A new synthesis of 1,4-thiazin-3-ones by a novel rearrangement of 1,4-oxathiins

Full text of DOI:10.1021/jo951723h

3894
J . Org. Chem. 1996, 61, 3894-3896
Ta ble 1. Con ver sion of
2-Meth yl-N-p h en yl-1,4-oxa th iin -3-ca r boxa m id e (1a ) to
2-Acetyl-4-p h en yl-2H-1,4-th ia zin -3(4H)-on e (2a ) w ith
Aqu eou s Acid s
A New Syn th esis of 1,4-Th ia zin -3-on es by a
Novel Rea r r a n gem en t of 1,4-Oxa th iin s
Hoh-Gyu Hahn,*,† Kee Dal Nam, Heduck Mah,‡ and
J um J ung Lee‡
solvent aqueous acid (%) temp (°C) reactn time yield (%)a
benzene
toluene
dixoane
THF
MeCN
MeCN
EtOH
HCl (10)
HCl (10)
HCl (10)
HCl (10)
HCl (10)
HCl (35)
HCl (10)
H2SO4 (50)
80
110
80
80
80
80
80
80
20 h
19 h
2 h
10 h
1.5 h
10 min
30 min
26 min
22
4
21
8
47
70
62
60
Organic Chemistry Laboratory, Korea Institute of Science
and Technology, P.O. Box 131,
Cheongryang, 136-791, Seoul, Korea
Received September 20, 1995 (Revised Manuscript Received
March 12, 1996)
MeCN
Much of the research in heterocyclic chemistry is
concerned with the development of new methods for ring
syntheses. There has been an increasing interest over
the past several years in the chemistry of 1,4-thiazin-3-
one derivatives. This is primarily due to their remark-
able spectrum of biological activity. Examples of their
biological activity are phospholipase A2, lipoxygenase and
cyclooxygenase inhibitors,1 protective agents against
endotoxin shock,2 and cardiotonics.3 However, very few
convenient syntheses of 1,4-thiazin-3-ones are currently
available.4 In this study we report a facile, general
synthesis of these compounds through an acid-catalyzed
rearrangement of 1,4-oxathiins 1.
a
Isolated yield.
Ta ble 2. Con ver sion of 1,4-Oxa th iin 1 to
1,4-Th ia zin -3-on es 2 in th e P r esen ce of Con cen tr a ted HCl
in MeCN
compd
R1
R2
mp (°C)
yield (%)a
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
phenyl
98-99
oil
115-117
oil
oil
oil
96-97
oil
70
77
59
84
55
100
73
69
55
53
84
51
67
69
18
2-methylphenyl
4-methylphenyl
2-chlorophenyl
4-chlorophenyl
2-methoxyphenyl
4-methoxyphenyl
2-nitrophenyl
2,6-dimethylphenyl
2,4-dimethoxyphenyl oil
2,4-dimethylphenyl
4-ethylphenyl
oil
oil
oil
127-130
oil
oil
C6H5 phenyl
CH3
CH3
methyl
ethyl
a
Isolated yield.
(HCl) in acetonitrile (MeCN) at 80 °C for 10 min afforded
2-acetyl-4-phenyl-2H-1,4-thiazin-3(4H)-one (2a ) in 70%
yield accompanied by a trace of acetoacetanilide (4%).
With this initial data in hand we decided to investigate
conditions under which this rearrangement proceeds.
Thus, a number of solvents were examined with varying
concentrations of HCl. For instance, reaction of 1a with
concentrated HCl in MeCN at 80 °C gave the 1,4-thiazin-
3-one 2a in 70% yield, whereas with 10% HCl the yield
was somewhat lower (47%). Additionally, product 2a
slowly decomposed to a complex mixture of products and
acetoacetanilide. Thus, it is conceivable that very short
reaction times and solvent are critical factors in obtaining
high yields of the products. Table 1 shows product yield
as a function of solvent, acid concentration, reaction
temperature, and time. From Table 1 it is clear that
MeCN is the solvent of choice, possibly due to the greater
solubility of aqueous HCl. Table 2 provides a listing of
the various compounds that were prepared, the yields,
and melting points.
The mechanism for the rearrangement can be ex-
plained as follows. Protonation of the amide carbonyl in
3 followed by addition of water6 resulted in hemiacetal 4
which can undergo a ring-opening to provide 5. Proto-
nation of the newly formed carbonyl in 6 can result in
trapping of the carbenium ion by either the lone pair on
nitrogen (path a) or the oxygen of the enol form of the
amide (path b).7 Through path a, the formed animal 7
undergoes dehydration to the 1,4-thiazin-3-one. Since
neither 9 or 10 was the observed product, path b can be
Resu lts a n d Discu ssion
The starting 1,4-oxathiin carboxamides 1 were pre-
pared through previously reported methods.5 Treatment
of the 1,4-oxathiin 1a with concentrated hydrochloric acid
† Tel.: +82-2-958-5139. FAX: +82-2-958-5189. E-mail: hghahn@
kistmail.kist.re.kr.
‡ Department of Chemistry, Kyonggi University, Suwon 440-270,
Seoul, Korea.
(1) Naka, T.; Hisano, M. J P 02,275,869; Chem. Abstr. 1991, 114,
185525p.
(2) Yamazaki, H.; Harada, H.; Matsuzaki, K.; Watanabe, T.; Saito,
H. Chem. Pharm. Bull. 1992, 40, 1025.
(3) Takase, M.; Yoshioka, K.; Yamazaki, H. PTC Int. Appl. WO 91
18,893; Chem. Abstr. 1992, 116, 106323m.
(4) (a) deStevens, G.; Halamandaris, A.; Dorfman, L. J . Am. Chem.
Soc. 1958, 80, 5198. (b) Hojo, M.; Masuda, R.; Kosaka, S.; Nagase, K.
Synthesis 1979, 272. (c) Bobek, M. J . Heterocycl. Chem. 1982, 19, 131.
(5) (a) Hahn, H. G.; Nam, K. D.; Chang, K. H. J . Korean Chem. Soc.
1995, 39, 127. (b) A new 2,N-diphenyl-1,4-oxathiin-3-carboxamide
(1m ) was prepared from the ethyl benzoylacetate using a method5a
similar to that for the preparation of 2-methyl-N-phenyl-1,4-oxathiin-
3-carboxamide (1a ). For 1m : mp 139-141 °C; 1H NMR (300 MHz,
CDCl3) δ 5.46 (d, 1H, J ) 5.2), 6.49 (d, 1H, J ) 5.2), 6.95 (br s, 1H),
7.00-7.51 (m, 10H).
(6) (a) Lee, W. S.; Hahn, H. G.; Nam, K. D. J . Org. Chem. 1986, 51,
2789. (b) Corbeil, M. A.; Curcumelli-Rodostamo, M.; Fanning, R. J .;
Graham, B. A.; Kulka, M.; Pierce, J . B. Can. J . Chem. 1973, 51, 2650.
S0022-3263(95)01723-3 CCC: $12.00 © 1996 American Chemical Society

Notes
J . Org. Chem., Vol. 61, No. 11, 1996 3895
13C NMR (78.5 MHz, CDCl3) δ 26.9, 51.4, 96.9, 127.3, 128.6,
129.9, 130.7, 141.2, 161.1, 199.6; IR 1705 (acetyl CdO), 1660
(amide CdO); MS 233 (M+, 44), 191 (M+ - OdCdCH2+, 100);
HRMS for C12H11NO2S calcd 233.0511, found 233.05213. Anal.
Calcd for C12H11NO2S: C, 61.8; H, 4.75; N, 6.00. Found: C,
61.99; H, 4.71; N, 6.00.
Sch em e 1
2-Acetyl-4-(2-m eth ylph en yl)-2H-1,4-th iazin -3(4H)-on e (2b),
1
a mixture of A isomer and B isomer (10:8): isomer A, H NMR
(300 MHz, CDCl3) δ 2.20 (s, 3H), 2.40 (s, 3H), 4.13 (d, 1H, J )
1.8), 5.55 (dd, 1H, J ) 1.8, 7.2), 6.28 (d, 1H, J ) 7.2), 7.26-7.31
1
(m, 4H); isomer B, H NMR δ 2.36 (s, 3H), 2.41 (s, 3H), 4.21 (d,
1H, J ) 1.8), 5.57 (dd, 1H, J ) 1.8, 7.2), 6.30 (d, 1H, J ) 7.2),
7.26-7.31 (m, 4H); IR 1713 (acetyl CdO), 1670 (amide CdO);
MS 247.3 (M+), 205 (M+ - COCH2+); HRMS for C13H13NO2S
calcd 247.0667, found 247.0669.
2-Acetyl-4-(4-m eth ylph en yl)-2H-1,4-th iazin -3(4H)-on e (2c):
1H NMR (300 MHz, CDCl3) δ 2.37 (s, 3H), 2.40 (s, 3H), 4.14 (d,
1H, J ) 1.7), 5.53 (dd, 1H, J ) 1.7, 7.1), 6.40 (d, 1H, J ) 7.1),
7.22-7.27 (m, 4H); IR 1716 (acetyl CdO), 1674 (amide CdO);
HRMS for C13H13NO2S calcd 247.0667, found 247.0667.
2-Acetyl-4-(2-ch lor oph en yl)-2H-1,4-th iazin -3(4H)-on e (2d):
1H NMR (300 MHz, CDCl3) δ 2.41 (s, 3H), 4.18 (s, 1H), 5.59 (d,
1H, J ) 7.0), 6.25 (d, 1H, J ) 7.0), 7.26-7.50 (m, 4H); IR 1715
(acetyl CdO), 1662 (amide CdO); MS 267 (M+, 26), 225 (M+
-
COCH2+, 100).
2-Acetyl-4-(4-ch lor oph en yl)-2H-1,4-th iazin -3(4H)-on e (2e):
1H NMR (300 MHz, CDCl3) δ 2.40 (s, 3H), 4.13 (d, 1H, J ) 1.3),
5.57 (dd, 1H, J ) 1.3, 7.3), 6.38 (d, 1H, J ) 7.3), 7.26-7.41 (m,
4H); IR 1668 (acetyl CdO), 1662 (amide CdO); MS 267 (M+,
39), 225 (M+ - COCH2+, 100); HRMS for C12H10NO2SCl calcd
267.0121, found 267.0121.
2-Ace t yl-4-(2-m e t h oxyp h e n yl)-2H -1,4-t h ia zin -3(4H )-
on e (2f): 1H NMR (300 MHz, CDCl3) δ 2.35 (s, 3H), 3.78 (s, 3H),
4.19 (s, 1H), 5.47 (br s, 1H), 6.20 (d, 1H, J ) 7.1), 6.92-7.38 (m,
4H); IR 1712 (acetyl CdO), 1666 (amide CdO); MS 263 (M+,
26), 221 (M+ - COCH2+, 100); HRMS for C13H13NO3S calcd
263.0616, found 263.0617.
2-Ace t yl-4-(4-m e t h oxyp h e n yl)-2H -1,4-t h ia zin -3(4H )-
on e (2g): 1H NMR (300 MHz, CDCl3) δ 2.40 (s, 3H), 3.82 (s,
3H), 4.13 (d, 1H, J ) 1.8), 5.52 (dd, 1H, J ) 1.8, 7.3), 6.39 (d,
1H, J ) 7.1), 6.93-7.23 (m, 4H); IR 1718 (acetyl CdO), 1674
(amide CdO); MS 263 (M+, 11), 221 (M+ - COCH2+, 100), 134
(51), 108 (C6H5OCH3); HRMS for C13H13NO3S calcd 263.0616,
found 263.0611.
ruled out. All of these thiazin-3-ones were characterized
by their elemental analyses and spectral data (see the
Experimental Section for details). As a final confirmation
of structure, we subjected 2 to reduction by sodium
borohydride. A diastereomeric mixture of products was
obtained in an ∼3:1 ratio and had spectral features
consistent with structure 11.
An interesting phenomenon was observed for 1,4-
thiazin-3-ones 2b and 2k , which have ortho substituents
in the aromatic nucleus (example R ) Me). The products
in these cases were obtained as an ∼5:4 mixture of two
isomers, presumably rotamers, as determined by proton
NMR spectroscopy. This is possibly due to the presence
of an ortho substituent in the aromatic ring which
inhibits free N-aryl bond rotation resulting in atropiso-
mers as in the case of substituted biphenyls. However,
we have not attempted separation of these isomers.
2-Acetyl-4-(2-n itr op h en yl)-2H-1,4-th ia zin -3(4H)-on e (2h ):
1H NMR (300 MHz, CDCl3) δ 2.41 (s, 3H), 4.23 (s, 1H), 5.68 (d,
1H, J ) 7.0), 6.35 (d, 1H, J ) 7.0), 7.10-8.68 (m, 4H); IR 1717
(acetyl CdO), 1672 (amide CdO); MS 278 (M+, 36), 236 (M+
-
COCH2+, 100); HRMS for C12H10N2O4S calcd 278.0361, found
278.0361.
2-Acet yl-4-(2,6-d im et h ylp h en yl)-2H -1,4-t h ia zin -3(4H )-
1
on e (2i): H NMR (300 MHz, CDCl3) δ 2.16 and 2.36 (2s, 6H),
2.41 (s, 3H), 4.21 (d, 1H, J ) 2.0), 5.63 (dd, 1H, J ) 2.0, 7.1),
6.18 (d, 1H, J ) 7.1), 7.08-7.17 (m, 3H); IR 1668 (acetyl CdO),
1662 (amide CdO); MS 261 (M+, 43), 219 (M+ - COCH2+, 100);
HRMS for C14H15NO2S calcd 261.0824, found 261.0823.
2-Acetyl-4-(2,4-d im eth oxyp h en yl)-2H-1,4-th ia zin -3(4H)-
on e (2j): 1H NMR (300 MHz, CDCl3) δ 2.42 (s, 3H), 3.81 and
3.82 (2s, 6H), 4.28 (br s, 1H), 5.52 (br s, 1H), 6.25 (d, 1H, J )
7.2), 6.50-7.30 (m, 3H); IR 1714 (acetyl CdO), 1676 (amide
CdO); MS 293 (M+, 59), 251 (M+ - COCH2+, 96), 138
(C6H4(OCH3)2, 100); HRMS for C14H15NO4S calcd 293.0722,
found 293.0724.
Exp er im en ta l Section
Melting points were obtained with an Electrothermal melting
point apparatus. All chromatographic isolations were accom-
plished on silica gel GF 254 (70-230 mesh). All reagents were
of commercial quality. J values are in hertz.
P r ep a r a tion of 1,4-Th ia zin -3-on es 2. Gen er a l P r oce-
d u r e. To a solution of 2-methyl-N-phenyl-1,4-oxathiin-3-car-
boxamide (1a ) (852 mg, 3.6 mmol) in MeCN (20 mL) was added
concentrated HCl (10 mL). The solution was placed in an 80 °C
oil bath with stirring for 10 min. The reaction mixture was
2-Acet yl-4-(2,4-d im et h ylp h en yl)-2H -1,4-t h ia zin -3(4H )-
on e (2k ), a mixture of A isomer and B isomer (10:8): isomer A,
1H NMR (300 MHz, CDCl3) δ 2.14 and 2.32 (2s, 6H), 2.39 (s,
3H), 4.13 (d, 1H, J ) 1.7), 5.55 (dd, 1H, J ) 1.7, 6.8), 6.27 (d,
diluted with methylene chloride, washed with
a saturated
sodium bicarbonate solution and water, and then dried (Na2-
SO4). The solvent was evaporated and the resulting residue was
purified by flash chromatography using n-hexane/ethyl acetate
(7/3) to give 2-acetyl-4-phenyl-2H-1,4-thiazin-3(4H)-one (2a ) (596
mg, 70%) as a colorless solid.
1
1H, J ) 7.2), 7.02-7.26 (m, 3H); isomer B, H NMR δ 2.16 and
2.33 (2s, 6H), 2.40 (s, 3H), 4.20 (d, 1H, J ) 1.8), 5.52 (dd, 1H, J
) 1.8, 6.8), 6.29 (d, 1H, J ) 6.8), 7.02-7.26 (m, 3H); HRMS for
C
14H15NO2S calcd 261.0824, found 261.0823.
2-Acetyl-4-p h en yl-2H-1,4-th ia zin -3(4H)-on e (2a ): 1H NMR
(300 MHz, CDCl3) δ 2.41 (s, 3H), 4.14 (d, 1H, J ) 1.7),8 5.56
(dd, 1H, J ) 1.7, 7.2), 6.44 (d, 1H, J ) 7.2), 7.30-7.47 (m, 5H);
2-Acetyl-4-(4-eth ylp h en yl)-2H-1,4-th ia zin -3(4H)-on e (2l):
1H NMR (300 MHz, CDCl3) δ 1.24 (t, 3H, J ) 7.6), 2.40 (s, 3H),
(8) This coupling was due to long range coupling (4J ) between a
methine proton on C-2 and a vinyl proton on C-6. A lone pair of
electrons on sulfur can serve as a p donor to the neighboring protons
and thereby make 4J more positive.
(7) Challis, B. C.; Challis, J . A. The Chemistry of Amids; Zabicky,
J ., Ed.; Interscience Publishers: London, 1970; pp 731-857 and
references cited therein.

3896 J . Org. Chem., Vol. 61, No. 11, 1996
Notes
5.53 (dd, 1H, J ) 1.5, 7.2), 6.42 (d, 1H, J ) 7.2), 7.20-7.27 (m,
3H); IR 1720 (acetyl CdO), 1676 (amide CdO); MS 261 (M+,
41), 219 (M+ - COCH2+, 100); HRMS for C14H15NO2S calcd
261.0824, found 261.0824.
borohydride (13 mg, 0.33 mmol) portionwise over 5 min. The
reaction mixture was stirred at 0 °C for 1 h. The reaction
mixture was poured into ice water (50 mL) and extracted with
methylene chloride. The organic layer was washed with water,
dried (Na2SO4), and evaporated to give a diastereomeric mixture
of the alcohol 11 (154 mg, 100%) as a colorless solid. A mixture
of A isomer and B isomer (3:1): mp 97-98 °C; IR 3450 (OsH),
1660 (CdO). Anal. Calcd for C12H13NO2S: C, 61.25; H, 5.57;
N, 5.95. Found C, 61.26; H, 5.57; N, 6.06.
2-Ben zoyl-4-p h en yl-2H-1,4-th ia zin -3(4H)-on e (2m ): 1H
NMR (300 MHz, CDCl3) δ 5.03 (d, 1H, J ) 2.04), 5.52 (dd, 1H,
J ) 2.0, 7.1), 6.51 (d, 1H, J ) 7.1), 7.35-7.94 (m, 10H); IR 1675
(acetyl CdO), 1665 (amide CdO), 1295; MS 295 (M+, 25), 105
(CO+C6H5, 100); HRMS for C17H13NO2S calcd 295.0667, found
295.0667.
Isomer A: 1H NMR (300 MHz, CDCl3) δ 1.41 (d, 3H, J ) 6.4),
3.06 (br s, 1H), 3.51 (dd, 1H, J ) 1.4, J ) 6.0),9 4.34-4.42 (m,
1H), 5.72 (dd, 1H, J ) 1.4, J ) 7.2), 6.43 (d, 1H, J ) 7.2), 7.23-
7.46 (m, 5H).
2-Acetyl-4-m eth yl-2H-1,4-th ia zin -3(4H)-on e (2n ): 1H NMR
(300 MHz, CDCl3) δ 2.34 (s, 3H), 3.23 (s, 3H), 4.04 (d, 1H, J )
1.8), 5.46 (dd, 1H, J ) 1.8, J ) 7.2), 6.27 (d, 1H, J ) 7.2); IR
1662 (acetyl CdO), 1718 (amide CdO); MS 171 (M+, 28), 129
(M+ - OdCdCH2+, 100); HRMS for C7H9NO2S calcd 171.0354,
found 171.0354.
Isomer B: 1H NMR (300 MHz, CDCl3) δ 1.41 (d, 3H, J ) 6.4),
3.06 (br s, 1H), 3.42 (d, 1H, J ) 8.8), 4.20-4.30 (m, 1H), 5.78 (d,
1H, J ) 7.2), 6.43 (d, 1H, J ) 7.2), 7.23-7.46 (m, 5H).
2-Acetyl-4-eth yl-2H-1,4-th ia zin -3(4H)-on e (2o): 1H NMR
(300 MHz, CDCl3) δ 1.23 (t, 3H, J ) 7.7), 2.35 (s, 3H), 3.62-
3.75 (m, 2H), 4.03 (d, 1H, J ) 1.8), 5.50 (dd, 1H, J ) 1.8, J )
7.1), 6.31 (d, 1H, J ) 7.1); IR 1656 (acetyl CdO), 1719 (amide
CdO); MS 185 (M+, 35), 143 (M+ - OdCdCH2+, 100); HRMS
for C8H11NO2S calcd 185.0511, found 185.0499.
Ack n ow led gm en t. We thank Dr. W. S. Lee and Dr.
M. K. Lakshman for assistance in preparing the
manuscript.
J O951723H
P r epar ation of 2-(2′-Hydr oxyeth yl)-N-ph en yl-1,4-th iazin -
3(4H)-on e (11). To a solution of 2a (153 mg, 0.66 mmol) in
ethanol (10 mL) cooled to 0 °C in an ice bath was added sodium
(9) This coupling was caused by 4J between a methine proton on
C-2 and a vinyl proton on C-6.