Efficient syntheses of benzothiazepines as antagonists for the mitochondrial sodium-calcium exchanger: Potential therapeutics for type II diabetes

Article abstract of DOI:10.1021/jo020446t

Type II diabetes mellitus is a chronic metabolic disorder that can lead to serious cardiovascular, renal, neurologic, and retinal complications. While several drugs are currently prescribed to treat type II diabetes, their efficacy is limited by mechanism-related side effects (weight gain, hypoglycemia, gastrointestinal distress), inadequate efficacy for use as monotherapy, and the development of tolerance to the agents. Consequently, combination therapies are frequently employed to effectively regulate blood glucose levels. We have focused on the mitochondrial sodium-calcium exchanger (mNCE) as a novel target for diabetes drug discovery. We have proposed that inhibition of the mNCE can be used to regulate calcium flux across the mitochondrial membrane, thereby enhancing mitochondrial oxidative metabolism, which in turn enhances glucose-stimulated insulin secretion (GSIS) in the pancreatic β-cell. In this paper, we report the facile synthesis of benzothiazepines and derivatives by S-alkylation using 2-aminobenzhydrols. The syntheses of other bicyclic analogues based on benzothiazepine, benzothiazecine, benzodiazecine, and benzodiazepine templates are also described. These compounds have been evaluated for their inhibition of mNCE activity, and the results from the structure-activity relationship (SAR) studies are discussed.

Full text of DOI:10.1021/jo020446t

Efficien t Syn th eses of Ben zoth ia zep in es a s An ta gon ists for th e
Mitoch on d r ia l Sod iu m -Ca lciu m Exch a n ger : P oten tia l
Th er a p eu tics for Typ e II Dia betes
Yazhong Pei,*,† Michael J . Lilly,‡ David J . Owen,‡ Lawrence J . D’Souza,† Xiao-Qing Tang,†
J inghua Yu,† Ramina Nazarbaghi,† Andrew Hunter,‡ Christen M. Anderson,† Susan Glasco,†
Nicholas J . Ede,‡ Ian W. J ames,‡ Uday Maitra,§ S. Chandrasekaran,§ Walter H. Moos,† and
Soumitra S. Ghosh†
MitoKor, Inc., 11494 Sorrento Valley Road, San Diego, California 92121, Mimotopes, Pty. Ltd.,
11 Duerdin Street, Clayton, Victoria 3168, Australia, and Department of Organic Chemistry,
Indian Institute of Science, Bangalore 560 012, India
peiy@mitokor.com
Received J uly 3, 2002
Type II diabetes mellitus is a chronic metabolic disorder that can lead to serious cardiovascular,
renal, neurologic, and retinal complications. While several drugs are currently prescribed to treat
type II diabetes, their efficacy is limited by mechanism-related side effects (weight gain,
hypoglycemia, gastrointestinal distress), inadequate efficacy for use as monotherapy, and the
development of tolerance to the agents. Consequently, combination therapies are frequently
employed to effectively regulate blood glucose levels. We have focused on the mitochondrial sodium-
calcium exchanger (mNCE) as a novel target for diabetes drug discovery. We have proposed that
inhibition of the mNCE can be used to regulate calcium flux across the mitochondrial membrane,
thereby enhancing mitochondrial oxidative metabolism, which in turn enhances glucose-stimulated
insulin secretion (GSIS) in the pancreatic â-cell. In this paper, we report the facile synthesis of
benzothiazepines and derivatives by S-alkylation using 2-aminobenzhydrols. The syntheses of other
bicyclic analogues based on benzothiazepine, benzothiazecine, benzodiazecine, and benzodiazepine
templates are also described. These compounds have been evaluated for their inhibition of mNCE
activity, and the results from the structure-activity relationship (SAR) studies are discussed.
In tr od u ction
proved useful, multidrug therapies are often required to
effectively control hyperglycemia. Commonly used sul-
fonylureas may lose their efficacy after prolonged drug
treatment as a result of overstimulation of pancreatic
â-cells, which leads to â-cell fatigue.3,5 More critically, the
available insulin secretagogues also stimulate insulin
secretion under fasting conditions, thereby increasing the
risk of hypoglycemia. Clearly, new therapeutic agents
that are orally effective and safe for chronic administra-
tion are needed for treating diabetes.
Mitochondrial oxidative metabolism plays a central
role in glucose-stimulated insulin secretion (GSIS) in the
â-cell.6-8 Elevation of blood glucose triggers uptake of
glucose by the pancreatic â-cell. Oxidative metabolism
of glucose transiently increases cellular ATP, causing
influx of calcium into the â-cell and subsequent uptake
of calcium by the mitochondria. The transient rise of
mitochondrial Ca2+ concentration after a nutrient load
acts as a “feed-forward” mechanism to control GSIS,6
because calcium-sensitive dehydrogenases of the tricar-
Type II diabetes mellitus accounts for about 90% of
diagnosed diabetes cases1 and is characterized by im-
paired insulin secretion, insulin resistance, and excessive
hepatic gluconeogenesis. This metabolic disorder affects
protein and lipid metabolism and leads to serious com-
plications that include peripheral nerve damage, kidney
damage, impaired blood circulation, and retinal diseases.
The incidence of such complications can be reduced by
aggressively treating diabetic individuals to maintain
blood glucose within the normal range.2 Existing treat-
ments for type II diabetes include insulin and modified
insulins, insulin secretagogues (sulfonylureas and me-
tiglinides), insulin sensitizers (thiazolidinediones and
biguanides), and blockers of glucose uptake (acarbose and
pramlintide).3-5 Although agents in each class have
† MitoKor, Inc.
‡ Mimotopes, Pty. Ltd.
§ Indian Institute of Science.
(1) Kenny, S. J .; Aubert, R. E.; Geiss, L. S. Prevalence and incidence
of non-insulin-dependent diabetes. In Diabetes In America. 2nd ed.;
National Diabetes Data Group; National Institutes of Health; National
Institute of Diabetes and Digestive and Kidney Diseases: Washington,
DC, 1995; NIH Publication no. 95-1468.
(2) U.K. Prospective Diabetes Study Group. Lancet 1998, 352(9131),
837.
(4) Nuss, J . M.; Wagman, A. S. Annu. Rep. Med. Chem. 2000, 35,
211.
(5) Krentz, A. J .; Ferner, R. E.; Bailey, C. J . Drug Safety 1994, 11(4),
223.
(6) Wollheim, C. B. Diabetologia 2000, 43, 265.
(7) Prentki, M. Eur. J . Endocrinol. 1996, 134, 272.
(8) Gerbitz, K. D.; Gempel, K.; Brdiczka, D. Diabetes 1996, 45, 113.
(3) DeFronzo, R. A. Ann. Intern. Med. 1999, 131, 281.
10.1021/jo020446t CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/20/2002
92
J . Org. Chem. 2003, 68, 92-103

Efficient Syntheses of Benzothiazepines
template and made changes in the cyclic skeleton. In
addition, we report a microwave-assisted one-pot conver-
sion of 2-aminobenzhydrol and methyl thioglycolate to
benzothiazepinones that is suitable for multigram syn-
thesis. The compounds have been evaluated for their
ability to functionally inhibit mNCE activity, and the
results from our initial SAR studies are presented.
Resu lts a n d Discu ssion
The synthesis of benzothiazepinones, described previ-
ously by Hirai et al., requires five steps starting from
2-aminobenzophenones.15 The key steps, which involve
the conversion of 2-aminobenzhydrol to the corresponding
2-aminobenzhydryl thio-alcohol via benzothiazine-2-
thione intermediates, proved highly variable in our
hands. Kuch et al. reported a two-step synthesis of
benzothiazepinones in excellent overall yield.16 This
approach was characterized by the S-alkylation of thiogly-
colic acid with 2-aminobenzhydrol in the presence of HCl,
followed by cyclization to furnish the benzothiazepinones.
However, the S-alkylation step was sluggish and takes
2-3 days to complete.
We have established an efficient S-alkylation method
using various benzhydrol derivatives in the presence of
TFA. On the basis of this method, alternative syntheses
for benzothiazepinones and their derivatives have been
developed, as illustrated in Scheme 1. These routes
employ fewer reaction steps and allow the straightfor-
ward incorporation of various substituents onto the
benzothiazepinone template. In method A, S-alkylation
of methyl thioglycolate with 2-aminobenzhydrols17 2 in
neat TFA gave thioethers 3 in good yield in a few hours.
In some cases, the corresponding N-trifluoroacetyl de-
rivatives of 3 were also obtained as a less polar compo-
nent in the crude product. The amides could be readily
converted to 3 upon treatment with aqueous NaOH
without affecting the overall yield of the benzothiazepi-
nones. The formation of the N-trifluoroacetyl byproduct
was minimized when the S-alkylation reaction was
carried out with 1 equiv of TFA in CH2Cl2. Ester 3 was
hydrolyzed under basic conditions to furnish the corre-
sponding acid, which was cyclized using EDC to afford
the desired benzothiazepinones 1.
F IGURE 1.
boxylic acid (TCA) cycle are activated, further enhancing
oxidative flux. Under normal conditions, mitochondria
take up Ca2+ through the mitochondrial calcium uni-
porter in response to the glucose-induced rise in cyto-
plasmic calcium, and they release calcium through the
mitochondrial sodium-calcium exchanger (mNCE).9-11
We have demonstrated that agents that inhibit the
mNCE increase the magnitude and duration of the
glucose-induced transient rise in mitochondrial Ca2+
concentration, and as a result, they enhance GSIS.12 We
propose that an important advantage of these agents over
the existing drugs will be their glucose-dependent ef-
ficacy. While such compounds are expected to correct
hyperglycemia, they should not lower fasting/basal blood
glucose levels, thus avoiding the liability of hypoglycemia.
Compounds from different structural classes, such as
CGP37157 (1,4-benzothiazepin-2-one), diltiazem (1,5-
benzothiazepin-2-one), clonazepam (1,4-benzodiazepin-
2-one), and prenylamine and fendiline (both phenylalky-
lamines), have been reported to inhibit mNCE activity13
(Figure 1). CGP37157 is the most potent inhibitor for
mNCE, with a reported IC50 of 0.4 µM. However, its poor
solubility and short half-life (t1/2 ) 0.9 h, in vivo)14
preclude its use for extensive preclinical studies. Phar-
macological studies around mNCE have been hampered
by the limited number of analogues from each class tested
thus far and particularly by the lack of structure activity
relationship (SAR) information for mNCE around the
benzothiazepine template. In this report, we describe
efficient syntheses of a series of benzothiazepinones and
derivatives based on the template A. To broaden the SAR
analysis of mNCE inhibition and to identify new mNCE
inhibitors with improved pharmacological profiles, we
have varied the substitutions on the benzothiazepinone
A one-step synthesis of benzothiazepinone 1 was also
achieved when 2 and methyl thioglycolate were heated
at 80-85 °C in neat TFA (method B). Under these
conditions, TFA also facilitated the intramolecular ami-
nolysis of the methyl ester 3 in situ to generate 1. The
reaction temperature appeared to be crucial for this one-
step process. When the reaction was carried out below
60 °C, no intramolecular cyclization was observed, and
thioether 3 was obtained as the sole product.
This TFA-facilitated S-alkylation reaction also worked
well with N-acylated benzhydrol (method C). 2-(N-Ben-
(9) Rizzuto, R.; Bernardi, P.; Pozzan, T. J . Physiol. 2000, 529, 37.
(10) Bernardi, P. Physiol. Rev. 1999, 79(4), 1127.
(11) Gunter, T. E.; Gunter, K. K.; Sheu, S.-S.; Gavin, C. E. Am. J .
Physiol. 1994, 267(2 Pt1), C313.
(12) Lee, B.; Vargas, L.; Glasco, S.; Kushnareva, Y.; Zapf-Colby, A.;
Anderson, C. M. Inhibitors of the mitochondrial sodium-calcium
exchanger enhance glucose-stimulated insulin secretion. Keystone
Symposia Diabetes Mellitus: Molecular mechanisms, genetics and new
therapies; Abstract 401; 2002.
(13) For review, see: Cox, D. A.; Matlib, M. A. Trends Pharmacol.
Sci. 1993, 14, 408 and references therein.
(15) Hirai, K.; Matsutani, S.; Ishiba, T.; Makino, I. U.S. Patent
4,297,280, 1981.
(16) Kuch, H.; Seidl, G.; Schmitt, K. Arch. Pharm. 1967, 300 Bd. 4,
299.
(17) 2-Aminobenzhydrol and derivatives were prepared from corre-
15
sponding benzophenones by reduction using NaBH4 or a modified
procedure using LiAlH4.18 The 2-aminobenzophenones used were
synthesized using established methods.19
(14) MitoKor, unpublished data.
J . Org. Chem, Vol. 68, No. 1, 2003 93

Pei et al.
SCHEME 1a
SCHEME 2a
a
Reagents and conditions: (i) t-BuLi, RCHO, THF, -78 °C; (ii)
methyl thioglycolate, 50% TFA in CH2Cl2, room temperature; (iii)
(a) 1.0 N aqueous NaOH, methanol, (b) EDC, DIEA, DMAP, THF,
room temperature.
aldehydes, afforded 7 in good yield. Treatment of 7 in
neat TFA at 80 °C with methyl thioglycolate effected
three reactions in one pot, namely, S-alkylation, pivala-
mide hydrolysis, and cyclization, to yield 1 in good overall
yield. This process is advantageous since benzothiazepi-
nones with various aromatic substitutions can be syn-
thesized from widely available anilines and aldehydes in
two steps.
a
Reagents and conditions. Method A: (i) methyl thioglycolate,
TFA (neat) or TFA/CH2Cl2, room temperature; (ii) (a) 1.0 N
aqueous NaOH, THF/CH3OH, room temperature, (b) EDC, DIEA,
DMAP, THF, room temperature. Method B: (iii) methyl thiogly-
colate, TFA (neat), 80-85 °C. Method C: (iv) methyl thioglycolate,
TFA, room temperature; (v) (a) 1.0 N aqueous NaOH, THF/
CH3OH, reflux; (b) EDC, DIEA, DMAP, THF, room temperature.
Method D: (vi) n-butyllithium, THF, -78 to 0 °C, 2 h; aldehydes,
0 °C to room temperature, 1 h; (vii) methyl thioglycolate, TFA
(neat), 80-85 °C, 24 h. Method E: (iix) methyl thioglycolate, TFA,
basic alumina, microwave radiation; saturated aqueous Na2CO3,
microwave radiation at reduced power.
We also discovered that benzothiazepinones could be
prepared by microwave-assisted one-pot conversion of
2-aminobenzhydrols and methyl thioglycolate (method E).
Conventional microwave irradiation of a slurry of ben-
zhydrol 2, methyl thioglycolate, TFA, and basic alumina
provided a mixture of the thioether 3 (major component),
the corresponding trifluoroacetamide of 3, and benzothi-
azepinone 1. The presence of basic alumina minimizes
the charring that can result from uneven heating.
Complete conversion to 1 was obtained by neutralizing
the mixture with saturated aqueous Na2CO3, followed by
microwave radiation at reduced power. The ratio of 2,
TFA, and basic alumina should be carefully controlled
at the beginning of this one-pot procedure (see Experi-
mental Section for detail), as excess TFA required more
Na2CO3 for neutralization in the following step. Partial
hydrolysis of 3 during the Na2CO3 treatment step was
also observed to give the corresponding acid as a minor
contaminant in the crude product. This hydrolysis was
minimized by adding the Na2CO3 solution in small
portions and exposure to microwave radiation after each
addition. The acid could be removed by basic aqueous
washes to furnish analytically pure benzothiazepinones
in good overall yield. This procedure was successfully
adapted for several large-scale (>10 g) syntheses of 1,
because it did not require silica gel chromatography
purification.
To examine further the effect of alterations at the C-5
position, several analogues with 5-alkyl replacements
were synthesized. To simplify the SAR comparisons, the
7-chloro substituent was retained in these analogues. As
shown in Scheme 2, ortho-lithiation of N-Boc-4-chloroa-
niline (8) using tert-butyllithium, followed by addition of
alkyl aldehydes at -78 °C, gave 9. This reaction had to
be kept at -78 oC and quenched within 2-3 h. Prolonged
reaction time and/or warming resulted in the formation
of benzoxazin-2-one 12 as a significant side product.
Benzyl alcohol 9 was reacted with methyl thioglycolate
zoylamino)benzhydrol20 4 underwent S-alkylation with
methyl thioglycolate in neat TFA to afford the corre-
sponding thioether 5 in 61% yield. Hydrolysis using
aqueous NaOH in THF/CH3OH under reflux simulta-
neously hydrolyzed the N-benzamide and methyl ester
groups of 5 to give the corresponding acid, which then
underwent EDC-facilitated lactam formation to furnish
1. Selective hydrolysis of the methyl ester was observed
when the hydrolysis was carried out at ambient temper-
ature. The route depicted for method C was not pursued
further because it was anticipated that the harsh hy-
drolysis conditions necessary for the removal of the
benzamide functionality would not be compatible with
other base-sensitive functionalities.
Method D outlines a more general synthetic route to
benzothiazepinones. Following a literature procedure,21
selective ortho-lithiation of pivaloylanilide 6 using n-
butyllithium, followed by condensation with aromatic
(18) To a solution of 2-aminobenzophenone (1.0 mmol) in THF (5
mL) at 0 °C was added lithium aluminum hydride (0.5 mL of 1.0 M
solution in diethyl ether). The progress of the reaction was monitored
using TLC. Normally, the reaction was complete within 1 h. Saturated
aqueous sodium bicarbonate (20 mL) was carefully added and the
resulting solution was extracted with ethyl acetate (3 × 50 mL). The
combined organic phase was dried over sodium sulfate, filtered, and
concentrated under reduced pressure to yield the corresponding
benzhydrol, which was used in the S-alkylation reaction without
further purification.
(19) (a) Walsh, D. A. Synthesis 1980, 677 and references therein.
(b) Frye, S. V.; J ohnson, M. C.; Valvano, N. L. J . Org. Chem. 1991, 56,
3750.
(20) Okabe, M.; Sun, R. C. Tetrahedron, 1995, 51(7), 1861.
(21) (a) Turner, J . A. J . Org. Chem. 1990, 55, 4744. (b) UÄ beda, J . I.;
Villacampa, M.; Avandan˜o, C. Synthesis 1998, 1176.
94 J . Org. Chem., Vol. 68, No. 1, 2003

Efficient Syntheses of Benzothiazepines
SCHEME 3a
SCHEME 5a
a
Reagents and conditions: (i) 1.0 N aqueous NaOH, THF/
CH3OH, room temperature; (ii) AcCl, DIEA, DMAP, THF, room
temperature, 3 h.
SCHEME 6a
a
Reagents and conditions: (i) mercaptoethanol, TFA, room
temperature; (ii) PPh3, CBr4, CH2Cl2, room temperature; (iii)
K2CO3, DMF.
SCHEME 4a
a
Reagents and conditions: (i) amine (neat), 140 °C; (ii)
NaBH3(CN), methanol/acetic acid, 0 °C to room temperature; (iii)
bromoacetyl bromide, 0 °C to room temperature, 18 h; DIEA, 50
°C, 5 h.
of various functionalities at the 4-position for further SAR
exploration. As illustrated in Scheme 6, 2-aminoben-
zophenone 23a was condensed with various amines to
give 30. Imine 30 was reduced using NaBH3(CN) to give
31. Reaction of 31 with bromoacetyl bromide in the
presence of DIEA gave 32.
a
Reagents and conditions: (i) methyl thioglycolate, TFA, room
temperature; (ii) LHMDS, THF, -78 °C.
in neat TFA to yield the thioether 10. In this reaction,
S-alkylation occurred in concert with the N-Boc depro-
tection. Hydrolysis of ester 10 using aqueous NaOH,
followed by EDC-mediated cyclization, furnished 5-alkyl-
benzothiazepinone 11.
To explore the contribution of the carbonyl at the
2-position of 1a toward mNCE inhibition, benzothiaz-
epine 15 with the aromatic substitution pattern con-
served was synthesized from 2a (Scheme 3). S-Alkylation
of mercaptoethanol with 2a in TFA gave 13. Thioether
alcohol 13 was converted to the corresponding bromide
14 using CBr4/Ph3P in CH2Cl2. Cyclization of 14 in the
presence of K2CO3 in DMF furnished 15.
The N-alkyl and N-acyl benzothiazepinones 18 and 20,
respectively, were synthesized to ascertain the influence
of N-substitution on mNCE activity (Schemes 4 and 5).
S-Alkylation of methyl thioglycolate with benzhydrol 16
in neat TFA gave thioether 17. Intramolecular aminolysis
of 17 in the presence of LHMDS furnished benzothiaz-
epinone 18. The corresponding N-acetyl derivative 20 was
obtained from acid 19 by treatment with an excess of
acetyl chloride.
Benzodiazepinone derivatives were also prepared to
examine the effect of replacing the sulfur at the 4-position
with nitrogen. These tertiary amine derivatives could
potentially have improved solubility and stability com-
pared to the thioethers. It also allowed the introduction
Str u ctu r e Activity Rela tion sh ip Stu d ies. Using the
strategies illustrated above, a diverse set of benzothiaz-
epinones and their derivatives were synthesized. These
compounds were evaluated for their ability to inhibit
mNCE function, wherein the exchanger-mediated Na+/
Ca2+ translocation in mitochondria in permeabilized cells
was monitored by using a Ca2+-sensing fluorescence-
based assay (see Experimental Section). The results are
summarized in Table 1.
CGP37157 (1a ) exhibited an IC50 of 1.4 µM in our assay
system, which was comparable to the reported literature
value of 0.4 µM.13 Substitutions on the 5-phenyl ring
appeared to be crucial for mNCE activity. The unsubsti-
tuted phenyl derivative 1b displayed a 10-fold reduction
in activity compared to that of analogue 1a containing
2-chlorophenyl. Monomethyl substitutions anywhere on
the phenyl ring all resulted in decreased activity (1a vs
1c-e), with 4-methyl substitution being the least toler-
ated (1e). In a similar vein, dimethyl substitution re-
sulted in decreased mNCE inhibitory activity (1a vs 1f-
j). Replacement of the 5-(2-chlorophenyl) functionality
with aromatic heterocycles also decreased mNCE activity
dramatically (1a vs 1k -n ). Substitutions at C7 in the
fused phenyl ring also played a critical role in mNCE
activity, with the chloro group being the most preferred
(1a vs 1p , 1b vs 1o, 1c vs 1q). Whereas the 5-alkyl
analogues were significantly weaker in their inhibition
J . Org. Chem, Vol. 68, No. 1, 2003 95

Pei et al.
TABLE 1. m NCE Activity of Ben zoth ia zep in es a n d Th eir Der iva tives
mNCE
(IC50, µM)
compd
R1
R2
R3
X
Y
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
7-Cl
7-Cl
7-Cl
7-Cl
7-Cl
7-Cl
7-Cl
7-Cl
7-Cl
7-Cl
7-Cl
7-Cl
7-Cl
7-Cl
7-NO2
H
2-Cl-C6H4-
C6H5-
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
1.4
12.6
6.3
2-Me-C6H4-
3- Me-C6H4-
4- Me-C6H4-
2,3-diMe-C6H3-
2,5-diMe-C6H3-
2,6-diMe-C6H3-
3,4-diMe-C6H3-
3,5-diMe-C6H3-
2-benzothiazolyl
2-thiophenyl
2-thiazolyl
4-pyridyl
12.6
39.8
10.0
25.1
25.1
20.0
15.9
20.0
25.1
200
31.6
20.0
15.9
25.1
3.2
15.9
50.1
25.1
6.3
39.8
20.0
3.2
C6H5-
2-Cl-C6H4-
2-Me-C6H4-
3-BnO-Pr-
cyclohexyl
isopropyl
isobutyl
2-Cl-C6H4-
2-Cl-C6H4-
2-Cl-C6H4-
2-Cl-C6H4-
2-Cl-C6H4-
2-Cl-C6H4-
2-Cl-C6H4-
2-Cl-C6H4-
H
11a
11b
11c
11d
15
7-Cl
7-Cl
7-Cl
7-Cl
7-Cl
7-Cl
7-Cl
7-Cl
7-Cl
7-Cl
7-Cl
7-Cl
H, H
O
O
O
O
O
O
O
18
20
Me2NCH2CH2
acetyl
32a
32b
32c
32d
32e
H
H
H
H
H
EtOCH2CH2CH2N
HO-CH2CH2N
2-(Pr)2NCH2CH2N
(MeOCH2CH2)2NCH2CH2N
3,4-(MeO)2PhCH2CH2N
7.9
6.3
2.0
5.0
SCHEME 7a
(1a vs 11b-d ), the exception was the derivative with the
more flexible 5-(3′-benzyloxypropyl) substituent, which
exhibited good mNCE inhibition (11a vs 1a ). Benzothi-
azepine 15 showed slightly decreased mNCE activity
(IC50 ) 6.3 µM) compared to that of 1a (IC50 ) 1.4 µM).
This indicated that the 2-carbonyl moiety may not play
a crucial role for mNCE inhibitory activity, particularly
when this observation is compared to the results obtained
with 1-substituted analogues 18 and 20. Both 18 and 20
caused a significant decrease in mNCE inhibition (IC50
) 39.8 and 20.0 µM, respectively), suggesting that the
amide NH may be involved as a hydrogen bond donor.
The benzodiazepinones 32a -e exhibited good mNCE
inhibitory activities that were comparable to that of 1a .
When compared to benzothiazepines, this compound
series is expected to display improved properties in terms
of solubility and stability because of the replacement of
the sulfur atom at the 4-position with a substituted
amino group. The lack of tolerance of substitution around
the benzothiazepine template has been noted above.
Unlike the benzothiazepine template, the benzodiazepi-
none system provides an additional attachment point at
the 4-position for various substituents, which allows the
exploration of new diversity elements. Initial results of
compounds 32a -e clearly indicate that substitutions at
this position are accommodated without having adverse
affects on inhibitory potency. Also, it should be noted that
replacement of the sulfur atom with a nitrogen atom
reduces the size of the seven-membered ring.
a
Reagents and conditions: (i) 3-mercaptopropionic acid, TFA
(neat), room temperature; (ii) EDC, DIEA, DMAP, THF, room
temperature.
[6,8]Bicyclic An a logu es. To examine the effects of
modifications of the benzothiazepinone skeleton, com-
pounds based on several [6,8]bicyclic templates were
prepared. Benzhydrol 2a was allowed to react with
3-mercaptopropionic acid in TFA to give 21. Cyclization
of 21 using EDC yielded 22 (Scheme 7).
1,4-Benzothiazocinones 26 were synthesized from ben-
zophenone 23 (Scheme 8). Benzophenone 23 was con-
verted to 24 using (Ph3PCH3)+Br- and t-C5H11OK. Sty-
rene 24 was allowed to react with methyl thioglycolate
in the presence of 1,1′-azobis(cyclohexanecarbonitrile) to
give thioether 25. Cyclization of 25 using LHMDS yielded
26.
Non-sulfur-containing [6,8]bicyclic analogues 28 were
obtained from the coupling reaction of 2-carboxyl ben-
zophenone 27 with ethylenediamine (Scheme 9). The
double bond in 2,5-benzodiazocin-1-one 28 was saturated
96 J . Org. Chem., Vol. 68, No. 1, 2003

Efficient Syntheses of Benzothiazepines
SCHEME 8a
azepinones and derivatives were prepared and evaluated
for their ability to inhibit the mNCE. We have estab-
lished broad SAR around these benzothiazepinones and
derivatives and defined core molecular elements for
activity. The SAR studies were expanded to include other
bicyclic analogues based on benzothiazecine, benzodiaz-
ecine, and benzodiazepine templates. This SAR informa-
tion provides a necessary foundation for further optimi-
zation. Initial data suggest that additional analogues
based on the benzodiazepine templates are worthy of
further investigation.
Exp er im en ta l Section
Gen er a l P r oced u r es. All commercially available reagents
were used without further purification, unless otherwise noted.
Anhydrous THF was distilled from Na/benzophenone. The
melting points are uncorrected. Unless otherwise noted, TLC
analysis was performed using glass plate or plastic sheet
precoated with silica gel 60 F254. Analytical HPLC was carried
out on a C18 (5 µm, 100 Å) 50 mm × 4.6 mm column using a
linear gradient of 0-100% solvent B over 11 min at 1.5 mL/
min (solvent A: 0.1% H3PO4 in H2O; solvent B: 0.1% H3PO4
in 90% aqueous CH3CN.) Wavelength detection was carried
out at 214 and 254 nm. ESMS was carried out using an
electrospray inlet. LC-MS analyses were performed using two
different systems (A and B). System A: A mass spectrometer
using electron spray ionization technique was employed. HPLC
was performed on a 5 µm C18 column (50 mm × 4.6 mm) using
a linear gradient of 0-100% solvent B over 11 min (solvent A:
0.01% TFA in H2O; solvent B: 0.01% TFA in 90% aqueous
CH3CN) at a flow rate of 1.5 mL/min. System B: A HPLC
system coupled with a mass spectrometer using electrospray
ionization technique. HPLC was performed on a 5 µm betasil
C8 column (100 mm × 2 mm) using a linear gradient of 5-95%
solvent B over 5 min followed by 95% solvent B for 3 min and
5% solvent B for two min (solvent A: 0.05% TFA in H2O;
solvent B: 0.05%TFA in CH3CN) at a flow rate of 0.30 mL/
min. IR was carried out with samples presented on disposable
microporous polyethylene disks.
Cell Cu ltu r e Meth od s. INS-1 cells were grown as de-
scribed by Asfari et al.22 in RMPI 1640 medium supplemented
with 10% fetal calf serum, 50 µM 2-mercaptoethanol, 10 mM
HEPES, 1 mM pyruvate, 100 IU/mL penicillin, and 100 µg/
mL streptomycin, in a humidified 5% CO2 atmosphere at 37
°C.
Mea su r em en t of Mitoch on d r ia l Sod iu m -Ca lciu m Ex-
ch a n ge Activity. INS-1 pancreatic â-cells were harvested by
trypsinization and resuspended at 10 × 106 cells/mL in 250
mM sucrose, 10 mM HEPES, 2.5 mM K2HPO4, and 5 mM
succinic acid, pH 7.4. Digitonin (final concentration 0.007%
v/v), Calcium Green 5 N (0.05 µM; membrane impermeant
form), rotenone (1 µM), cyclosporin A (1 µM), and calcium
chloride (60 µM) were added, followed by 1 µM ruthenium red.
The cells were transferred to 96 well plates (106 cells/well),
and test agents were added. Fluorescence was monitored
continuously before, during, and after the addition of 20 mM
NaCl. Activity was reported as the slope of the fluorescent
signal following NaCl addition.
a
Reagents and conditions: (i) Ph3PMeBr, t-C5H11OK, THF; (ii)
HSCH2CO2Me, 1,1′-azobis(cyclohexanecarbonitrile), 1,4-dioxane;
(iii) LHMDS, THF.
SCHEME 9a
a
Reagents and conditions: (i) ethylenediamine, CDI, DMF,
room temperature; (ii) 10% Pd/C, formic acid.
TABLE 2. n NCE Activity of 2,5-Ben zod ia zocin -1-on es
mNCE
compd
R
(IC50, µM)
28a
28b
29a
29b
phenyl
4-methylphenyl
phenyl
159
100
63.1
79.4
4-methylphenyl
using palladium on activated carbon in formic acid to give
29. Attempted transformation of 28 to 29 using other
conditions, including Pd/C under hydrogen atmosphere,
NaBH3(CN) in DMF/acetic acid, and LiAlH4, failed to
provide satisfactory yields.
The 1,5-benzothiazocinone 22 exhibited an IC50 of 12.6
µM for mNCE, whereas the 1,4-benzothiazocinone 26a
(R ) Cl) and 26b (R ) F) showed IC50 values of 6.3 and
15.9 µM, respectively. As shown in Table 2, compounds
based on the 2,5-benzodiazocin-1-one template failed to
inhibit mNCE significantly. It should be noted that the
geometry of the amide moiety in 28 and 29 has been
reversed compared to that in 22. The inhibitory activities
of these compounds underscore the desirable character-
istics of the benzothiazepine system and the 2-chloro
substituent in the pendant phenyl ring as discussed in
earlier sections.
[(2-Am in o-5-ch lor op h en yl)-(2-ch lor op h en yl)-m et h yl-
su lfa n yl]-a cetic Acid Meth yl Ester (3a ). To a stirred
solution of 2-amino-2′,5-dichlorobenzhydrol (2a ) (268 mg, 1.0
mmol) in TFA (2 mL) at room temperature was added methyl
thioglycolate (0.357 mL, 4.0 mmol). After 96 h of stirring, the
TFA was evaporated, and the residue was partitioned between
CH2Cl2 and 10% aqueous NaOH. The aqueous layer was
extracted with CH2Cl2 twice. The combined organic layers were
washed with brine, dried over anhydrous sodium sulfate, and
Con clu sion
In this report, we have provided the efficient syntheses
of several benzothiazepinones and derivatives via several
alternative pathways involving a key S-alkylation reac-
tion using 2-aminobenzhydrols. A diverse set of benzothi-
(22) Asfari M.; J anjic D.; Meda P.; Li, G.; Halban, P. A.; Wollheim,
C. B. Endocrinology 1992, 130, 167.
J . Org. Chem, Vol. 68, No. 1, 2003 97

Pei et al.
1
filtered. The filtrate was concentrated under vacuum to give
the crude product, which was purified on a silica gel column
using petroleum ether and ethyl acetate as eluents to give 3a
as a pale yellow solid (167 mg, 47%). Rf [petroleum ether/ethyl
acetate (5:1)] ) 0.40; HPLC (214 nm) tR ) 9.20 (98.2%) min;
1H NMR (400 MHz, CDCl3) δ 3.14 (d, J ) 16.0 Hz, 1H), 3.22
(d, J ) 16.0 Hz, 1H), 3.73 (s, 3H), 4.52 (brs, 2H), 5.80 (s, 1H),
6.75 (d, J ) 8.4 Hz, 1H), 6.81 (d, J ) 2.4 Hz, 1H), 7.05 (dd, J
) 2.4, 8.8 Hz, 1H), 7.27-7.31 (m, 1H), 7.37-7.42 (m, 2H),
7.91-7.93 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 33.6,
46.1, 52.6, 118.1, 123.8, 125.2, 127.2, 128.1, 128.5, 129.2, 130.1,
130.3, 134.7, 135.4, 142.6, 170.9 ppm; ESMS m/z 250.3 [M -
C3H4O2S]+, 356.2 [M + H]+; LC-MS tR (system A) 9.27 (356.0
[M + H]+) min.
tR ) 9.06 (92.7%) min; H NMR (400 MHz, CDCl3) δ 2.33 (s,
3H), 2.97 (d, J ) 12.2 Hz, 1H), 3.33 (d, J ) 12.2 Hz, 1H), 5.61
(s, 1H), 6.95 (d, J ) 2.2 Hz, 1H), 7.00 (s, 1H), 7.04-7.07 (m,
2H), 7.24 (dd, J ) 2.2, 8.4 Hz, 1H), 8.52 (s, 1H) ppm; 13C NMR
(100 MHz, CDCl3) δ 21.3, 31.5, 47.2, 125.1, 127.1, 128.5, 128.7,
130.2, 133.0, 134.8, 135.8, 136.7, 138.5, 170.5 ppm; ESMS m/z
318.3 [M + H]+, 635.0 [2M + H]+; LC-MS tR (system A) ) 9.47
(318.0 [M + H]+, 635.1 [2M + H]+, 954.1 [3M + H]+) min;
HRMS [M + Na]+
) 340.0539, [M + Na]+
) 340.0529;
calcd
obsd
IR 3202, 1681, 1482, 1357, 1115, 816 cm-1
.
7-Ch lor o-5-(2-b en zot h ia zolyl)-1,2,3,5-t et r a h yd r o-4,1-
ben zoth ia zep in -2-on e (1k ). Compound 1k was obtained
from 2k using Method B as an off-white solid (19.6 mg, 17.7%
yield): Rf [petroleum ether/ethyl acetate (2:1)] ) 0.33; HPLC
(214 nm) tR ) 7.57 (85.0%) min; 1H NMR (400 MHz, CDCl3) δ
3.10 (d, J ) 12.4 Hz, 1H), 3.20 (d, J ) 12.4 Hz, 1H), 5.65 (s,
1H), 7.02 (d, J ) 9.0 Hz, 1H), 7.34-7.40 (m, 3H), 7.41 (dd, J
) 1.1, 7.3 Hz, 1H), 7.77 (brs, 1H), 7.86 (d, J ) 8.0 Hz, 1H),
7.93 (d, J ) 8.0 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ
30.8, 47.0, 121.7, 123.3, 125.4, 126.2, 126.3, 129.7, 133.4, 134.7,
135.8, 153.8, 169.1, 171.1 ppm; ESMS m/z 379.3 [M + H]+;
LC-MS tR (system A) ) 7.89 (347.2 [M + H]+, 693.2 [2M +
Using similar procedures, additional examples 3b-g, 3i,
and 3o,p were also synthesized. Their experimental details
are described in Supporting Information.
7-Ch lor o-5-(2-ch lor op h en yl)-1,2,3,5-tetr a h yd r o-4,1-ben -
zoth ia zep in -2-on e (1a ). Step (a). To a stirred solution of 3a
(1.128 g 3.2 mmol) in 120 mL of THF/methanol (1/1) at room
temperature was added 60 mL of 1.0 M aqueous NaOH. After
1 h of stirring, the solvents were evaporated, and the residue
was partitioned between brine and CH2Cl2. The aqueous phase
was titrated to pH 7.0 with 10% aqueous HCl and extracted
with CH2Cl2 twice. The combined organic layers were dried
over anhydrous sodium sulfate. The drying agent was removed
by filtration. The filtrate was concentrated under vacuum to
give the crude carboxylic acid, which was used in the following
step without further purification.
H]+) min; HRMS [M + Na]+
) 368.9899, [M + Na]+
)
calcd
obsd
368.9899; IR 1682, 1489, 1473, 1462 1116, 759 cm-1
.
7-Ch lor o-5-(2-t h iop h en yl)-1,2,3,5-t et r a h yd r o-4,1-b en -
zoth ia zep in -2-on e (1l). Compound 1l was obtained from 2l
using Method B as an off-white solid (33.4 mg, 23.7% yield):
Rf [petroleum ether/ethyl acetate (2:1)] ) 0.21; HPLC (214 nm)
tR ) 7.82 (97.9%) min; 1H NMR (400 MHz, CDCl3) δ 3.01 (d, J
) 12.3 Hz, 1H), 3.31 (d, J ) 12.3 Hz, 1H), 5.83 (s, 1H), 7.04-
7.06 (m, 2H), 7.11 (d, J ) 2.2 Hz, 1H), 7.17 (d, J ) 3.5 Hz,
1H), 7.28 (dd, J ) 2.2, 8.3 Hz, 1H), 7.32 (d, J ) 5.1 Hz, 1H),
8.52 (s, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 31.8, 42.5,
125.4, 126.1, 127.3, 127.7, 128.5, 128.9, 133.2, 134.6, 136.3,
139.8, 170.3 ppm; ESMS m/z 296.2 [M + H]+; LC-MS tR
(system A) ) 8.13 (295.9 [M + H]+, 591.2 [2M + H]+, 887.9
Step (b). To a stirred solution of the crude carboxylic acid
(3.2 mmol) in THF (300 mL, high dilution to minimize
intermolecular coupling) at room temperature was added
DIEA (0.84 mL, 4.8 mmol), EDC (0.842 mL, 4.8 mmol), and
DMAP (39 mg, 0.32 mmol). After 20 h of stirring, the solvent
was removed under vacuum. The residue was dissolved in CH2-
Cl2 (300 mL); washed successively with 10% aqueous citric acid
(150 mL), saturated aqueous sodium bicarbonate (150 mL),
and brine (150 mL); dried over sodium sulfate; filtered; and
concentrated under vacuum. The crude product was purified
by flash chromatography on a silica gel column using a mixture
of petroleum ether and ethyl acetate as eluent to give 1a a
white solid (0.462 g, 45%). Rf [petroleum ether/ethyl acetate
(2:1)] ) 0.30; HPLC (214 nm) tR ) 8.42 (92.6%) min; 1H NMR
(400 MHz, CDCl3) 3.04 (dd, J ) 1.6, 12.0 Hz, 1H), 3.33 (d, J )
12.0 Hz, 1H), 6.15 (s, 1H), 6.73 (d, J ) 1.6 Hz, 1H), 7.05 (d, J
) 8.4 Hz, 1H), 7.26-7.44 (m, 5H), 7.82-7.84 (m, 1H) ppm;
13C NMR (100 MHz, CDCl3) 31.3, 43.5, 125.1, 127.1, 128.0,
128.7, 129.6, 130.3, 130.8, 133.2, 134.0, 134.1, 134.9, 135.4,
169.9 ppm; ESMS m/z 324.2 [M + H]+; LC-MS tR (system A)
8.64 (323.8 [M + H]+, 647.1 [2M + H]+) min; HRMS [M +
Na]+calcd ) 345.9836, [M + Na]+obsd ) 345.9832; IR 3201, 1681,
[3M + H]+) min; HRMS [M + Na]+
) 317.9790, [M +
calcd
Na]+obsd ) 317.9779; IR 3199, 1680, 1482, 1358, 1111, 710 cm-1
.
7-Ch lor o-5-(2-th iazolyl)-1,2,3,5-tetr ah ydr o-4,1-ben zoth i-
a zep in -2-on e (1m ). Compound 1m was obtained from 2m
using Method B as a mustard brown solid (66 mg, 21.5%
yield): Rf [petroleum ether/ethyl acetate (1:1)] ) 0.15; HPLC
(214 nm) tR ) 6.10 (92.8%) min; 1H NMR (400 MHz, CDCl3) δ
3.16 (d, J ) 12.4 Hz, 1H), 3.21 (d, J ) 12.4 Hz, 1H), 5.64 (s,
1H), 7.01 (d, J ) 8.4 Hz, 1H), 7.23 (d, J ) 2.3 Hz, 1H), 7.32
(dd, J ) 2.3, 8.4 Hz, 1H), 7.38 (d, J ) 3.2 Hz, 1H), 7.70 (d, J
) 3.2 Hz, 1H), 8.14 (s, 1H) ppm; 13C NMR (100 MHz, CDCl3)
δ 31.0, 45.9, 120.8, 126.0, 129.4, 129.5, 133.1, 134.7, 134.9,
143.7, 169.4, 169.8 ppm; ESMS m/z 297.2 [M + H]+; LC-MS
tR (system A) ) 6.22 (297.0 [M + H]+) min; HRMS [M +
Na]+calcd ) 318.9742, [M + Na]+obsd ) 318.9739; IR 3195, 1681,
1483, 1355, 1114, 755 cm-1
.
1490, 1351, 1115, 811 cm-1
.
Using similar procedures, additional examples 1b-g, 1i,
and 1o,p were also synthesized. Their experimental details
are described in Supporting Information.
Syn th esis of [(2-Ben zam idoph en yl)-(2-m eth ylph en yl)-
m eth ylsu lfa n yl]-a cetic Acid Meth yl Ester (5). To a stirred
solution of 4 (287 mg, 0.904 mmol) in TFA (5.0 mL) under a
nitrogen atmosphere at room temperature was added methyl
thioglycolate (0.323 mL, 4 equiv). After 18 h of stirring, the
TFA was evaporated, and the residue was partitioned between
CH2Cl2 and aqueous NaOH (1 M). The aqueous phase was back
extracted with CH2Cl2, and the combined organics were dried
with brine and sodium sulfate, filtered, and evaporated to give
the crude product (317 mg) as a yellow solid. The crude
material was purified by flash chromatography on silica (15
g) by eluting with petroleum ether/ethyl acetate (5:1 then 2:1)
to give the thioether 5 as a yellow oil (225 mg, 61%): Rf
[petroleum ether/ethyl acetate (2:1)] ) 0.65; 1H NMR (400
MHz, CDCl3) δ 8.90 (brs, 1H), 8.01 (d, J ) 7.6 Hz, 1H), 7.88-
7.96 (m, 2H), 7.70 (dd, J ) 0.8, 7.6 Hz, 1H), 7.40-759 (m, 3H),
7.01-7.36 (m, 6H), 5.83 (s, 1H), 3.41 (s, 3H), 3.13 (s, 2H), 2.11
(s, 3H) ppm; 13C NMR (100 MHz, CDCl3) 170.79, 165.98,
Gen er a l P r oced u r e for Meth od B. 2-Aminobenzhydrol
2 (1.0 mmol) was mixed with methyl thioglycolate (6 equiv)
and TFA (2 mL). The mixture was stirred at 85 °C for 18 h.
The black solution was diluted with CH2Cl2 (80 mL) and
washed with 1.0 M aqueous NaOH (20 mL) and brine (20 mL).
The organic layer was dried over sodium sulfate, filtered, and
concentrated under vacuum. The crude product was purified
by flash chromatography on a silica gel column using a mixture
of petroleum ether and ethyl acetate as eluent to give 1. In
some cases, the corresponding thioether 3 was also isolated
as a minor component from the crude products. Using this
general procedure the following compounds were synthesized:
7-Ch lor o-5-(3,5-d im eth ylp h en yl)-1,2,3,5-tetr a h yd r o-4,1-
ben zoth ia zep in -2-on e (1j). Compound 1j was obtained from
2j using Method B as an off-white solid (86.7 mg, 28% yield):
Rf [petroleum ether/ethyl acetate (2:1)] ) 0.31; HPLC (214 nm)
98 J . Org. Chem., Vol. 68, No. 1, 2003

Efficient Syntheses of Benzothiazepines
137.35, 136.22, 135.46, 134.76, 133.50, 131.77, 131.11, 130.12,
129.08, 128.55, 128.49, 128.44, 127.89, 127.53, 126.46, 125.26,
124.61, 52.25, 46.41, 33.27, 19.12 ppm; ESMS m/z 406.1 [M +
1]+.
H]+; LC-MS tR (system A) ) 9.74 (328.1 [M - OH]+, 346.3 [M
+ H]+, 691.4 [2M + H]+) min.
Syn th esis of 1h a n d 1n . A solution of benzhydrol 7 (1.8
mmol) in methyl thioglycolate (0.5 mL) and TFA (2 mL) was
stirred at 80 °C for 24 h. The mixture was diluted with CH2-
Cl2 (50 mL) and washed with brine (20 mL), 1.0 N aqueous
NaOH (20 mL), and brine (20 mL). The combined aqueous
layers were back extracted with CH2Cl2 (10 mL). The combined
organic layers were dried over sodium sulfate, filtered, and
concentrated under vacuum. The residue was purified by flash
chromatography on a silica gel column using a mixture of
petroleum ether and ethyl acetate as eluent to yield 1.
5-(2-Meth ylp h en yl)-1,2,3,5-tetr a h yd r o-4,1-ben zoth ia z-
ep in -2-on e (1q). Step (a). To a stirred solution of 6 in THF (3
mL) and methanol (3 mL) was added 1.0 N NaOH (3 mL). The
mixture was refluxed for 18 h. The solvents were evaporated,
and the residue was partitioned between brine and CH2Cl2.
The aqueous phase was titrated to pH 7.0 with 10% HCl and
then was back extracted twice with CH2Cl2. The combined
organic layers were extracted with brine, dried over anhydrous
sodium sulfate, filtered, and evaporated to give the crude
carboxylic acid/amine (117 mg, 83% crude yield) as a white
solid. Rf [petroleum ether/ethyl acetate (2:1)] ) 0.
Step (b). To a stirred solution of the crude carboxylic acid
(117 mg, ∼0.407 mmol) in THF (40.7 mL, to give an overall
concentration of ∼10 mM) under a nitrogen atmosphere at
room temperature were added DIEA (0.213 mL, 1.22 mmol),
EDC (117 mg, 0.61 1 mmol), and DMAP (5 mg, 0.041 mmol).
After 18 h of stirring, the THF was evaporated, and the residue
was dissolved in CH2Cl2, partitioned against 10% citric acid
and saturated aqueous NaHCO3, and finally washed with
brine. The organic layer was dried over anhydrous sodium
sulfate, filtered, and evaporated. The crude material (116 g)
was adsorbed onto silica (1 g) and purified by flash chroma-
tography on silica (5 g) with petroleum ether/ethyl acetate (2:
1) to give 5 as an off-white solid (20 mg, 20% yield for two
steps): Rf [petroleum ether/ethyl acetate (2:1)] ) 0.30; HPLC
(214 nm) tR ) 7.89 (88.8%) min; 1H NMR (400 MHz, CDCl3) δ
7.89 (brs, 1H), 7.77 (d, J ) 7.6 Hz, 1H), 7.23-7.37 (m, 3H),
7.08-7.23 (m, 3H), 7.78 (dd, J ) 0.8, 7.6 Hz 1H), 5.97 (s, 1H),
3.37 (d, J ) 12.0 Hz, 1H), 3.02 (dd, J ) 2.0, 12.0 Hz, 1H), 2.05
(s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 170.43, 136.47,
136.43, 135.18, 134.02, 130.91, 129.27, 128.42, 128.19, 127.98,
127.69, 126.15, 123.50, 43.63, 31.49, 19.35 ppm; ESMS m/z
270.0 [M + 1]+, 539.1 [2M + 1]+; LC-MS tR (system A) ) 8.06
(270.3 [M + H]+, 339.4 [2M + H]+, 808.1 [3M + 1]+) min.
7-Ch lor o-5-(2,6-d im eth ylp h en yl)-1,2,3,5-tetr a h yd r o-4,1-
ben zoth ia zep in -2-on e (1h ) was obtained as a white amor-
phous solid (11.3 mg, 24.6%): Rf [petroleum ether/ethyl acetate
(1:1)] ) 0.55; HPLC (214 nm) tR ) 8.72 (97.8%) min; 1H NMR
(400 MHz, CDCl3) δ 2.44 (s, 6H), 2.97 (dd, J ) 1.9, 12.6 Hz,
1H), 3.58 (d, J ) 12.6 Hz, 1H), 6.28 (s, 1H), 6.96 (d, J ) 2.3
Hz, 1H), 7.06 (d, J ) 8.4 Hz, 1H), 7.10-7.12 (m, 2H), 7.17 (d,
J ) 7.5 Hz, 1H), 7.27 (dd, J ) 2.3, 8.4 Hz, 2H), 8.11 (s, 1H)
ppm; 13C NMR (100 MHz, CDCl3) δ 22.5, 31.5, 41.7, 125.2,
128.3, 128.7, 129.9, 132.2, 132.6, 132.8, 135.5, 170.6 ppm; LC-
MS tR (system A) ) 9.04 (317.9 [M + H]+, 358.8 [M + CH3-
CN]+, 635.2 [2M + H]+) min; HRMS [M + Na]+calcd ) 340.0539,
[M + Na]+obsd ) 340.0541; IR 3201, 1681, 1482, 1116, 772 cm-1
.
7-Ch lor o-5-(4-pyr idin yl)-1,2,3,5-tetr ah ydr o-4,1-ben zoth i-
a zep in -2-on e (1n ) was obtained as a white amorphous solid
(40.5 mg, 42%): Rf [petroleum ether/ethyl acetate (1:1)] ) 0.10;
HPLC (214 nm) tR ) 4.85 (93.3%) min; 1H NMR (400 MHz,
CDCl3) δ 3.12 (d, J ) 12.3 Hz, 1H), 3.19 (d, J ) 12.3 Hz, 1H),
5.43 (s, 1H), 7.01 (s, 1H), 7.02 (d, J ) 8.4 Hz, 1H), 7.05 (d, J
) 2.4 Hz, 1H), 7.33 (dd, J ) 2.4, 8.4 Hz, 1H), 7.40 (d, J ) 5.0
Hz, 2H), 8.63 (d, J ) 5.0 Hz, 2H) ppm; 13C NMR (100 MHz,
CDCl3) δ 31.0, 47.4, 123.8, 126.2, 129.4, 129.5, 133.5, 135.0,
135.8, 146.8, 150.4, 169.4 ppm; ESMS m/z 291.4 [M + H]+;
LC-MS tR (system A) ) 4.86 (290.9 [M + H]+, 581.0 [2M +
H]+, 872.9 [3M + H]+) min; HRMS [M + Na]+
) 313.0178,
calcd
[M + Na]+
) 313.0188; IR 3053, 1688, 1484, 1416, 1352
obsd
848 cm-1
.
Syn th esis of 7a ,b. To a solution of 6 (2.4 mmol) in THF
(10 mL) under an atmosphere of nitrogen at -78 °C was added
n-butyllithium (2.5 mL, 2.4 M solution in diethyl ether) over
5 min. The reaction was allowed to warm to 0 °C and kept at
this temperature for 2 h. A solution of aldehyde (4.8 mmol) in
THF (2 mL) was added. The mixture was allowed to warm to
room temperature over 1 h. The reaction was quenched with
1.0 N aqueous HCl (10 mL) and extracted with ethyl acetate
(3 × 50 mL). The combined organic layers were dried over
sodium sulfate, filtered, and concentrated under vacuum. The
residue was purified on a silica gel column using petroleum
spirit/ethyl acetate as eluents.
Micr ow a ve-Assisted On e-P ot Syn th esis of 1a (Meth od
E). To a mixture of 2a (1.0 g, 3.75 mmol), HSCH2COOMe (1.40
mL, 15.0 mmol), and TFA (4.0 mL, 52.0 mmol) in a 50-mL
beaker was added basic alumina (13.0 g). The heterogeneous
mixture was mixed well and subjected to microwave irradia-
tion in a domestic oven for 7 min at full power (800 W). TLC
of the reaction mixture showed a small amount of the desired
product 1a , a less polar spot, and a major amount of compound
3a . To the above reaction mixture was added saturated
aqueous Na2CO3 (5 mL). The mixture was stirred well with a
glass rod and microwaved for 5 min at 20% power. This
procedure (addition of saturated aqueous Na2CO3 followed by
microwave irradiation at 20% power) was repeated four times.
TLC indicated complete disappearance of 3a and the formation
of 1a (major) and a small amount of the hydrolysis product of
3a . The mixture was extracted with 10% MeOH/CHCl3. The
combined organic extracts were concentrated under vacuum,
redissolved in CH2Cl2, washed with saturated aqueous Na2-
CO3 and brine, dried over anhydrous Na2SO4, filtered, and
concentrated under vacuum to give pure 1a (0.61 g, 51%)
whose analytical data were identical with the sample obtained
using method A above.
Syn th eses of 9a . To a solution of 8 (3 g, 1.32 mmol) at -78
°C in dry THF (10 mL) was added t-BuLi (22 mL, 1.6 M in
THF, 3.3 mmol) slowly over a period of 30 min. The mixture
was stirred at 0 °C for 2 h and cooled to -78 °C. A solution of
4-benzyloxy-1-butanal (2.6 g, 1.45 mmol) in THF (5 mL) was
added slowly. The reaction mixture was stirred for an ad-
ditional 2 h, quenched with saturated aqueous NH4Cl (30 mL),
and extracted with EtOAc (3 × 30 mL). The combined organic
layers were washed with water, saturated aqueous NaHCO3,
and brine and dried over anhydrous sodium sulfate. The
solvents were filtered and evaporated, and the crude material
N-{4-Ch lor o-2-[(2,6-dim eth yl-ph en yl)-h ydr oxy-m eth yl]-
p h en yl}-2,2-d im eth yl-p r op ion a m id e (7a ) was obtained as
white crystals (585 mg, 76%): Rf [petroleum ether/ethyl
acetate (1:1)] ) 0.31; HPLC (214 nm) tR ) 8.20 (98.1%) min;
1H NMR (400 MHz, CDCl3) δ 1.04 (s, 9H), 5.74 (s, 1H), 7.07
(d, J ) 2.4 Hz, 1H), 7.24-7.30 (m, 4H), 8.10 (d, J ) 8.8 Hz,
1H), 8.34 (d, J ) 5.7 Hz, 2H), 9.08 (s, 1H) ppm; 13C NMR (100
MHz, CDCl3) δ 27.2, 39.5, 73.9, 121.4, 124.4, 128.8, 129.0,
132.5, 135.9, 149.0, 151.2, 177.1 ppm; ESMS m/z 319.3 [M +
H]+, 637.3 [2M + H]+; LC/MS tR (system A) ) 5.22 (319.1 [M
+ H]+, 637.1 [2M + H]+) min.
N-{4-Ch lor o-2-[(4-p yr id yl)-h yd r oxy-m et h yl]-p h en yl}-
2,2-d im eth yl-p r op ion a m id e (7b) was obtained as a viscous
oil (285 mg, 44% yield): Rf [petroleum ether/ethyl acetate (1:
1
1)] ) 0.41; HPLC (214 nm) tR ) 9.42 (84.4%) min; H NMR
(400 MHz, CDCl3) δ 1.21 (s, 9H), 2.18 (s, 6H), 6.23 (s, 1H),
6.51 (d, J ) 2.4 Hz, 1H), 6.99-7.01 (m, 2H), 7.11 (s, 1H), 7.13
(dd, J ) 2.4, 8.8 Hz, 1H), 8.04 (d, J ) 8.8 Hz, 2H), 9.67 (s, 1H)
ppm; 13C NMR (100 MHz, CDCl3) δ 20.9, 27.5, 39.8, 71.0, 123.4,
127.0, 128.0, 128.2, 128.4, 128.5, 129.6, 130.9, 136.1, 136.6,
137.1, 177.4 ppm; ESMS m/z 328.4 [M - OH]+, 346.5 [M +
J . Org. Chem, Vol. 68, No. 1, 2003 99

Pei et al.
was purified over flash silica gel column chromatography using
a mixture of ethyl acetate and hexane as eluent to give 9a as
an oil (2 g, 37%). The undesired product 12a was isolated in
30% yield: 1H NMR (500 MHz, CDCl3) δ 1.28 (m, 2H), 1.48 (s,
9H), 1.97 (m, 2H), 3.53 (m, 2H), 4.52 (s, 2H), 4.70 (s, 1H), 7.08
(d, 1H, J ) 2.3 Hz), 7.20 (m, 1H), 7.34 (m, 6H) ppm; LC-MS tR
(system B) ) 8.58 (288 [M + H - (Boc + H2O)]+) min.
Syn th esis of 10a . To a solution of 9a (0.6 g, 1.48 mmol) in
dry CH2Cl2 (3 mL) were added methyl thioglycolate (0.78 g,
7.4 mmol) and TFA (3.4 g, 29 mmol). The mixture was stirred
at room temperature for 18 h. The solvent was removed under
vacuum. The residue was dissolved in CH2Cl2 (30 mL); washed
with saturated aqueous NaHCO3 solution, water, and brine;
and dried over anhydrous sodium sulfate. The crude material
was purified using silica gel chromatography (40-60% ethyl
acetate in hexane) to give 10a as an oil (0.35 g, 60%): 1H NMR
(500 MHz, CDCl3) δ 1.64 (m, 2H), 2.05 (s, 2H), 3.01 (d, J )
12.25 Hz, 1H), 3.13 (d, J ) 12.25 Hz, 1H), 3.48 (m, 2H), 3.66
(s, 3H), 4.11 (m, 1H), 4.47 (s, 2H), 6.57 (d, J ) 9.0 Hz, 1H),
7.00 (m, 1H), 7.12 (s, 1H), 7.34 (m, 6H) ppm; LC-MS tR (system
B) ) 8.39 (289 [M + H - (SCH2COOMe)]+) min.
Syn th esis of 7-Ch lor o-5-[(3-ben zoxyl)p r op yl]-1,2,3,5-
tetr a h yd r o-4,1-ben zoth ia zep in -2-on e (11a ). Step (a). To a
solution of compound 10a (0.3 g, 0.76 mmol) in MeOH (2 mL)
at 0 °C was added a solution of NaOH (0.62 g, 1.5 mmol) in
water (0.5 mL). The mixture was stirred for an additional 2 h
at 0 °C. The solvent was removed under vacuum. The residue
was dissolved in ethyl acetate (30 mL) and carefully acidified
using 1 N HCl. The organic layer was separated, washed with
water and brine, dried over sodium sulfate, filtered, and
concentrated to give the acid (0.29 g, 0.76 mmol), which was
used in the next step without further purification.
8.30 Hz), 7.27 (m, 1H), 7.30 (m, 1H), 7.80 (s, 1H) ppm; LC-MS
tR (system B) ) 7.20 (270 [M + H]+) min.
Syn th esis of 13. To a solution of 2a (1 g, 3.7 mmol) and
mercaptoethanol (1.448 g, 19 mmol) in dry CH2Cl2 (7 mL) was
added TFA (7.4 mL, 65 mmol). The mixture was stirred at
room temperature for 18 h. The solvent was removed under
vacuum. The residue was dissolved in CH2Cl2 (30 mL); washed
with saturated aqueous NaHCO3, water, and brine; dried over
sodium sulfate; filtered; and concentrated under vacuum. The
crude material was purified using silica gel column chroma-
tography (40-60% ethyl acetate in hexane) to give 13 as a
white solid (0.65 g, 54%): mp 104-105 °C; 1H NMR (500 MHz,
CDCl3) δ 2.657 (t, J ) 6.00 Hz, 2H), 3.79 (m, 2H), 5.66 (s, 1H),
6.63 (d, J ) 8.30 Hz, 1H), 7.05 (m, 1H), 7.13 (d, J ) 2.1 Hz,
1H), 7.265 (m, 1H), 7.33 (m, 1H), 7.42 (d, J ) 7.0 Hz, 1H),
7.65 (d, 8.73 Hz, 1H) ppm; LC-MS tR (system B) ) 7.12 (250
[M + H - SCH2CH2OH]+) min.
Syn th esis of 14. To a solution of 13 (0.25 g, 0.76 mmol) in
dry CH2Cl2 (5 mL) at 0 °C were added triphenylphosphine
(0.81 g, 3.1 mmol), imidazole (0.26 g, 3.8 mmol), and carbon
tetrabromide (0.3 g, 0.9 mmol). After 2 h, the mixture was
diluted with CH2Cl2 (30 mL) and quenched with water (20 mL).
The organic layer was separated, washed with water and
brine, dried over sodium sulfate, filtered, and concentrated
under vacuum. The crude product was purified using silica
gel column chromatography (40-60% ethyl acetate in hexane)
to give 14 as pale yellow semisolid (0.25 g, 86%): 1H NMR
(500 MHz, CDCl3) δ 2.90 (t, J ) 7.5 Hz, 2H), 3.50 (t, J ) 7.5
Hz, 2H), 3.95 (s 2H), 5.65 (s, 1H), 6.65 (d, J ) 8.5 Hz, 1H),
7.05 (m, 1H), 7.13 (d, J ) 2.1 Hz, 1H), 7.265 (m, 1H), 7.33 (m,
1H), 7.42 (d, J ) 7.0 Hz, 1H), 7.65 (d, J ) 8.5 Hz, 1H) ppm;
LC-MS tR (system B) ) 8.66 (250 [M + H - (SCH2CH2Br)]+)
min.
Step (b). A solution of the acid from above (0.29 g, 0.76
mmol) in DMF (10 mL) was added via a syringe pump to a
solution of EDC (0.22 g, 1.14 mmol), HOBt (0.31 g, 2.3 mmol),
and DMAP (0.018 g, 0.15 mmol) in dry DMF (5 mL) over a
period of 24 h. The mixture was stirred for an additional 24
h. The DMF was removed under high vacuum. The residue
was dissolved in CH2Cl2 (30 mL), thoroughly washed with
water and brine, dried over sodium sulfate, filtered, and
concentrated. The crude material was purified using silica gel
column chromatography (40-60% ethyl acetate in hexane) to
give 11a as a white solid (0.15 g, 56% overall yield for two
steps); the starting acid (26%) was also recovered. Data for
Syn th esis of 7-Ch lor o-5-(2-ch lor op h en yl)-1,2,3,5-tet-
r a h yd r o-4,1-ben zoth ia zep in e (15). To a solution of 14 (0.1
g, 0.26 mmol) in dry DMF (2 mL) was added powdered K2CO3
(0.07 g, 0.51 mmol), and the solution was heated at 80 °C for
5 h. The reaction was quenched with water (20 mL), and the
product was extracted with ethyl acetate (3 × 20 mL). The
combined organic layers were thoroughly washed with water
(50 mL), brine (50 mL), dried over anhydrous Na2SO4, filtered,
and concentrated under vacuum. The crude residue was
purified using silica gel column chromatography (40-60%
ethyl acetate in hexane) to give 15 as a semisolid (0.069 g,
89%): 1H NMR (500 MHz, CDCl3) δ 2.84 (m, 1H), 3.05 (m,
1H), 3.18 (m, 1H), 3.68 (m, 1H), 3.79 (s, 1H), 5.73 (s, 1H), 6.54
(d, 1H, J ) 2.00 Hz), 6.85 (d, 1H, J ) 8.30 Hz), 7.02 (m, 1H),
7.28 (m, 1H), 7.38 (m, 2H), 7.58 (m, 1H) ppm; LC-MS tR (system
B) ) 8.10 (310 [M + H]+) min.
Syn th esis of 17. Using a similar procedure as for 10a ,
compound 17 was synthesized from 16 as a pale yellow oil (0.05
g, 50%): 1H NMR (500 MHz, CDCl3) δ 2.97 (s, 6H), 3.14 (d, J
) 17.5 Hz, 1H), 3.24 (d, J ) 17.5 Hz, 1H), 3.50 (m, 2H), 3.72
(m, 2H), 3.76 (s, 3H), 5.67 (s, 1H), 6.63 (d, J ) 8,73 Hz, 1H),
6.54 (d, J ) 2.70 Hz, 1H), 7.13 (m, 1H), 7.30 (m, 1H), 7.375
(m, 1H), 7.44 (m, 1H), 8.07 (m, 1H) ppm; LC-MS tR (system B)
) 6.64 (321 [M + H - (SCH2COOMe)]+) min.
Syn th esis of 18. To a solution of 17 (0.05 g, 0.12 mmol) in
dry THF (2 mL) at -78 °C was added LHMDS (1 M THF, 0.175
mL, 0.18 mmol) slowly, and the mixture was stirred for 5 h at
the same temperature. The reaction was quenched with
saturated aqueous NH4Cl (10 mL) and extracted with ethyl
acetate (3 × 20 mL). The combined organic portions were
washed with water, saturated aqueous NaHCO3, and brine;
dried over anhydrous Na2SO4; filtered; and concentrated under
vacuum. The crude product was purified using flash silica gel
column chromatography (5-10% MeOH/ CH2Cl2) to give 18
as a pale yellow oil (0.030 g, 66%): 1H NMR (500 MHz, CDCl3)
δ 2.27 (s, 6H), 2.53 (m, 1H), 2.74 (m, 1H), 3.02 (d, 1H, J )
12.3 Hz), 3.20 (d, 1H, J ) 12.3 Hz), 3.65 (m, 1H), 4.28 (m, 1H),
1
11a : mp 122-123 °C; H NMR (500 MHz, CDCl3) δ 1.68 (m,
1H), 1.81 (m, 1H), 2.02 (m, 1H), 2.17 (m, 1H), 2.93 (d, 1H, J )
12.28 Hz), 3.11 (d, 1H, J ) 12.28 Hz), 3.53 (m, 2H), 4.30 (t,
1H, J ) 7.46 Hz), 4.50 (s, 2H), 7.01 (d, 1H, J ) 8.30 Hz), 7.25
(m, 2H), 7.33 (m, 5H), 7.60 (s, 1H); LC-MS tR (system B) )
7.53 (362 [M + H]+) min.
Compounds 11b-c were synthesized following the same
route as illustrated above from 8 to 11a .
Compound 11b was obtained as a white solid (0.08 g, 35%
1
overall yield for four steps): mp 170-171 °C; H NMR (500
MHz, CDCl3) δ 0.74 (m, 1H), 0.98 (m, 1H), 1.20 (m, 2H), 1.32
(m, 2H), 1.61 (m, 2H), 1.81 (m, 1H), 2.11 (m, 1H), 2.34 (m,
1H), 2.87 (d, 1H, J ) 12.28 Hz), 3.10 (d, 1H, J ) 12.28 Hz),
3.73 (d, 1H, J ) 10.94 Hz), 6.99 (d, 1H, J ) 8.01 Hz), 7.27 (m,
2H, J ) 2.10 Hz), 7.44 (s, 1H); LC-MS tR (system B) ) 7.49
(296 [M + H]+) min.
Compound 11c was obtained as a white solid (0.15 g, 30%
1
overall yield for four steps): mp 113-114 °C; H NMR (500
MHz, CDCl3) δ 0.785 (d, 3H, J ) 6.87 Hz), 1.25 (d, 3H, J )
6.84 Hz), 2.45 (m, 1H), 2.89 (d, 1H, J ) 12.3 Hz), 3.08 (d, 1H,
J ) 12.3 Hz), 3.67 (d, 1H, J ) 10.6 Hz), 7.02 (d, 1H, J ) 7.9
Hz), 7.25 (m, 1H), 7.26 (m, 1H), 8.00 (s, 1H) ppm; LC-MS tR
(system B) ) 6.74 (256 [M + H]+) min.
Compound 11d was obtained as a white solid (0.10 g, 43%
1
overall yield for four steps): mp 106-107 °C; H NMR (500
MHz, CDCl3) δ 0.95 (d, 3H, J ) 10.34 Hz), 0.96 (d, 3H, J )
10.34 Hz), 1.76 (m, 1H), 1.85 (t, 2H, J ) 7.23 Hz), 2.91 (d, 1H,
J ) 12.25 Hz), 3.12 (d, 1H, J ) 12.25 Hz), 7.02 (d, 1H, J )
100 J . Org. Chem., Vol. 68, No. 1, 2003

Efficient Syntheses of Benzothiazepines
5.94 (s, 1H), 6.53 (s, 1H), 7.40 (m, 3H), 7.45 (m, 2H), 7.79 (d,
1H, J ) 7.8 Hz) ppm; LC-MS tR (system B) ) 6.16 (395 [M +
H]+) min.
were added diisopropylethylamine (0.257 mL, 1.47 mmol) and
bis(2-oxo-3-oxazolidinyl)phosphinic chloride (150 mg, 0.589
mmol). After 48 h of stirring, the reaction mixture was filtered,
and the THF was evaporated. The residue was partitioned
between brine and CH2Cl2, and the aqueous layer was back
extracted twice with CH2Cl2. The combined organic phase was
dried with anhydrous sodium sulfate, filtered, and evaporated.
The crude material was purified by flash chromatography on
silica (15 g) by eluting with 40-60 petroleum ether/ethyl
acetate (1:1) to give lactam 22 as a white solid (97.0 mg,
98%): Rf [40-60 petroleum ether/ethyl acetate (1:1)] ) 0.25;
HPLC (214 nm) tR ) 8.16 (96.3%) min; 1H NMR (400 MHz,
CDCl3) δ 2.38-2.47 (m, 1H), 2.71-2.80 (m, 1H), 2.87-2.95 (m,
1H), 3.20 (dd, J ) 14.4, 10.4 Hz, 1H), 5.33 (s, 1H), 6.96 (d, J
) 2.4 Hz, 1H), 7.11 (d, J ) 8.4 Hz, 1H), 7.16 (dd, J ) 8.4, 2.4
Hz, 1H), 7.20-7.29 (m, 2H), 7.35-7.41 (m, 1H), 7.65-7.71 (m,
1H), 8.68 (brs, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 28.4,
35.6, 43.5, 127.0, 127.4, 127.7, 128.3, 128.9, 129.0, 129.6, 132.0,
133.0, 134.4, 138.2, 143.3, 174.6 ppm; ESMS m/z 379.2 [M +
CH3CN + H]+; LC-MS tR (system A) ) 8.39 (337.8 [M + H]+,
379.0 [M + CH3CN + H]+, 675.0 [2M + H]+) min; HRMS [M
Syn th esis of 19. To a stirred solution of 3a (684 mg, 1.92
mmol) in THF/methanol (1/1, 40 mL) at room temperature was
added 1.0 M aqueous NaOH (20 mL). After 1 h of stirring, the
solvents were evaporated, and the residue was partitioned
between brine and CH2Cl2. The aqueous phase was titrated
to exactly pH 7.0 with 10% aqueous HCl and extracted with
CH2Cl2 twice. The combined organic layers were dried over
anhydrous sodium sulfate. The drying agent was removed by
filtration, and the filtrate was concentrated under vacuum to
give analytically pure 19 as a white solid (657 mg, 100%
yield): Rf [CH2Cl2/methanol (9:1)] ) 0.25; HPLC (214 nm) tR
) 8.27 (94.2%) min; 1H NMR (400 MHz, CDCl3) δ 3.20 (d, J )
16.0 Hz, 1H), 3.22 (d, J ) 16.0 Hz, 1H), 6.02 (s, 1H), 7.07 (d,
J ) 2.4 Hz, 1H), 7.31-7.37 (m, 2H), 7.40-7.47 (m, 2H), 7.80-
7.89 (m, 2H), 9.02 (s, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ
32.8, 45.0, 126.1, 127.6, 129.0, 129.8, 129.9, 130.5, 131.7, 132.6,
132.7, 133.9, 134.6, 175.0 ppm; ESMS m/z 250.2 [(M - HSCH2-
CO2H + H)]+, 342.1 [(M + H)]+. LC-MS tR (system A) ) 8.66
(346.0 [(M - HSCH2CO2H + CF3CO + H)]+, 438.1 [(M + CF3-
CO + H)]+, 874.8 [(2(M + CF3CO) + H)]+ min.
+ Na]+
) 359.9993, [M + Na]+
) 359.9985; IR 3058,
calcd
obsd
1665, 1487, 1472, 1111, 747 cm-1
.
1-Acetyl-7-ch lor o-5-(2-ch lor oph en yl)-1,2,3,5-tetr ah ydr o-
4,1-ben zod ia zep in -2-on e (20). To a stirred solution of car-
boxylic acid 19 (100 mg, 0.292 mmol) in THF (5.0 mL) under
a nitrogen atmosphere at room temperature were added
diisopropylethylamine (0.508 mL, 2.92 mmol), acetyl chloride
(104 µL, 1.46 mmol), and DMAP (3.6 mg, 0.029 mmol). After
3 h of stirring, the reaction mixture was partitioned between
CH2Cl2 and brine. The aqueous phase was back extracted twice
with CH2Cl2 and the combined organic phase was dried with
sodium sulfate, then filtered and concentrated under vacuum.
The crude material was purified by flash chromatography first
on silica (15 g) by eluting with dichloromethane:methanol (10:
1) and then again on silica (10 g) with dichloromethane (100%)
to give 20 as a bright yellow solid (45 mg, 40%): Rf [silica,
CH2Cl2 (100%) ) 0.50; HPLC (214 nm) tR ) 9.16 (96.7%) min;
1H NMR (400 MHz, CDCl3) δ 2.79 (s, 3H), 3.14 (s, 2H), 5.93
(s, 1H), 6.69 (d, J ) 2.4 Hz, 1H), 7.16 (d, J ) 8.4 Hz, 1H), 7.35
(dd, J ) 8.4, 2.4 Hz, 1H), 7.39 (dd, J ) 7.6, 1.6 Hz, 1H), 7.42-
7.49 (m, 2H), 7.76 (dd, J ) 7.6, 1.6 Hz, 1H) ppm; 13C NMR
(100 MHz, CDCl3) δ 27.7, 34.9, 43.0, 126.5, 127.2, 128.7, 129.5,
129.9, 130.4, 132.8, 134.4, 135.0, 35.5, 168.7, 172.0 ppm; ESMS
m/z 366.0 [M+H]+, 383.9 [M + H2O + H]+; LC-MS tR (system
A) ) 9.36 (365.9 [M + H]+, 748.1 [2M + NH4]+) min.
Syn th esis of 21. To a stirred solution of 2a (500 mg, 1.86
mmol) in TFA (10 mL) under a nitrogen atmosphere at room
temperature was added 3-mercaptopropionic acid (989 mg,
9.32 mmol). After 96 h of stirring, the reaction mixture was
partitioned between CH2Cl2 and brine (80 mL) containing
aqueous NaOH (10 M × 20 mL). The aqueous phase was
titrated to exactly pH 7.0 using concentrated HCl and then
extracted three times with CH2Cl2. The combined organic
phase was washed with brine, dried over anhydrous sodium
sulfate, filtered, and evaporated to give the crude thioether
(873 mg) as a brown oil. The crude material was purified by
flash chromatography on silica (20 g) by eluting with 40-60
petroleum ether/ethyl acetate (2:1 then 1:1) to give 21 as a
yellow gum (311 mg, 47%): Rf [40-60 petroleum ether/ethyl
acetate (1:1)] ) 0.42; HPLC (214 nm) tR ) 8.28 (86.7%) min;
1H NMR (400 MHz, CDCl3) δ 2.64-2.76 (m, 4H), 5.66 (s, 1H),
6.63 (d, J ) 8.4 Hz, 1H), 6.83 (s, 3H), 7.03-7.08 (m, 2H), 7.25
(ddd, J ) 7.6, 7.6, 1.2 Hz, 1H), 7.30-7.36 (m, 1H), 7.38-7.40
(m, 1H), 7.74 (dd, J ) 8.0, 1.2 Hz, 1H) ppm; 13C NMR (100
MHz, CDCl3) d 27.1, 34.0, 45.7, 118.1, 123.8, 125.8, 127.3,
128.30, 128.34, 128.9, 129.8, 130.4, 133.9, 136.2, 142.7, 177.4
ppm; ESMS m/z 250.0 [M - HS(CH2)2CO2H + H]+, 356.1 [M
+ H]+; LC-MS tR (system A) ) 8.43 (250.0 [M - HS(CH2)2-
CO2H + H]+, 355.9 [M + H]+, 710.9 [2M + H]+) min.
Gen er a l P r oced u r e for th e P r ep a r a tion of 24a ,b. To a
solution of Ph3PMeBr (1.5 equiv) in dry THF was added
t-C5H11OK (1.5 equiv) in portions under argon. After the
mixture was stirred at room temperature for 0.5 h, a solution
of the corresponding benzophenone derivative 23 in THF was
added dropwise. The reaction mixture was then stirred at room
temperature under argon overnight. The reaction mixture was
quenched with H2O and extracted twice with EtOAc. The
combined organic layers were washed with saturated NaHCO3
and brine, dried over anhydrous sodium sulfate, filtered,and
concentrated, and the residue was purified by column chro-
matography on silica gel.
F or 24a : following the general procedure, 23a (2.66 g, 10.0
mmol), t-C5H11OK (1.74 g, 15.0 mmol), and Ph3PMeBr (5.36
g, 15.0 mmol) were employed to give 24a as slightly orange
oil (1.95 g, 73%) after chromatography (EtOAc/hexane 10:90):
1H NMR (500 MHz, CDCl3) δ 3.66 (b, 2H), 5.61 (s, 1H), 5.87
(s, 1H), 6.57 (d, J ) 8.4 Hz, 1H), 7.06 (m, 2H), 7.17-7.23 (m,
3H), 7.26-7.31 (m, 1H) ppm; LC-MS tR (system B) ) 7.78
(264.0 [M + H]+) min.
F or 24b: following the general procedure, 23b (7.50 g, 30.0
mmol), t-C5H11OK (5.22 g, 45.0 mmol), and Ph3PMeBr (16.08
g, 45.0 mmol) were employed to give 24b (5.93 g, 80%) as
colorless oil after chromatography (EtOAc/hexane 10:90): 1H
NMR (500 MHz, CDCl3) δ 3.67 (b, 2H), 5.61 (s, 1H), 5.86 (s,
1H), 6.62 (d, J ) 8.3 Hz, 1H), 7.04-7.10 (m, 3H), 7.16-7.19
(m, 1H), 7.25-7.35 (m, 2H) ppm; LC-MS tR (system B) ) 7.53
(248 [M + H]+) min.
Gen er a l P r oced u r e for th e P r ep a r a tion of 25a ,b. To a
solution of the corresponding styrene derivative 24 and
HSCH2CO2Me (3.0 equiv) in 1,4-dioxane was added 1,1′-azobis-
(cyclohexanecarbonitrile) (0.1 equiv). The reaction mixture was
then warmed to 80 °C under argon and stirred at that
temperature overnight. Additional 1,1′-azobis(cyclohexanecar-
bonitrile) (0.05-0.1 equiv) was added to the reaction mixture,
which was stirred at 80 °C until TLC analysis indicated
disappearance of 24. The reaction mixture was diluted with
EtOAc, washed with saturated NaHCO3 and brine, dried over
anhydrous sodium sulfate, filtered, and concentrated, and the
residue was purified by column chromatography on silica gel.
F or 25a : following the general procedure, 24a (2.66 g, 10.08
mmol), HSCH2CO2Me (3.21 g, 30.23 mmol), and 1,1′-azobis-
(cyclohexanecarbonitrile) (369 mg, 1.51 mmol) were employed
to give 25a (3.15 g, 84%) as colorless oil after chromatography
(EtOAc/hexane 15:85):1H NMR (500 MHz, CDCl3) δ 3.10-3.30
(m, 2H), 3.18 and 3.23 (AB q, J ) 14.8 Hz, 2H), 3.74 (s, 3H),
4.68 (t, J ) 7.7 Hz, 1H), 6.60 (d, J ) 8.9 Hz, 1H), 7.02 (t, J )
Syn th esis of 22. To a stirred solution of 21 (105 mg, 0.294
mmol) in THF (29.4 mL) at room temperature under nitrogen
J . Org. Chem, Vol. 68, No. 1, 2003 101

Pei et al.
2.0 Hz, 1H), 7.03 (s, 1H), 7.16-7.26 (m, 3H), 7.40 (d, J ) 8.5
Hz, 1H) ppm; LC-MS tR (system B) ) 7.37 (370.1 [M + H]+)
min.
Syn th esis of 30a . In a sealed reaction tube were stirred
2-amino-2′,5-dichlorobenzophenone (0.5 g, 1.88 mmol) and
3-ethoxypropylamine (3 mL, 25 mmol) at 140 °C for 18 h. The
mixture was cooled to room temperature and diluted with CH2-
Cl2. The CH2Cl2 solution was washed with water, dried over
anhydrous magnesium sulfate, filtered, and concentrated
under vacuum. The crude product was purified using silica
gel column chromatography (hexane/ethyl acetate 6:1 then 4:1)
to give 30a as a light yellow oil (0.59 g, 88.5%): 1H NMR (500
MHz, CDCl3) δ 7.50-7.48 (m, 1H), 7.41-7.35 (m, 2H), 7.09-
7.03 (m, 2H), 6.80 (brs, 1H), 6.65-6.63 (m, 2H), 3.52-3.49 (m,
2H), 3.46-3.42 (m, 2H), 3.32-3.28 (m, 1H), 3.26-3.22 (m, 1H),
1.97-1.94 (m, 2H), 1.16 (t, J ) 6.9 Hz, 3H) ppm. LC-MS tR
(system B) ) 7.88 (351 [M + H]+) min.
Syn th esis of 31a . To a stirred solution of 30a (0.57 g 1.6
mmol) in 10 mL of MeOH/AcOH (100/1) at 0 °C was added
NaBH3(CN) (0.5 g, 8.12 mmol). The mixture was stirred for
18 h and allowed to warm to room temperature. The reaction
mixture was diluted with CH2Cl2, washed with water, dried
over anhydrous magnesium sulfate, filtered, and concentrated
to pure 31a as a light yellow oil (0.57 g, 100%): 1H NMR (500
MHz, CDCl3) δ 7.39 (t, J ) 6.6 Hz, 2H), 7.29-7.23 (m, 2H),
7.03 (dd, J ) 8.3, 2.5 Hz, 1H), 6.95 (d, J ) 2.5 Hz, 1H), 6.60
(d, J ) 8.3 Hz, 1H), 5.24 (s, 1H), 3.51-3.44 (m, 4H), 2.77-
2.71 (m, 2H), 1.83-1.81 (m, 2H), 1.16 (t, J ) 7.0 Hz, 3H) ppm;
LC-MS tR (system B) ) 5.83 (353 [M + H]+) min.
F or 25b: following the general procedure, 24b (1.74 g, 7.03
mmol), HSCH2CO2Me (2.25 g, 21.2 mmol), and 1,1′-azobis-
(cyclohexanecarbonitrile) (258 mg, 1.06 mmol) were employed
to give 25b (2.05 g, 82%) as a colorless oil after chromatogra-
phy (EtOAc/hexane 20:80): 1H NMR (500 MHz, CDCl3) δ 3.18
and 3.23 (AB q, J ) 15.2 Hz, 2H), 3.22-3.34 (m, 2H), 3.74 (s,
3H), 3.77 (b, 2H), 4.54 (t, J ) 7.8 Hz, 1H), 6.59 (d, J ) 8.7 Hz,
1H), 7.00-7.26 (m, 6H) ppm; LC-MS tR (system B) ) 7.15 (354
[M + H]+) min.
Gen er a l P r oced u r e for th e P r ep a r a tion of 26a ,b. To a
solution of the corresponding ester 25 in dry THF was added
dropwise a solution of LiHMDS (1.0 M, 2 equiv) in THF at
-78 °C under argon. The reaction mixture was then stirred
at -78 °C to room temperature overnight. The reaction
mixture was quenched with aqueous NH4Cl solution and
extracted twice with CH2Cl2. The combined organic layers were
washed with saturated NaHCO3 and brine, dried over anhy-
drous sodium sulfate, filtered, and concentrated, and the
residue was purified by column chromatography on silica gel
(MeOH/CH2Cl2 2:98).
Da ta for 26a : white solid (125 mg, 90%); mp 238-239 °C;
1H NMR (500 MHz, CDCl3) δ 3.00 (d, J ) 13.8 Hz, 1H), 3.05
(d, J ) 13.8 Hz, 1H), 3.23 (dd, J ) 13.5 Hz, 9.5 Hz, 1H), 3.33
(d, J ) 13.5 Hz, 1H), 4.91 (d, J ) 9.4 Hz, 1H), 6.91 (s, 1H),
7.15 (d, J ) 8.4 Hz, 1H), 7.19 (d, J ) 8.6 Hz, 1H), 7.24 (t, J )
7.7 Hz, 1H), 7.31 (d, J ) 7.9 Hz, 1H), 7.40 (t, J ) 7.4 Hz, 1H),
7.52 (d, J ) 7.6 Hz, 1H), 7.87 (s, 1H) ppm; LC-MS tR (system
B) ) 6.85 (337.9 [M + H]+) min.
Da ta for 26b: white solid (210 mg, 82%); mp 181-182 °C;
1H NMR (500 MHz, CDCl3) δ 3.01 (s, 2H), 3.20-3.33 (m, 2H),
4.82 (d, J ) 9.3 Hz, 1H), 6.99 (t, J ) 9.2 Hz, 1H), 7.04 (d, J )
1.9 Hz, 1H), 7.15-7.29 (m, 4H), 7.40 (t, J ) 7.1 Hz, 1H), 7.98
(s, 1H) ppm; LC-MS tR (system B) ) 6.75 (322 [M + H]+) min.
Gen er a l P r oced u r e for th e P r ep a r a tion of 28a ,b. To a
solution of 27 (10 mmol) in dry DMF (3.3 mL) were added 1,1-
carbonyldiimidazole (1.6 g, 10 mmol) and ethylenediamine (6.7
mL, 100 mmol) at room temperature. The mixture was then
stirred at room temperature for 18 h. The mixture was diluted
with ethyl acetate (100 mL), washed with saturated aqueous
NaHCO3 (100 mL × 3), dried over anhydrous sodium sulfate,
filtered, and concentrated under vacuum to give analytically
pure 28.
Compound 28a was prepared from 27a as a white solid (2.48
g, 99%): 1H NMR (500 MHz, MeOH-d4), 2.77 (s, 2H), 2.99 (s,
2H), 7.36 (m, 5H), 7.52 (m, 3H), 7.56 (d, J ) 7.4 Hz, 2H) ppm;
LC-MS tR (system B) ) 4.63 (251 [M + H]+) min.
Compound 28b was prepared from 27b as a yellowish oil
(2.56 g, 96%): 1H NMR (500 MHz, MeOH-d4), 2.31 (s, 3H),
2.79 (s, 2H), 2.99 (s, 2H), 7.05 (s, 1H), 7.18 (m, 1H), 7.24(m,
2H), 7.52 (m, 2H), 7.57 (s, 1H), 7.77 (d, J ) 7.3 Hz, 1H), 7.97
(S, 1H) ppm; LC-MS tR (system B) ) 5.57 (265 [M + H]+) min.
Gen er a l P r oced u r e for th e P r ep a r a tion of 29a ,b. To a
solution of corresponding 28 (0.025 g, 0.1 mole) in formic acid
(1 mL) was added palladium, 10 wt % on activated carbon
(0.015 g). The mixture was stirred at room temperature under
a hydrogen atmosphere for 18 h. The catalyst was removed
by filtration through a bed of Celite. The filtrate was concen-
trated under vacuum to give analytically pure 29.
Syn th esis of 32a . To the stirred solution of 31a (0.067 g,
0.189 mmol) in 1.5 mL of CH2Cl2 at 0 °C was added bro-
moacetyl bromide (0.020 mL, 0.228 mmol), and the mixture
was stirred at 0 °C for 1 h and then at room temperature for
18 h. DIEA (0.5 mL, 2.87 mmol) was added, and the mixture
was stirred at 50 °C for 5 h. The mixture was cooled to room
temperature and diluted with CH2Cl2. The CH2Cl2 solution was
washed with water and dried over anhydrous magnesium
sulfate. After filtration, the filtrate was concentrated to
dryness, and the crude product was purified using silica gel
chromatography (hexane/ethyl acetate 4:1 then 2:1) to give 32a
as a white solid (0.052 g, 70%): mp 54.5-56 °C; 1H NMR (500
MHz, CDCl3) δ 8.01 (s, 1H), 7.54 (d, J ) 6.7 Hz, 1H), 7.39 (d,
J ) 8.5 Hz, 1H), 7.34-7.21 (m, 3H), 6.93 (d, J ) 8.5, 1H), 6.63
(d, J ) 2.0 Hz, 1H), 5.23 (s, 1H), 3.50-3.39 (m, 6H), 2.75-
2.69 (m, 2H), 1.86-1.82 (m, 2H), 1.13 (t, J ) 7.0 Hz, 3H) ppm;
LC-MS tR (system B) ) 7.60 (393 [M + H]+) min. Using similar
procedures as illustrated above from 30a to 32a , the following
compounds were synthesized:
1
Da ta for 32b: light yellow oil (0.6 g, 59%); H NMR (500
MHz, CDCl3) δ 8.29(s, 1H), 7.46-7.44 (m, 1H), 7.31-7.24 (m,
4H), 6.97 (d, J ) 8.5 Hz, 1H), 6.82 (d, J ) 2.2, 1H), 5.40 (s,
1H), 3.77-3.65 (m, 2H), 3.5 (s, 2H), 2.96-2.86 (m, 2H), 2.46
(t, J ) 6.1 Hz, 3H) ppm; LC-MS tR (system B) ) 6.20 (351 [M
+ H]+) min.
Da ta for 32c: light yellow oil (0.034 g, 65%); 1H NMR (500
MHz, CDCl3) δ 7.81 (s, 1H), 7.66 (d, J ) 6.8 Hz, 1H), 7.39 (d,
J ) 8.1 Hz, 1H), 7.34 (t, J ) 6.8 Hz, 1H), 7.29 (t, J ) 6.8 Hz,
1H), 7.21 (d, J ) 8.3 Hz, 1H), 6.92 (d, J ) 8.3 Hz, 1H), 6.60 (s,
1H), 5.24 (s, 1H), 3.47 (s, 2H), 2.85-2.73 (m, 1H), 2.65-2.53
(m, 3H), 2.30 (t, J ) 7.5 Hz, 4H), 1.41-1.35 (m, 4H), 0.81 (t,
J ) 7.3 Hz, 6H) ppm; LC-MS tR (system B) ) 5.97 (434 [M +
H]+) min.
Da ta for 32d : light yellow oil (0.033 g, 49%); 1H NMR (500
MHz, CDCl3) δ 7.87 (s, 1H), 7.61 (d, J ) 6.7 Hz, 1H), 7.39 (d,
J ) 8.1 Hz, 1H), 7.34 (t, J ) 6.8 Hz, 1H), 7.29 (t, J ) 6.8 Hz,
1H), 7.21 (d, J ) 8.4 Hz, 1H), 6.92 (d, J ) 8.4 Hz, 1H), 6.60 (s,
1H), 5.25 (s, 1H), 3.50-3.43 (m, 2H), 3.39 (t, J ) 5.9 Hz, 4H),
3.29 (s, 6H), 2.86-2.75 (m, 4H), 2.74-2.65 (m, 4H) ppm; LC-
MS tR (system B) ) 5.75 (466 [M + H]+) min.
Compound 29a was prepared from 28a as a white solid (18.9
mg, 75%): 1H NMR (500 MHz, MeOH-d4), 1.99 (s, 1H), 3.06
(m, 3H), 3.35 (m, 2H), 5.75 (S, 1H), 7.37 (m, 4H), 7.41 (m, 3H),
7.57 (m, 1H), 7.88 (d, J ) 7.2 Hz, 2H) ppm; LC-MS tR (system
B) ) 4.95 (253 [M + H]+) min.
Da ta for 32e: white solid (0.018 g, 32%); 1H NMR (500
MHz, CDCl3) δ 7.59 (s, 1H), 7.37-7.33 (m, 2H), 7.28-7.19 (m,
3H), 6.92 (d, J ) 8.3 Hz, 1H), 6.75 (d, J ) 8.2 Hz, 1H), 6.63 (d,
J ) 8.3 Hz, 1H), 6.57 (s, 1H), 6.62 (s, 1H), 5.22 (s, 1H), 3.85 (s,
3H), 3.79 (s, 3H), 3.51 (s, 2H), 2.98-2.95 (m, 1H), 2.75-2.83
Compound 29b was prepared from 28b as a white solid (19.2
mg, 72%): 1H NMR (500 MHz, MeOH-d4) 1.99 (s, 1H), 3.31 (s,
3H), 3.05 (m, 2H), 3.37 (m, 2H), 5.70 (s, 1H), 7.10 (m, 2H),
7.24 (m, 2H), 7.58 (m, 3H), 7.86(m, 2H) ppm; LC-MS tR (system
B) ) 5.48 (267 [M + H]+) min.
102 J . Org. Chem., Vol. 68, No. 1, 2003

Efficient Syntheses of Benzothiazepines
(m, 1H), 2.84-2.75 (m, 2H) ppm; LC-MS tR (system B) ) 7.63
(471 [M + H]+) min.
scale syntheses of benzothiazepinones and intermedi-
ates.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails for compounds 1b-g, 1i, 1o,p , 3b-g, 3i, and 3o,p and
Ack n ow led gm en t. We dedicate this paper to the
memory of Professor Henry Rapoport, whose teaching
and guidance were a source of great inspiration. We also
thank Piyali Datta Chaudhuri and V. Pramela Devi at
the Indian Institute of Science who helped in the large-
1
copies of H NMR, 13C NMR, and LC-MS spectra of all new
compounds reported in this manuscript. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O020446T
J . Org. Chem, Vol. 68, No. 1, 2003 103