Synthesis of 4,4-disubstituted-4H-benzo[d][1,3]oxathiin-2-ones, a new class of compounds

Article abstract of DOI:10.1080/00397910500522140

4,4-Dialkyl and 4,4-diaryl-4H-benzo[d][1,3]oxathiin-2-ones were synthesized by the reaction of 2-(mercapto-phenyl)-dialkyl- (or diaryl)-methanol with CDI in excellent yield. The 2-(mercaptophenyl)-dialkyl- (or diaryl)-methanols were prepared by the reaction of commercially available methylthiosalicylate with an ppropriate alkyl or aryl Grignard reagent. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910500522140

Synthetic Communicationsw, 36: 1419–1429, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500522140
Synthesis of 4,4-Disubstituted-4H-
benzo[d][1,3]oxathiin-2-ones, a New Class of
Compounds
Sukanta Kamila, Omair Khan, Hongming Zhang, and
Edward R. Biehl
Department of Chemistry, Southern Methodist University, Dallas
Texas, USA
Abstract: 4,4-Dialkyl and 4,4-diaryl-4H-benzo[d][1,3]oxathiin-2-ones were syn-
thesized by the reaction of 2-(mercapto-phenyl)-dialkyl- (or diaryl)-methanol with
CDI in excellent yield. The 2-(mercaptophenyl)-dialkyl- (or diaryl)-methanols were
prepared by the reaction of commercially available methylthiosalicylate with an appro-
priate alkyl or aryl Grignard reagent.
Keywords: CDI, cyclization, Grignard reagent, oxathiin-2-one, PR antagonist
Progesterone receptor- (PR), a group of ligand-activated nuclear transcription
factors,[1] are members of the steroid receptor subfamily of the nuclear
receptor superfamily. Current steroidal PR agonists are usually administered
with steroidal estrogen for oral contraception and postmenopausal hormone
therapy. However, various side effects such as nausea, headache, bloating,
weight gain, breast tenderness, and moodiness are associated with these
steroids. More important, coupling PR agonists with estrogen can lead to
potential stroke, myocardial infarction, and venous thromboembolism. Theor-
etically, identifying novel, nonsteroidal PR drugs that target key tissues would
Received in the USA October 25, 2005
Address correspondence to Edward R. Biehl, Department of Chemistry, Southern
Methodist University, DallasTX 75275, USA. Tel.: 214-768-2735; Fax: 214764089;
E-mail: ebiehl@smu.edu
1419

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S. Kamila et al.
prove to be less harmful than the current methods of steroidal chemotherapy.
A number of nonsteroidal PR antagonists have been reported in the litera-
ture.[2–7] Among them Mifepristone (1), 6-arylbezimidazolones (2), 6-aryl
benzoxazines (3),[8,9] and 6-aryl-1,4-dihydrobenzoxazin-2-ones (4)[10]
(Figure 1) proved that this class of drug is not only potent but selective as
well. To further study of the effects of variants of this class of PR modulators,
a number of analogs were prepared in which the N-H group was replaced by
sulfur because novel PR antagonists that are structurally distinct from the
steroid class may have greater potential for selectivity against other steroid
receptors.[11–13] We hope that this new class of drugs will also act as
selective, highly potent PR antagonists. A detailed synthesis of these types
of compounds is discussed herein.
4,4-Disubstituted-4H-benzo[d][1,3]oxathiin-2-one (8a–8g) were syn-
thesized from methylthiosalicylate (5) according to the procedure shown in
Scheme 1.
Methyl thiosalicylate 5 was prepared from thiosalicylic acid in refluxing
anhydrous MeOH in the presence of a catalytic amount (1 drop) of concen-
trated sulfuric acid. Ester 5 was then treated with various Grignard reagents
(6a–g),[14] affording the corresponding 2-(mercapto-phenyl)-dialkyl 7a–c
and diaryl)-methanol 7d–g in excellent yields (.90%). Compounds 7a–c
and 7d–g were then treated with excess N,N0-carbonyldiimidazole (CDI) in
boiling THF solution to give the target molecules 8a–c and 8d–g, respect-
ively. The yields of 8a–g listed in Table 1 are very good.
The products were fully characterized by 1H NMR, 13C NMR, elemental
analysis, and in the case of 8c, X-ray crystallography. An ORTEP drawing 8c
is shown in Figure 3.
A possible mechanism, shown in Figure 2, involves a nucleophilic attack
by the –OH group of the dialkyl (or aryl) methanol to the carbonyl carbon of
the CDI and subsequent elimination of imidazole. In the next step, a second
Figure 1. Typical examples of nonsteroidal PR antagonists.

Synthesis of Oxathiin-2-one
1421
Scheme 1. Synthesis of oxathiin-2-ones.
nucleophilic attack involving the –S2 group onto the carbonyl carbon gives
adduct 9, which eliminates a second imidazole moiety, affording the target
molecule 8.
In summary, we have developed a new synthetic route for the synthesis of
novel 4,4-dialkyl (or diaryl)-4H-benzo[d][1,3]oxathiin-2-ones. To our
knowledge, there are no reports on the synthesis of this class of compounds.
Work is in progress for detailed biological testing of these compounds.
EXPERIMENTAL
Melting points were taken on a Mel-Temp capillary apparatus and are
1
uncorrected with respect to stem correction. H and 13C NMR spectra were
recorded on a 400-MHz Bruker Advance DRX-400 Multinuclear NMR
spectrometer. Chemical shifts are reported in reference to TMS as internal
standard. IR spectra were taken in Nicolet Magna-IR-560-Spectrometer
(E.S.P). Elemental analysis were obtained from Southern Methodist Univer-
sity (SMU) Analytical Service Laboratories. All chemicals were purchased
from Fisher Scientific or Aldrich chemicals.
General Procedure for the Preparation of 2-(Mercaptophenyl)-
dialkyl (or Diaryl) Alcohols
Magnesium (0.72 g, 2.5 equiv, 29.7 mmol) dried over P2O5 in vacuo was
placed in a 50-mL reaction flask. A THF (10 mL) solution of alkyl or aryl
halide (2.5 equiv, 29.7 mmol) was added over a period of 30 min, and the
reaction was completed by stirring the resulting mixture for 1 hr at rt. The
Grignard reagent 6 was then added dropwise to a cold (08C) solution of
methyl thiosalicylate 5 (2.0 g, 11.9 mol) in THF over a period of 30 min.
After stirring overnight at rt, the mixture was poured into 100 mL of a
solution of saturated aqueous solution of ammonium chloride. The product
was extracted with ethyl acetate (3 ꢀ 200 mL), and the combined extracts
were dried (Na2SO4). The solvent was then evaporated under reduced
pressure, and the crude products were chromatographed on a silica-gel
column using hexane–ethyl acetate (9 : 1, v/v) as eluent.

Table 1. Synthesis of 4,4-disubstituted-4H-benzo[d][1,3]oxathiin-2-ones
Entry Grignard reagent Dialkyl/Diaryl methanol
Yield
98%
Oxathiindole-2-one
Yield
99%
CH3MgBr
6a
1
CH3CH2MgBr
6b
2
3
92%
98%
98%
99%
4
92%
96%

Synthesis of Oxathiin-2-one
1423

1424
S. Kamila et al.
Figure 2. Possible mechanism for formation of titled compounds.
Physical Properties of Compounds (7a–h)
(7a): 2-(2-Mercaptophenyl)-propan-2-ol. Separated as a colorless oil. IR
1
(KBr, CHCl3) nmax: 3585 cm21 (–OH). H NMR (CDCl3): d 1.71 (s, 6H,
CH3 ꢀ 2), 2.64 (s, 1H, –SH), 4.14 (s, 1H, OH), 7.10 (dd, J ¼ 7.8, 8.0 Hz,
2H, aromatic), 7.26 (d, J ¼ 7.8 Hz, 1H, aromatic), 7.37 (d, J ¼ 8.0 Hz, 1H,
Figure 3.

Synthesis of Oxathiin-2-one
1425
aromatic). 13C NMR (CDCl3): d 30.1, 74.2, 125.9, 126.6, 127.9, 130.4, 133.3,
145.2. Anal. calcd. for C9H12OS: C, 64.25; H, 7.19. Found: C, 64.40; H, 7.25.
(7b): 3-(2-Mercaptophenyl)-pentan-3-ol. Separated as a colorless oil. IR
: d 0.80
3485 cm21(–OH). 1H NMR (CDCl3):
(KBr, CHCl3) nmax
(t, J ¼ 8.0 Hz, 6H, –CH3 ꢀ 2), 1.95–2.16 (m, 4H, –CH2 ꢀ 2), 2.19 (s, 1H,
SH), 3.84 (s, 1H, –OH), 7.11 (dd, J ¼ 7.6, 7.8 Hz, 2H, aromatic), 7.23
(d, J ¼ 7.8 Hz, 1H, aromatic), 7.34 (d, J ¼ 7.8 Hz, 1H, aromatic). 13C NMR
(CDCl3): d 8.4 (–CH3 ꢀ 2), 32.5 (–CH2 ꢀ 2), 79.4, 125.5, 127.5, 128.6,
130.3, 133.2, 142.3. Anal. calcd. for C11H16OS: C, 67.30; H, 8.15. Found:
C, 67.45; H, 8.20.
(7c): 3-(2-Mercaptophenyl)-2,4-dimethyl-pentan-3-ol. Separated as a
1
reddish oil. IR (KBr, CHCl3) nmax: 3587 cm21(–OH). H NMR (CDCl3): d
0.84 (d, J ¼ 4 Hz, 6H, –CH3 ꢀ 2), 0.99 (d, J ¼ 4 Hz, 6H, –CH3 ꢀ 2), 2.03
(s, 1 H, -SH), 2.31–2.33 (m, 2H, –CH–), 3.61 (s, 1H, –OH), 7.07
(d, J ¼ 7.8 Hz, 1H, aromatic), 7.19 (d, J ¼ 7.8 Hz, 1H, aromatic), 7.26 (dd,
J ¼ 7.8, 8.0 Hz, 2H, aromatic), 13C NMR (CDCl3): d 17.0 (–CH3 ꢀ 2),
18.1 (–CH3 ꢀ 2), 36.0 (–CH ꢀ 2), 84.7, 124.6, 127.1, 130.6, 132.2, 133.1,
140.1. Anal. calcd. for C13H20OS: C, 69.59; H, 8.98. Found: C, 69.65; H, 9.03.
(7d): (2-Mercaptophenyl)-diphenyl-methanol. Separated as a reddish
1
brown oil. IR (KBr, CHCl3) nmax: 3680 cm21 (–OH). H NMR (CDCl3): d
3.47 (s, 1H, –SH), 5.13 (s, 1H, –OH), 6.67–7.09 (m, 2H, aromatic), 7.20–
7.32 (m, 2H, aromatic), 7.33–7.41 (m, 10H, aromatic). 13C NMR (CDCl3):
d 83.2, 125.5, 126.6, 127.8, 127.9, 128.3, 128.5, 129.5, 129.7, 130.2, 131.1,
133.4, 135.0, 146.1, 146.5. Anal. calcd. for C19H16OS: C, 78.05; H, 5.52.
Found: C, 78.24; H, 5.62.
(7e): (2-Mercaptophenyl)-bis-(4-methoxyphenyl)-methanol. Separated as
1
a reddish oil. IR (KBr, CHCl3) nmax: 3287 cm21(–OH). H NMR (CDCl3):
d 2.08 (s, 1H, –SH), 3.76 (s, 3H, –OMe), 3.79 (s, 3H, –OMe), 4.16 (s, 1H,
–OH), 6.86 (d, J ¼ 8 Hz, 4H, aromatic), 7.03 (dd, J ¼ 7.8, 8.0 Hz, 1H,
aromatic), 7.17 (d, J ¼ 8.0 Hz, 4H, aromatic), 7.57 (dd, J ¼ 7.8, 8.0 Hz, 2H,
aromatic), 7.76 (d, J ¼ 7.8 Hz, 1H, aromatic). 13C NMR (CDCl3): d 55.6,
55.8, 82.7, 112.2, 114.4, 127.0, 127.4, 128.6, 129.2, 129.8, 130.1, 130.7,
131.0, 133.2, 133.8, 134.1, 135.7, 144.1, 155.1, 155.8. Anal. calcd. for
C21H20O3S: C, 71.56; H, 5.72. Found: C, 71.73; H, 5.78.
(7f): Bis-(2,3-dimethylphenyl)-(2-mercaptophenyl)-methanol. Separated
1
as a reddish brown oil. IR (KBr, CHCl3) nmax: 3679 cm21(–OH). H NMR
(CDCl3): d 2.18 (s, 3H, –CH3), 2.21 (s, 6H, –CH3 ꢀ 2), 2.36 (s, 3H,
–CH3), 3.50 (s, 1H, –SH), 5.06 (s, 1H, –OH), 6.54 (d, J ¼ 8.0 Hz, 1H,
aromatic), 6.68 (d, J ¼ 8.0 Hz, 1H, aromatic), 6.79 (d, J ¼ 8.0 Hz, 1H,
aromatic), 6.96 (dd, J ¼ 7.8, 8.0 Hz, 2H, aromatic), 7.10 (dd, J ¼ 7.8,
8.0 Hz, 2H, aromatic), 7.19 (dd, J ¼ 7.8, 8.0 Hz, 1H, aromatic), 7.21–7.33
(m, 2H, aromatic). 13C NMR (CDCl3): d 17.1, 19.1, 19.4, 19.5, 86.9, 124.8,

1426
S. Kamila et al.
125.0, 126.7, 127.4, 127.9, 128.1, 129.5, 129.9, 130.0, 132.1, 132.9, 135.5,
137.9, 139.1, 139.6, 143.6, 143.7. Anal. calcd. for C23H24OS: C, 79.27; H,
6.94. Found: C, 79.32; H, 6.99.
(7g): Bis-(3,4-dimethylphenyl)-(2-mercaptophenyl)-methanol. Separated
as a reddish oil. IR (KBr, CHCl3) nmax: 3585 cm21(–OH). 1H NMR
(CDCl3): d 3.5 (s, 1H, –SH), 3.83 (s, 6H, –OMe ꢀ 2), 3.87 (s, 6H,
–OMe ꢀ 2), 5.1 (s, 1H, –OH), 6.56 (s, 2H, aromatic), 6.65 (d, J ¼ 7.8 Hz,
2H, aromatic), 6.68 (d, J ¼ 7.8 Hz, 2H, aromatic), 6.96 (dd, J ¼ 7.8, 8.0 Hz,
1H, aromatic), 7.03 (dd, J ¼ 7.8, 8.0 Hz, 2H, aromatic), 7.10 (d, J ¼ 8.0 Hz,
1H, aromatic). 13C NMR (CDCl3): d 55.9, 56.1, 56.2, 56.3, 83.1, 115.1,
115.3, 115.6, 121.3, 121.7, 125.7, 126.7, 128.7, 129.7, 132.5, 136.3, 136.7,
143.7, 155.1, 155.2, 159.1, 159.2. Anal. calcd. for C23H24O5S: C, 66.97; H,
5.86. Found: C, 67.03; H, 5.90.
General Procedure for the Preparation of 4,4-Dialkyl- (or Diaryl)-
4H-benzo[d][1,3]oxathiin-2-ones
N,N0-Carbonyldiimidazole (CDI) (1.31 g, 8 mmol) was added to a solution of
the propan-2-ol 7a–g (4.0 mmol) in dry THF (10 mL) under argon atmosphere,
and the resulting reaction solution was heated overnight at 508C. The solvent
was removed in vacuo, and the residue was dissolved in ethyl acetate (100 mL).
The solution was then washed with 1 N aqueous hydrochloride solution
(2 ꢀ 50 mL) and brine (20 mL) and then dried over Na2SO4. The solvent
was removed in vacuo, affording the crude product, which was purified by
column chromatography using silica-gel packing and ethylacetate–hexane
mixture (9 : 1, v/v) as eluent.
Products 8a–g
(8a): 4,4-Dimethyl-4H-benzo[d][1,3]oxathiin-2-one. Separated as
.
a
colorless gummy liquid. IR (KBr, CHCl3) nc¼o: 1693 cm21 1H NMR
(CDCl3): d 1.81 (s, 6H, –CH3 ꢀ 2), 7.18 (d, J ¼ 7.8 Hz, 1H, aromatic),
7.30 (dd, J ¼ 7.8 Hz, 8.0 Hz, 2H, aromatic), 7.37 (d, J ¼ 7.8 Hz, 1H,
aromatic). 13C NMR (CDCl3): d 27.2, 87.0, 124.8, 126.6, 128.1, 128.7,
129.3, 135.5, 165.3. Anal. calcd. for C10H10O2S: C, 61.83; H, 5.19. Found:
C, 61.86; H, 5.22.
(8b): 4,4-Diethyl-4H-benzo[d][1,3]oxathiin-2-one. Separated as yellowish
1
solid, mp 58–608C. IR (KBr) nc¼o: 1692 cm21. H NMR (CDCl3): d 0.93
(t, J ¼ 8.0 Hz, 6H, –CH3 ꢀ 2), 2.15 (q, J ¼ 8.0 Hz, 4H, –CH2 ꢀ 2), 7.20
(dd, J ¼ 7.8, 8.0 Hz, 2H, aromatic), 7.25 (d, J ¼ 7.8 Hz, 1H, aromatic), 7.29
(d, J ¼ 8.0 Hz, 1H, aromatic). 13C NMR (CDCl3): d 8.4 (–CH3 ꢀ 2), 30.4

Synthesis of Oxathiin-2-one
1427
(–CH2– ꢀ 2), 93.5, 126.6, 126.7, 127.4, 129.0, 129.6, 132.0, 165.3. Anal.
calcd. for C12H14O2S: C, 64.83; H, 6.35. Found: C, 64.89; H, 6.44.
(8c): 4,4-Diisopropyl-4H-benzo[d][1,3]oxathiin-2-one. Separated as a white
crystaline solid, mp 93–958C. IR (KBr) nc¼o:1677 cm21. 1H NMR (CDCl3): d
0.90 (d, J ¼ 8.0 Hz, 6H, –CH3 ꢀ 2), 1.03 (d, J ¼ 8.0 Hz, 6H, –CH3 ꢀ 2),
2.53–2.59 (m, 2H, –CH– ꢀ 2), 7.07 (d, J ¼ 7.8 Hz, 1H, aromatic), 7.19
(d, J ¼ 8.0 Hz, 1H, aromatic), 7.26 (dd, J ¼ 7.8 Hz, 8.0 Hz, 2H, aromatic).
13C NMR (CDCl3): d 16.8, 18.3, 36.5, 100.2, 125.8, 126.8, 126.9, 128.5,
128.6, 129.8, 164.3. Anal. calcd. for C14H18O2S: C, 64.25; H, 7.19. Found:
C, 74.33; H, 64.31.
(8d): 4,4-Diphenyl-4H-benzo[d][1,3]oxathiin-2-one. Separated as
a
brownish solid, mp 85–878C. IR (KBr) nc¼o: 1689 cm21. 1H NMR (CDCl3):
d 7.07–7.09 (m, 2H, aromatic), 7.21–7.29 (m, 10 H, aromatic), 7.30–7.32
(m, 2H, aromatic). 13C NMR (CDCl3): d 82.7, 125.1, 126.2, 126.9, 127.0,
127.3, 127.6, 128.3, 128.6, 128.7, 129.8, 130.0, 131.6, 133.6, 137.8, 141.3,
164.5. Anal. calcd. for C20H14O2S: C, 75.45; H, 4.43. Found: C, 75.44; H, 4.57.
(8e): 4,4-Bis-(4-methoxyphenyl)-4H-benzo[d][1,3]oxathiin-2-one. Separated
as a reddish solid, mp 98–998C. IR (KBr) nc¼o: 1678cm21 1H NMR
(CDCl3): d 3.81 (s, 3H, –OMe), 3.82 (s, 3H, –OMe), 6.67 (d, J ¼ 8.0 Hz,
4H, aromatic), 6.86 (d, J ¼ 8.0 Hz, 4H, aromatic), 7.04 (dd, J ¼ 7.8, 8.0 Hz,
1H, aromatic), 7.17 (d, J ¼ 8.0 Hz, 2H, aromatic), 7.51 (dd, J ¼ 7.8, 8.0 Hz,
1H, aromatic). 13C NMR (CDCl3): d 55.6, 55.7, 88.1, 113.7, 114.0, 114.1,
124.4, 125.8, 126.3, 128.8, 129.4, 129.5, 129.7, 130.0, 130.2, 132.5, 135.3,
144.1, 159.1, 159.8, 163.9. Anal. calcd. for C22H18O4S: C, 69.82; H, 4.79.
Found: C, 69.88; H, 4.89.
(8f): 4,4-Bis-(2,3-dimethylphenyl)-4H-benzo[d][1,3]oxathiin-2-one. Separated
as a colorless gummy liquid. IR (CHCl3) nc¼o: 1678 cm21. 1H NMR (CDCl3): d
2.19 (s, 6H, –CH3 ꢀ 2), 2.26 (s, 6H, –CH3 ꢀ 2), 6.63 (d, J ¼ 7.8 Hz, 2H,
aromatic), 6.95 (d, J ¼ 7.8 Hz, 2H, aromatic), 6.97 (dd, J ¼ 7.8, 8.0 Hz, 2H,
aromatic), 7.09 (dd, J ¼ 7.8, 8.0 Hz, 1H, aromatic), 7.18–7.20 (m, 3H,
aromatic). 13C NMR (CDCl3): d 17.2, 18.9, 19.1, 19.3, 82.3, 123.7, 125.7,
126.3, 127.9, 128.0, 128.1, 129.3, 129.5, 130.0, 132.1, 132.8, 135.5, 136.3,
137.2, 139.6, 143.6, 143.9, 164.5. Anal. calcd. for C24H22O2S: C, 76.97; H,
5.92. Found: C, 76.91; H, 5.99.
(8g): 4,4-Bis-(3,4-dimethoxyphenyl)-4H-benzo[d][1,3]oxathiin-2-one. Sepa-
1
rated as a yellowish oil. IR (CHCl3) nc¼o: 1679 cm21. H NMR (CDCl3): d
3.81 (s, 6H, –OMe ꢀ 2), 3.86 (s, 6H, –OMe ꢀ 2), 6.55 (s, 2H, aromatic), 6.69
(d, J ¼ 7.8 Hz, 4H, aromatic), 6.71 (d, J ¼ 7.8 Hz, 2H, aromatic), 6.98 (dd,
J ¼ 7.8, 8.0 Hz, 2H, aromatic). 13C NMR (CDCl3): d 55.6, 55.9, 56.1, 56.2,
87.8, 114.9, 115.1, 115.6, 121.3, 121.5, 125.6, 126.5, 128.8, 130.1, 132.1,
136.5, 136.9, 144.1, 155.0, 155.5, 159.1, 159.3, 164.3. Anal. calcd. for
C24H22O6S: C, 65.74; H, 5.06. Found: C, 65.77; H, 5.11.

1428
S. Kamila et al.
ACKNOWLEDGMENTS
We thank the Welch Foundation, Houston, Texas, for partial financial support
of this work.
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