 124.3,
121.2, 120.3, 114.1, 109.0, 73.0, 66.2, 40.0, 29.0, 25.7. Anal.
Calcd for C18H18N4O2: C, 67.07; H, 5.63; N, 17.38. Found: C,
66.62; H, 5.57; N, 17.34.
1
mp 116-118 °C; yield, 91%; H NMR δ 7.92 (d, J ) 7.6 Hz,
1H), 7.61 (t, J ) 7.3 Hz, 1H), 7.53 (t, J ) 7.3 Hz, 1H), 7.43 (d,
J ) 7.3 Hz, 1H), 7.20 (d, J ) 8.6 Hz, 1H), 7.06 (t, J ) 8.6 Hz,
1H), 6.71 (d, J ) 7.6 Hz, 1H), 6.30 (s, 1H), 3.95-3.93 (m, 2H),
3.19-3.11 (m, 1H), 3.01-2.95 (m, 1H), 2.53 (s, 3H); 13C NMR
δ 168.5, 143.8, 141.2, 139.5, 135.7, 132.6, 131.3, 130.3, 128.4,
127.7, 125.1, 124.2, 123.9, 63.6, 42.0, 32.4, 21.9. Anal. Calcd
for C17H15NOS: C, 72.57; H, 5.37; N, 4.98. Found: C, 72.65;
H, 5.44; N, 4.97.
1,5,6,11b-Tetr a h yd r op yr r olo[1,2-d ][1,4]ben zoxa zep in -
1
3(2H)-on e (13): brown oil; yield, 72%; H NMR δ 7.27-7.23
(m, 2H), 7.13-7.05 (m, 2H), 4.94-4.88 (m, 1H), 4.35-4.27 (m,
2H), 3.85-3.76 (m, 1H), 3.40-3.37 (m, 1H), 2.57-2.38 (m, 4H);
13C NMR δ 173.9, 159.0, 131.9, 129.2, 126.0, 124.0, 122.3, 70.9,
59.1, 43.4, 29.9, 24.0. Anal. Calcd for C12H13NO2: C, 70.92; H,
6.45; N, 6.89. Found: C, 70.68; H, 6.65; N, 6.87.
2-Ch lor o-6,7-d ih yd r oisoin d olo[2,1-d ][1,4]b e n zot h i-
a zep in -9(13bH)-on e (10c): colorless needles (from CH2Cl2/
1
Et2O); mp 154-155 °C; yield, 94%, H NMR δ 7.95 (d, J ) 7.3
Hz, 1H), 7.68 (t, J ) 7.3 Hz, 1H), 7.62-7.56 (m, 2H), 7.48 (d,
J ) 7.3 Hz, 1H), 7.25 (dd, J ) 8.2, 2.3 Hz, 1H), 6.89 (d, J )
2.0 Hz, 1H), 6.16 (s, 1H), 4.12 (ddd, J ) 14.3, 6.4, 2.9 Hz, 1H),
3.93 (ddd, J ) 14.0, 8.7, 2.9 Hz, 1H), 3.16 (ddd, J ) 13.4, 6.4,
2.9 Hz, 1H), 3.02 (ddd, J ) 13.0, 8.7, 2.9 Hz, 1H); 13C NMR δ
168.7, 142.6, 141.1, 135.2, 134.6, 134.5, 132.6, 131.9, 129.0,
128.8, 127.7, 124.3, 124.2, 63.2, 42.9, 32.7. Anal. Calcd for
P r oced u r e for th e P r ep a r a tion of 3-(1H-1,2,3-Ben zo-
tr ia zol-1-yl)-2-(2-p h en oxyeth yl)-1-isoin d olin on e (14) a n d
6,7-Dih yd r oisoin d olo[2,1-d ][1,4]b en zoxa zep in -9(13bH )-
on es (15). 2-Formylbenzoic acid (8, 3.0 g, 20 mmol), 2-phen-
oxy-1-ethanamine (11, 2.74 g, 20 mmol), benzotriazole (4, 3.6
g, 30 mmol), and p-toluenesulfonic acid monohydrate (0.36 g,
2 mmol) were dissolved in toluene (60 mL) and heated under
refluxing using a Dean Stark apparatus. After 24 h, the
reaction mixture was cooled. The white solid was filtered off
and washed with toluene three times to give crude 14, which
was used for the subsequent cyclization without further
purification. The sample for microanalysis was purified by
column chromatography (hexanes/EtOAc ) 6/1-2/1).
C
16H12ClNOS: C, 63.68; H, 4.01; N, 4.64. Found: C, 63.60; H,
4.09; N, 4.88.
2-Me t h yl-6,7-d ih yd r oisoin d olo[2,1-d ][1,4]b e n zot h i-
a zep in -9(13bH)-on e (10d ): colorless needles (from CH2Cl2/
Et2O); mp 162-163 °C; yield, 96%; 1H NMR δ 7.95 (d, J ) 7.3
Hz, 1H), 7.65 (t, J ) 7.3 Hz, 1H), 7.57 (t, J ) 7.3 Hz, 1H), 7.51

5594 J . Org. Chem., Vol. 66, No. 16, 2001
Katritzky et al.
To a solution of 3-(1H-1,2,3-benzotriazol-1-yl)-2-(2-phenoxy-
ethyl)-1-isoindolinone (14, 0.37 g, 1.0 mmol) in CH2Cl2 (15 mL)
was added TiCl4 (2.0 mmol, 1.2 mL, 1.71 M in CH2Cl2), and
the mixture was stirred at room temperature for 48 h. The
solution was washed with 2 M NaOH twice and brine and
dried over Na2SO4. After removal of solvents in vacuo, the
residue was the pure product (1H and 13C NMR spectra). The
sample for elemental analysis was additional purified by
column chromatography (hexanes/EtOAc ) 6/1-3/1).
123.5, 121.1, 120.4, 114.3, 109.9, 73.7, 65.7, 39.9. Anal. Calcd
for C22H18N4O2: N, 15.13. Found: N, 14.85.
6,7-Dih yd r oisoin dolo[2,1-d][1,4]ben zoxa zep in -9(13bH)-
on e (15): colorless needles (from EtOAc/hexanes); yield, 89%;
1
mp 145-146 °C; H NMR δ 7.94 (d, J ) 7.6 Hz, 1H), 7.69-
7.54 (m, 3H), 7.29 (t, J ) 7.6 Hz, 1H), 7.16-7.10 (m, 2H), 7.02
(t, J ) 7.6 Hz, 1H), 5.83 (s, 1H), 4.60-4.49 (m, 2H), 3.94-3.85
(m, 1H), 3.76-3.66 (m, 1H); 13C NMR δ 168.1, 159.8, 142.2,
132.7, 131.1, 129.9, 129.8, 128.7, 127.0, 124.8, 124.5, 124.2,
122.1, 71.8, 61.6, 44.3. Anal. Calcd for C16H13NO2: C, 76.48;
H, 5.21; N, 5.57. Found: C, 76.25; H, 5.20; N, 5.55.
3-(1H -1,2,3-Ben zot r ia zol-1-yl)-2-(2-p h en oxyet h yl)-1-
isoin d olin on e (14). Colorless plates (from CH2Cl2); mp 148-
1
149 °C; yield, 76%; H NMR δ 8.08 (d, J ) 8.5 Hz, 1H), 8.05
(d, J ) 7.3 Hz, 1H), 7.70 (s, 1H), 7.66 (t, J ) 7.3 Hz, 1H), 7.58
(t, J ) 7.3 Hz, 1H), 7.34-7.18 (m, 5H), 6.91 (t, J ) 7.3 Hz,
1H), 6.75 (d, J ) 8.2 Hz, 2H), 6.53 (d, J ) 8.5 Hz, 1H), 4.17-
4.07 (m, 3H), 3.38-3.30 (m, 1H); 13C NMR δ 167.4, 158.0,
147.0, 139.6, 133.0, 131.6, 130.8, 129.3 (2), 128.1, 124.5, 124.1,
Su p p or tin g In for m a tion Ava ila ble: Characterization
data for compounds 6b-e and 9b-f. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O010179B