Novel syntheses of 2,3-dihydro-1,5-benzothiazepin-4(5H)-ones and 2H-1,4-benzothiazin-3(4H)-ones

Article abstract of DOI:10.1021/jo0101959

Nucleophilic additions of α-mercaptoalkanoate esters and β-mercaptoalkanoate acids to benzoquinone diimines, followed by cyclization with trifluoroacetic acid or 1,3-dicyclohexylcarbodiimide (DCC), provide novel, high-yielding syntheses of 2H-1,4-benzothiazin-3(4H)-ones (3a-f) and 2,3-dihydro-1,5-benzothiazepin-4(5H)-ones (5a-c), respectively.

Full text of DOI:10.1021/jo0101959

6792
J . Org. Chem. 2001, 66, 6792-6796
Novel Syn th eses of 2,3-Dih yd r o-1,5-ben zoth ia zep in -4(5H)-on es a n d
2H-1,4-Ben zoth ia zin -3(4H)-on es
Alan R. Katritzky,* Herman H. Odens,‡ and Suoming Zhang§
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida,
Gainesville, Florida 32611-7200
Charles J . Rostek and Otto W. Maender
Flexsys America L. P., 260 Springside Drive, Akron, Ohio 44333
katritzky@chem.ufl.edu
Received February 20, 2001
Nucleophilic additions of R-mercaptoalkanoate esters and â-mercaptoalkanoate acids to benzo-
quinone diimines, followed by cyclization with trifluoroacetic acid or 1,3-dicyclohexylcarbodiimide
(DCC), provide novel, high-yielding syntheses of 2H-1,4-benzothiazin-3(4H)-ones (3a -f) and 2,3-
dihydro-1,5-benzothiazepin-4(5H)-ones (5a -c), respectively.
In tr od u ction
as A, B, and C10 (Scheme 1). In the approach A, nucleo-
philic attack of substituted 2-aminothiophenols or 2-ni-
trothiophenols on aliphatic electrophiles, such as â-ha-
lopropionic acids,11 R,â-unsaturated carboxylic acids,12
â-propionolactones,13 malonic acids, or arylglycidic
esters,14a,b afforded the desired products. In the approach
B, 2-fluoronitroarenes were treated with a â-mercapto
acid, followed by nitro group reduction and cyclization.15
A solid-phase synthesis using approach B has been
reported.10 In the approach C, ring expansion via Beck-
mann or Schmidt rearrangements of thiochromanone or
thioflavone precursors produced the desired 6,7-fused
ring systems16a,b (Scheme 1).
Over the past 20 years, syntheses of benzothiazepin-
ones and benzothiazinones have been of great interest,
due to the broad spectrum of biological activities of these
types of compounds.
1,5-Benzothiazepin-4-ones participate as calcium an-
tagonists by interacting with the L-type voltage gated
Ca2+ channel.1a,b Their uses for the treatment of cardio-
vascular disorders as vasodilators,2 as hypertension and
isochemic cardiopathy agents,3 as spasmolytic,4 and
angiotensive converting enzyme inhibitors5 and as
squalene synthetase inhibitors6 have been well docu-
mented. Various benzothiazinones have been patented
as therapeutic agents having calcium-antagonistic proper-
ties7a,b and several other biological activities.8
In the case of benzothiazinones, similar nucleophilic
reactions of 2-aminothiophenols have been employed.
Benzothiazinones can be prepared (i) by condensation of
2-aminobenzenethiol with â-benzoylacrylic acids, maleam-
ic acids,17 maleanilic/fumaranilic acids or esters,12 acety-
lenic nitriles or esters,18 (ii) by treatment of N-unsubsti-
tuted and N,N′-dialkyldithiodianilines with â-ketoesters,19
and (iii) by reaction of 2-aminobenzenethiol with R-ha-
loacetic acids or esters.20a,b Ring enlargement of 2-chlo-
The importance and utility of benzothiazepinones and
benzothiazinones have led to the development of numer-
ous synthetic routes.9 For benzothiazepinones, the major
approaches are cyclization and ring expansion. Depend-
ing on the retrosynthetic disconnection of the basic
skeleton, these approaches can be subdivided into dif-
ferent categories; three of the most important are shown
(10) Schwarz, M. K.; Tumelty, D.; Gallop, M. A. J . Org. Chem. 1999,
64, 2219.
(11) Floyd, D. M.; Moquin, R. V.; Atwal, K. S.; Ahmed, S. Z.; Spergel,
S. H.; Gougoutas, J . Z.; Malley, M. F. J . Org. Chem. 1990, 55, 5572.
(12) Balasubramaniyan, V.; Balasubramaniyan, P.; Shaikh, A. S.
Tetrahedron 1986, 42, 2731
(13) Ambrogi, V.; Grandolini, G. Synthesis 1987, 724.
(14) (a) Schwartz, A.; Madan, P. B.; Mohacsi, E.; O’Brien, J . P.;
Todaro, L. J .; Coffen, D. L. J . Org. Chem. 1992, 57, 851. (b) Lancelot,
J . C.; Letois, B.; Rault, S.; Saturnino, C.; Robba, M. J . Heterocycl. Chem.
1992, 29, 1605.
(15) Slade, J .; Stanton, J . L.; Ben-David, D.; Mazzenga, G. C. J . Med.
Chem. 1985, 28, 1517.
(16) (a) Kaye, P. T.; Mphahlele, M. J . Synth. Comm. 1995, 25, 1495.
(b) Bose, A. K.; Hoffman, W. A., III; Manhas, M. S. J . Chem. Soc.,
Perkin Trans. 1 1976, 2343.
(17) Kirchner, F. K.; Alexander, E. J . J . Am. Chem. Soc. 1959, 81,
1721.
(18) Liso, G.; Trapani, G.; Berardi, V.; Latrofa, A.; Marchini, P. J .
Heterocycl. Chem. 1980, 793.
(19) Trapani, G.; Latrofa, A.; Reho, A.; Franco, M.; Liso, G. J .
Heterocycl. Chem. 1992, 29, 1155.
‡ Present address: CB Research and Development, 27 McCullough
Drive, New Castle, DE 19720.
§ Present address: Neurogen Corporation, 35 Northeast Industrial
Road, Branford, CT 06405.
(1) (a) Rampe, D.; Triggle, D. J . Prog. Drug. Res. 1993, 40, 191. (b)
Chaffman, M.; Brogden, R. N. Drugs 1985, 29, 387.
(2) Ferrari, R. Eur. Heart J . 1997, 18 (Suppl. A), A56.
(3) Salimbeni, A.; Caliari, S.; Fici, F.; Manghisi, E. U.S. Patent
5,571,807, 1996; Chem Abstr. 1992, 116, 255647x.
(4) Narita, H.; Gaino, M.; Suzuki, T.; Kurosawa, H.; Inoue, H.;
Nagao, T. Chem. Pharm. Bull. 1990, 38, 407.
(5) Inada, Y.; Itoh, K.; Kamiya, K.; Sugihara, H.; Nishikawa, K. J pn.
J . Pharmacol. 1988, 47, 135.
(6) Hamanaka, E. S.; Hayward, C. M.; Hawkins, J . M. U.S. Patent
5,770,594, 1998; Chem Abstr. 1996, 125, 168038s.
(7) (a) Lerch, U.; Henning, R. U.S. Patent 4,831,028,1989; Chem
Abstr. 1988, 108, 37851c. (b) Henning, R.; Lerch, U.; Kaiser, J . U.S.
Patent 4,595,685, 1986; Chem Abstr. 1986, 104, 88571m.
(8) Sainsbury, M. Comprehensive Heterocyclic Chemistry; Boulton,
A. J ., McKillop, A., Eds.; Pergamon Press: Oxford, 1984; Vol. 3, p
1036-1038.
(9) For a recent review on benzothiazepinones, see: Levai, A. J .
Heterocycl. Chem. 2000, 37, 199.
(20) (a) Unger, O. Chem. Ber. 1897, 30, 607. (b) Unger, O.; Graff,
G. Chem. Ber. 1897, 30, 2389.
10.1021/jo0101959 CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/08/2001

Syntheses of 2,3-Dihydro-1,5-Benzothiazepin-4(5H)-ones
J . Org. Chem., Vol. 66, No. 20, 2001 6793
Sch em e 1
F igu r e 1. Ring inversion of compound 5.
2,3-Dih yd r o-1,5-ben zoth ia zep in -4(5H)-on es (5a -
c). Alkyl 3-{[5-anilino-2-(alkyl-amino)phenyl]sulfanyl}-
propanoates 4a -f were prepared in 86-92% yields by
treatment of N-4-[(alkyl)imino]-2,5-cyclohexadien-1-yl-
ideneanilines (1a -c) with the corresponding â-mercapto-
alkanoate esters (Scheme 4, Table 2). The assignment of
protons at the C-3, C-6 and C-4 positions in the NMR
spectra of compounds 4a -f was comparable with that of
compounds 2a -f.
romethylbenzothiazole21 and ring contraction of benzothi-
azepinones22 have also been reported to produce benzothi-
azinones (Scheme 2).
Subsequently, cyclization of compounds4a -f by heat-
ing with trifluoroacetic acid at 70 °C was attempted.
Compounds 4a -f failed to provide the desired cyclized
5a -f under these reaction conditions. Refluxing com-
pounds 4d -f in chlorobenzene for 2 days led only to
recovery of the starting materials. When Decalin was
used as a solvent, decomposition of the starting materials
occurred after heating at 190 °C for 3 days. We then
approached the synthesis of benzothiazepinones by treat-
ing benzoquinone diimines 1a -c with 3-mercaptopropi-
onic acid. It was envisioned that once the addition
products, 3-{[5-anilino-2-(alkylamino)phenyl]sulfanyl}-
propanoic acids 6a -c were made, cyclization could be
achieved upon addition of 1,3-dicyclohexylcarbodiimide
(DCC) (Scheme 4, Table 2). Intermediate compounds
During an investigation on the synthesis of 2-alkylthio-
1,4-benzoquinone diimines,23 we determined that the
nucleophilic addition of methyl 3-mercaptopropanoate
ester to N-{4-[(1,3-dimethylbutyl)imino]-2,5-cyclohexa-
dien-1-ylidene}aniline (1a ) proceeded regioselectively by
addition at the C-3 position of the benzoquinoid ring
forming methyl 3-(5-anilino-2-[(1,3-dimethylbutyl)amino]-
phenylsulfanyl)propanoate (4a ). The structure of adduct
4a was established23 on the basis of NOE and 2D NMR
experiments. In the present work, we have investigated
the syntheses of benzothiazepinones and benzothiazin-
ones via additions of R- or â-mercaptoalkanoate esters
and acids to benzoquinone diimines followed by cycliza-
tion.
1
6a -c were isolated (but characterized only by H NMR)
and further used in the final cyclization step to obtain
5a -c.
Resu lts a n d Discu ssion
Treatment of the intermediates 6a -c with DCC, and
subsequent purification by flash column chromatography
gave the compounds 5a -c in 81-97% yields. Compounds
Some generalized NMR discussion for compounds (2,
3, 4, and 6) is provided in the beginning of the Supporting
Information section.
1
5a ,b were obtained as mixtures of conformers:24 their H
2H-1,4-Ben zoth ia zin -3(4H)-on es (3a -f). N1-(Alkyl)-
2-(alkylsulfanyl)-N4-phenyl-1,4-benzenediamines 2a -f
were prepared in 87-97% yields by treatment of N-4-
[(alkyl)imino]-2,5-cyclohexadien-1-ylideneanilines (1a -
c) with the corresponding R-mercaptoalkanoate esters.
The 1H NMR spectra of 2a -f displayed a consistent
chemical shift pattern containing a doublet (overlapped
by a triplet from the anilino group signals) at 7.12-7.21
ppm, a doublet at 6.70-6.72 ppm and a doublet of
doublets at 6.47-6.50 ppm for the principal phenyl ring
core with a sulfur atom at the meta position to the
phenylamino group. These three signals could be as-
signed to the protons attached to the C-3, C-6 and C-4
positions, respectively (see Scheme 3).
NMR showed sets of two multiplets in a 1:1 ratio at 4.78-
4.84 and at 4.68-4.75 ppm for 5a and at 4.68-4.75 and
4.50-4.57 ppm for 5b. These signals were assigned to
the CH proton adjacent to the alkylamido group (1′-H,
Figure 1). After cyclization with DCC, the sets of two
triplets assigned to the CH2 groups in 6a ,b became a set
of two broad multiplets at 3.20-3.28 (2-H) and 2.41-
1
2.52 ppm (3-H) in the H NMR spectra of 5a ,b (Table 3,
Figure 1). This broadening of these signals can be
attributed to slow conformational changes of the CH2
groups in the benzothiazepinone ring. The 13C NMR
spectra also displayed two peaks per carbon in both the
aromatic and the alkyl region and the signal of the new
lactam carbonyl group was found at 172.1 ppm for both
5a and 5b.
To justify our conclusions that the seven-membered
rings display two different conformations at room tem-
perature, a sealed tube variable high-temperature 1H
NMR experiment was performed. At 75 °C, coalescence
began to take effect, showing two broad singlets with
chemical shifts at 4.69 and 4.76 ppm for 5a and at 4.50
and 4.70 ppm for 5b . By 90 °C, a narrower peak was
observed at 4.73 ppm for 5a and a doublet with a
2H-1,4-Benzothiazin-3(4H)-ones 3a -f were prepared
in 89-97% yields by intramolecular cycloadditions of
compounds 2a -f on treatment with trifluoroacetic acid
under reflux overnight (Table 1). The structures 3a -f
were supported by CHN analytical data, high-resolution
1
mass spectra, and H and 13C NMR spectra. In 13C NMR
spectra, the signal of the newly formed quaternary lactam
carbonyl in compounds 3a -f is shifted upfield (about 6
ppm) to around 164.0-167.0 ppm.
(21) Florio, S.; Capriati, V.; Colli, G. Tetrahedron 1997, 53, 5839.
(22) Erker, T.; Bartsch, H. Liebigs Ann. Chem. 1992, 403.
(23) Katritzky, A. R.; Odens, H. H.; Voronkov, M. V.; Rostek, C. J .;
Maender, O. W. Rubber Chem. Technol., submitted.
(24) Pihlaja, K.; Kleinpeter, E. Carbon-13 NMR Chemical Shifts in
Structural and Stereochemical Analysis; Marchand, A. P., Ed.; VCH
Publisher: New York, 1994.

6794 J . Org. Chem., Vol. 66, No. 20, 2001
Katritzky et al.
Sch em e 2
1
Sch em e 3
Systematic variable temperature H NMR study of meth-
yl- and phenyl-substituted 1,5-benzodiazepines and 1,5-
benzothiazepines disclosed several cases of conforma-
tional changes at room temperature.26b Variable tempera-
ture 1H NMR spectra of 1-substituted 1,3,4,5-tetrahydro-
2H-1-benzazepin-2-ones gave ring inversion barriers from
the observed coalescence temperatures: boat to boat
conformational inversion via rapid ring inversion with
no significant rotation about the CO-N bond was
proposed.26a
In summary, we have developed a new method to
produce benzothiazepinones and benzothiazinones. This
clean and efficient two-step synthesis for these target
compounds provides a novel synthetic route for their
preparation. Employing an N-phenyl group at the C-1
position as an electron accepting group to accommodate
for the addition of an R- or â-mercaptoalkanoate ester or
acid nucleophile at the C-3 position of the benzoquinone
diimine enables control of the regioselectivity of the
nucleophilic attack resulting in only one regioisomer.
Exp er im en ta l Section
chemical shift at 4.59 ppm was observed for 5b. After
100 °C, coalescence is at full, and a sharp singlet was
observed at 4.71 and 4.62 ppm for compounds 5a and 5b
accordingly. Significantly, the signals assigned to the
methyl groups in the N-alkyl chain also showed some
changes with temperature, being a complex set of dou-
blets at room temperature but becoming a set of broad
singlets at 100 °C. Using the Eyring equation,24 the
coalescence temperature indicates an energy barrier of
ca. 17 kcal. Slow rotation around the 5-1′ bond is
involved in compounds 5a ,b (Figure 1).
Gen er a l Meth od s. Absolute ethanol was used as a solvent
for the addition of thiol esters and acids to benzoquinone
diimines. Trifluoroacetic acid and starting material 1a are
commercially available, whereas 1b,c were obtained upon
oxidation of the corresponding commercially available ben-
zenediamines with Ag2O.23 All cyclization reactions were
carried out under nitrogen atmosphere. Column chromatog-
raphy was conducted with silica gel 230-400 mesh. NMR was
run at 300 MHz (1H) or 75 MHz (13C).
Gen er al P r ocedu r e for th e P r epar ation of N-4-[(Alkyl)-
im in o]-2,5-cycloh exa d ien -1-ylid en ea n ilin es 1b -c. The
corresponding 1,4-benzenediamine (10.0 mmol) was dissolved
in toluene (25 mL) and treated with Ag2O (4.63 g, 20.0 mmol)
and MgSO4 (3.37 g, 28.0 mmol) for 20 h. The orange slurry
was filtered (Celite), the solvent was evaporated and the
residue was purified by flash silica gel column chromatography
[Hex/EtOAc (9:1) and (1:1)] to give the corresponding N-4-
[(alkyl)imino]-2,5-cyclohexadien-1-ylideneaniline as a mixture
of stereoisomers.
This conformational phenomenon can be compared
with those of benzothiazepinones,25 and other seven-
membered ring analogues.26a,b Spectroscopic investiga-
tions using 1H and 13C NMR selective decoupling and
two-dimensional NMR techniques demonstrate ring in-
version for benzothiazepinones: the dominant conformer
was determined by analysis of the coupling constants.25
N-[4-(P h en ylim in o)-2,5-cycloh exa d ien -1-ylid en e]-2-oc-
ta n a m in e (1b). Yield 99%: (as a 6:4 ratio mixture of stereo-
1
isomers), orange oil. H NMR δ (major isomer): 7.37 (d, J )
(25) Duddeck, H.; Kaiser, M.; Le´vai, A. Liebigs Ann. Chem. 1985,
869.
(26) (a) J ohnson, G. P.; Marples, B. A. J . Chem. Soc., Perkin Trans.
1 1988, 3399. (b) Hunter, P. W. W.; Webb, G. A. Tetrahedron 1973,
29, 147.
7.6 Hz, 2H), 7.15 (t, J ) 7.0 Hz, 1H), 6.99-6.92 (m, 2H), 6.88-
6.80 (m, 2H), 6.77-6.71 (m, 2H), 3.96-3.83 (m, 1H), 1.66-
1.61 (m, 2H), 1.27-1.19 (m, 11H), 0.87-0.85 (m, 3H). 13C NMR
δ (major isomer): 158.7, 157.2, 150.1, 139.1, 136.8, 128.9,

Syntheses of 2,3-Dihydro-1,5-Benzothiazepin-4(5H)-ones
Sch em e 4
J . Org. Chem., Vol. 66, No. 20, 2001 6795
Ta ble 1. P r ep a r a tion of N1-(Alk yl)-2-(a lk ylsu lfa n yl)-N4-p h en yl-1,4-ben zen ed ia m in es (2a -f) a n d
2H-1,4-Ben zoth ia zin -3(4H)-on es (3a -f)
yield
(%)
yield
(%)
entry
R
R1
entry
R
R1
2a
2b
2c
2d
2e
2f
2-methylpropyl
2-methylpropyl
n-hexyl
Me
H
Me
H
Me
H
90
87
97
95
89
94
3a
3b
3c
3d
3e
3f
2-methylpropyl
2-methylpropyl
n-hexyl
Me
H
Me
H
Me
H
91
97
93
90
93
89
n-hexyl
n-hexyl
Me
Me
Me
Me
Ta ble 2. P r ep a r a tion of Alk yl 3-{[5-a n ilin o-2-(a lk yla m in o)p h en yl]su lfa n yl}p r op a n oa tes (4a -f),
3-{[5-a n ilin o-2-(a lk yla m in o)p h en yl]su lfa n yl}p r op a n oic Acid 6a -c a n d 2,3-Dih yd r o-1,5-Ben zoth ia zep in -4(5H)-on es (5a -c)
yield
(%)
yield
(%)
entry
R
R1
R2
entry
R
R1
4a a
4b
4c
4d
4e
4f
2-methylpropyl
n-hexyl
H
H
H
Me
Me
Me
Et
90
89
86
88
90
92
5a
5b
5c
6a
6b
6c
2-methylpropyl
n- hexyl
Me
2-methylpropyl
n-hexyl
Me
H
H
H
H
H
H
85
97
81
71
63
70
methyl
2-methylpropyl
n-hexyl
Methyl
HN-Fmoc
HN-Fmoc
HN-Fmoc
Et
Et
a
The preparation of compound 4a has been described in a previous paper.23
Ta ble 3. Va r ia ble Tem p er a tu r e 300 MHz 1H NMR
Sp ectr oscop y of 2,3-Dih yd r o-1,5-Ben zoth ia zep in -
4(5H)-on es 5a a n d 5b
dissolved in ethanol (25 mL) and treated with a mercaptoester
derivative (3.0 mmol) under a constant gentle stream of air.
The dark reaction mixture was stirred for 20 h. The solvent
was evaporated and the dark brown slurry was purified by
silica gel column chromatography [Hex/EtOAc (9:1), (7:3), and
(1:1)] to give the corresponding 2-alkylthio-1,4-benzenedi-
amines.
temp (°C)
25
1′-H (ppm)
2-H (ppm)
3-H (ppm)
4.78-4.84 (m) 3.20-3.28 (m) 2.41-2.51 (m)
4.68-4.75 (m)
50
75
4.78-4.85 (m) 3.22-3.28 (m) 2.40-2.50 (m)
4.68-4.75 (m)
Eth yl 2-(5-a n ilin o-2-[(1-m eth ylh ep tyl)a m in o]p h en yl-
su lfa n yl)a ceta te (2d ). Yield: 95%, orange oil. 1H NMR δ
7.21-7.12 (m, 3H), 6.90 (d, J ) 7.8 Hz, 2H), 6.81 (t, J ) 7.2
Hz, 1H), 6.76 (d, J ) 2.7 Hz, 1H), 6.49 (dd, J ) 7.8, 2.7 Hz,
1H), 6.19 (s, 1H), 4.05 (q, J ) 7.2 Hz, 2H), 3.47 (s, 2H), 3.40-
3.35 (m, 1H), 3.27 (br s, 1H), 1.53-1.46 (m, 1H), 1.37-1.20
(m, 9H), 1.16 (t, J ) 6.6 Hz, 6H), 0.88 (t, J ) 6.6 Hz, 3H). 13C
NMR δ 170.0, 145.0, 143.4, 133.5, 129.1, 126.2, 123.9, 121.9,
119.4, 118.0, 115.8, 114.6, 113.9, 61.3, 48.9, 37.1, 31.7, 29.3,
26.0, 22.5, 20.6, 14.0. Anal. Calcd for C24H34N2O2S: N, 6.76.
Found: N, 6.78.
5a
4.76 (br s)
4.69 (br s)
4.73 (d)
3.50 (br s)
2.47 (br s)
90
100
25
3.25 (br s)
3.25 (br s)
2.46 (br s)
2.46 (br s)
4.71 (br s)
4.72-4.79 (m) 3.24-3.27 (m) 2.41-2.52 (m)
4.53-4.59 (m)
50
75
4.68-4.75 (m) 3.26-3.29 (m) 2.44-2.50 (m)
4.50-4.57 (m)
5b
4.70 (br s)
4.50 (br s)
4.59 (d)
3.26 (br s)
2.48 (br s)
90
100
3.26 (br s)
3.25 (br s)
2. 47 (br s)
2.47 (br s)
4.62 (br s)
Met h yl 2-{[5-a n ilin o-2-(isop r op yla m in o)p h en yl]su l-
fa n yl}a ceta te (2f). Yield: 94%, yellow microcrystals. Mp:
47-50 °C. H NMR δ 7.21-7.13 (m, 3H), 6.91 (d, J ) 7.8 Hz,
2H), 6.80 (t, J ) 7.3 Hz, 1H), 6.78 (d, J ) 2.6 Hz, 1H), 6.50
(dd, J ) 7.8, 2.6 Hz, 1H), 6.20 (s, 1H), 4.05 (q, J ) 7.2 Hz,
2H), 3.57-3.53 (m, 1H), 3.47 (s, 2H), 3.18 (br s, 1H), 1.19 (d,
J ) 6.2 Hz, 6H), 1.16 (t, J ) 7.2 Hz, 3H). 13C NMR δ 170.0,
144.9, 143.1, 133.7, 129.1, 126.1, 121.8, 119.4, 118.2, 115.9,
124.7, 120.4, 56.3, 38.4, 31.7, 29.2, 26.6, 22.6, 22.3, 14.0. 13C
NMR δ (minor isomer): 158.7, 157.0, 150.1, 137.9, 134.3, 124.7,
122.3, 121.8, 56.4, 38.4, 31.7, 29.2, 26.6, 22.4, 22.3, 14.0. Anal.
Calcd for C20H26N2: N, 9.51. Found: N, 9.59.
1
Gen er a l P r oced u r e for th e P r ep a r a tion of N1-(Alk yl)-
2-(alkylsu lfan yl)-N4-ph en yl-1,4-ben zen ediam in es 2a-f an d
4a -f. The corresponding benzoquinone diimine (3.0 mmol) was

6796 J . Org. Chem., Vol. 66, No. 20, 2001
Katritzky et al.
114.9, 61.4, 44.6, 37.2, 22.9, 13.9. Anal. Calcd for C19H24
N2O2S: C, 66.25; H, 7.02; N, 8.13. Found: C, 66.18; H, 7.31;
N, 8.11.
-
127.6, 124.3, 121.3, 111.6, 111.0, 48.4, 36.9, 32.3, 31.6, 29.1,
25.9, 22.4, 20.5, 14.0. Anal. Calcd for C22H28N2OS: C, 71.70;
H, 7.66; N, 7.60. Found: C, 71.92; H, 7.61; N, 7.61.
Meth yl 3-({5-an ilin o-2-[(1-m eth ylh eptyl)am in o]ph en yl}-
su lfa n yl)p r op a n oa te (4b). Yield: 89% orange oil. H NMR
7-An ilin o-4-isop r op yl-2H -1,4-b en zot h ia zin -3(4H )-on e
(3f). Yield: 89%, white microcrystals. Mp: 87-89 °C. 1H NMR
δ 7.35 (t, J ) 7.3 Hz, 2H), 7.26 (t, J ) 7.3 Hz, 1H), 7.12 (d, J
) 7.3 Hz, 2H), 6.46 (d, J ) 2.4 Hz, 1H), 6.22 (d, J ) 8.8 Hz,
1H), 6.13 (dd, J ) 8.8, 2.4 Hz, 1H), 3.47-3.37 (m, 4H), 1.07
(d, J ) 6.1 Hz, 6H). 13C NMR δ 164.3, 143.6, 139.5, 131.6,
129.4, 128.4, 127.6, 121.3, 111.8, 111.2, 44.1, 32.3, 22.7. Anal.
Calcd for C17H18N2OS: C, 68.42; H, 6.08; N, 9.39. Found: C,
68.42; H, 6.46; N, 9.35.
Gen er a l P r oced u r e for th e P r ep a r a tion of Ben zoth i-
a zep in on es 5a -c. The corresponding 2-alkylthio-1,4-ben-
zenediamine (3.4 mmol) was dissolved in THF (15 mL) in an
ice bath and treated with DCC (3.4 mmol). The reaction
mixture was allowed to stir at 0 °C for 1 h and at room
temperature for 20 h under nitrogen. THF was evaporated and
water (50 mL) was added to the yellowish slurry and the
reaction mixture was extracted with CH2Cl2. The organic layer
was dried (MgSO4), and filtered (Celite). The solvent was
evaporated and the dark slurry was purified by silica gel
column chromatography [Hex/EtOAc (9:1), (7:3), and (1:1)] to
give the desired benzothiazepinones.
8-An ilin o-5-(1,3-d im et h ylb u t yl)-2,3-d ih yd r o-1,5-b en -
zoth ia zep in -4(5H)-on e (5a ). Yield: 85% (as a 1.3:1 ratio
mixture of conformers), yellow microcrystals. Mp: 68-71 °C.
1H NMR δ (major conformer): 7.31 (pseudo t, J ) 7.6 Hz, 3H),
7.26-7.05 (m, 3H), 7.00 (t, J ) 7.6 Hz, 2H), 6.06 (s, 1H), 4.88-
4.81 (m, 1H), 3.29-3.19 (m, 2H), 2.56-2.41 (m, 2H), 1.78-
1.66 (m, 1H), 1.56-1.44 (m, 1H), 1.40 (d, J ) 6.4 Hz, 3H),
1.35-1.13 (m, 1H), 1.11-0.95 (m, 3H), 0.88 (d, J ) 6.4 Hz,
3H). 1H NMR δ (minor conformer): 7.31 (pseudo t, J ) 7.6
Hz, 3H), 7.26-7.05 (m, 3H), 7.00 (t, J ) 7.6 Hz, 2H), 6.06 (s,
1H), 4.79-4.72 (m, 1H), 3.29-3.19 (m, 2H), 2.56-2.41 (m, 2H),
1.78-1.66 (m, 1H), 1.56-1.44 (m, 1H), 1.40 (d, J ) 6.4 Hz,
3H), 1.35-1.13 (m, 1H), 1.11-0.95 (m, 3H), 0.77 (d, J ) 6.4
Hz, 3H). 13C NMR δ (major conformer): 172.1, 142.8, 141.8,
136.5, 130.7, 129.4, 126.6, 122.9, 122.0, 118.9, 117.0, 51.4, 45.9,
43.1, 34.6, 25.2, 23.0, 21.1, 18.4. 13C NMR δ (minor con-
former): 171.8, 142.8, 141.8, 136.5, 130.6, 129.4, 126.5, 122.9,
122.0, 118.8, 117.0, 51.4, 45.9, 43.1, 33.9, 24.9, 22.4, 21.1, 18.4.
Anal. Calcd for C21H26N2OS: N, 7.90. Found: N, 8.01. HRMS
(FAB) calcd for C21H26N2OS (M): 354.1766, found: 354.1768.
8-An ilin o-5-isop r op yl-2,3-d ih yd r o-1,5-ben zoth ia zep in -
4(5H)-on e (5c). Yield: 81%, yellow microcrystals. Mp: 163-
166 °C. 1H NMR δ 7.37-7.30 (m, 2H), 7.23-7.15 (m, 3H), 6.84
(t, J ) 2.7 Hz, 1H), 6.80 (d, J ) 8.8 Hz, 1H), 6.46 (dd, J ) 8.8,
2.7 Hz, 1H), 3.66-3.48 (m, 2H), 3.40 (br s, 2H), 2.71 (br s, 2H),
1.22 (d, J ) 6.3 Hz, 6H). 13C NMR δ 171.9, 146.3, 142.3, 136.0,
128.9, 128.8, 127.5, 127.1, 126.3, 118.2, 114.2, 44.2, 34.4, 34.1,
22.9. Anal. Calcd for C18H20N2OS: N, 8.97. Found: N, 8.75.
HRMS (FAB) calcd for C18H20N2OS (M): 312.1299, found:
312.1296.
1
δ 7.21-7.13 (m, 3H), 6.91 (d, J ) 7.8 Hz, 2H), 6.80 (t, J ) 7.2
Hz, 1H), 6.70 (d, J ) 2.7 Hz, 1H), 6.48 (dd, J ) 7.8, 2.7 Hz,
1H), 6.06 (s, 1H), 3.61 (s, 3H), 3.41-3.35 (m, 1H), 3.28 (br s,
1H), 2.94 (t, J ) 7.2 Hz, 2H), 2.55 (t, J ) 6.9 Hz, 2H), 1.55-
1.49 (m, 1H), 1.44-1.20 (m, 9H), 1.16 (d, J ) 6.3 Hz, 3H), 0.88
(t, J ) 6.9 Hz, 3H). 13C NMR δ 172.1, 145.0, 143.2, 133.6, 129.1,
125.8, 121.5, 119.5, 118.2, 115.9, 114.2, 51.7, 48.9, 37.1, 33.9,
31.7, 29.4, 29.3, 26.0, 22.5, 20.7, 14.0. Anal. Calcd for
C24H34N2O2S: C, 69.53; H, 8.27;N, 6.76. Found: C, 69.81; H,
8.40; N, 7.08.
Eth yl (2R)-3-{[5-a n ilin o-2-(isop r op yla m in o)p h en yl]su l-
fa n yl}-2-{[(9H -flu or en -9-yl-m et h oxy)ca r b on yl]a m in o}-
p r op a n oa te (4f). Yield: 92%, beige microcrystals. Mp: 58-
61 °C. 1H NMR δ 7.75 (d, J ) 7.3 Hz, 2H), 7.56 (d, J ) 7.3 Hz,
2H), 7.38 (t, J ) 7.3 Hz, 2H), 7.28 (t, J ) 7.3 Hz, 2H), 7.20 (t,
J ) 7.9 Hz, 2H), 7.12 (d, J ) 8.8 Hz, 2H), 6.94 (d, J ) 7.9 Hz,
2H), 6.83 (t, J ) 7.3 Hz, 1H), 6.78 (s, 1H), 6.47 (dd, J ) 8.8,
2.0 Hz, 1H), 6.06 (s, 1H), 5.71 (d, J ) 7.3 Hz, 1H), 4.58-4.56
(m, 1H), 4.36-4.25 (m, 2H), 4.20-4.10 (m, 2H), 4.07-3.98 (m,
1H), 3.55-3.49 (m, 1H), 3.35-3.17 (m, 2H), 1.20-0.88 (m, 9H).
13C NMR δ 170.4, 155.5, 144.8, 143.8, 143.0, 141.2, 134.3,
129.2, 127.6, 127.0, 125.1, 125.0, 121.5, 119.9, 119.8, 119.1,
116.5, 115.0, 67.2, 61.8, 54.1, 47.1, 44.7, 37.4, 23.0, 14.0. Anal.
Calcd for C35H37N3O4S: C, 70.56; H, 6.26; N, 7.05. Found: C,
70.63; H, 6.70; N, 6.90.
Gen er al P r ocedu r e for th e P r epar ation of 3-{[5-An ilin o-
2-(a lk yla m in o)p h en yl]-su lfa n yl}p r op a n oic a cid s 6a -c.
The corresponding benzoquinone diimine (3.0 mmol) was
dissolved in ethanol (25 mL) and treated with 3-mercaptopro-
pionic acid (0.33 mL, 3.0 mmol) under a constant gentle stream
of air. The dark reaction mixture was allowed to stir for 20 h.
The solvent was evaporated and the dark brown slurry was
purified by silica gel column chromatography [Hex/EtOAc (9:
1), (7:3), and (1:1)] to give the corresponding 3-{[5-anilino-2-
(alkylamino)phenyl]sulfanyl}propanoic acid.
3 -{( 5 -A n i l i n o -2 -[ ( 1 , 3 -d i m e t h y l b u t y l ) a m i n o ] -
p h en ylsu lfa n yl)}p r op a n oic a cid (6a ). Yield: 71% brown
oil, used without further purification. 1H NMR δ 7.42-6.29
(m, 10H), 3.48 (br s, 1H), 2.88 (t, J ) 7.0 Hz, 2H), 2.52 (t, J )
7.0 Hz, 2H), 1.86-1.65 (m, 1H), 1.62-1.46 (m, 1H), 1.34-1.19
(m, 2H), 1.15 (d, J ) 6.1 Hz, 3H), 0.96-0.80 (m, 6H).
Gen er a l P r oced u r e for th e P r ep a r a tion of Ben zoth i-
a zin on es 3a -f. The corresponding 2-alkylthio-1,4-benzene-
diamine 2 (3.4 mmol) was dissolved in trifluoroacetic acid (15
mL) and the dark reaction mixture was allowed to stir at 70
°C (reflux) for 20 h under nitrogen. Trifluoroacetic acid was
evaporated and CH2Cl2 (50 mL) was added to the dark slurry.
The organic layer was washed with saturated sodium bicar-
bonate and water, dried (MgSO4), and filtered (Celite). The
solvent was evaporated and the dark slurry was purified by
silica gel column chromatography [Hex/EtOAc (9:1), (7:3), and
(1:1)] to give the desired benzothiazinones.
Ack n ow led gm en t. We thank Dr. Novruz Akhme-
dov for discussion of the NMR spectra.
7-An ilin o-4-(1-m eth ylh eptyl)-2H-1,4-ben zoth iazin -3(4H)-
1
on e (3d ). Yield: 90%, yellow oil. H NMR δ 7.43 (t, J ) 7.3
Hz, 2H), 7.33 (t, J ) 7.3 Hz, 1H), 7.20 (d, J ) 8.2 Hz, 2H),
6.53 (s, 1H), 6.30 (d, J ) 8.8 Hz, 1H), 6.21 (d, J ) 8.8 Hz, 1H),
3.51-3.46 (m, 3H), 3.35-3.33 (m, 1H), 1.49-1.47 (m, 1H),
1.42-1.27 (m, 9H), 1.12 (d, J ) 6.1 Hz, 3H), 0.87 (t, J ) 6.1
Hz, 3H). 13C NMR δ 164.3, 143.8, 139.6, 131.5, 129.3, 128.4,
Su p p or tin g In for m a tion Ava ila ble: Experimental data.
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