Preparation of benzothieno[2,3-f]-1,4-oxazepin- and -thiazepin-5(2H)-ones and of benzothieno[3,2-e]-1,4-diazepin-5-ones

Full text of DOI:10.1021/jo960235m

6
060
J . Org. Chem. 1996, 61, 6060-6062
P r ep a r a tion of
Ben zoth ien o[2,3-f]-1,4-oxa zep in - a n d
th ia zep in -5(2H)-on es a n d of
Ben zoth ien o[3,2-e]-1,4-d ia zep in -5-on es
Sch em e 1
-
†
,†
Sonya S. Khatana, Diane H. Boschelli,*
†
†
J ames B. Kramer, David T. Connor,
‡
‡
Hubert Barth, and Peter Stoss
Department of Medicinal Chemistry, Parke-Davis
Pharmaceutical Research, Division of Warner-Lambert,
Ann Arbor, Michigan 48105, and Department of Chemical
Development, Godecke Laboratories, Freiburg, Germany
Received February 5, 1996
The antiinflammatory agent PD 144795, 1a , reduces
the expression of adhesion molecules on the surface of
activated endothelial cells.1 This property is shared by
additional benzo[b]thiophene-2-carboxamides of structure
A, including 1b, 1c, and 1d . We were interested in
preparing the novel tricyclic derivatives of A, namely B,
that contain a seven-membered ring.3
,2
the oxazepine 8. The thiazepine analog, 10, was readily
2
obtained by reaction of 9 with cysteamine-HCl and 1,8-
4
diazabicyclo[5.4.0]undec-7-ene. As in the preparation of
Treatment of readily available 2 with Raney cobalt
3
, the intermediate amine was not isolated. Since
and hydrogen under elevated pressure yielded the ox-
azepine 3 directly (Scheme 1). Due to ether cleavage
occurring under these conditions varying amounts of 4
were also obtained. Reduction of 2 with other hydrogen-
ation catalysts including 10% rhodium and 2% Pd/C gave
displacement of the 3-chloro group of 9 does not occur
with amines unless the benzo[b]thiophene sulfur is first
6
oxidized to the corresponding sulfone or sulfoxide,
a
different route was required to prepare the diazepine
analog of 3.
exclusively 4. Compound 6 was prepared by reaction of
5
The reaction of 2-(4,5-dihydro-1H-imidazol-2-yl)ben-
zenethiol, 11, with 2-bromo-4′-chloroacetophenone was
reported to provide the hydrobromide salt of the ben-
zothieno-1,4-diazepine 12.7 By analogy, reaction of 11
with methyl chloroacetate followed by treatment with
base could be expected to yield the desired benzothieno-
5
with chloroacetonitrile in the presence of potassium
tert-butoxide. After unsuccessful attempts to cyclize 6
to 8 by the Raney cobalt method, we employed a two-
step protocol. The nitrile group of 6 was reduced with
borane-methyl sulfide to the corresponding amine 7,
which upon treatment with sodium methoxide provided
1
,4-diazepine-5-one, 13. However, a 1975 paper claimed
†
that this reaction provided not 13 but the isomeric
imidazo-1,4-benzothiazepin-5(6H)-one, 15, via intermedi-
ate 14.8 A patent by these same workers also claimed
that reaction of 11 with 2,4′-dichloroacetophenone fol-
lowed by treatment with sodium methoxide provided 16,
an isomer of 12.9
Parke-Davis Pharmaceutical Research.
Godecke Laboratories.
‡
(
1) Boschelli, D. H.; Kramer, J . B.; Connor, D. T.; Lesch, M. E.;
Schrier, D. J .; Ferin, M. A.; Wright, C. D. J . Med. Chem. 1994, 37,
17.
2) Boschelli, D. H.; Kramer, J . B.; Khatana, S. S.; Sorenson, R. J .;
Connor, D. T.; Ferin, M. A.; Wright, C. D.; Lesch, M. E.; Imre, K.;
Okonkwo, G. C.; Schrier, D. J .; Conroy, M. C.; Ferguson, E.; Woelle,
J .; Saxena, U. J . Med. Chem. 1995, 38, 4597.
7
(
In our hands, reaction of 11 with methyl chloroacetate
and subsequent treatment with sodium methoxide pro-
(
3) A search of Chemical Abstracts and Beilstein did not find any
examples of the desired ring system except for 7,12-dihydro-6H-[1]-
benzothieno[3,2-b][1,5]benzo-diazepin-6-one 5,5-dioxide which contains
an aromatic ring fused to the seven-membered ring: Chem.-Ztg. 1983,
(6) Kramer, J . B.; Connor, D. T.; Boschelli, D. H. National Organic
Symposium, Willamsburg, Virginia, 1995.
1
07, 369.
(
(
4) Beck, J . R. J . Heterocycl. Chem. 1975, 12, 1037.
5) Connor, D. T.; Cetenko, W. A.; Mullican, M. D.; Sorenson, R. J .;
(7) den Hartog, J . A. J .; van Stuivenberg, H. H.; van Wijngaarden,
I. US Patent 5,140,024, 1993; Chem Abstr., 1990, 113, 191405v.
(8) Hagen, H.; Fleig, H. Liebigs Ann. Chem. 1975, 1994.
(9) Hagen, H.; Amann, A.; Giertz, H. US Patent 3,882,141, 1975;
Chem Abstr. 1974, 80, 14970e.
Unangst, P. C.; Weikert, R. J .; Adolphson, R. L.; Kennedy, J . A.;
Thueson, D. O.; Wright, C. D.; Conroy, M. C. J . Med. Chem. 1992, 35,
58.
9
S0022-3263(96)00235-6 CCC: $12.00 © 1996 American Chemical Society

Notes
J . Org. Chem., Vol. 61, No. 17, 1996 6061
Sch em e 2
vided material with a melting point, combustion analysis,
and mass spectrum corresponding to that reported for
Exp er im en ta l Section
Melting points are uncorrected. Elemental analyses were
performed by the Parke-Davis Analytical Chemistry staff. Reac-
tions were run under an atmosphere of nitrogen or argon unless
otherwise noted. Flash chromatography was performed with E.
Merck silica gel 60, 230-400 mesh. The THF, DMSO, and DMF
used were Sure-Seal solvents purchased from Aldrich Chemical
Co.
1
5. However, the NMR spectrum of the product was not
consistent with this structure (Scheme 2). Instead of a
signal for the two methylene protons the NMR showed
the presence of two exchangeable protons, suggesting
that the product was the benzothiophene derivative 13.
Our attempts to isolate the product of the acylation of
3
,4-Dih yd r o[1]b en zot h ien o[2,3-f]-1,4-oxa zep in -5(2H )-
1
1 with methyl chloroacetate gave traces of 14, but the
on e (3). A mixture of methyl 3-(cyanomethoxy)benzo[b]-
NMR spectrum of the major product showed three
exchangeable protons. The mass spectrum and combus-
tion analysis implied that this material was isomeric to
4
thiophene-2-carboxylate, 2 (405 mg, 1.64 mmol), and 0.5 mL of
Et
1
3
N was treated with 0.5 g of Raney cobalt in 50 mL of THF at
00 °C and 1200 psi of hydrogen. After 14 h the reaction mixture
was concentrated in vacuo. Column chromatography eluting
1
4. All attempts at purification of 14 resulted in conver-
with a gradient of 1:1 hexane/ethyl acetate to all ethyl acetate
1
provided 199 mg (55%) of 3: mp 244-245 °C; H NMR (DMSO-
d ) δ 3.54 (m, 2H), 4.56 (m, 2H), 7.41 (t, J ) 7 Hz, 1H), 7.51 (t,
6
J ) 7 Hz, 1H), 7.76 (d, J ) 8 Hz, 1H), 7.88 (d, J ) 8 Hz, 1H),
.37 (m, 1H-NH); MS(CI) (m + 1)/z 220. Anal. Calcd for C11
NO S: C, 60.26; H, 4.14; N, 6.39. Found: C, 60.00; H, 4.13; N,
.43.
8
9
H -
2
6
Meth yl 3-(Cyan om eth oxy)-5-m eth oxyben zo[b]th ioph en e-
2
-ca r boxyla te (6). To a solution of 5 5 (2.0 g, 8.4 mmol) in 35
sion to the isomeric material that was assigned the
benzothiophene structure 17. Treatment of 17 with
sodium methoxide provided 13. As additional confirma-
tion, we repeated the reaction of 11 with 2-bromo-4′-
chloroacetophenone. The NMR spectrum of the isolated
material confirmed the product to be the hydrobromide
salt of 12, not 16. Treatment of this salt with sodium
methoxide provided a solid with spectral and analytical
data consistent with 12.
mL of DMSO at room temperature was added potassium tert-
butoxide (990 mg, 8.8 mmol). The mixture was stirred for 15
min, and chloroacetonitrile (1.6 mL, 25.2 mmol) was added. The
reaction was stirred at 40 °C for 1.5 h and then partitioned
between ethyl acetate and 0.5 N HCl. The organic phase was
washed three times with water and once with brine, dried over
MgSO , filtered, and concentrated in vacuo to provide a yellow-
4
brown solid. The residue was crystallized from methanol/water
to give 1.9 g (82%) of 6. Recrystallization from ethyl acetate/
hexane provided an analytical sample of 6: mp 159.5-160.0 °C;
1
6
H NMR (DMSO-d ) δ 3.86 (s, 3H), 3.88 (s, 3H), 5.33 (s, 2H),
As reported, we obtained the expected 18 in the
reaction of 11 with methyl 2-bromopropionate and base,
7
.26 (dd, J ) 9, 2.5 Hz, 1H), 7.36 (d, J ) 2.5 Hz, 1H), 7.93 (d, J
9 Hz, 1H); MS(CI) (m + 1)/z 278; Anal. Calcd for C13
NO S: C, 56.31; H, 4.00; N, 5.05. Found: C, 56.26; H, 3.94; N,
5.18.
)
11
H -
since in this case the R-methyl group prevents rearrange-
4
ment.8 An alternative route to 18 by treatment of 11
with 2-chloropropionyl chloride has also been published.10
3,4-Dih ydr o-9-m eth oxy[1]ben zoth ien o[2,3-f]-1,4-oxazepin -
(2H)-on e (8). A solution of 6 (2.5 g, 9.0 mmol) in 50 mL of
5
We modified this reaction and reacted 11 with bro-
moacetyl bromide, followed by base, and obtained an
authentic sample of 15, as confirmed by NMR, MS, and
analytical data.
THF was heated to reflux. Borane-methyl sulfide (9.0 mL, 90.2
mmol) was rapidly added and heating continued for 25 min with
THF being added as it evaporated. An additional amount of
borane-methyl sulfide (4.0 mL) was added and heating contin-
ued for 10 min. The reaction mixture was cooled to 0 °C, and
Although 11 was first prepared in 1929, via reaction
5
0 mL of 6 N HCl was carefully added, maintaining the
temperature of the reaction mixture below 40 °C. A solution of
N NaOH (451 mL) was added, and the resultant precipitate
of 4,5-benzo-1,2-dithiole-2-thione with 1,2-ethylenedi-
amine,11 there are only limited reports in the literature
1
utilizing this versatile compound. We are therefore
continuing to investigate the usefulness of 11 in the
preparation of additional novel heterocyclic systems.
was collected by filtration, washed with water, and dried in
vacuo to give 2.3 g of 7.
The solid (7) (2.3 g, 8.2 mmol) was added to a freshly prepared
solution of sodium methoxide (from 1.9 g, 82.0 mmol of sodium)
in 40 mL of MeOH. The reaction mixture was warmed to 50 °C
for 2 h and then heated at reflux for 2 h. After the mixture was
cooled to 0 °C, the precipitate was collected and washed with
(
(
10) Ried, W; Von der Eltz, A. Liebigs Ann. Chem. 1988, 599.
11) McClelland, E. W.; Warren, L. A.; J ackson, J . H. J . Chem. Soc.
1
929, 1582.

6
062 J . Org. Chem., Vol. 61, No. 17, 1996
Notes
cold MeOH followed by cold diethyl ether. Drying the solid in
vacuo overnight gave 1.2 g (52%) of 8. An analytical sample of
heated at reflux for 2.5 h and then cooled to room temperature
and allowed to stand overnight. The precipitated salt was
collected by filtration to provide 150 mg of the HBr salt of 12 as
an orange-yellow solid. Concentration of the filtrate provided
an additional 142 mg (66% total) of the HBr salt: mp 316-318
8
was obtained by recrystallization from ethyl acetate/hexane:
1
mp 264-265 °C; H NMR (DMSO-d
6
) δ 3.51-3.58 (m, 2H), 3.82
(
7
4
s, 3H), 4.55 (t, J ) 3.5 Hz, 2H), 7.13 (dd, J ) 8.5, 2.5 Hz, 1H),
7
1
.18 (d, J ) 2.5 Hz, 1H), 7.76 (d, J ) 8.5 Hz, 1H), 8.32 (t, J )
.5 Hz, 1H-NH); MS(CI) (m + 1)/z 250. Anal. Calcd for C12
S: C, 57.82; H, 4.45; N, 5.62. Found: C, 57.42; H, 4.25; N,
.37.
,4-Dih ydr o-9-m eth oxy[1]ben zoth ien o[2,3-f]-1,4-th iazepin -
(2H)-on e (10). To a solution of methyl 3-chloro-5-methoxy-
°C (lit. mp 317-318 °C); H NMR (DMSO-d
) δ 3.78-4.08 (br
6
H
11
-
s, 4H), 7.53 (t, J ) 8 Hz, 1H), 7.66 (t, J ) 8 Hz, 1H), 7.73 (d, J
) 8.5 Hz, 2H), 7.80 (d, J ) 8.5 Hz, 2H), 7.87 (d, J ) 8 Hz, 1H),
8.35 (d, J ) 8 Hz, 1H), 10.14 (br s, 1H), 11.16 (br s, 1H); MS(CI)
(m + 1)/z 313.
NO
5
3
3
5
5-(4-Ch lor op h en yl)-2,3-d ih yd r o-1H-[1]ben zoth ien o[3,2-
e]-1,4-d ia zep in e (12). A solution of the hydrobromide salt of
12 (50 mg, 0.13 mmol) and 130 µL of 1 M sodium methoxide in
10 mL of MeOH was heated at reflux for 1 h. The reaction
mixture was cooled to room temperature, and the solvent was
removed in vacuo to provide a yellow oil. Ethyl acetate and
hexane were added, and the mixture was filtered. The filtrate
was concentrated in vacuo to give 18 mg (45%) of 12 as a bright
2
benzo[b]thiophene-2-carboxylate, 9 (500 mg, 1.95 mmol), in 20
mL of DMF at room temperature was added cysteamine-HCl
(885 mg, 7.79 mmol) followed by 1,8-diazabicyclo[5.4.0]undec-
7
-ene (2.33 mL, 15.58 mmol). The reaction mixture was stirred
at room temperature for 1.5 h and then warmed to 70 °C. The
mixture was diluted with ethyl acetate and washed with aqueous
HCl, water, and brine. The organic layer was dried over MgSO ,
4
filtered, and concentrated in vacuo. Recrystallization from
yellow solid: mp 180-182 °C (lit.
9
mp 191 °C); H NMR (DMSO-
1
hexane/ethyl acetate provided 380 mg (74%) of 10: mp 209-
d6) δ 3.51 (br s, 2H), 4.07 (br s, 2H), 7.37-7.44 (m, 2H), 7.46 (d,
J ) 8.5 Hz, 2H), 7.61 (d, J ) 8.5 Hz, 2H + obscured 1H-NH),
7.73 (d, J ) 8 Hz, 1H), 7.98 (d, J ) 8 Hz, 1H); MS(CI) (m + 1)/z
1
2
(
(
09.5 °C; H NMR (DMSO-d
6
) δ 3.39-3.43 (m, 2H), 3.61-3.67
m, 2H), 3.84 (s, 3H), 7.16-7.20 (m, 2H), 7.88-7.92 (m, 1H), 8.49
t, J ) 5.5 Hz, 1H-NH); MS(EI) m/z 265. Anal. Calcd for
313; Anal. Calcd for C17
Found: C, 64.87; H, 4.39; N, 8.84.
,3-Dih yd r oim id a zo[1,2-d ][1,4]b en zot h ia zep in -5(6H )-
13 2
H N S: C, 65.27; H, 4.19; N, 8.96.
12 2 2
C H11NO S : C, 54.32; H, 4.18; N, 5.28. Found: C, 54.01; H,
3
.96; N, 5.14.
Meth yl 3-[(2-Am in oeth yl)a m in o]ben zo[b]th iop h en e-2-
ca r boxyla te Hyd r och lor id e (17). A solution of 2-(4,5-dihydro-
H-imidazol-2-yl)benzenethiol, 118 (1.00 g, 5.62 mmol), and
2
on e (15). A solution of 11 (300 mg, 1.68 mmol) and bromoacetyl
bromide (373 mg, 1.85 mmol) in 5 mL of THF was heated at
reflux for 90 min. After the solution was cooled to room
temperature, the precipitated salt was dissolved in 4 mL of water
and made basic with 1 N NaOH. The solution was extracted
with several portions of ethyl acetate, and the organic layers
1
methyl chloroacetate (610 mg, 5.62 mmol) in 15 mL of MeOH
was heated at reflux for 90 min. The reaction was cooled to room
temperature and filtered. The filtrate was concentrated to
dryness and the residue dissolved in hot chloroform. After
several hours the resulting precipitate was collected and dried.
The mother liquor afforded a second crop of crystals, giving 17
4
were combined, dried over MgSO , and concentrated in vacuo.
The product was purified by chromatography, eluting with ethyl
1
acetate, to afford 117 mg (32%) of 15: mp 135-136 °C; H NMR
1
in an overall yield of 61%: mp 219-220 °C; H NMR (DMSO-
6
(DMSO-d ) δ 3.75 (s, 2H), 3.87 (d, J ) 9 Hz, 2H), 4.00 (d, J ) 9
d
2
7
6
) δ 3.11 (t, J ) 6.5 Hz, 2H), 3.81 (s, 3H), 3.90 (q, J ) 6.5 Hz,
Hz, 2H), 7.40-7.47 (m, 2H), 7.54 (d, J ) 7 Hz, 1H) 8.02 (d, J )
Hz, 1H); MS(CI) (m + 1)/z 219. Anal. Calcd for C11 OS:
C, 60.53; H, 4.62; N, 12.83. Found: C, 60.42; H, 4.61; N, 12.67.
,3-Dih yd r o-6-m eth ylim id a zo[1,2-d ][1,4]ben zoth ia zep in -
(6H)-on e (18). A solution of 11 (300 mg, 1.68 mmol) and
H), 7.40-7.44 (m, 2H, includes 1H-NH), 7.54 (t, J ) 8 Hz, 1H),
.90 (d, J ) 8 Hz, 1H), 8.13 (br s, 2H), 8.22 (d, J ) 8 Hz, 1H);
7
10 2
H N
MS(CI) (m + 1)/z 250. Anal. Calcd for C12
5
14 2 2
H N O S‚HCl: C,
2
0.26; H, 5.27; N, 9.77. Found: C, 50.16; H, 5.15; N, 9.49.
,2,3,4-Tetr ah ydr o-5H-[1]ben zoth ien o[3,2-e]-1,4-diazepin -
-on e (13). A solution of 17 (339 mg, 1.18 mmol) and freshly
5
1
methyl 2-bromopropionate (309 mg, 1.85 mmol) in 5 mL of
MeOH was heated at reflux for 3 h. The reaction was cooled to
room temperature, concentrated, and redissolved in 5 mL of
MeOH. A solution of sodium methoxide in MeOH (prepared
from 91 mg, 1.68 mmol, of sodium) was added, and the reaction
was heated at reflux for 90 min and then stirred at room
temperature for 18 h. The mixture was concentrated and
purified by chromatography, eluting with ethyl acetate, to give
5
prepared sodium methoxide (from 134 mg, 2.48 mmol, of sodium)
in 5 mL of MeOH was heated at reflux for 18 h. After the
mixture was cooled to room temperature, the reaction was
neutralized with 25 mL of 1 N HCl and cooled to 0 °C for 1 h.
The resulting yellow crystalline material was filtered and dried
under vacuum at 60 °C for several hours to provide 165 mg (64%)
of 13. Chromatography, eluting with a gradient of 2% methanol
in ethyl acetate to 5% methanol in ethyl acetate, gave an
8
,10
1
1
3
33 mg (34%) of 18 as a white solid: mp 110-112 °C (lit.
mp
) δ 1.34 (d, J ) 7 Hz, 3H), 3.79-
.97 (m, 4H), 4.06-4.13 (m, 1H), 7.40-7.48 (m, 2H), 7.54 (d, J
7.5 Hz, 1H), 8.08 (d, J ) 7.5 Hz, 1H); MS(CI) (m + 1)/z 233.
Anal. Calcd for C12 OS: C, 62.04; H, 5.21; N, 12.06.
1
15, 119 °C); H NMR (DMSO-d
6
1
analytically pure sample: mp 210-212 °C; H NMR (DMSO-
d
6
) δ 3.34-3.37 (m, 2H), 3.49-3.51 (m, 2H), 7.34 (t, J ) 7.5 Hz,
)
1
H), 7.42 (t, J ) 7.5 Hz, 1H), 7.49 (t, J ) 4 Hz, 1H-NH), 7.75
7.79 (m, 2H, includes 1H-NH), 7.93 (d, J ) 8 Hz, 1H); MS(CI)
m + 1)/z 219. Anal. Calcd for C11 OS: C, 60.53; H, 4.62;
N, 12.83. Found: C, 60.51; H, 4.71; N, 12.71.
-(4-Ch lor op h en yl)-2,3-d ih yd r o-1H-[1]ben zoth ien o[3,2-
e]-1,4-d ia zep in e Hyd r obr om id e (12-HBr ). A solution of 11
200 mg, 1.12 mmol) and 2-bromo-4′-chloroacetophenone (262
12 2
H N
-
(
Found: C, 62.00; H, 5.26; N, 11.96.
10 2
H N
5
Ack n ow led gm en t. We thank the Parke-Davis Ana-
lytical Chemistry Department for the spectral data and
combustion analyses and Don J ohnson and Norm Colbry
for performing the high-pressure reactions.
(
mg, 1.12 mmol) in 5 mL of 2-ethoxyethanol was heated at reflux.
After 30 min additional 2-ethoxyethanol (5 mL) was added to
dissolve the orange solid that formed. The reaction solution was
J O960235M