1,4-Thiazepines, 1,4-benzothiazepin-5-ones, and 1,4-benzothioxepin orthoamides via multicomponent reactions of isocyanides

Article abstract of DOI:10.1021/jo026614z

The intramolecular Ugi four-component condensation between 6-oxo-4-thiacarboxylic acids, benzylamines, and cyclohexyl isocyanide gave hexahydro-1,4-thiazepin-5ones and 1,4-benzothiazepin-5-ones, in some cases with high stereoselectivity, and the intramole

Full text of DOI:10.1021/jo026614z

agent diltiazem,6 and its inclusion into peptidic chains
has led to new bradykinin agonists7 and growth hormone
secretagogues.8 These pharmacological achievements
were accompanied by extensive synthetic research.9 In
contrast, 1,4-benzothiazepin-5-ones have been much less
studied due to their lower biological activity and because
their traditional synthetic approaches by the Schmidt
reaction10 or the Beckmann rearrangement11 usually gave
mixtures of isomers. Nevertheless, tricyclic 1,4-benzothi-
azepin-5-one derivatives have been tested as inhibitors
of HIV-1 integrase12 and antitumor antibiotics.13 Very few
selective syntheses are available for these heterocycles.14
The usefulness of 1,4-thiazepine and 1,4-benzothiazepine
derivatives as pharmaceutical tools calls for rapid and
atom-economical15 methods that give access to molecular
diversity in parallel to modern protein structure-based
design of new medicinal leads. Multicomponent reac-
tions16 are best suited to achieve this goal and oxocar-
boxylic acids constitute useful starting materials for this
purpose.17 In continuation of our studies on the synthesis
of heterocyclic compounds from isocyanides18 we wish to
report on a novel synthetic route to hexahydro-1,4-thi-
1,4-Th ia zep in es, 1,4-Ben zoth ia zep in -5-on es,
a n d 1,4-Ben zoth ioxep in Or th oa m id es via
Mu lticom p on en t Rea ction s of Isocya n id es
Stefano Marcaccini,*,† Daniel Miguel,‡
Toma´s Torroba,*,§ and Mar´ıa Garc´ıa-Valverde§
Dipartimento di Chimica Organica “Ugo Schiff”,
Universita` di Firenze, 50019-Sesto Fiorentino, Firenze, Italy,
Departamento de Quı´mica Inorga´nica,
Facultad de Ciencias, Universidad de Valladolid,
47005 Valladolid, Spain, and Departamento de Qu´ımica,
Facultad de Ciencias, Universidad de Burgos,
09001 Burgos, Spain
ttorroba@ubu.es
Received October 27, 2002
Abstr a ct: The intramolecular Ugi four-component conden-
sation between 6-oxo-4-thiacarboxylic acids, benzylamines,
and cyclohexyl isocyanide gave hexahydro-1,4-thiazepin-5-
ones and 1,4-benzothiazepin-5-ones, in some cases with high
stereoselectivity, and the intramolecular Passerini three-
component reaction, in the presence of catalytic amine, gave
tetracyclic 1,4-benzothioxepin orthoamides.
(5) 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, 2922-2938.
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Moquin, R. V.; Lago, M. W.; Duff, K. J .; Lee, V. G.; White, R. E.;
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Hedberg, S. A.; Cucinotta, G. G. J . Med. Chem. 1992, 35, 756-772
and references therein.
Hexahydro-1,4-thiazepin-5-one derivatives have been
the subject of intense chemical and pharmacological
research after the early discovery that some members of
the group were angiotensin-converting enzyme inhibi-
tors.1 This led to the development of temocapril,2 a drug
used for the treatment of hypertension. Very recently
some thiazepinones have shown nanomolar affinity for
a specific domain of a tyrosine kinase enzyme, the Src
SH2, after structure-based rational drug design.3 5-Oxo-
1,4-thiazepin-2-carboxylic acids have been studied by
several groups as ring-constrained dipeptide mimetics4
with potential angiotensin-converting enzyme and neu-
tral endopeptidase dual inhibitor characteristics. On the
other hand, 1,5-benzothiazepin-2-ones can act as calcium
channel blockers and this fact, and the readily available
synthetic methods for this heterocycle, has led to new
cardiovascular drugs5 as well as to the antihypertensive
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Lam, Y.; Lee, S. Y. Tetrahedron Lett. 2001, 42, 109-111. (c) Ali, A.;
Ahmad, V. U.; Leistner, J .; Liebscher, J . J . Chem. Soc., Perkin Trans.
1 2000, 1897-1902. (d) Schwarz, M. K.; Tumelty, D.; Gallop, M. A. J .
Org. Chem. 1999, 64, 2219-2231. (e) Woydowski, K.; Fleischhauer,
J .; Schffer, J .; Liebscher, J . J . Chem. Soc., Perkin Trans. 1 1999, 149-
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(11) Dostert, P.; Kyburz, E. Helv. Chim. Acta 1970, 53, 1813-1827.
(12) 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, 2235-2244.
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Fabrizi, G.; Fiorini, I.; Lamba, D.; Nacci, V. Eur. J . Med. Chem. 1993,
28, 213-220.
* Corresponding author.
† Universita` di Firenze.
‡ Universidad de Valladolid.
§ Universidad de Burgos.
(1) Yanagisawa, H.; Ishihara, S.; Ando, A.; Kanazaki, T.; Miyamoto,
S.; Koike, H.; Iijima, Y.; Oizumi, K.; Matsushita, Y.; Hatat, T. J . Med.
Chem. 1987, 30, 1984-1991.
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Valverde, M. Tetrahedron Lett. 2002, 43, 8591-8593. (b) Marcaccini,
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10.1021/jo026614z CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/25/2003
J . Org. Chem. 2003, 68, 3315-3318
3315

SCHEME 1
SCHEME 2
SCHEME 3
azepin-5-ones and 1,4-benzothiazepin-5-ones via intramo-
lecular Ugi condensations.
The Ugi four-component condensation between bifunc-
tional 6-oxo-4-thiacarboxylic acids 1 and 2, obtained
following known methods,19 commercial benzylamines
3a -c, and the commercial cyclohexylisocyanide 4a took
place smoothly in boiling methanol to give monocyclic and
bicyclic 5-oxohexahydro-1,4-thiazepin-3-carboxamides
5a -c and 6a -c, respectively, in good yields (71-88%)
(Scheme 1). In a typical experiment, a solution of cyclo-
hexyl isocyanide 4a (4 mmol) in methanol (4 mL) was
added to a solution of 1 or 2 (4 mmol) and 3a -c (4 mmol)
in methanol (4 mL). The resulting mixture was refluxed
for 3 h and then evaporated to dryness under reduced
pressure. The residue was dissolved in ethyl acetate (30
mL) and washed with 0.5% NaOH in water. The organic
layer was separated, washed with water, and dried (Na2-
SO4). Removal of the solvent left a residue, which was
amines 3a -c, resulting in the trans-diastereomer being
favored when 3a was employed and the cis-diastereomer
when 3b-c were used, probably mediated by π-π
interactions. Stereoselectivity was irrelevant for other
amines. Diastereomeric excesses were determined by
1
integration of the HNMR signals on reaction mixtures.
When we used ammonia as amine we obtained 11d in
low yield, in addition to a new compound 12a (40%)
whose HRMS and microanalysis (as a 1:1 adduct with
methanol) apparently corresponded to the product from
a three-component Passerini reaction.16b But the 13C
NMR spectrum of 12a showed a single carbonyl group
(δ 172) and two quaternary carbon atoms at δ 108 and δ
83 instead of two carbonyl groups and one quaternary
carbon, although the total number of carbon signals
i
recrystallized from PrOH/iPr2O to give the products.
The structure of compounds 5a -c and 6a -c was
confirmed by their analytical and spectral data. The
bicyclic hexahydro-1,4-thiazepin-5-ones 6a -c were ob-
tained stereoselectively, probably due to 1,2-stereoinduc-
tion by the steric strain of the cyclohexane ring. The
relative configuration of bicyclic compounds 6a -c was
1
established by their HNMR spectra and NOESY experi-
ments on the major diastereomer. These showed that the
proton at the C-9a was trans with respect to the proton
NH of the amide at C-5a. The reduction of compounds
6a -c with LiAlH4/AlCl3 took place chemoselectively. The
cyclic carbonyl group was reduced, whereas the N-
cyclohexylcarboxamide group remained unchanged, giv-
ing bicyclic 1,4-thiazepine-3-carboxamides 7a -c.
In the same way, the synthesis of 1,4-benzothiazepine-
5-ones was achieved by the intramolecular Ugi condensa-
tion beetween bifunctional oxoacids 8 and 9, obtained
following known methods,20 amines 3a -e, and cyclohexyl
isocyanide 4a (Scheme 3).
As in previous examples, the reaction took place easily
in refluxing methanol for 3 h, giving the expected
products 10a -c and 11a -e in excellent yield. The
stereoselectivity of the reaction that gave tricyclic sys-
tems 11a -d depended on the benzyl substitution for
1
corresponded to the sum of those for 9 plus 4a . The H
NMR of 12a showed a broad signal at δ 4, confirmed by
a strong signal at 3427 cm-1 in the IR, indicating the
presence of an OH group instead of the expected NH
group (the methanol present in the sample was also
detected by characteristic signals in IR and 1H NMR).
Single-crystal X-ray diffraction of 12a showed a tetracy-
clic structure (Figure 1) that included the expected 1,4-
benzothioxepin group and a unexpected oxazolidinone
ring, probably formed by a nucleophilic attack of the
amide nitrogen to the lactone carbonyl group of the
Passerini intermediate 13, catalyzed by ammonia, with
formation of a rare orthoamide group (Scheme 4). 12a
was obtained as the only product (91%) by performing
the reaction in the absence of ammonia, but in the
presence of a catalytic amount of tributylamine (product
12a was also obtained at room temperature in the
absence of base in 88% yield). Analogously, 12b,c were
prepared (87 and 73%) from isocyanides 4b,c (Scheme
4). The same reaction conditions starting from acid 2 and
(19) Baker, B. R.; Querry, M. V.; Bernstein, S.; Safir, S. R.;
Subbarow, Y. J . Org. Chem. 1947, 12, 167-174.
(20) Rodionov, V. M.; Bogoslovskii, B. M.; Kazakova, Z. S. Izv. Akad.
Nauk. SSSR, Oldel Khim. Nauk. 1948, 536-545.
3316 J . Org. Chem., Vol. 68, No. 8, 2003

ployed and permits a large structural diversity in the
final products from simple structural changes in the
starting materials.
Exp er im en ta l Section
Gen er a l P r oced u r e for th e Syn th esis of Hexa h yd r o-1,4-
th ia zep in -5-on es 5a -c. A solution of cyclohexyl isocyanide 4a
(0.44 g, 4 mmol) in methanol (4 mL) was added to a solution of
1,2 or 8,9 (4 mmol) and 3a -d (4 mmol) in methanol (4 mL).
The resulting mixture was heated under reflux for 3 h and then
the solvent was evaporated under reduced pressure. The residue
was dissolved in ethyl acetate (30 mL) and washed with an
aqueous solution of NaOH (0.5% w/v, 10 mL). The organic layer
was separated, washed with water, and dried (Na2SO4). Removal
i
of the solvent gave a residue that was recrystallized from PrOH/
iPr2O. CH3, CH2, and CH assignments were performed from
DEPT experiments on representative examples.
F IGURE 1. The molecular structure of 12a .
4-Ben zyl-3-m et h yl-5-oxo-2,3,4,5,6,7-h exa h yd r o-1,4-t h i-
a zep in -3-(N-cycloh exylca r boxa m id e), 5a : White solid, 1.05
g (73%), mp 150-151 °C; IR (KBr, cm-1) ν 3337 (NH), 1667 (CO),
1632 (CO). 1H NMR (CDCl3, 500 MHz) δ 0.98-1.97 (m, 13 H),
2.66-2.86 (m, 5 H), 3.36 (d, J ) 15.6 Hz, 1 H), 3.41-3.60 (m, 1
H), 4.36 (d, J ) 15.8 Hz, 1 H), 4.94 (d, J ) 15.8 Hz, 1 H), 5.98
(d, J ) 7.0 Hz, 1 H, NH), 7.04-7.48 (m, 5 H, HAr); 13C NMR
(CDCl3, 100 MHz) δ 24.0, 24.5 and 25.3 (3 × CH2, DEPT), 26.7
(CH3, DEPT), 31.9, 32.6, 35.8 and 38.0 (4 × CH2, DEPT), 48.6
(CH, DEPT), 48.8 (CH2, DEPT), 67.3 (Cq), 127.2, 127.4 and 128.8
(3 × CHAr, DEPT), 139.1 (CAr), 172.2 and 173.8 (2 × CO); MS
(EI, m/z, %) 361 (M + 1, 46), 136 (100); HRMS (EI) (M + 1)found
361.1957, C20H29N2O2S requires 361.1950. Anal. Calcd for
SCHEME 4
C
20H28N2O2S: C, 66.63; H, 7.83; N, 7.77. Found: C, 66.52; H,
8.00; N, 7.64.
4-(4-Ch lor oben zyl)-3-m eth yl-5-oxo-2,3,4,5,6,7-h exa h yd r o-
1,4-th iazepin -3-(N-cycloh exylcar boxam ide), 5b: White solid,
1.12 g (71%), mp 165-167 °C; IR (KBr, cm-1) ν 3352 (NH), 1651
(CO); 1H NMR (CDCl3, 400 MHz) δ 0.98-1.98 (m, 13 H), 2.63-
2.90 (m, 5 H), 3.26 (d, J ) 16.0 Hz, 1 H), 3.41-3.60 (m, 1 H),
4.43 (d, J ) 16.0 Hz, 1 H), 4.70 (d, J ) 16.0 Hz, 1 H), 5.98 (d,
J ) 7.6 Hz, 1 H, NH), 7.19-7.51 (m, 4 H, HAr); 13C NMR (CDCl3,
100 MHz) δ 23.9, 24.7 and 25.3 (3 × CH2), 26.2 (CH3), 32.0, 32.5,
35.7 and 37.9 (4 × CH2), 48.5 (CH), 48.6 (CH2), 67.3 (Cq), 128.8
(CHAr), 132.9 and 137.4 (2 × CAr), 171.8 and 173.7 (2 × CO).
Anal. Calcd for C20H27ClN2O2S: C, 60.82; H, 6.89; N, 7.09.
Found: C, 60.71; H, 6.97; N, 7.00.
SCHEME 5
isocyanide 4a gave the corresponding orthoamide 14, but
in very low yield (Scheme 5).
5-Ben zyl-4-oxo-2,3,4,5,5a ,6,7,8,8a ,9-d eca h yd r oben zo[1,5]-
th ia zep in -5a -(N-cycloh exylca r boxa m id e), 6a : White solid,
1.41 g (88%), mp 202-204 °C; IR (KBr, cm-1) ν 3345 (NH), 1669
(CO), 1629 (CO); 1H NMR (CDCl3, 400 MHz) δ 0.98-1.98 (m,
17 H), 2.35-2.41 (m, 1 H), 2.80-3.10 (m, 4 H), 3.41 (dd, J )
11.7, 3.6 Hz, 1 H), 3.57-3.61 (m, 1 H), 4.58 (d, J ) 15.8 Hz, 1
H), 4.68 (d, J ) 15.8 Hz, 1 H), 7.04 (d, J ) 7.6 Hz, 1 H, NH),
7.10-7.32 (m, 5 H, HAr); 13C NMR (CDCl3, 100 MHz) δ 22.5,
24.5, 25.5, 26.5, 31.4, 32.1, 32.8, 37.4 and 37.6 (9 × CH2, DEPT),
46.4 and 48.3 (2 × CH, DEPT), 48.6 (CH2, DEPT), 70.6 (Cq),
126.7, 126.9 and 128.4 (3 × CHAr, DEPT), 139.2 (CAr), 169.3 and
173.7 (2 × CO); MS (EI, m/z, %) δ 400 (M+, 1), 274 (39), 91 (100);
The N-amidoalkoxycarbinol moiety (orthoamide) was
considered as an unstable intermediate in the reaction
of ester with amide anion or imide with alkoxy anion,
and the only known stable compounds having this
structural feature were peptide ergot alkaloids (ergopep-
tines)21 and very few synthetic compounds.22 The reported
reaction constitutes a new and highly stereoselective path
to stable polycyclic orthoamides.
In conclusion, the reported reactions constitute fast and
useful methods for the one-pot syntheses of hexahydro-
1,4-thiazepines, 1,4-benzothiazepines, and 1,4-benzothiox-
epin orthoamides from commercial or easily available
starting materials. The method gives a fair cis:trans
diastereoselectivity when cyclohexyl ketoacids are em-
HRMS (EI) M+
400.2200, C23H32N2O2S requires 400.2184.
found
Anal. Calcd for C23H32N2O2S: C, 68.96; H, 8.05; N, 6.99. Found:
C, 69.01; H, 8.12; N, 6.91.
5-(4-Ch lor ob e n zyl)-4-oxo-2,3,4,5,5a ,6,7,8,8a ,9-d e ca h y-
d r ob en zo[1,5]t h ia zep in -5a -(N-cycloh exylca r b oxa m id e),
6b: White solid, 1.44 g (83%), mp 207-209 °C; IR (KBr, cm-1
)
ν 3326 (NH), 1668 (CO), 1624 (CO); 1H NMR (CDCl3, 400 MHz)
δ 0.94-2.00 (m, 17 H), 2.42-2.48 (m, 1 H), 2.80-3.10 (m, 4 H),
3.47 (dd, J ) 12.0, 2.9 Hz, 1H), 3.57-3.61 (m, 1 H), 4.50 (d, J )
15.6 Hz, 1 H), 4.61 (d, J ) 15.6 Hz, 1H), 7.09-7.26 (m, 4H, HAr);
13C NMR (CDCl3, 100 MHz) δ 22.6, 24.7, 25.5, 26.7, 31.5, 32.1,
32.6, 37.1 and 37.2 (9 × CH2, DEPT), 46.4 (CH, DEPT), 48.2
(CH2, DEPT), 48.4 (CH, DEPT), 70.8 (Cq), 128.4 (CHAr, DEPT),
132.3 and 137.7 (2 × CAr), 168.9 and 173.2 (2 × CO); MS (EI,
(21) (a) Cvak, L.; J egorov, A.; Pakhomova, S.; Kratochvil, B.;
Sedmera, P.; Havlicek, V.; Minar, J . Phytochemistry 1997, 44, 365-
369. (b) Cvak, L.; Minar, J .; Pakhomova, S.; Ondracek, J .; Kratochvil,
B.; Sedmera, P.; Havlicek, V.; J egorov, A. Phytochemistry 1996, 42,
231-233.
(22) (a) Drew, M. G. B.; Fengler-Veith, M.; Harwood, L. M.; J ahans,
A. W. Tetrahedron Lett. 1997, 38, 4521-4524. (b) Arrhenius, G.;
Baldridge, K. K.; Richards-Gross, S.; Siegel, J . S. J . Org. Chem. 1997,
62, 5522-5525. (c) Laurenti, D.; Santelli-Rouvier, C.; Pe`pe, G.; Santelli,
M. J . Org. Chem. 2000, 65, 6418-6422 and references therein.
m/z, %) δ 434 (M+, 1), 308 (29), 125 (100); HRMS (EI) M+
found
434.1808, C23H31ClN2O2S requires 434.1795. Anal. Calcd for
J . Org. Chem, Vol. 68, No. 8, 2003 3317

C23H31ClN2O2S: C, 63.50; H, 7.18; N, 6.44. Found: C, 63.57; H,
7.27; N, 6.42.
358.1709, C20H26N2O2S requires 358.1715. Anal. Calcd for
20H26N2O2S: C, 67.01; H, 7.31; N, 7.81. Found: C, 66.97; H,
C
4-Ben zyl-3-m et h yl-5-oxo-2,3,4,5-t et r a h yd r o[1,4]b en zo-
th ia zep in e-3-(N-cycloh exylca r boxa m id e), 10a : White solid,
1.42 g (87%), mp 127-129 °C; IR (KBr, cm-1) ν 3389 (NH), 1668
(CO), 1621 (CO); 1H NMR (CDCl3, 200 MHz) δ 0.75-1.61 (m,
13 H), 2.60 (d, J ) 12.8 Hz, 1 H), 3.00-3.04 (m, 1 H), 4.32 (d,
J ) 12.8 Hz, 1 H), 5.02 (d, J ) 15.8 Hz, 1 H), 5.13 (d, J ) 15.8
Hz, 1 H), 5.49 (d, J ) 7.3 Hz, 1 H, NH), 7.25-7.54 (m, 9 H, HAr);
13C NMR (CDCl3, 50 MHz) δ 24.5, 24.8 and 25.6 (3 × CH2,
DEPT), 28.2 (CH3, DEPT), 32.2, 32.7, 43.0 and 47.8 (4 × CH2,
DEPT), 49.0 (CH, DEPT), 66.6 (Cq), 127.7, 127.8, 128.7, 129.2,
131.0, 131.6 and 133.1 (7 × CHAr, DEPT), 139.6 and 141.1 (2 ×
CAr), 171.2 and 172.6 (2 × CO); MS (EI, m/z, %) 408 (M+, 1),
7.23; N, 7.79.
Gen er a l P r oced u r e for th e Syn th esis of 12a-c. A solution
of tributylamine in methanol (1:10 w/w, 0.25 mL) was added to
a solution of isocyanide 4a -c (1 mmol) and 9 (250 mg, 1 mmol)
in methanol (4 mL). The resulting mixture was stirred at room
temperature for 24 h and then filtered. The collected solid was
washed with methanol to give 12a -c. Removal of the solvent
gave a residue that was recrystallized from methanol to give
additional amounts of 12a -c.
7-Aza -4,5-ben zo-7-cycloh exyl-6-h yd r oxy-9-oxa -8-oxo-1,2-
(tetr a m eth ylen e)-3-th ia bicyclo[4.2.1]n on a n e, 12a : White
solid, 0.36 g (91%), mp 134-135 °C; IR (KBr, cm-1) ν 3427 (OH),
1
282 (39), 91 (100); HRMS (EI), M+
408.1852, C24H28N2O2S
1684 (CO); H NMR (CDCl3, 400 MHz) δ 0.91-2.26 (m, 17 H),
found
requires 408.1871. Anal. Calcd for C24H28N2O2S: C, 70.55; H,
6.91; N, 6.86. Found: C, 70.23; H, 6.97; N, 6.62.
3.16-3.27 (tt, J ) 12.0, 4.0 Hz, 1 H), 3.32 (dd, J ) 12.0, 4.0, 1
H), 3.5 (br s, 1 H, OH), 7.17-7.28 (m, 2 H, HAr), 7.40-7.49 (m,
1 H, HAr), 7.78-7.87 (m, 1 H, HAr); 13C NMR (CDCl3, 100 MHz)
δ 22.4, 25.2, 25.4, 26.1, 26.4, 28.5, 29.4, 30.9 and 34.4 (9 × CH2,
DEPT), 53.6 and 53.9 (2 × CH, DEPT), 82.9 and 107.9 (2 × Cq),
126.9, 127.7, 129.3 and 132.2 (4 × CHAr, DEPT), 133.5 and 141.0
(2 × CAr), 171.8 (CO); MS (EI, m/z, %) 359 (M+, 72), 277 (20),
4-(4-Ch lor ob en zyl)-3-m et h yl-5-oxo-2,3,4,5-t et r a h yd r o-
[1,4]b en zot h ia zep in e-3-(N-cycloh exylca r b oxa m id e), 10b :
White solid, 1.58 g (89%), mp 217-218 °C; IR (KBr, cm-1) ν 3340
(NH), 1651 (CO), 1618 (CO); 1H NMR (CDCl3, 400 MHz) δ 0.76-
1.61 (m, 13 H), 2.55 (d, J ) 12.7 Hz, 1 H), 2.99-3.06 (m, 1 H),
4.30 (d, J ) 12.7 Hz, 1 H), 4.91 (d, J ) 15.8 Hz, 1 H), 5.16 (d,
J ) 15.8 Hz, 1 H), 5.38 (d, J ) 7.3 Hz, 1 H, NH), 7.14-7.50 (m,
8 H, HAr); 13C NMR (CDCl3, 100 MHz) δ 24.5, 24.8 and 25.6
(3 × CH2, DEPT), 28.2 (CH3, DEPT), 32.3, 32.7, 43.0 and 47.1
(4 × CH2, DEPT), 49.1 (CH, DEPT), 66.6 (Cq), 128.7, 129.2 and
129.3 (3 × CHAr, DEPT), 130.0 (CAr), 131.0, 131.7 and 133.1
(3 × CHAr, DEPT), 133.6, 137.9 and 140.9 (3 × CAr), 171.0 and
172.6 (2 × CO); MS (EI, m/z, %) 442 (M+, 2), 316 (100), 125 (62);
HRMS (EI), M+found 442.1495, C24H27ClN2O2S requires 442.1482.
Anal. Calcd for C24H27ClN2O2S: C, 65.07; H, 6.14; N, 6.32.
Found: C, 64.97; H, 5.96; N, 6.29.
206 (60), 193 (80), 137 (100); HRMS (EI) M+
359.1554,
found
C20H25NO3S requires 359.1555. Anal. Calcd for C20H25NO3S‚CH3-
OH: C, 64.42; H, 7.47; N, 3.58. Found: C, 64.42; H, 7.80; N,
3.68.
Cr ysta l Str u ctu r e Deter m in a tion for 12a ‚MeOH: This
material is available from the Cambridge Crystallographic Data
Centre, including atomic coordinates, thermal parameters, and
a full list of bond lengths and angles (CCDC 202033).
7-Aza -4,5-ben zo-7-bu tyl-6-h yd r oxy-9-oxa -8-oxo-1,2-(tet-
r a m eth ylen e)-3-th ia bicyclo[4.2.1]n on a n e 12b: White solid,
0.32 g (87%), mp 165-166 °C; IR (KBr, cm-1) 3420-3060 (OH),
1
10-Ben zyl-11-oxo-5a ,6,7,8,9,9a ,10,11-octa h yd r od iben zo-
[b,f][1,4]th iazepin -9a-(N-cycloh exylcar boxam ide), 11a: White
solid, 1.52 g (85%), mp 214-215 °C; IR (KBr, cm-1) ν 3367 (NH),
1688 (CO); H NMR (CDCl3, 400 MHz) δ 0.78 (t, J ) 7.3, 3 H),
1.16-1.32 (m, 4 H), 1.48-1.88 (m, 6 H), 2.16-2.22 (m, 2 H),
2.83-2.90 (m, 1 H), 3.21-3.29 (m, 1 H), 3.34 (dd, J ) 6.5, 4.4
Hz, 1 H), 4.44 (br s, 1 H, NH), 7.18-7.25 (m, 2 H, HAr), 7.42-
7.45 (m, 1 H, HAr), 7.82-7.84 (m, 1 H, HAr); 13C NMR (CDCl3,
100 MHz) δ 13.8 (CH3), 20.6, 22.4, 25.2, 28.5, 30.2, 34.2 and 40.1
(7 × CH2), 53.7 (CH), 83.6 and 108.0 (2 × Cq), 127.0, 127.9, 129.4
and 132.3 (4 × CHAr), 133.2 and 141.2 (2 × CAr), 172.5 (CO);
1
1661 (CO), 1630 (CO); H NMR (CDCl3, 400 MHz) δ 0.61-2.13
(m, 18 H), 2.82-2.97 (m, 1 H), 4.59 (dd, J ) 12.7, 3.9 Hz, 1 H),
4.76 (d, J ) 16.1 Hz, 1 H), 5.36 (d, J ) 7.0 Hz, 1 H, NH), 5.73
(d, J ) 16.1 Hz, 1 H), 7.24-7.53 (m, 9 H, HAr); 13C NMR (CDCl3,
50 MHz) δ 23.8, 24.2, 24.4, 25.0, 25.6, 28.3, 32.2, 32.5, 35.9 and
48.6 (10 × CH2, DEPT), 48.9 and 53.1 (2 × CH, DEPT), 68.7
MS (EI, m/z, %) 333 (M+, 71), 180 (100), 137 (69); HRMS, M+
found
(Cq), 127.1, 127.8, 128.4, 129.5, 131.1, 131.6 and 132.5 (7 × CHAr
,
333.1401, C21H20N2O5S requires 333.1399. Anal. Calcd for
C18H23NO3S‚CH3OH: C, 62.44; H, 7.45; N, 3.83. Found: C,
62.90; H, 7.75; N, 3.65.
DEPT), 140.3 and 141.4 (2 × CAr), 172.5 and 173.4 (2 × CO);
MS (EI, m/z, %) 448 (M+, 5), 322 (100), 91 (51). HRMS (EI),
M+
448.2179, C27H32N2O2S requires 448.2184. Anal. Calcd
7-Aza-4,5-ben zo-7-(4-n itr oben zyl)-6-h ydr oxy-9-oxa-8-oxo-
1,2-(tetr a m eth ylen e)-3-th ia bicyclo[4.2.1]n on a n e, 12c: White
solid, 0.30 g (73%), mp 241-242 °C; IR (KBr, cm-1) ν 3290 (OH),
1687 (CO); 1H NMR (DMSO, 400 MHz) δ 1.28-2.17 (m, 8 H),
3.39 (dd, J ) 6.5, 4.0 Hz, 1 H), 4.21 (d, J ) 15.6 Hz, 1 H), 4.29
(d, J ) 15.6 Hz, 1 H), 7.10-7.25 (m, 3 H, HAr), 7.38-7.40 (m, 2
H, HAr), 7.61-7.64 (m, 1 H, HAr), 7.93-8.26 (m, 2 H, HAr); 13C
NMR (CDCl3, 100 MHz) δ 22.4, 24.9, 28.6, 34.0, and 42.9 (5 ×
CH2, DEPT), 53.7 (CH, DEPT), 83.0 and 107.6 (2 × Cq), 123.3,
127.2, 128.3, 129.6, 130.1 and 132.0 (6 × CHAr, DEPT), 132.8,
141.6, 144.7 and 147.1 (4 × CAr), 172.1 (CO); MS (EI, m/z, %)
found
for C27H32N2O2S: C, 72.29; H, 7.19; N, 6.24. Found: C, 72.19;
H, 7.35; N, 6.27.
10-(4-Ch lor oben zyl)-11-oxo-5a,6,7,8,9,9a,10,11-octah ydr o-
d ib e n zo[b,f][1,4]t h ia ze p in -9a -(N -cycloh e xylca r b oxa m -
id e), 11b: White solid, 1.62 g (84%), mp 221-222 °C; IR (KBr,
cm-1) ν 3414 (NH), 1651 (CO), 1633 (CO); 1H NMR (CDCl3, 200
MHz) δ 0.75-1.98 (m, 17 H), 2.89-3.02 (m, 2 H), 3.33 (dd, J )
12.8, 4.4 Hz, 1 H), 4.86-5.17 (m, 2 H), 5.30 (d, J ) 7.0 Hz, 1 H),
7.24-7.49 (m, 8 H, HAr); 13C NMR (CDCl3, 50 MHz) δ 21.8, 24.4,
24.8, 25.6, 25.9, 32.0, 32.8, 33.8, 40.2 and 46.3 (10 × CH2), 48.6
and 57.3 (2 × CH), 68.3 (Cq), 127.6, 128.6, 128.9, 129.3, 131.2,
131.5 and 132.3 (7 × CHAr), 133.5, 138.4 and 139.3 (3 × CAr),
169.8 and 172.9 (2 × CO); MS (EI, m/z, %) 482 (M+, 3), 356 (85),
125 (100); HRMS (EI), M+found 482.1807, C27H31ClN2O2S requires
482.1795. Anal. Calcd for C27H31ClN2O2S: C, 67.13; H, 6.47; N,
5.80. Found: C, 66.99; H, 6.62; N, 5.74.
412 (M+, 37), 259 (37), 136 (57), 109 (100); HRMS, M+
found
412.1099, C21H20N2O5S requires 412.1093. Anal. Calcd for
C21H20N2O5S: C, 61.15; H, 4.89; N, 6.79. Found: C, 61.06; H,
4.76; N, 6.78.
Ack n ow led gm en t. We gratefully acknowledge fi-
nancial support from the Direccio´n General de Inves-
tigacio´n of Spain (Project ref. BQU2001-0258).
11-Oxo-5a ,6,7,8,9,9a ,10,11-octa h yd r od iben zo[b,f][1,4]th i-
a zep in -9a -(N-cycloh exylca r boxa m id e), 11e: White solid,
0.79 g (55%), mp 199-200 °C; IR (KBr, cm-1) ν 3387 (NH), 3271
(NH), 1645 (CO); 1H NMR (CDCl3, 200 MHz) δ 0.63-1.97 (m,
17 H), 2.18-2.22 (m, 1H), 3.09-3.23 (m, 2 H), 4.47 (dd, J ) 11.8,
4.8 Hz, 1 H), 5.86 (d, J ) 7.8 Hz, 1 H, NH), 7.18-7.41 (m, 4 H,
HAr), 7.56-7.60 (m, 1 H, NH); 13C NMR (CDCl3, 50 MHz) δ 21.2,
25.0, 30.2, 32.6, 32.8 and 38.6 (6 × CH2, DEPT), 48.9 and 52.3
(2 × CH, DEPT), 63.3 (Cq), 128.1, 130.8, 132.0 and 133.0 (4 ×
CHAr, DEPT), 135.8 and 139.2 (2 × CAr), 171.4 and 172.4 (2 ×
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedure and characterization of 1, 2, 5c, 6, 7a -c, 8, 9, 10c,
11c,d , and 14; details of the crystal structure determination
and crystallographic data (excluding structure factors) for 12a .
This material is available free of charge via the Internet at
http://pubs.acs.org.
CO); MS (EI, m/z, %) 358 (M+, 28), 232 (100); HRMS (EI), M+
J O026614Z
found
3318 J . Org. Chem., Vol. 68, No. 8, 2003