Derivatives of 2,3-dihydroimidazo[1,5,4-ef][1,2,5]benzothiadiazepin-6(4H,7H)-thione 1,1-dioxide, a new heterocyclic system related to TIBO

Article abstract of DOI:10.1002/jhet.5570390111

The synthesis of derivatives of 2,3-dihydroimidazo[1,5,4-ef][1,2,5]benzothiadiazepin-6(4H,7H)-thione 1,1-dioxide is reported starting from N-substituted ethyl 2-(5-chloro-2-nitrobenzenesulfonamido)-2-alkylacetates. Fundamental steps of the synthetic pathw

Full text of DOI:10.1002/jhet.5570390111

Jan-Feb 2002
Derivatives of 2,3-Dihydroimidazo[1,5,4-ef][1,2,5]-
benzothiadiazepin-6(4H,7H)-thione 1,1-Dioxide,
a New Heterocyclic System Related to TIBO
Roberta Costi, Roberto Di Santo and Marino Artico*
81
Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Studi Farmaceutici,
Università di Roma "La Sapienza", P.le Aldo Moro 5, I-00185 Roma, Italy
Silvio Massa
Dipartimento Farmaco Chimico Tecnologico, Università di Siena,
via Aldo Moro, San Miniato I-53100 Siena, Italy
Received May 5, 2001
The synthesis of derivatives of 2,3-dihydroimidazo[1,5,4-ef][1,2,5]benzothiadiazepin-6(4H,7H)-thione
1,1-dioxide is reported starting from N-substituted ethyl 2-(5-chloro-2-nitrobenzenesulfonamido)-2-alkyl-
acetates. Fundamental steps of the synthetic pathway were: i) intramolecular cyclization of N-substituted
2-(2-amino-5-chlorobenzenesulfonamido)-2-alkylacetic acids in the presence of N-(3-dimethyl-
aminopropyl)-N'-ethyl carbodiimide hydrochloride-N,N-dimethylaminopyridine complex; ii) building of
imidazole ring from 2-alkyl-8-chloro-2,3-dihydro-3-methyl-1,2,5-benzothiadiazepin-4(5H)-one 1,1-dioxide
to achieve 2-alkyl-9-chloro-2,3-dihydro-3-methylimidazo[1,5,4-ef][1,2,5]benzothiadiazepin-6(4H,7H)-one
1,1-dioxide; iii) preparation of thiocarbonyl derivative by treatment with Lawesson's reagent. Introduction of
a 3-methyl-2-butenyl chain at position 2 of above imidazobenzothiadiazepinone required protection at the 7
position with thermally removable tert-butoxycarbonyl moiety, due to the fact that alkylation of unprotected
structure proved to be regioselective for the 7 position.
J. Heterocyclic Chem., 39, 81 (2002).
Search for novel tricyclic heteroaromatic ring systems
tetrahydroimidazobenzodiazepinethiones (TIBO) (2)
[2-5] and pyrrolobenzothiadiazepines (PBTD) (3) [6] are
derivatives of dipyridodiazepine, imidazo[4,5,1-jk]-
[1,4]benzodiazepine and pyrrolo[1,2-c][1,2,5]-
benzothiadiazepine rings, respectively. As a common
feature, compounds 1-3 assume the "butterfly-like"
spatial arrangement [7], a peculiar determinant for the
biological activity.
have been deeply pursued after the discovery of potent
anti-HIV-1 reverse transcriptase (RT) agents having a
diazepine or benzodiazepine moiety annulated with other
heterocyclic rings, such as pyridine, imidazole and
®
pyrrole. Nevirapine (Viramune , 1) (Chart 1) [1],
4H-Imidazo[1,5,4-ef][1,2,5]benzothiadiazepine (4), a
new tricyclic ring system that shares chemical similarities
with both imidazo[4,5,1-jk][1,4]benzodiazepine and
pyrrolo[1,2-c][1,2,5]benzothiadiazepine, is a potential
biophore for the design of novel antiretroviral agents
useful for AIDS therapy.
Structure-activity relationship (SAR) studies on TIBO
derivatives have shown that the presence of alkyl/alkenyl
substituents at the position 2 of TIBO is a determinant for
their anti-HIV-1 activity. Therefore, introduction of
appropriate substituents at position 2 of the new TIBO-like
structure 4 is a forced step for the design of new
anti-HIV-1 agents. This reason pulsed us to synthesize
derivatives 5 and 6 as cyclic sulfone analogues of potent
antiretroviral TIBOs.
As a first approach we prepared 9-chloro-2,3-dihydro-3-
methylimidazo[1,5,4-ef][1,2,5]benzothiadiazepin-
6(4H,7H)-one 1,1-dioxide (10), a possible intermediate for
achieving 5 and 6 by alkylation of the 2 position with ethyl
iodide and 3-methyl-2-butenyl bromide, respectively.
For the synthesis of 10 we used 8-chloro-2,3-dihydro-3-
methyl-1,2,5-benzothiadiazepin-4(5H)-one 1,1-dioxide (7)
[8], which was nitrated with concentrated nitric acid to

82
R. Costi, R. Di Santo and M. Artico
Vol. 39
afford 8-chloro-2,3-dihydro-3-methyl-6-nitro-1,2,5-
benzothiadiazepin-4(5H)-one 1,1-dioxide (8). Reduction
of both carbonyl and nitro groups of 8 was accomplished
by treatment with lithium aluminum hydride. The diamine
9 which formed underwent cyclization with triphosgene
with formation of the required 9-chloro-2,3-dihydro-3-
methylimidazo[1,5,4-ef][1,2,5]benzothiadiazepin-
6(4H,7H)-one 1,1-dioxide (10) (Scheme 1). Treatment of
10 with Lawesson's reagent led to the corresponding thio-
carbonyl derivative 11.
was reacted with the equivalent amount of ethyl iodide in
the presence of anhydrous potassium carbonate, alkylation
occurred selectively at position 7 leaving position 2
unaffected and giving as the sole product derivative
12 (Scheme 2).
Failure of direct alkylation of 10 pulsed us to synthesize
5 by a different pathway as depicted in Scheme 3.
By this approach alkylation with ethyl iodide was per-
formed before ring closure, thus assuring introduction of
alkyl group only at position 2 of the tricyclic ring. As
expected, ethylation of ethyl 2-(5-chloro-2-nitrobenzene-
sulfonamido)-2-propanoate (13b) [8] or the related acetate
13a furnished ethyl 2-(5-chloro-N-ethyl-2-nitrobenzene-
sulfonamido)-2-alkylacetate derivatives 14, which were
reduced with iron powder in glacial acetic acid to amines
15. Alkaline hydrolysis of the last derivatives afforded
acids 16 which underwent intramolecular cyclization cat-
alyzed by N-(3-dimethylaminopropyl)-N'-ethyl carbodi-
imide hydrochloride-N,N-dimethylaminopyridine complex
to provide 17.
At this point we used compound 10 as an appropriate
material for introducing substituents at position 2 by
treatment with alkyl/alkenyl halides. However, when 10
Finally, transformation of benzothiadiazepinones 17 into
tricyclic derivatives 5 and 21 was performed via the corre-
sponding intermediates 18-20.
Unfortunately, preparation of 6 by this procedure failed
the goal (Scheme 4) because nitration of 25, obtained
starting from 13b through the intermediates 22-24, did not
take place in the same conditions employed for the
synthesis of 18. In fact, only unworkable mixtures were
obtained from nitration, probably as a consequence of
disruption of the allylic unsaturated side-chain.

Jan-Feb 2002
Derivatives of 2,3-Dihydroimidazo[1,5,4-ef][1,2,5]benzothiadiazepin
83
However, we were able to synthesize 6 by a
protection/deprotection procedure as depicted in
Scheme 5. 9-Chloro-2,3-dihydro-3-methylimidazo-
[1,5,4-ef][1,2,5]benzothiadiazepin-6(4H,7H)-one 1,1-
dioxide (10) was acylated at position 7 by treatment with
di-tert-butyldicarbonate in the presence of N,N-dimethyl-
aminopyridine.
7-Tert-butyloxycarbonyl-9-chloro-2,3-dihydro-3-
methylimidazo[1,5,4-ef][1,2,5]benzothiadiazepin-6-
(4H,7H)-one 1,1-dioxide (26) which formed was reacted
with 3-methyl-2-butenyl bromide to afford 7-tert-butyl-
oxycarbonyl-9-chloro-2,3-dihydro-3-methyl-2-(3-methyl-
2-butenyl)imidazo[1,5,4-ef][1,2,5]benzothiadiazepin-
6(4H,7H)-one 1,1-dioxide (27).

84
R. Costi, R. Di Santo and M. Artico
Vol. 39

Jan-Feb 2002
Derivatives of 2,3-Dihydroimidazo[1,5,4-ef][1,2,5]benzothiadiazepin
85
thin layer chromatography. Elemental analyses were performed
by Dr. M. Zancato, Dipartimento di Scienze Farmaceutiche,
Università degli Studi di Padova, Italy and were found within ±
0.4 of the theoretical values. Organic extracts were dried over
anhydrous sodium sulfate. Evaporation of solvents after reactions
and extractions involved the use of a rotatory evaporator (Büchi)
operating at reduced pressure (approximately 20 bar).
Thermal decomposition of 27 gave the 7-deacyl derivative
28, which was then treated with Lawesson's reagent to
achieve the desired 9-chloro-2,3-dihydro-3-methyl-2-(3-
methyl-2-butenyl)imidazo[1,5,4-ef][1,2,5]benzothiadia
zepin-6(4H,7H)-thione 1,1-dioxide (6). This procedure was
also useful for the synthesis of 5 starting from 26 (Scheme 6).
Ethylation of this compound followed by thermal treatment
of the intermediate 7-tert-butyloxycarbonyl-9-chloro-2,3-
dihydro-3-methyl-2-ethylimidazo[1,5,4-ef][1,2,5]benzothia-
diazepin-6(4H,7H)-one 1,1-dioxide (29) furnished
compound 20b, the precursor of 5.
In conclusion, we have therein described a profitable
procedure for obtaining derivatives of 4, a novel tricyclic
ring system useful as lead structure for the design of novel
non-nucleoside reverse transcriptase (NNRT) agents of
therapeutic interest. Furthermore, we have also remarked
that alkylation of 9-chloro-2,3-dihydro-3-methyl-
imidazo[1,5,4-ef][1,2,5]benzothiadiazepin-6(4H,7H)-one
1,1-dioxide (10) with the equivalent amount of alkylating
agent gave only 7-substituted derivatives, e.g. compound
12, without formation of the related 2-mono substituted
isomers. Similarly, acylation of 10 was regioselective for
the 7 position with formation of 26 as the sole product.
8-Chloro-2,3-dihydro-3-methyl-6-nitro-1,2,5-benzothiadiazepin-
4(5H)-one 1,1-Dioxide (8).
Finely powdered benzothiadiazepine 7 (1.0 g, 3.8 mmol) was
carefully added into 90% nitric acid (15 ml) cooled at -10°. After
stirring at this temperature for 1 hour, the solution was poured
onto crushed ice and the mixture was extracted with ethyl acetate
(3 x 50 ml). The organic extracts were collected, washed with
brine (3 x 100 ml), saturated solution of sodium hydrogen
carbonate (3 x 100 ml) and brine again (3 x 100 ml). The organic
solution was then dried and the solvent was evaporated to obtain
crude product which was chromatographed on silica gel column
(chloroform/ethyl acetate 9:1 as eluent) to obtain 180 mg (15%
yield) of 8, mp 193-194° (from ethanol); ir: ν 3300 and 3150
-1 1
(NH amide and NH sulfonamide), 1700 (CO) cm ; H nmr
(dimethylsulfoxide-d ): δ 1.20 (d, 3H, CH ), 4.95 (q, 1H, CH),
6
3
4.50 (s, broad, 1H, SO NH), 8.03 and 8.42 (2d, 2H, J = 1.8 Hz,
2
m
benzothiadiazepine C7-H and C9-H), 9.55 (s, broad, 1H,
CONH).
Anal. Calcd. for C H ClN O S: C, 35.36; H, 2.64; Cl, 11.60;
N, 13.75; S, 10.49. Found: C, 35.41; H, 2.71; Cl, 11.75; N, 13.84;
S, 10.54.
9
8
3 5
EXPERIMENTAL
Melting points were determined on an Electrothermal IA6304
apparatus and are uncorrected. Infrared spectra (nujol mulls)
were run on a Perkin Elmer 1310 spectrophotometer. The H nmr
6-Amino-8-chloro-3-methyl-2,3,4,5-tetrahydro-1,2,5-benzo-
thiadiazepine 1,1-Dioxide (9).
1
spectra were recorded with a Bruker AC 200 (200 MHz) using
tetramethylsilane as the internal standard. Column chroma-
tography purifications were performed on silica gel Merck
(70-230 Mesh). Silica gel/TLC-cards Fluka (silica gel precoated
aluminum cards with fluorescent indicator 254 nm) were used for
A solution of 8 (500 mg, 1.6 mmol) in anhydrous tetrahydro-
furan (25 ml) was dropped into a well stirred suspension of
lithium aluminum hydride (410 mg, 10.7 mmol) in the same
solvent (9 ml), cooled at 0°. After stirring at room temperature
for 15 minutes, crushed ice was carefully added and the inorganic

86
R. Costi, R. Di Santo and M. Artico
Vol. 39
precipitate that formed was removed by filtration. The filtrate
was evaporated and the residue was extracted with ethyl acetate
(3 x 20 ml). The collected organic extracts were washed with
brine (3 x 50 ml), dried and the solvent was removed to afford
crude diamine 9 (420 mg, 100% yield), which was used for the
next reaction without chromatographic purification because of its
instability.
Anal. Calcd. for C H ClN O S: C, 45.64; H, 4.47; Cl, 11.23;
12 14 3 3
N, 13.31; S, 10.15. Found: C, 45.70; H, 4.46; Cl, 11.20; N, 13.43;
S, 10.21.
Ethyl 2-(5-Chloro-2-nitrobenzenesulfonamido)acetate (13a).
A solution of 5-chloro-2-nitrobenzenesulfonyl chloride (35 g,
0.136 mol) in dichloromethane (150 ml) was dropped into a well
stirred solution of glycine ethyl ester hydrochloride (19.1 g,
0.136 mol) and triethylamine (27.7 g, 38.1 ml, 0.279 mol) in the
same solvent (200 ml). After 2.5 hours water was added (300 ml)
and the mixture was extracted with chloroform (3 x 200 ml). The
organic extracts were collected, washed with brine (3 x 500 ml),
dried and the solvent was evaporated. The crude product was
chromatographed on silica gel column to obtain pure 13a (43.9 g
100% yield), mp 109-110° (from benzene/cyclohexane); ir: ν
9-Chloro-2,3-dihydro-3-methylimidazo[1,5,4-ef][1,2,5]-
benzothiadiazepin-6(4H,7H)-one 1,1-Dioxide (10).
A well stirred solution of 9 (2.6 g, 9.9 mmol) and triphosgene
(3.0 g, 9.9 mmol) in chlorobenzene (50 ml) was heated at 120°
for 15 minutes. Then the solvent was removed and the residue
was treated with ethyl acetate (100 ml). The organic solution was
washed with brine (3 x 100 ml), dried and the solvent was
evaporated to afford the crude product which was
chromatographed on a silica gel column (ethyl acetate as eluent)
to obtain pure 10 (970 mg, 34% yield), mp >300° (from ethanol);
ir: ν 3200 (NH imidazolone and NH sulfonamide), 1690 (CO)
-1
1
3300 (NH), 1730 (CO) cm ; H nmr (deuterochloroform): δ
1.19 (t, 3H, CH ), 4.03-4.14 (m, 4H, CH COOC H and
3
2
2
5
OCH CH ), 6.13 (s, broad, 1H, NH), 7.69 (dd, 1H, J = 8.5 Hz,
2
3
o
J
= 2.3 Hz, benzene C4-H), 7.93 (d, 1H, J = 8.5 Hz, benzene
m
o
-1
1
C3-H), 8.07 (d, 1H, J = 2.3 Hz, benzene C6-H).
m
cm ; H nmr (dimethylsulfoxide-d ): δ 1.28 (d, 3H, CH ),
6
3
Anal. Calcd. for C H ClN O S: C, 37.22; H, 3.44; Cl, 10.99;
10 11
2 6
3.72-4.37 (m, 3H, CH and CH ), 7.22 (s, 2H, imidazobenzo-
2
N, 8.68; S, 9.93. Found: C, 37.11; H, 3.41; Cl, 11.07; N, 8.70; S,
9.91.
thiadiazepine C8-H and C10-H), 8.38 (d, J = 6.3 Hz, SO NH),
2
11.58 (s, broad, 1H, CONH).
Anal. Calcd. for C H ClN O S: C, 41.75; H, 3.50; Cl, 12.32;
N, 14.60; S, 11.14. Found: C, 41.68; H, 3.47; Cl, 12.43; N, 14.81;
S, 11.21.
Ethyl 2-(5-Chloro-N-ethyl-2-nitrobenzenesulfonamido)acetate
(14a).
10 10
3 3
A mixture of 13a (25.7 g, 80 mmol), anhydrous potassium
carbonate (11 g, 80 mmol) and ethyl iodide (14.9 g, 96 mmol) in
dry N,N-dimethylformamide (110 ml) was stirred at room
temperature for 15 hours. Then water (300 ml) was added and the
oily precipitate was extracted with ethyl acetate (3 x 150 ml). The
organic extracts were collected, washed with brine (3 x 300 ml)
and dried. Evaporation of the solvent gave pure 14a (28 g, 100%
9-Chloro-2,3-dihydro-3-methylimidazo[1,5,4-ef][1,2,5]-
benzothiadiazepin-6(4H,7H)-thione 1,1-Dioxide (11).
A solution of 10 (200 mg, 0.7 mmol) and Lawesson's reagent
(240 mg, 0.6 mmol) in anhydrous dioxane (2 ml) was heated at
100° for 10 hours. After cooling, the solvent was evaporated and
the residue was chromatographed on a silica gel column (chloro-
form/ethyl acetate 1:5) to obtain pure 11 (130 mg, 66% yield), mp
>270° (from ethanol); ir: ν 3280 (NH sulfonamide), 3080 (NH
yield), mp 39-41° (from benzene/cyclohexane); ir: ν 1730 (CO)
-1 1
cm ; H nmr (deuterochloroform): δ 1.16-1.26 (m, 6H, CH ),
3
3.48 (m, 2H, NCH CH ), 4.08-4.18 (m, 4H, CH COOC H and
2
3
2
2 5
-1
1
imidazolethione) cm ; H nmr (dimethylsulfoxide-d ): δ 1.32
6
OCH CH ), 7.61 (m, 2H, benzene C3-H and C4-H), 8.08 (d, 1H,
2
3
(d, 3H, CH ), 4.11 (m, 1H, CH), 4.45 (dd, 1H, J
= 14.9 Hz,
3
gem
J = 2.0 Hz, benzene C6-H).
m
J = 11.8 Hz, CH CH), 5.67 (dd, 1H, J
= 14.9 Hz, J = 4.5 Hz,
1
2
gem
2
Anal. Calcd. for C H ClN O S: C, 41.09; H, 4.31; Cl, 10.11;
12 15
2 6
CH CH), 7.42 (s, 2H, imidazobenzothiadiazepine C8-H and
2
N, 7.99; S, 9.14. Found: C, 41.15; H, 4.37; Cl, 10.03; N, 8.06; S,
9.20.
C10-H), 8.50 (d, 1H, J = 6.2 Hz, SO NH), 13.45 (s, broad, 1H,
2
CSNH).
Ethyl 2-(2-Nitro-5-chloro-N-ethylbenzenesulfonamido)-
propanoate (14b).
Anal. Calcd. for C
H ClN O S : C, 39.54; H, 3.32; Cl,
10 10 3 2 2
11.67; N, 13.83; S, 21.11. Found: C, 39.57; H, 3.41; Cl, 11.84; N,
13.78; S, 21.10.
Derivative 14b was obtained as reported for 14a; evaporation
of the solvent of organic extracts gave pure 14b (90% yield) as a
9-Chloro-2,3-dihydro-7-ethyl-3-methylimidazo[1,5,4-
ef][1,2,5]benzothiadiazepin-4,6(7H)-dione 1,1-Dioxide (12).
-1 1
yellow oil; ir: ν 1720 (CO) cm ; H nmr (deuterochloroform): δ
1.17 and 1.26 (2t, 6H, CH CH ), 1.55 (d, 3H, CHCH ), 3.26 and
2
3
3
A mixture of 10 (250 mg, 0.9 mmol), anhydrous potassium
carbonate (120 mg, 0.9 mmol) and ethyl iodide (140 mg,
0.9 mmol) in dry N,N-dimethylformamide (2 ml) was stirred at
room temperature for 6 hours. Then water (30 ml) was added and
the precipitate that formed was extracted with ethyl acetate (3 x
15 ml). The organic extracts were collected, washed with brine
(3 x 30 ml) and dried. Evaporation of the solvent gave pure 12
(250 mg, 91% yield), mp 174-175° (from ethanol); ir: ν 3300
3.54 (2m, 2H, NCH CH ), 4.08 (m, 2H, OCH CH ), 4.75 (q, 1H,
2
3
2
3
CH), 7.57 (d, 1H, J = 8.5 Hz, benzene C3-H), 7.64 (dd, 1H, J =
o
o
8.5 Hz, J = 2.0 Hz, benzene C4-H), 8.06 (d, 1H, J = 2.0 Hz,
m
m
benzene C6-H).
Anal. Calcd. for C H ClN O S: C, 42.80; H, 4.70; Cl, 9.72; N,
13 17
2 6
7.68; S, 8.79. Found: C, 42.85; H, 4.70; Cl, 9.59; N, 7.71; S, 8.84.
Ethyl 2-(2-Amino-5-chloro-N-ethylbenzenesulfonamido)acetate
(15a).
-1
1
(NH), 1690 (CO) cm ; H nmr (deuterochloroform): δ 1.04
(t, 3H, CH CH ), 1.31 (d, 3H, CHCH ), 3.27 (q, 2H, CH CH ),
A well stirred solution of 14a (29.7 g, 85 mmol) in glacial
acetic acid (500 ml) was heated at 60°, then iron powder (37.8 g,
0.67 mol) was added portionwise over 1 hour. After evaporation
of the solvent, the residue was treated with crushed ice and ethyl
2
3
3
2
3
3.83-4.00 (m, 3H, CH and CH CH), 7.22 (s, 2H, imidazo-
2
benzothiadiazepine C8-H and C10-H), 8.38 (d, 1H, J = 6.3 Hz,
SO NH).
2

Jan-Feb 2002
Derivatives of 2,3-Dihydroimidazo[1,5,4-ef][1,2,5]benzothiadiazepin
87
acetate (3 x 200 ml) and the upper phases were separated. The
organic extracts were collected, washed with brine (3 x 300 ml)
and dried. Removal of the solvent provided pure 15a (23.7 g,
Anal. Calcd. for C H ClN O S: C, 43.07; H, 4.93; Cl, 11.56;
11 15 2 4
N, 9.13; S, 10.45. Found: C, 43.00; H, 4.90; Cl, 11.67; N, 9.15; S,
10.39.
87% yield), mp 78-80° (from benzene/cyclohexane); ir: ν 3440
8-Chloro-2,3-dihydro-2-ethyl-1,2,5-benzothiadiazepin-4(5H)-
one 1,1-Dioxide (17a).
-1 1
and 3320 (NH ), 1720 (CO) cm ; H nmr (deuterochloroform):
2
δ 1.13 and 1.23 (2t, 6H, CH ), 3.35 (q, 2H, NCH CH ), 4.07
3
2
3
(s, 2H, CH COOC H ), 4.13 (q, 2H, OCH CH ), 5.06 (s, broad,
A solution of 16a (19.4 g, 66 mmol) in dichloromethane (640
ml) was treated with N-(3-dimethylaminopropyl)-N'-ethyl
carbodiimide hydrochloride (12.6 g, 66 mmol) and N,N-
dimethylaminopyridine (8.1 g, 66 mmol). After stirring at room
temperature for 15 hours, water was added (500 ml) and the
mixture was extracted with ethyl acetate (3 x 300 ml). The
organic extracts were collected, washed with brine (3 x 300 ml),
1 N hydrochloric acid (3 x 300 ml), saturated solution of sodium
hydrogen carbonate (3 x 300 ml), with brine again (3 x 300 ml)
and then dried. Removal of the solvent furnished pure 17a (14.9
g, 82% yield), mp 193-195° (from ethanol); ir: ν 3200 (NH),
2
2
5
2
3
2H, NH ), 6.65 (d, 1H, J = 8.7 Hz, benzene C3-H), 7.23 (dd, 1H,
2
o
J = 8.7 Hz, J = 2.7 Hz, benzene C4-H), 7.66 (d, 1H, J = 2.7
o
m
m
Hz, benzene C6-H).
Anal. Calcd. for C H ClN O S: C, 44.93; H, 5.34; Cl, 11.05;
12 17
2 4
N, 8.73; S, 9.99. Found: C, 44.98; H, 5.20; Cl, 11.00; N, 8.65; S,
9.87.
Ethyl 2-(2-Amino-5-chloro-N-ethylbenzenesulfonamido)-
propanoate (15b).
Obtained as reported for 15a. Compound 15b was obtained in
82% yield, mp 114-115° (from benzene/cyclohexane); ir : ν 3440
-1
1
1670 (CO) cm ; H nmr (deuterochloroform): δ 1.21 (t, 3H,
CH ), 3.18 (q, 2H, CH CH ), 4.39 (s, 2H, CH CO), 7.13 (d, 1H,
-1 1
and 3330 (NH ), 1710 (CO) cm ; H nmr (deuterochloroform):
3
2
3
2
2
J = 8.7 Hz, benzothiadiazepine C6-H), 7.46 (dd, 1H, J = 8.7 Hz,
δ 1.14-1.25 (m, 6H, CH CH ), 1.48 (d, 3H, CHCH ), 3.23 and
o
o
2
3
3
J = 2.4 Hz, benzothiadiazepine C7-H), 7.91 (d, 1H, J = 2.4 Hz,
3.38 (2m, 2H, NCH CH ), 4.05 (m, 2H, OCH CH ), 4.64 (q, 1H,
m
m
2
3
2
3
benzothiadiazepine C9-H), 9.53 (s, broad, 1H, NH).
CH), 5.06, (s, broad, 2H, NH ), 6.63 (d, 1H, J = 8.6 Hz, benzene
2
o
Anal. Calcd. for C H ClN O S: C, 43.72; H, 4.04; Cl, 12.91;
C3-H), 7.21 (dd, 1H, J = 8.6 Hz, J = 2.6 Hz, benzene C4-H),
10 11
2 3
o
m
N, 10.20; S, 11.67. Found: C, 43.58; H, 4.02; Cl, 12.86; N, 10.11;
S, 11.59.
7.63 (d, 1H, J = 2.6 Hz, benzene C6-H).
m
Anal. Calcd. for C H ClN O S: C, 46.64; H, 5.72; Cl, 10.59;
13 19
2 4
N, 8.37; S, 9.58. Found: C, 46.61; H, 5.84; Cl, 10.68; N, 8.23; S,
9.55.
8-Chloro-2,3-dihydro-2-ethyl-3-methyl-1,2,5-benzothiadi-
azepin-4(5H)-one 1,1-Dioxide (17b).
2-(2-Amino-5-chloro-N-ethylbenzenesulfonamido)acetic Acid
(16a).
Derivative 17b was synthesized with the same procedure
reported for 17a. 17b (12.7 g, 87% yield), mp 212-214° (from
benzene); ir: ν 3190 (NH), 1660 (CO) cm ; H nmr (deutero-
-1 1
A solution of 15a (26.9 g, 83 mmol) in ethanol/tetrahydrofuran
1:1 (400 ml) was treated with 1 N sodium hydroxide (160 ml) and
stirred at room temperature for 2.5 hours. After evaporation of
the solvent the residue was treated with a saturated solution of
sodium hydrogen carbonate and the mixture extracted with ethyl
acetate (200 ml). Organic extract was discarded and the alkaline
solution was made acid with 1 N hydrochloric acid until pH 4 and
then extracted with ethyl acetate (3 x 200 ml). The organic
extracts were collected, washed with brine (6 x 300 ml) and
dried. Evaporation of the solvent afforded pure 16a (21.1 g, 87%
chloroform): δ 1.25 (t, 3H, CH CH ), 1.65 (d, 3H, CHCH ),
2
3
3
3.09-3.33 (m, 2H, CH ), 4.56 (q, 1H, CH), 7.05 (d, 1H, J = 8.8
2
o
Hz, benzothiadiazepine C6-H), 7.45 (dd, 1H, J = 8.8 Hz, J
=
o
m
2.4 Hz, benzothiadiazepine C7-H), 7.90 (d, 1H, J = 2.4 Hz,
m
benzothiadiazepine C9-H), 9.01 (s, broad, 1H, NH).
Anal. Calcd. for C H ClN O S: C, 45.76; H, 4.54; Cl, 12.28;
11 13
2 3
N, 9.70; S, 11.10. Found: C, 45.78; H, 4.61; Cl, 12.35; N, 9.67; S,
11.20.
8-Chloro-2,3-dihydro-2-ethyl-6-nitro-1,2,5-benzothiadiazepin-
4(5H)-one 1,1-Dioxide (18a).
yield), mp 145-148° (from toluene); ir: ν 3440 and 3340 (NH ),
2
-1 1
2900 (OH), 1710 (CO) cm ; H nmr (dimethylsulfoxide-d ): δ
6
0.99 (t, 3H, CH ), 3.20 (q, 2H, CH CH ), 4.03 (s, 2H,
Synthesized as reported for 8. Pure 18a was obtained without
chromatography (82% yield), mp 143-145° (the compound was
not recrystallized because of its decomposition when heated in
3
2
3
CH COOH), 6.20 (s, broad, 2H, NH ), 6.86 (d, 1H, J = 8.7 Hz,
2
2
o
benzene C3-H), 7.31 (dd, 1H, J = 8.7 Hz, J = 2.5 Hz, benzene
o
m
-1 1
C4-H), 7.48 (d, 1H, J = 2.5 Hz, benzene C6-H), 12.77 (s, broad,
benzene/cyclohexane); ir: ν 3340 (NH), 1670 (CO) cm ; H nmr
m
1H, OH).
(deuterochloroform): δ 1.22 (t, 3H, CH ), 3.22 (q, 2H, CH CH ),
3 2 3
Anal. Calcd. for C H ClN O S: C, 41.03; H, 4.48; Cl, 12.11;
4.31 (s, 2H, CH CO), 8.23 and 8.38 (2d, 2H, J = 2.4 Hz,
2 m
10 13
2
4
N, 9.57; S, 10.95. Found: C, 40.89; H, 4.45; Cl, 12.10; N, 9.61; S,
10.84.
benzothiadiazepine C7-H and C9-H), 10.60 (s, broad, 1H, NH).
Anal. Calcd. for C H ClN O S: C, 37.57; H, 3.15; Cl, 11.09;
10 10
3 5
N, 13.14; S, 10.03. Found: C, 37.60; H, 3.10; Cl, 11.01; N, 13.15;
S, 10.09.
2-(2-Amino-5-chloro-N-ethylbenzenesulfonamido)propanoic
Acid (16b).
8-Chloro-2,3-dihydro-2-ethyl-3-methyl-6-nitro-1,2,5-benzothia-
diazepin-4(5H)-one 1,1-Dioxide (18b).
Derivative 16b was synthesized as reported for 16a. 16b (15.9
g, 100% yield), mp 117-119° (from benzene); ir: ν 3460 and 3340
-1 1
(NH ), 2900 (OH), 1700 (CO) cm ; H nmr (dimethylsulfoxide-
Prepared as already shown for 18a. 18b (95% yield), mp
2
-1 1
d ): δ 1.06 (t, 3H, CH CH ), 1.35 (d, 3H, CHCH ), 3.20 (m, 2H,
203-205° (from benzene); ir: ν 3280 (NH), 1670 (CO) cm ; H
6
2
3
3
CH CH ), 4.53 (q, 1H, CH), 6.19 (s, broad, 2H, NH ), 6.85
nmr (dimethylsulfoxide-d ): δ 1.05 (t, 3H, CH CH ), 1.40
2
3
2
6 2 3
(d, 1H, J = 8.8 Hz, benzene C3-H), 7.30 (dd, 1H, J = 8.8 Hz,
(d, 3H, CHCH ), 3.20 (m, 2H, CH ), 4.27 (q, 1H, CH), 8.08 and
3 2
o
o
J
= 2.4 Hz, benzene C4-H), 7.47 (d, 1H, J = 2.4 Hz, benzene
8.45 (2d, 2H, J = 2.3 Hz, benzothiadiazepine C7-H and C9-H),
m
m
m
C6-H), 12.60 (s, broad, 1H, OH).
10.33 (s, broad, 1H, NH).

88
R. Costi, R. Di Santo and M. Artico
Vol. 39
Anal. Calcd. for C H ClN O S: C, 39.59; H, 3.62; Cl, 10.62;
N, 12.59; S, 9.61. Found: C, 39.66; H, 3.51; Cl, 10.54; N, 12.66;
S, 9.60.
9-Chloro-2,3-dihydro-2-ethylimidazo[1,5,4-ef][1,2,5]benzo-
thiadiazepin-6(4H,7H)-thione 1,1-Dioxide (21).
11 12
3 5
Thioderivative 21 was prepared as already reported for 11.
Reaction time 22 hours; chromatographic system: silica gel
column (chloroform/ethyl acetate 9:1 as eluent). 21 (93% yield),
6-Amino-8-chloro-2-ethyl-2,3,4,5-tetrahydro-1,2,5-benzothia-
diazepine 1,1-Dioxide (19a).
-1
1
mp 252-254° (from ethanol); ir: ν 3100 (NH) cm ; H nmr
(dimethylsulfoxide-d ): δ 1.08 (t, 3H, CH ), 3.25 (q, 2H,
Title derivative was prepared as already reported for 9;
reaction time 45 minutes; chromatographic system: silica gel
6
3
CH CH ), 3.89 and 4.60 (2m, 4H, CH CH ), 7.42 (s, 2H, imidazo-
2
3
2
2
column (chloroform/ethyl acetate 1:1 as eluent). 19a (39% yield),
benzothiadiazepine C8-H and C10-H), 13.48 (s, broad, 1H, NH).
Anal. Calcd. for C H ClN O S : C, 41.57; H, 3.81; Cl,
-1
unstable in presence of the air; ir: ν 3350 (NH and NH ) cm ;
2
11 12
3 2 2
1
H nmr (deuterochloroform): δ 1.10 (t, 3H, CH ), 2.95 (q, 2H,
3
11.16; N, 13.22; S, 20.18. Found: C, 41.71; H, 3.80; Cl, 11.15; N,
13.40; S, 20.10.
CH CH ), 3.08 (m, 2H, CH CH NSO ), 3.48 (m, 2H,
2
3
2
2
2
CH CH NSO ) 3.75 (s, broad, 3H, NH and NH ), 6.75 (d, 1H,
2
2
2 ,
2
J = 2.3 Hz, benzothiadiazepine C7-H), 7.12 (d, 1H, J = 2.3 Hz,
benzothiadiazepine C9-H).
9-Chloro-2,3-dihydro-2-ethyl-3-methylimidazo[1,5,4-ef]-
[1,2,5]benzothiadiazepin-6(4H,7H)-thione 1,1-Dioxide (5).
m
m
6-Amino-8-chloro-2-ethyl-3-methyl-2,3,4,5-tetrahydro-1,2,5-
benzothiadiazepine 1,1-Dioxide (19b).
Synthesized as shown for 21; reaction time 10 hours. 5 (29%
yield), mp 230-232° (from ethanol); ir: ν 3080 (NH) cm ; H
-1 1
nmr (dimethylsulfoxide-d ): δ 0.89 (t, 3H, CH CH ), 1.41 (d,
6
2
3
Synthesized as above depicted for 19a. 19b (22% yield),
unstable in presence of the air, mp 130° dec.; ir: ν 3370 (NH and
3H, CHCH ), 3.14 (m, 2H, CH CH ), 4.01 (m, 1H, CH), 4.42
3
2
3
(dd, 1H, J
= 14.8 Hz, J = 11.9 Hz, CHCH ), 5.05 (dd, 1H,
gem
1 2
-1
1
NH ) cm ; H nmr (dimethylsulfoxide-d ): δ 1.08 (t, 3H,
2
6
J
= 14.8 Hz, J = 4.6 Hz, CHCH ), 7.39 (s, 2H, imidazo-
gem
2 2
CH CH ), 1.22 (d, 3H, CHCH ), 3.08 (m, 2H, CH CH ),
2
3
3
2
3
benzothiadiazepine C8-H and C10-H), 13.45 (s, broad, 1H, NH).
Anal. Calcd. for C ClN O S : C, 43.43; H, 4.25; Cl,
3.20-3.72 (m, 3H, CH and CHCH ), 5.35 and 5.48 (2s, broad,
2
H
12 14
3 2 2
3H, NH and NH ), 6.72 and 6.78 (2d, 2H, J = 2.1 Hz, benzo-
2
m
10.68; N, 12.66; S, 19.32. Found: C, 43.56; H, 4.14; Cl, 10.70; N,
12.71; S, 19.25.
thiadiazepine C7-H and C9-H).
9-Chloro-2,3-dihydro-2-ethyl-imidazo[1,5,4-ef][1,2,5]benzothia-
diazepin-6(4H,7H)-one 1,1-Dioxide (20a).
Ethyl 2-[5-Chloro-N-(3-methyl-2-butenyl)-2-nitrobenzenesul-
fonamido]propanoate (22).
Compound 20a was obtained as shown for 10; reaction time
5 minutes; chromatographic system: silica gel column (chloro-
form/ethyl acetate 1:1 as eluent). 20a (52% yield), mp 235-237°
A mixture of ethyl 2-(5-chloro-2-nitrobenzenesulfon-
amido)propanoate (11.5 g, 34 mmol) (13b), anhydrous potassium
carbonate (4.7 g, 34 mmol) and 3-methyl-2-butenyl bromide
(7.1 g, 48 mmol) in dry N,N-dimethylformamide (50 ml) was
stirred at 70° for 4 hours. Then water was added (200 ml) and the
precipitate that formed was extracted with ethyl acetate (3 x
150 ml). The organic extracts were collected, washed with brine
(3 x 200 ml) and dried. Evaporation of the solvent gave pure 22
-1
1
(from ethanol); ir: ν 2900 (NH), 1690 (CO) cm ; H nmr
(dimethylsulfoxide-d ): δ 1.10 (t, 3H, CH ), 3.23 (q, 2H,
6
3
CH CH ), 3.83 and 4.10 (2m, 4H, CH CH ), 7.23 (s, 2H,
2
3
2
2
imidazobenzothiadiazepine C8-H and C10-H), 11.62 (s, broad,
1H, NH).
Anal. Calcd. for C H ClN O S: C, 43.79; H, 4.01; Cl, 11.75;
11 12
3 3
(13.6 g, 99% yield), mp 55-56° (from cyclohexane); ir: ν 1730
N, 13.93; S, 10.62. Found: C, 43.84; H, 3.85; Cl, 11.83; N, 13.90;
S, 10.70.
-1 1
(CO) cm ; H nmr (deutrochloroform): δ 1.23 (t, 3H, CH CH ),
2
3
1.48 (d, 3H, CHCH ), 1.61 and 1.67 (2s, 6H, =C-CH ), 3.85
3
3
9-Chloro-2,3-dihydro-2-ethyl-3-methylimidazo[1,5,4-ef]-
[1,2,5]benzothiadiazepin-6(4H,7H)-one 1,1-Dioxide (20b).
(m, 1H, NCH ), 4.04-4.20 (m, 3H, NCH and CH CH ), 4.80
2
2
2
3
(q, 1H, CHCH ), 5.07 (m, 1H, =CH-), 7.61 and 8.04 (2m, 3H,
3
benzene H).
Method A.
Anal. Calcd. for C H ClN O S: C, 47.47; H, 5.23; Cl, 8.76;
16 21
2 6
Synthesized as reported for 20a (56% yield).
N, 6.92; S, 7.92. Found: C, 47.56; H, 5.20; Cl, 8.66; N, 6.98; S,
7.89.
Method B.
Ethyl 2-[2-Amino-5-chloro-N-(3-methyl-2-butenyl)benzene-
sulfonamido]propanoate (23).
Derivative 29 (50 mg; 0.12 mmol) was heated neat at 185° for
5 minutes until the gas evolution stopped. After this time the
product was stirred at the same temperature for 10 minutes more,
then was cooled and chromatographed on silica gel column
(chloroform as eluent) to afford pure 20b (38 mg, 100% yield).
Amine 23 was obtained as reported for 15a: reaction time
5 hours, 88% yield. 23, mp 78-79° (from benzene/cyclohexane);
-1
1
ir: ν 3460 and 3360 (NH ), 1730 (CO) cm
;
H nmr
2
20b, mp 215-216° (from ethanol); ir: ν 3100 (NH), 1710 (CO)
(deutrochloroform): δ 1.21 (t, 3H, CH CH ), 1.48 (d, 3H,
2
3
-1 1
cm ; H nmr (dimethylsulfoxide-d ): δ 0.94 (t, 3H, CH CH ),
CHCH ), 1.54 and 1.61 (2s, 6H, =C-CH ), 3.81 (m, 2H, NCH ),
6
2
3
3 3 2
1.36 (d, 3H, CHCH ), 3.13 (m, 2H, CH CH ), 3.96-4.36 (m, 3H,
4.07 (q, 2H, CH CH ), 4.63 (q, 1H, CHCH ), 5.09 (m, 3H, =CH-
2 3 3
3
2
3
and NH ), 6.64 (d, 1H, J = 8.6 Hz, benzene C3-H), 7.21 (dd, 1H,
CH and CHCH ), 7.20 and 7.22 (2d, 2H, J = 1.8 Hz,
2
o
2
m
J = 8.6 Hz, J = 2.4 Hz, benzene C4-H), 7.65 (d, 1H, J = 2.4
imidazobenzothiadiazepine C8-H and C10-H), 11.62 (s, broad,
1H, NH).
o
m
m
Hz, benzene C6-H).
Anal. Calcd. for C H ClN O S: C, 51.26; H, 6.18; Cl, 9.46;
Anal. Calcd. for C H ClN O S: C, 45.64; H, 4.47; Cl, 11.23;
16 23
2 4
12 14
3 3
N, 13.31; S, 10.15. Found: C, 45.51; H, 4.53; Cl, 11.41; N, 13.20;
S, 10.16.
N, 7.47; S, 8.55. Found: C, 51.11; H, 6.24; Cl, 9.41; N, 7.53;
S, 8.55.

Jan-Feb 2002
Derivatives of 2,3-Dihydroimidazo[1,5,4-ef][1,2,5]benzothiadiazepin
89
2-[2-Amino-5-chloro-N-(3-methyl-2-butenyl)benzenesulfon-
amido]propanoic Acid (24).
-1 1
ν 1730 (CO butoxycarbonyl and CO imidazolone) cm ; H nmr
(deuterochloroform): δ 1.46 (d, 3H, J = 6.6 Hz, CHCH ), 1.57
3
(m, 6H, C=CCH ), 1.71 (s, 9H, CCH ), 3.68-3.83 (m, 3H,
Title compound was prepared as reported for 16a; reaction
time was 15 hours (100% yield). 24, mp 115-116° (from
3
3
CHCH and CH CH=C), 4.48-4.55 (m, 2H, CH CH), 4.91
3
2
2
(m, 1H, CH=C), 7.55 and 8.00 (2d, 2H, J = 1.9 Hz, imidazo-
benzene); ir: ν 3460 and 3360 (NH ), 2950 (OH), 1720 (CO)
m
2
-1 1
benzothiadiazepine C8-H and C10-H).
cm ; H nmr (deuterochloroform): δ 1.40-1.65 (m, 9H, CH ),
3
Anal. Calcd. for C H ClN O S: C, 52.68; H, 5.75; Cl, 7.78;
3.78 (m, 2H, CH ), 4.65 (q, 1H, CHCH ), 4.98 (m, 1H, =CH-),
20 26
3 5
2
3
N, 9.22; S, 7.03. Found: C, 52.71; H, 5.80; Cl, 7.82; N, 9.34; S,
7.09.
6.50-6.80 (m, 3H, benzene C3-H and NH ), 7.20 (dd, 1H, J = 8.5
2
o
Hz, J = 2.0 Hz, benzene C4-H), 7.60 (d, 1H, J = 2.0 Hz,
m
m
benzene C6-H), 12.50 (s, broad, 1H, OH).
9-Chloro-2,3-dihydro-3-methyl-2-(3-methyl-2-butenyl)-
imidazo[1,5,4-ef][1,2,5]benzothiadiazepin-6(4H,7H)-one 1,1-
Dioxide (28).
Anal. Calcd. for C H ClN O S: C, 48.48; H, 5.52; Cl, 10.22;
14 19
2 4
N, 8.08; S, 9.24. Found: C, 48.49; H, 5.60; Cl, 10.15; N, 8.02;
S, 9.21.
Derivative 28 was synthesized as reported for 20b, method B.
28: (100% yield), mp 197-199° (from toluene); ir: ν 3080 (NH),
8-Chloro-2,3-dihydro-3-methyl-2-(3-methyl-2-butenyl)-1,2,5-
benzothiadiazepin-4(5H)-one 1,1-Dioxide (25).
-1
1
1730 (CO) cm ; H nmr (deuterochloroform): δ 1.47-1.59
(m, 9H, CH ), 3.78-3.85 (m, 3H, CHCH and CH CH=C), 4.52
Obtained as reported for 17a: reaction time 5 hours (72%
yield). 25, mp 157-158° (from benzene); ir: ν 3200 (NH), 1660
3
3
2
(m, 2H, CH CH), 4.95 (m, 1H, CH=C), 7.24 and 7.46 (2d, 2H,
2
-1
1
(CO) cm ; H nmr (deuterochloroform): δ 1.57-1.66 (m, 9H,
CH ), 3.79 (m, 2H, CH ), 4.42 (q, 1H, CHCH ), 5.03 (m, 1H,
J
= 1.9 Hz, imidazobenzothiadiazepine C8-H and C10-H),
m
10.58 (s, broad, 1H, NH).
3
2
3
=CH-), 7.07 (d, 1H, J = 8.7 Hz, benzothiadiazepine C6-H), 7.44
Anal. Calcd. for C H ClN O S: C, 50.63; H, 5.10; Cl, 9.96;
o
15 18
3 3
(dd, 1H, J = 8.7 Hz, J = 2.4 Hz, benzothiadiazepine C7-H),
N, 11.81; S, 9.01. Found: C, 50.51; H, 5.15; Cl, 9.84; N, 11.89; S,
9.05.
o
m
7.85 (d, 1H, J = 2.4 Hz, benzothiadiazepine C9-H), 9.21
m
(s, broad, 1H, NH).
Anal. Calcd. for C H ClN O S: C, 51.14; H, 5.21; Cl, 10.78;
N, 8.52; S, 9.75. Found: C, 51.11; H, 5.27; Cl, 10.84; N, 8.60; S,
9.67.
9-Chloro-2,3-dihydro-3-methyl-2-(3-methyl-2-butenyl)-
imidazo[1,5,4-ef][1,2,5]benzothiadiazepin-6(4H,7H)-thione
1,1-Dioxide (6).
14 17
2 3
Compound 6 was obtained starting from 28, as already
reported for 5. Chromatographic system: silica gel column,
chloroform as eluent, 44% yield, mp 186-187° (from toluene);
7-tert-Butoxycarbonyl-9-chloro-2,3-dihydro-3-methyl-
imidazo[1,5,4-ef][1,2,5]benzothiadiazepin-6(4H,7H)-one 1,1-
Dioxide (26).
-1
1
ir: ν 3080 (NH) cm
;
H nmr (deuterochloroform): δ
A solution of di-tert-butyldicarbonate (150 mg, 0.7 mmol) and
N,N-dimethylaminopyridine (90 mg, 0.7 mmol) in anhydrous
tetrahydrofuran (5 ml) was slowly dropped into a well stirred
suspension of 10 (200 mg, 0.7 mmol) in the same solvent (5 ml).
After stirring for 15 minutes at room temperature, the mixture was
treated with 1 N hydrochloric acid (30 ml) and the precipitate
which formed was extracted with ethyl acetate (3 x 30 ml). The
collected organic extracts were washed with brine (6 x 50 ml) and
dried. Evaporation of the solvent gave crude product which was
then chromatographed on silica gel column (chloroform as eluent)
to afford pure 26 (240 mg, 88% yield), mp > 300° (from ethanol);
ir: ν 3280 (NH), 1800 (CO butoxycarbonyl), 1710 (CO imida-
1.52-1.57 (m, 9H, CH ), 3.78-3.85 (m, 3H, CHCH and
3
3
CH CH=C), 4.79 (m, 2H, CH CH and CH=C), 5.21 (dd, 1H,
2
2
J
J
= 14.9 Hz, J = 5.0 Hz, CH CH), 7.38 and 7.59 (2d, 2H,
= 1.6 Hz, imidazobenzothiadiazepine C8-H and C10-H),
gem
1 2
m
11.28 (s, broad, 1H, NH).
Anal. Calcd. for C H ClN O S : C, 48.44; H, 4.88; Cl, 9.53;
15 18
3 2 2
N, 11.30; S, 17.24. Found: C, 48.50; H, 4.91; Cl, 9.48; N, 11.45;
S, 17.11.
7-tert-Butoxycarbonyl-9-chloro-2,3-dihydro-2-ethyl-3-
methylimidazo[1,5,4-ef][1,2,5]benzothiadiazepin-6(4H,7H)-one
1,1-Dioxide (29).
-1 1
zolone) cm ; H nmr (deuterochloroform): δ 1.47 (d, 3H, J = 6.6
Title derivative was obtained as reported for 14a. 29 was
obatined in 87% yield, mp 138-139° dec (from benzene); ir: ν
Hz, CHCH ), 1.71 (s, 9H, CCH ), 4.04 (m, 1H, CH), 4.30
3
3
(dd, 1H, J = 7.1 Hz, J
= 14.9 Hz, CH ), 4.63 (dd, 1H, J = 3.9
1
gem
2 2
-1 1
1730 (CO butoxycarbonyl and CO imidazolone) cm ; H nmr
Hz, J
= 14.9 Hz, CH ), 5.46 (d, 1H, J = 4.5 Hz, NH), 7.50 and
gem
2 3
(deuterochloroform): δ 1.02 (t, 3H, CH CH ), 1.31 (d, 3H,
2
3
7.98 (2d, 2H, J = 1.9 Hz, imidazobenzothiadiazepine C8-H and
m
CHCH ), 1.47 (m, 6H, C=CCH ), 1.69 (s, 9H, CCH ), 3.20
3
3
3
C10-H).
(q, 2H, CH CH ), 3.75 (q, 1H, CHCH ), 4.51 (m, 2H, CH CH),
Anal. Calcd. for C H ClN O S: C, 46.45; H, 4.68; Cl, 9.14; N,
2
3
3
2
15 18
3 5
7.56 and 7.98 (2d, 2H, J = 2.0 Hz, imidazobenzothiadiazepine
10.83; S, 8.27. Found: C, 46.40; H, 4.75; Cl, 9.14; N, 10.91; S, 8.41.
m
C8-H and C10-H).
7-tert-Butoxycarbonyl-9-chloro-2,3-dihydro-3-methyl-2-(3-
methyl-2-butenyl)imidazo[1,5,4-ef][1,2,5]benzothiadiazepin-
6(4H,7H)-one 1,1-Dioxide (27).
Anal. Calcd. for C H ClN O S: C, 49.10; H, 5.33; Cl, 8.52;
17 22
3 5
N, 10.10; S, 7.71. Found: C, 49.20; H, 5.15; Cl, 8.47; N, 10.08; S,
7.84.
Compound 27 was obtained with a procedure similar to that
reported for 22, reaction time 15 hours in acetone at room
temperature, 84% yield. 27, mp 137-142° dec (from benzene); ir:
Acknowledgements.
Authors thank Italian CNR and MURST for partial support.

90
R. Costi, R. Di Santo and M. Artico
Vol. 39
REFERENCES AND NOTES
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