Novel synthesis of 3-alkyl-2,5-diaryl-1,4-oxathiepin-7-ones

Article abstract of DOI:10.1016/S0040-4039(01)00807-3

N-Acetyl-N-methyl-3-aryl-3-[1-(aroyl)ethylthio]-2-propaneamides, prepared from thioaroylketene S,N-acetals, Hg(OAc)₂ and silyl enol ethers of aryl-1-propanones in CH₂Cl₂ at rt, reacted with NaH in THF to give the title compounds in excellent yields.

Full text of DOI:10.1016/S0040-4039(01)00807-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4637–4640
Novel synthesis of 3-alkyl-2,5-diaryl-1,4-oxathiepin-7-ones
Bo Sung Kim and Kyongtae Kim*
School of Chemistry and Molecular Engineering, Seoul National University, Seoul 151-742, South Korea
Received 21 March 2001; revised 8 May 2001; accepted 11 May 2001
Abstract—N-Acetyl-N-methyl-3-aryl-3-[1-(aroyl)ethylthio]-2-propaneamides, prepared from thioaroylketene S,N-acetals,
Hg(OAc)2 and silyl enol ethers of aryl-1-propanones in CH2Cl2 at rt, reacted with NaH in THF to give the title compounds in
excellent yields. © 2001 Elsevier Science Ltd. All rights reserved.
Although some of dihydro-1,4-oxathiepins appeared to
be useful in the preparation of drugs and
agrochemicals1 and antifungal compounds,2 little has
been explored about their synthetic methods and reac-
tions. A survey of the literature shows that 5H-1,4-
oxathiepin-2(3H)-one was obtained by intramolecular
ene reaction of the intermediate allyl thioxoacetate,
generated by thermolysis of pent-4-enyl 2-thiabicyclo-
presence of mercury(II) acetate in CH2Cl2 at rt to give
2-substituted 5-aryl-3-methylaminothiophenes via
nucleophilic attack of the enolic carbon to the imino
carbon atom of the intermediate 2 (path a).8 In a
continuation of our research on the synthetic utility of
compound 1, we were interested in finding ketones
whose enolic carbon would attack the sulfur atom (path
b) instead of the imino carbon atom, so that the
carbanion 3 generated at a position to the carbonyl
group in the presence of base would be utilized as an
intermediate for the synthesis of a new compound.
With this in mind, the reaction of 1 with trimethylsilyl
enol ethers of alkyl aryl ketones were studied. We wish
to report the preliminary result.
[2,2,1]hept-5-ene-endo-3-carboxylate.3
2,3-Dihydro-
5-(6-hydroxyheptyl)-1,4-oxathiepin-7-one was observed
as a by-product in the total synthesis of ( )-diplodia-
lide-A.4 Reaction of polyfluoro-2-alkynoic acids with
thioethanol gave polyfluorinated oxathiepins.5 Simi-
larly, the reaction of ethyl 2-thiobenzoates with chloro-
hydrin and glycerol chlorohydrin gave the
corresponding intermediates which were converted to
benzoxathiepinones.6 All the reactions lack the general-
ity for the synthesis of 1,4-oxathiepinones. In addition,
it is interesting to note that much has been studied for
other seven-membered analogs, i.e. 1,4-dioxepinones
and 1,4-dithiepinones compared with that for 1,4-
oxathiepinones.7
The reaction of 1a (Ar=Ph) with acetophenone for 1 h
under the same conditions as described previously9
afforded 2-methyl-5-phenylisothiazol-3-one (4) (65%)
along with thiophene derivative 5a (Ar=R1=Ph) (9%),
whereas the reaction with trimethylsilyl enol ether of
acetophenone gave 5a in 75% yield10 (Scheme 1). Simi-
larly, the reactions with silyl enols ether of methyl
ketones under the same conditions gave thiophene
derivatives 5b–d (5b, Ar=Ph, R1=4-ClC6H4, 79%; 5c,
Ar=Ph, R1=CHꢀCHOMe, 69%; 5d, Ar=Ph, R1=
CHꢀC(OMe)TMS, 66%).
We have previously reported that thioaroylketene S,N-
acetals 1 reacted readily with enolizable ketones in the
OH
R2
R1
Ar
Ar
SMe
a
O
SMe
Ar
SMe
S
NMe
R1
b
N
S
N
Ph
Me
R2
S
NHMe
S
Hg
OAc
O
1
3
4
2
Keywords: ketene acetals; mercury and compound; thiophenes; enol ethers.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00807-3

4638
B. S. Kim, K. Kim / Tetrahedron Letters 42 (2001) 4637–4640
OTMS
NHMe
R1
O
R1
N
Ar
Ph
Me
S
S
R1: alkyl, aryl
O
5
CH2Cl2
rt
4
Hg(OAc)2
1
OTMS
Me
N
R2
Ar
Me
R1
4
R1: aryl, R2: Me, Et
S
O
R1
O
R2
O
6
Scheme 1.
In contrast, with silyl enol ethers of 1-aryl-1-
propanones and 1-aryl-1-n-butanones the correspond-
ing N-acetyl-N-methyl 3-aryl-3-[1-(aroyl)alkylthio]-
2-propen-amides 6 were obtained as major products
together with a small amount of 4. No thiophene
derivatives 5 were detected. The reaction with silyl enol
ether of 1-(4-bromophenyl)-2-methylpropanone, how-
ever, gave compounds 10 and 4 in 7 and 41% yields,
respectively. This result indicates that steric effect at the
enolic carbon atom is crucial to the formation of com-
pound 6. (Scheme 2). Reaction times and yields of
compounds 4 and 6 are summarized in Table 1.
NaH in THF at rt gave 3-alkyl-2,5-diaryl-1,4-
oxathiepin-7-ones 11 in good to excellent yields11
(Scheme 3). Reaction times and yields of compounds 11
are summarized in Table 2.
Although 2,3-dihydro-1,4-oxathiepin-7-one was repor-
ted, to the best of our knowledge, compounds 11 are
the first examples for 1,4-oxathiepin-7-ones.
R2
Ar
S
NaH
R1
6
O
The structures of compounds 6a–g were determined
based on the spectroscopic data (1H and 13C NMR, IR,
MS) and elemental analysis.
THF, rt
O
11
It has been found that treatment of compounds 6 with
Scheme 3.
Me
OTMS
Me
Ph
N
Me
CH2Cl2
rt
S
O
O
Hg(OAc)2
4
1a
Me
Me
Me
Br
Br
O
41%
10
7%
Scheme 2.
Table 1. Reaction times and yields of compounds 4 and 6
Compound
Ar
R1
R2
Time (h)
Yielda (%)
6a
6b
6c
6d
6e
6f
Ph
Ph
Ph
Ph
Ph
Me
Et
3
3
3
2
2
2
3
58 (5)
50 (trace)
58 (trace)
47 (5)
44 (5)
47 (3)
3-MeOC6H4
Me
Me
Me
Me
Me
Ph
Ph
Ph
Ph
4-MeOC6H4
4-ClC6H4
4-BrC6H4
2-Naphthyl
6g
53 (5)
a Isolated yields. Number in parentheses represent yields of compound 4.

B. S. Kim, K. Kim / Tetrahedron Letters 42 (2001) 4637–4640
Table 2. Reaction times, yields and mp of compounds 11
4639
..
HOAc
OAc
SMe
Ar
Ar
SMe
Ar
SMe
Me
S
NH Me
R1
S
N
R1
S
N
Ar
SMe
- Hg(0)
Hg(OAc)2
- HOAc
Me
R2
Hg
R2
R2
S
NHMe
Me3Si
OAc
OAc
O
O
Me3Si
O
R1
12
1
- MeSH
O
Me
N
Ar
S
O
Ar
Me
Ar
O
Me
OAc
- OAc
N
R1
Me
S
O
R1
O
Ac2O
+
S
N
R1
Me
R2
R2
R2
O
O
O
6
14
13
base
Me
N
Me
N
Ar
Me
Ar
Me
O
Ar
Me
N
S
O
R1
O
S
O
O
Me
H
O
S
+
O
R2
R2
O
R1
R2
O
R1
MeCONHMe
15a
15b
11
.
Scheme 4.

4640
B. S. Kim, K. Kim / Tetrahedron Letters 42 (2001) 4637–4640
The mechanism for the formation of 6 may be rational-
ized based on the formation of an intermediate 12,
which then undergoes acetolysis to give imidoyl acetate
13 (Scheme 4). This species are known to be unstable.12
Acetolysis of 13 would lead to acetic anhydride and an
intermediate 14, which lead to amide 6. The formation
of compounds 11 may be explained by an intramolecu-
lar nucleophilic attack of the enolate ion 15b, existing
as an equilibrium mixture with its carbanion ion 15a,
on the amide carbonyl carbon.
mmol) in CH2Cl2 (8 ml) at rt was added silyl enol ethers
(0.177–0.225 mmol). The mixture was stirred for an
appropriate time (refer to Table 1). After solids were
filtered, the solvent of the filtrated was evaporated in
vacuo to give a residue which was chromatographed on a
silica gel (1.5×15 cm). (i) Elution with a mixture of
EtOAc and n-hexane (1:4) gave compounds 5. (ii) For
compounds 6 elution with the same solvent mixture (1:3)
gave 6. Elution with the same solvent mixture (1:1) gave
compound 4.
Selected compound 6a: 1H NMR (300 MHz, CDCl3) l
1.43 (3H, d, J=7.1 Hz, CHCH3), 2.45 (3H, s, COCH3),
3.22 (3H, s, NCH3), 4.44 (1H, q, J=7.1 Hz, CHCH3),
6.52 (1H, s, vinyl), 7.26–7.35 (7H, m, ArH), 7.49–7.53
(3H, m, ArH); 13C NMR (75 MHz, CDCl3) l 18.09,
26.24, 32.04, 45.35, 121.021, 128.20, 128.26, 128.40,
128.74, 129.25, 133.11, 135.19, 138.70, 157.03, 167.62,
173.15, 197.68; IR (neat) 1667, 1094, 970, 696 cm−1; FAB
MS m/z 368 (M++1, 21.0) 326 (5.3), 295 (100), 234 (74.9),
202 (17.1). Anal. calcd for C21H21NO3S: C, 68.64; H,
5.76; N, 3.81; S, 8.73. Found: C, 68.76; H, 5.81; N, 3.88;
S, 8.70.
Acknowledgements
This work was supported by Korea Research Founda-
tion Grant (KRF–2000).
References
1. Masaoka, K.; Nemoto, F.; Shimizu, H.; Nakayama, N.
Jpn. Kokai 01265087 (1990) (Chem. Abstr. 1990, 112,
179040).
11. Typical procedure: To a solution of NaH (60%, 3 mg,
0.075 mmol) in THF (5 mL) under a nitrogen atmosphere
6a was added dropwise (16 mg, 0.044 mmol) in 2 mL
portions. The mixture was stirred for 30 min, followed by
addition of aqueous NaHCO3, which was extracted with
ethyl ether (20 mL×2). The extracts were dried over
MgSO4. After removal of the solvent, the residue was
chromatographed on a silica gel (1.5×15 cm) with a
mixture of EtOAc and n-hexane (1:6) as an eluent to give
6a (12 mg, 93%). 1H NMR (300 MHz, CDCl3) l 2.36
(3H, s, Me), 7.17 (1H, s, vinyl), 7.25–7.28 (1H, m, ArH),
7.33–7.39 (2H, m, ArH), 7.35–7.57 (4H, m, ArH), 7.62–
7.68 (1H, m, ArH), 8.20–8.24 (2H, m, ArH); 13C NMR
(75 MHz, CDCl3) l 11.46, 117.80, 124.36, 125.19, 127.50,
128.65, 128.85, 129.22, 130.20, 133.69, 134.12, 138.66,
143.50, 164.39; IR (neat) 1736, 1592, 1562, 1499, 1443,
1262, 1112, 1051, 754, 707 cm−1; MS m/z 294 (M+, 27.0),
189 (2.7), 105 (100). Anal. calcd for C18H14O2S: C, 64.84;
H, 6.35; S, 814.42. Found: C, 64.76; H, 6.28; S, 14.29.
12. (a) Khorana, H. G. Chem. Rev. 1953, 53, 145–148; (b)
Doleschall, G.; Lembert, K. Tetrahedron Lett. 1963, 781,
1195–1197; (c) Schaefer, F. C. In The Chemistry of the
Cyano Group; Rappoport, Z., Ed.; John Wiley and Sons:
New York, 1970; pp. 239–305.
2. Konosu, T.; Takeda, N.; Tajima, Y.; Yasuda, H.; Oida,
S. Chem. Pharm. Bull. 1990, 38, 1258–1265.
3. (a) Choi, S. S.-M.; Kirby, G. W.; Mahajan, M. P. J.
Chem. Soc., Chem. Commun. 1990, 138–140; (b) Chio, S.
S.-M.; Kirby, G. W.; Mahajan, M. P. J. Chem. Soc.,
Perkin Trans. 1 1992, 191–198.
4. Ishida, T.; Wada, K. J. Chem. Soc., Perkin Trans. 1 1979,
323–327.
5. Yamanaka, H.; Tamura, K.; Funabiki, K.; Fukunishi,
K.; Ishihara, T. J. Fluorine Chem. 1992, 57, 177–190.
6. Gilbert, J.; Rousselle, D.; Rumpf, P. Bull. Soc. Chim. Fr.
1975, 277–279.
7. Frauenrath, H. In Comprehensive Heterocyclic Chemistry
II; Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V., Eds.;
Pergamon, 1996; Vol. 9, pp. 271–297.
8. Kim, B. S.; Kim, K. J. Org. Chem. 2000, 65, 3690–3699.
9. Refer to the following references for the synthesis of silyl
ethers: (a) Corey, E. J.; Gross, A. W. Tetrahedron Lett.
1984, 25, 495–498; (b) Fataftah, Z. A.; Kopka, I. E.;
Rathke, M. W. J. Am. Chem. Soc. 1980, 102, 3959–3960.
10. General procedure: To a mixture of thioaroylketene S,N-
acetals (0.179–0.224 mmol) and Hg(OAc)2 (0.270–0.336
.