Thionation of N-(ω-halogenoalkyl)-substituted amides with Lawesson's reagent: Facile synthesis of 4,5-dihydro-1,3-thiazoles and 5,6-dihydro-4H-1,3- thiazines

Article abstract of DOI:10.1002/hlca.200590000

The thionation and cyclization of N-(ω-halogenoalkyl)-substituted amides (and related compounds) with Lawesson's reagent (LR = 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide) has been investigated. Treatment of the amides 1 with LR gav

Full text of DOI:10.1002/hlca.200590000

Helvetica Chimica Acta ± Vol. 88 (2005)
187
Thionation of N-(w-Halogenoalkyl)-Substituted Amides with Lawessonꢀs
Reagent: Facile Synthesis of 4,5-Dihydro-1,3-thiazoles and 5,6-Dihydro-4H-
1,3-thiazines
by Yasuhiro Kodamaa), Mayuko Oria), and Takehiko Nishio*b)
a) Graduate School of Environmental Sciences, University of Tsukuba, Tsukuba-shi, Ibaraki, 305-8571 Japan
b) Department of Chemistry, University of Tsukuba, Tsukuba-shi, Ibaraki, 305-8571 Japan
The thionation and cyclization of N-(w-halogenoalkyl)-substituted amides (and related compounds) with
Lawessonꢀs reagent (LR ˆ 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide) has been in-
vestigated. Treatment of the amides 1 with LR gave the corresponding thioamides 2 in moderate to good yields
(Table). The latter, upon treatment with base, afforded, either in a separate step or in a one-pot procedure, the
cyclized title compounds, i.e., the 4,5-dihydro-1,3-thiazoles 3 or the corresponding 5-6-dihydro-4H-thiazines 4
via dehydrohalogenation.
Introduction. ± ꢁ1,3-Thiazolinesꢀ (ˆ4,5-dihydro-1,3-thiazoles) and 1,3-thiazines are
a class of heterocycles that have received considerable attention due to their interesting
biological activities. Consequently, a number of methods for the synthesis of these
compounds have been reported [1]. The well-known Lawessonꢀs reagent (LR ˆ 2,4-
bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide), one of the best
thionation reagents, converts a wide range of carbonyls to thiocarbonyl compounds [2].
Several S- [3] and P-containing [4] heterocycles have been synthesized by reacting
LR with the compounds possessing multiple funtional groups. We have reported that
LR can be used for the direct conversion of alcohols to thiols [5], as well as for a novel
synthesis of S-containing heterocycles by reaction of LR with substrates containing two
functional groups, e.g., hydroxy amides [3g,h], acylamino alcohols [3g,h,l,p], acylamino
ketones [3n,q], and oxo amides [3m]. To extend the scope of such reactions with LR,
we have now investigated N-(w-halogenoalkyl)-substituted amides of type 1 as
substrates (and related compounds) for the synthesis of S-containing 5- and 6-
membered heterocycles.
Results and Discussion. ± The reaction of the N-(w-halogenoalkyl)amides 1a ± 1h,
1j, 1l, and 1m with 0.5 equiv. of LR in toluene at reflux temperature under Ar gas for
60 min yielded the corresponding halogenated thioamides 2a ± 2h, 2j, 2l, and 2m as the
sole products in yields of 40 ± 86% (Table). Treatment of compounds 2b and 2e with
ꢂ 2005 Verlag Helvetica Chimica Acta AG, Zürich

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Et3N in toluene then afforded the cyclized products, i.e., 4,5-dihydro-2-(phenoxymeth-
yl)-1,3-thiazole (3a) and 5,6-dihydro-2-(phenoxymethyl)-4H-1,3-thiazine (4d) in
quantitative yields, respectively. Analogously, the corresponding thiazoles 3a, g, h, j,
l, n, p and thiazines 4d, i, k, m, o, q were produced, when the corresponding substrates
1a ± 1q were exposed, in an one-pot procedure, to LR, followed by in situ treatment
with base (Et3N or NaHCO3).
Table. Specification of Substrates 1 and Yields of Products 2 ± 4. For synthetic details, see the Exper. Part.
Entry
No.
R
n
X
Method
Isolated Yield [%]
2
3
4
1
2
3
4
5
6
7
8
9
1a
1a
1a
1b
1b
1b
1b
1c
1c
1d
1d
1d
1e
1e
1e
1f
1f
1g
1g
1h
1h
1i
1j
1j
1k
1l
1l
1m
1m
1n
1o
1p
1q
PhOCH2
PhOCH2
PhOCH2
PhOCH2
PhOCH2
PhOCH2
PhOCH2
PhOCH2
PhOCH2
PhOCH2
PhOCH2
PhOCH2
PhOCH2
PhOCH2
PhOCH2
PhOCH2
PhOCH2
PhCH2
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
1
1
1
1
2
1
1
2
1
1
2
2
1
2
1
2
Cl
Cl
Cl
Br
Br
Br
Br
I
A
B
8
±
±
8
±
54
±
8
±
79
±
±
8
±
±
77
±
48±
±
40
±
±
44
±
±
63
±
55
±
±
±
±
5
6
±
±
±
±
77
±
±
Ba)
A
42b)
B
71
±
±
±
Ac)
Ba)
A
±
51d)
6
60
±
±
±
1
±
±
±
±
±
±
±
±
I
B
A
B
±
±
8
44
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
Cl
Cl
Cl
Br
Br
Br
I
5
Ba)
A
B
78
57
±
Ba)
A
I
B
A
B
A
B
B
A
B
B
A
B
A
B
B
B
B
68
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
±
PhCH2
Ph
Ph
Ph
76
±
8
±
±
76
±
±
8
±
±
±
3
1
±
4
8
±
±
79
±
4ÀMeÀC6H4
4ÀMeÀC6H4
4ÀMeÀC6H4
4ÀClÀC6H4
4ÀClÀC6H4
4ÀClÀC6H4
4ÀClÀC6H4
2-Thienyl
2-Thienyl
2-Furyl
±
±
±
8
±
8
±
8
5
7
4
8
8
±
2-Furyl
B
±
±
93
a) Treatment of 1 with P2S5 (0.5 equiv.) instead of LR, followed by addition of Et3N (5 equiv.) in situ.
b) Together with 16% of 5. c) P2S5 (0.5 equiv.) was used instead of LR. d) Together with 15% of 5.

Helvetica Chimica Acta ± Vol. 88 (2005)
189
Djerassi and Scholz have reported that treatment of N-(2-bromoethyl)-2-phenox-
yacetamide (1b; n ˆ 1) and its homolog 1e (n ˆ 2) with P2S5 in refluxing toluene gave
the thiazole 3a and the thiazine 4d in 9 and 37% yield, respectively [6]. Therefore, we
re-examined the reaction of 1b with P2S5. In our hands, treatment of 1b with P2S5
yielded the open-chain thio derivative 2b as the sole product in 54% yield (Entry 6 in
the Table). However, the 4,5-dihydro-1,3-thiazole 3a was obtained after the usual
workup (extraction) of the reaction mixture. Compound 3a was also produced in 51%
yield when 1b was treated with P2S5, followed by addition of base (one-pot procedure;
Entry 7). In a similar manner, compounds 3a and 4d, derived from 1a and from 1d or 1e,
respectively, were obtained upon treatment with P2S5; however, in moderate yields only
(Entries 3, 12, and 15). A small amount of the sulfanyl derivative 5, which was probably
formed by hydrolysis of 2a, was produced in the reaction of compounds 1a,b with P2S5
and base.
A reasonable mechanism for the formation of five- and six-membered heterocycles
of type 3 and 4, respectively, involves initial thionation of the N-(halogenoalkyl) amides
1 to the corresponding thioamides, followed by dehydrohalogenation and intra-
molecular cyclization upon treatment with base.
Next, we investigated substrates with non-halogen leaving groups (X; see Scheme),
namely the b-hydroxy (1r), b-ethoxy (1s), b-(benzyloxycarbonyl) (1t), b-[(4-methyl-
Scheme

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phenyl)sulfanyl] (1u), b-[(4-methylphenyl)sulfonyl] (1v), and b,b-diethoxy (1w)
analogs. Compound 1r was treated with 0.5 equiv. of LR under the same condition as
described above to give N-(2-mercaptoethyl)-2-phenoxyacetamide (5) in 72% yield.
Further treatment of 5 with LR gave the cyclized dihydrothiazole 3a in almost
quantitative yield; this result is identical with those previously published [3o,p].
Treatment of 1s ± 1v with LR afforded the corresponding thioacetamide derivatives
2s ± 2v in good yields. However, these ꢁintermediatesꢀ could not be cyclized, not even
upon treatment with base.
In the case of N-(2,2-diethoxyethyl)-2-phenoxyacetamide (1w), exposure to LR
afforded a mixture of the thiazole 7 (13%), the 2-ethoxyvinyl derivative 6 (7%), and
the 4,5-dihydro-5-ethoxy-1,3-thiazole 3w (70%; Scheme). Thereby, the latter com-
pound would be readily converted to 7 upon treatment with base (elimination of
EtOH). In contrast, treatment of the N-(2-halogenophenyl)-2-phenoxyacetamides 8
with LR gave the corresponding thioacetamides 9 exclusively (Scheme).
Conclusions. ± We have developed a one-pot procedure for the facile synthesis of
4,5-dihydro-1,3-thiazoles (3) and 5,6-dihydro-4H-1,3-thiazines (4). These compounds
can be readily accessed by treatment of N-(w-halogenoalkyl)-substituted amides with
Lawessonꢀs reagent (LR), followed by addition of base.
Experimental Part
General. Flash-column chromatography (FC): Wakogel C-300 and Merck 60 silica gel. M.p.: Yanaco MP-J3
micro-melting-point apparatus; uncorrected. B.p.: Shibata GTO-350-RD glass-tube-oven distillation apparatus.
1
IR Spectra: Jasco FT/IR-300 spectrophotometer; in cmÀ1. H- and 13C-NMR Spectra: Jeol JNM-EX-270 (270/
67.5 MHz) or Varian Gemini-200 (200/50 MHz); in CDCl3, unless otherwise noted, with Me4Si as internal
standard; d in ppm, J in Hz.
General Procedure (Method A) for the Thionation of N-(w-halogenoalkyl)acetamides. A soln. of the
substrate 1 (2 mmol) and Lawesssonꢀs reagent (LR; 1 mmol)1) in toluene (20 ml) was heated to reflux under Ar
gas for 1 h. After removal of the solvent, the residue was subjected to FC (SiO2; toluene/AcOEt 2 :1) or
recrystallized (MeOH/AcOEt) to afford the thioamides 2 (see Table).
General Procedure (Method B) for the One-Pot Cyclization of N-(w-halogenoalkyl)acetamides. A soln. of
the substrate 1 (2 mmol) and LR (1 mmol) in toluene (20 ml) was heated to reflux under Ar gas for 1 h. After
cooling down to r.t., Et3N (5 ml) or a sat. aq. NaHCO3 soln. (5 ml) was added, and this mixture was stirred for
30 ± 60 min (TLC control). Usual workup (extraction) and purification by FC or recrystallization afforded the
heterocyclic products 3 or 4 (see Table).
N-(2-Chloroethyl)-2-phenoxyethanethioamide (2a). M.p. 140 ± 1428. 1H-NMR (CD3OD): 3.10 ± 3.27 (m,
4 H); 4.89 (s, 2 H); 6.95 ± 7.04 (m, 3 H); 7.25 ± 7.35 (m, 2 H). 13C-NMR (CD3OD): 23.9; 38.4; 71.7; 113.9; 121.4;
128.8; 157.2; 197.6.
1
4,5-Dihydro-2-(phenoxymethyl)-1,3-thiazole (3a). B.p. 1608/3 Torr2). H-NMR: 3.31 (t, J ˆ 8.4, 2 H); 4.32
(t, J ˆ 8.4); 4.89 (s, 2 H); 6.94 ± 7.03 (m, 3 H); 7.25 ± 7.34 (m, 2 H). 13C-NMR: 32.8; 64.5; 67.4; 113.6; 121.5; 129.4;
157.8; 169.5.
N-(2-Bromoethyl)-2-phenoxyethanethioamide (2b). M.p. 147 ± 1488. 1H-NMR (CD3OD): 3.88 (t, J ˆ 9.2,
2 H); 4.51 (t, J ˆ 9.2, 2 H); 5.37 (s, 2 H); 7.04 ± 7.09 (m, 3 H); 7.32 ± 7.38( m, 2 H). 13C-NMR (CD3OD): 33.8; 56.0;
67.5; 116.8; 124.6; 131.7; 159.0; 196.3. Anal. calc. for C10H12BrNOS: C 43.80, H 4.41, N 5.11; found: C 43.58,
H 4.60, N 4.98.
1
)
)
Alternatively, P2S5 (1 mmol) can be used.
M.p. of the corresponding picrate: 177 ± 1798 [6].
2

Helvetica Chimica Acta ± Vol. 88 (2005)
191
N-(2-Iodoethyl)-2-phenoxyethanethioamide (2c). M.p. 190 ± 1928. 1H-NMR (CD3OD): 3.86 (t, J ˆ 9.4, 2 H);
4.50 (t, J ˆ 9.4, 2 H); 4.50 (t, J ˆ 9.4, 2 H); 5.38( s, 2 H); 6.98± 7.11 ( m, 3 H); 7.31 ± 7.42 (m, 2 H). 13C-NMR
(CD3OD): 33.0; 55.5; 66.8; 116.1; 123.8; 131.0; 158.3; 184.2. Anal. calc. for C10H12INOS: C 37.39, H 3.37, N 4.36;
found: C 37.47, H 3,60, N 4.19.
1
N-(3-Chloropropyl)-2-phenoxyethanethioamide (2d). M.p. 137 ± 1398. H-NMR (CD3OD): 2.19 ± 2.29 (m,
2 H); 3.36 (t, J ˆ 5.8, 2 H); 3.76 (t, J ˆ 5.1, 2 H); 5.14 (s, 2 H); 6.89 ± 7.07 (m, 3 H); 7.28± 7.36 ( m, 2 H). 13C-NMR
(CD3OD): 17.6; 25.7; 41.9; 67.6; 114.2; 122.0; 129.0; 154.2; 188.8.
5,6-Dihydro-2-(phenoxymethyl)-4H-1,3-thiazine (4d). B.p. 1458/3 Torr2). 1H-NMR: 1.78± 1.91 ( m, 2 H);
3.02 (t, J ˆ 5.9, 2 H); 3.73 (t, J ˆ 5.9, 2 H); 4.63 (s, 2 H); 6.89 ± 7.02 (m, 3 H); 7.26 ± 7.36 (m, 2 H). 13C-NMR: 18.7;
25.1; 46.6; 72.2; 114.3; 120.8; 128.9; 157.6; 158.7.
1
N-(3-Bromopropyl)-2-phenoxyethanethioamide (2e). M.p. 136 ± 1378. H-NMR (CD3OD): 2.24 ± 2.36 (m,
2 H); 3.41 (t, J ˆ 6.0, 2 H); 3.82 (t, J ˆ 5.5, 2 H); 5.19 (s, 2 H); 6.93 ± 7.10 (m, 3 H); 7.30 ± 7.40 (m, 2 H). 13C-NMR
(CD3OD): 18.3; 26.5; 42.2; 68.0; 114.9; 122.8; 156.4; 185.3. Anal. calc. for C11H14BrNOS: C 45.84, H 4.90, N 4.86;
found: C 45.73, H 4.96, N 4.86.
N-(3-Iodopropyl)-2-phenoxyethanethioamide (2f). M.p. 138± 140 8. 1H-NMR (CD3OD): 2.25 ± 2.38( m,
2 H); 3.43 (t, J ˆ 5.6, 2 H); 3.83 (t, J ˆ 5.6, 2 H); 5.19 (s, 2 H); 7.03 ± 7.10 (m, 3 H); 7.31 ± 7.41 (m, 2 H). 13C-NMR
(CD3OD): 19.8; 28.0; 44.1; 69.9; 116.4; 124.1; 131.1; 158.4; 183.4. Anal. calc. for C11H14INOS: C 37.39, H 3.77,
N 4.36; found: C 37.47, H 3.75, N 4.19.
N-(2-Chloroethyl)-2-phenylethanethioamide (2g). M.p. 107 ± 1098. 1H-NMR (CD3OD): 3.68( t, J ˆ 9.3,
2 H); 4.41 (s, 2 H); 4.55 (t, J ˆ 9.3, 2 H); 7.25 ± 7.38( m, 5 H). 13C-NMR (CD3OD): 31.6; 37.8; 54.3; 128.8; 129.4;
132.3; 195.4.
4,5-Dihydro-2-(phenylmethyl)-1,3-thiazole (3g). B.p. 1158/3 Torr ([7]: 137 ± 1398/6 Torr). 1H-NMR: 3.26 (t,
J ˆ 8.4, 2 H); 3.82 (s, 2 H); 4.24 (t, J ˆ 8.4, 2 H); 7.21 ± 7.38 (m, 5 H). 13C-NMR: 33.5; 40.1; 64.0; 126.5; 128.0;
128.5; 135.5; 170.0.
N-(2-Chloroethyl)benzenecarbothioamide (2h). M.p. 118± 120 8. 1H-NMR: 3.83 (t, J ˆ 8.9, 2 H); 4.72 (t, J ˆ
8.9, 2 H); 6.18 (br. s, 1 H); 7.55 ± 7.63 (m, 2 H); 7.71 ± 7.85 (m, 1 H); 8.24 ± 8.29 (m, 2 H). 13C-NMR (CD3OD):
31.1; 55.3; 125.5; 129.8; 130.6; 136.5; 185.8.
1
4,5-Dihydro-2-phenyl-1,3-thiazole (3h). B.p. 1108/3 Torr (lit. b.p. 105 ± 1078/2 Torr [7]). H-NMR: 3.42 (t,
J ˆ 8.4, 2 H); 4.46 (t, J ˆ 8.4, 2 H); 7.36 ± 7.51 (m, 3 H); 7.82 ± 7.88 (m, 2 H). 13C-NMR: 33.6; 65.2; 128.5; 131.2;
133.3; 157.4; 168.6.
5,6-Dihydro-2-phenyl-4H-1,3-thiazine (4i). B.p. 1258/3 Torr (lit. b.p. 1248/1.5 Torr [8]). 1H-NMR: 1.86 ± 1.98
(m, 2 H); 3.16 (t, J ˆ 6.0, 2 H); 3.92 (t, J ˆ 5.4, 2 H); 7.32 ± 7.46 (m, 3 H); 7.71 ± 7.81 (m, 2 H). 13C-NMR: 19.1;
26.5; 48.0; 126.3; 128.3; 130.4; 139.6; 158.3.
N-(2-Chloroethyl)-4-methylbenzenecarbothioamide (2j). M.p. 115 ± 1178. 1H-NMR: 2.46 (s, 3 H); 3.8 2 (t,
J ˆ 8.8, 2 H); 4.69 (t, J ˆ 8.6, 2 H); 7.38 (d, J ˆ 8.1, 2 H); 8.17 (d, J ˆ 8.1, 2 H). 13C-NMR: 22.1; 30.9; 54.6; 122.7;
130.5; 130.8; 148.7; 185.9.
4,5-Dihydro-2-(4-methylphenyl)-1,3-thiazole (3j). M.p. 39.5 ± 40.58 (lit. m.p. 41.5 ± 42.58 [9]). 1H-NMR:
2.38( s, 3 H); 3.39 (t, J ˆ 8.3, 2 H); 4.44 (t, J ˆ 8.3, 2 H); 7.20 (d, J ˆ 8.1, 2 H); 7.72 (d, J ˆ 8.1, 2 H). 13C-NMR:
21.4; 33.6; 65.2; 128.4; 129.2; 130.7; 141.6; 168.4.
5,6-Dihydro-2-(4-methylphenyl)-4H-1,3-thiazine (4k). M.p. 44 ± 458. 1H-NMR: 1.84 ± 1.93 (m, 2 H); 2.36 (s,
3 H); 3.14 (t, J ˆ 6.1, 2 H); 3.90 (t, J ˆ 6.1, 2 H); 6.17 (d, J ˆ 8.1, 2 H); 7.67 (d, J ˆ 8.1, 2 H). 13C-NMR: 19.2; 21.3;
26.5; 47.9; 126.2; 129.0; 136.8; 140.8; 158.4. Anal. calc. for C 11H13NS: C 69.09, H 6.85, N 7.33; found: C 68.97,
H 6.58, N 7.11.
4-Chloro-N-(2-chloroethyl)benzenecarbothioamide (2l). M.p. 101 ± 1028. 1H-NMR: 3.89 (t, J ˆ 9.0, 2 H);
4.70 (t, J ˆ 9.0, 2 H); 7.58( d, J ˆ 8.8, 2 H); 8.17 (d, J ˆ 8.8, 2 H). 13C-NMR: 31.4; 54.9; 123.8; 130.2; 131.7; 143.6;
185.6.
1
2-(4-Chlorophenyl)-4,5-dihydro-1,3-thiazole (3l). M.p. 50 ± 518 ([9]: 53.5 ± 558). H-NMR: 3.42 (t, J ˆ 8.4,
2 H); 4.45 (t, J ˆ 8.4, 2 H); 7.38 (d, J ˆ 8.6, 2 H); 7.76 (d, J ˆ 8.6, 2 H). 13C-NMR: 33.9; 65.2; 128.4; 128.7; 129.6;
131.7; 137.1; 167.2.
4-Chloro-N-(3-chloropropyl)benzenecarbothioamide (2m). M.p. 135 ± 1378. 1H-NMR: 2.27 ± 2.39 (m, 2 H);
3.44 (t, J ˆ 5.8, 2 H); 4.04 (t, J ˆ 5.8, 2 H); 7.52 (d, J ˆ 8.6, 2 H); 8.03 (d, J ˆ 8.6, 2 H). 13C-NMR: 18.6; 28.0;
43.2; 129.3; 129.5; 129.9; 141.9, 178.9.
2-(4-Chlorophenyl)-5,6-dihydro-4H-1,3-thiazine (4m). B.p. 1408/3 Torr. 1H-NMR: 1.84 ± 1.97 (m, 2 H); 3.15
(t, J ˆ 5.8, 2 H); 3.90 (t, J ˆ 5.8, 2 H); 7.34 (d, J ˆ 8.6, 2 H); 7.72 (d, J ˆ 8.6, 2 H). 13C-NMR: 19.0; 26.5; 48.0;
127.5; 128.4; 136.2; 137.9; 156.8. Anal. calc. for C10H10ClNS: C 56.73, H 4.67, N 6.67; found: C 56.76, H 4.92,
N 6.33.

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4,5-Dihydro-2-(2-thienyl)-1,3-thiazole (3n). M.p. 41 ± 428 ([9]: 40.5 ± 41.58). 1H-NMR: 3.15 (t, J ˆ 8.2, 2 H);
4.39 (t, J ˆ 8.2, 2 H); 7.06 (dd, J ˆ 3.8, 5.6, 1 H); 7.42 ± 7.46 (m, 2 H). 13C-NMR: 34.4; 64.7; 127.6; 129.7; 130.8;
137.1; 161.7.
5,6-Dihydro-2-(2-thienyl)-4H-1,3-thiazine (4o). M.p. 60.5 ± 62.58. 1H-NMR: 1.86 ± 1.98 (m, 2 H); 3.14 (t, J ˆ
6.0, 2 H); 3.86 (t, J ˆ 6.0, 2 H); 7.01 (dd, J ˆ 3.6, 5.0, 2 H); 7.33 ± 7.37 (m, 2 H); 7.43 ± 7.46 (m, 1 H). 13C-NMR:
19.1; 25.8; 47.2; 125.7; 126.7; 127.5; 143.5; 151.5. Anal. calc. for C8H9NS2: C 52.46, H 4.95, N 7.65; found: C 52.12,
H 4.91, N 7.47.
1
2-(2-Furyl)-4,5-dihydro-1,3-thiazole (3p) [10]. Oil. H-NMR: 3.40 (t, J ˆ 8.2, 2 H); 4.42 (t, J ˆ 8.2, 2 H);
6.49 (dd, J ˆ 1.6, 3.6, 1 H); 6.91 (d, J ˆ 3.6, 1 H); 7.53 (d, J ˆ 1.6, 1 H). 13C-NMR: 33.0; 64.3; 111.4; 113.4; 147.7;
157.7.
2-(2-Furyl)-5,6-dihydro-4H-1,3-thiazine (4q) [10]. Oil. 1H-NMR: 1.87 ± 1.99 (m, 2 H); 3.17 (t, J ˆ 4.8, 2 H);
3.90 (t, J ˆ 4.8, 2 H); 6.43 (dd, J ˆ 1.8, 3.4, 1 H); 6.81 (d, J ˆ 3.4, 1 H); 7.47 (d, J ˆ 1.8, 1 H). 13C-NMR: 19.0;
25.4; 46.9; 109.9; 110.8; 143.4; 143.5; 151.0.
Reaction of the 2-Phenoxyacetamides 1r± v Containing Non-Halogen Substituents. A soln. of the substrate 1
(2 mmol) and LR (1 mmol) in toluene (20 ml) was heated to reflux under Ar gas for 0.5 ± 5 h. After removal of
the solvent, the residue was subjected to FC (SiO2; toluene/AcOEt 4:1 ! 2:1) to give the products 5, 3a, 2s ± w, 6,
and 7.
N-(2-Mercaptoethyl)-2-phenoxyethanethioamide (5). B.p. 1558/3 Torr. IR (film): 3316, 2560, 1668.
1H-NMR: 1.34 (t, J ˆ 8.6, 1 H); 2.64 ± 2.75 (m, 2 H); 3.49 ± 3.59 (m, 2 H); 4.52 (s, 2 H); 6.91 ± 7.07 (m, 3 H);
7.22 ± 7.38( m, 2 H). 13C-NMR: 24.5; 41.8; 67.3; 114.7; 122.3; 129.9; 157.2; 168.5.
1
N-(2-Ethoxyethyl)-2-phenoxyethanethioamide (2s). M.p. 58± 59 8. H-NMR: 1.14 (t, J ˆ 7.0, 3 H); 3.46 (q,
J ˆ 7.0, 2 H); 3.62 (t, J ˆ 5.2, 2 H); 4.91 (s, 2 H); 3.90 ± 3.99 (m, 2 H); 6.88 ± 7.07 (m, 3 H); 7.22 ± 7.38( m, 2 H).
13C-NMR: 14.5; 44.0; 66.1; 66.8; 73.3; 114.1; 121.9; 129.4; 156.5; 196.3. Anal. calc. for C12H17NO2S: C 60.22,
H 7.16, N 5.85; found: C 60.32, H 7.33, N 6.01.
2-[(2-Phenoxyethanethioyl)amino]ethyl Phenylacetate (2t). B.p. 1508/3 Torr. IR (film): 3325, 1757, 1250,
1
1204. H-NMR: 3.86 ± 4.07 (m, 2 H); 4.46 (t, J ˆ 5.2, 2 H); 4.91 (s, 2 H); 4.54 (s, 2 H); 4.8 6 (s, 2 H); 6.82 ± 7.05
(m, 5 H); 7.22 ± 7.36 (m, 5 H); 8.58 (br. s, 1 H). 13C-NMR: 43.3; 61.9; 64.6; 73.3; 114.1; 114.4; 121.5; 122.0; 127.9;
129.5; 156.7; 168.8; 197.6.
N-{2-[(4-Methylphenyl)sulfanyl]ethyl}-2-phenoxyethanethioamide (2u). M.p. 94.5 ± 968. 1H-NMR: 2.28( t,
3 H); 3.15 (t, J ˆ 6.1, 3 H); 3.93 (m, 2 H); 4.8 3 (s, 2 H); 6.88 ± 6.94 (m, 2 H); 7.04 ± 7.09 (m, 2 H); 7.21 ± 7.36 (m,
5 H); 8.70 (br. s, 1 H). 13C-NMR: 20.5; 32.2; 42.7; 73.3; 114.5; 121.9; 129.5; 129.6; 131.0; 137.1; 156.4; 197.4. Anal.
calc. for C17H19NOS2: C 64.31, H 6.03, N 4.41; found: C 64.18, H 6.22, N 4.52.
N-{2-[(4-Methylphenyl)sulfonyl]ethyl}-2-phenoxyethanethioamide (2v). M.p. 128± 130 8. 1H-NMR: 2.40 (s,
3 H); 3.42 ± 3.47 (m, 2 H); 4.13 ± 4.19 (m, 2 H); 4.8 1 (s, 2 H); 6.93 ± 7.08( m, 3 H); 7.24 ± 7.36 (m, 4 H); 7.71 (d,
J ˆ 8.3, 2 H); 9.12 (br. s, 1 H). 13C-NMR: 21.6; 38.3; 53.6; 73.5; 114.9; 122.3; 127.9; 129.8; 130.2; 135.4; 145.4;
156.7; 197.5. Anal. calc. for C17H10NOS2: C 64.31, H 6.03, N 4.41; found: C 64.18, H 6.22, N 4.52.
N-(2-Ethoxyethenyl)-2-phenoxyethanamide (6). Oil. IR (film): 3422, 1685. 1H-NMR: 1.28( t, J ˆ 7.0, 3 H);
3.86 (q, J ˆ 7.0, 2 H); 4.55 (s, 2 H); 5.73 (d, J ˆ 4.9, 1 H); 6.19 (dd, J ˆ 4.9, 10.6, 1 H); 6.93 ± 7.06 (m, 3 H); 7.23 ±
7.39 (m, 2 H); 8.26 (br. s, 1 H). 13C-NMR: 14.6; 66.6; 67.8; 101.9; 114.2; 121.6; 129.2; 132.6; 156.6; 164.1.
2-(Phenoxymethyl)-1,3-thiazole (7). B.p. 1258/3 Torr3). 1H-NMR: 5.39 (s, 2 H); 6.98± 7.04 ( m, 3 H); 7.21 ±
7.31 (m, 2 H); 7.36 (d, J ˆ 3.4, 1 H); 7.80 (d, J ˆ 3.4, 1 H). 13C-NMR: 66.8; 114.5; 119.5; 121.3; 129.3; 142.1; 157.5,
166.9.
5-Ethoxy-4,5-dihydro-2-(phenoxymethyl)-1,3-thiazole (3w). This compound easily decomposed to 7.
1H-NMR: 1.16 (t, J ˆ 6.9, 3 H); 3.26 ± 3.40 (m, 1 H); 3.47 ± 3.59 (m, 1 H); 4.12 ± 4.23 (m, 1 H); 4.53 (d, J ˆ
14.3, 1 H); 4.94 (s, 2 H); 5.61 (d, J ˆ 5.3, 1 H); 6.93 ± 7.02 (m, 3 H); 7,23 ± 7.37 (m, 2 H). 13C-NMR: 13.2; 63.8;
67.4; 70,8; 90.3; 113.3; 121.2; 129.1; 157.6; 167.0.
Thionation of N-(2-Halogenophenyl)-2-phenoxyethanamides 8. A soln. of 8 (2 mmol) and LR (1 mmol) in
toluene (20 ml) was heated at reflux under Ar gas for 0.5 ± 5 h (TLC control). After removal of the solvent, the
residue was subjected to FC (SiO2; toluene/AcOEt 4 :1 ! 2 :1) to afford the corresponding thioamides 9. The
latter could not be cyclized in the presence of base (see Scheme).
N-(2-Chlorophenyl)-2-phenoxyethanethioamide (9a). M.p. 89 ± 908. 1H-NMR: 5.00 (s, 2 H); 6.99 ± 7.06 (m,
3 H); 7.09 ± 7.47 (m, 5 H); 8.89 ± 8.95 (m, 1 H); 10.33 (br. s, 1 H). 13C-NMR: 75.0; 115.1; 122.7; 124.0; 126.5;
3
)
M.p. of the picrate: 154 ± 1568 [11].

Helvetica Chimica Acta ± Vol. 88 (2005)
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127.3; 127.6; 129.6; 130.0; 134.5; 156.8; 195.1. Anal. calc. for C14H12ClNOS: C 60.53, H 4.35, N 5.04; found:
C 60.30, H 4.48, N 4.95.
1
N-(2-Bromophenyl)-2-phenoxyethanethioamide (9b). M.p. 94.5 ± 95.58. H-NMR: 5.01 (s, 2 H); 7.07 ± 7.19
(m, 4 H); 7.25 ± 7.43 (m, 3 H); 7.60 ± 7.65 (m, 1 H); 8.84 ± 8.90 (m, 1 H); 10.30 (br. s, 1 H). 13C-NMR: 75.0; 115.1;
116.9; 122.6; 124.5; 127.9; 128.1; 130.0; 132.9; 135.6; 156.9; 195.1. Anal. calc. for C14H12BrNOS: C 52.18, H 3.75,
N 4.35; found: C 52.02, H 3.98, N 4.24.
REFERENCES
[1] A. Dondoni, P. Merino, in ꢁComprehensive Heterocyclic Chemistry IIꢀ, Eds. A. R. Katritzky, C. W. Rees,
E. F. V. Scriven, Pergamon Press, Oxford, 1996, Vol. 3, p. 373; H. Quiniou, O. Guillton, in ꢁAdvances in
Heterocyclic Chemistryꢀ, Ed. A. R. Katritzky, Academic Press, San Diego, California, 1990, Vol. 50, p. 85; J.
Liebscher, in ꢁ Houben-Weylꢀ, 4th ed., Ed. E. Schaumann, Thieme, Stuttgart, 1994, Vol. E8b, p. 1; M.
Sainsbury, in ꢁComprehensive Heterocyclic Chemistry IIꢀ, Eds. A. R. Katritzky, C. W. Rees, E. F. V.
Scriven, Pergamon Press, Oxford, 1996, Vol. 6, p. 301, 383.
[2] M. P. Cava, M. L. Levinson, Tetrahedron 1985, 41, 5061; R. A. Cherkasov, G. A. Kutyrev, A. N. Pudovik,
Tetrahedron 1985, 41, 5061; D. Brillon, Sulfur Rep. 1992, 297.
[3] a) K. Clausen, S.-O. Lawesson, Bull. Soc. Chim. Belg. 1979, 88, 305; b) K. Clausen, S.-O. Lawesson, Nouv. J.
Chim. 1980, 4, 43; c) A. Ishii, J. Nakayama, M.-X. Ding, N. Kotaka, M. Hoshino, J. Org. Chem. 1990, 55,
2421; d) J. Nakayama, H. Motoyama, H. Machida, M. Shimomura, M. Hoshino, Heterocycles 1984, 22,
1527; e) A Ishii, T. Omata, K. Umezawa, J. Nakayama, Bull. Chem. Soc. Jpn. 2000, 73, 729; f) P. N. Nugara,
N.-Z. Huang, M. V. Lakshmikanthan, M. P. Cava, Heterocycles 1991, 32, 1559; g) T. Nishio, Tetrahedron
Lett. 1995, 36, 6113; h) T. Nishio, H. Sekiguchi, Tetrahedron 1999, 55, 5017; i) K. Kang, H. S. U, Synth.
Commun. 1995, 25, 2647; j) T. Ozturk, Tetrahedron Lett. 1996, 37, 2821; k) C. W. Ong, C. M. Chen, L. F.
Wang, P. C. Shieh, Tetrahedron Lett. 1998, 39, 9191; l) T. Nishio, J. Org. Chem. 1997, 62, 1106; m) T. Nishio,
Helv. Chim. Acta 1998, 81, 1207; n) M. Ori, T. Nishio, Heterocycles 2000, 52, 111; o) M. Ori, T. Nishio,
Heterocycles 2001, 54, 201; p) T. Nishio, Y. Konno, M. Ori, M. Sakamoto, Eur. J. Org. Chem. 2001, 3553;
q) T. Nishio, M. Ori, Helv. Chim. Acta 2001, 84, 2347; r) A. A. Kiryanov, P. Sampson, A. J. Seed, J. Org.
Chem. 2001, 66, 7925.
[4] B. S. Pederson, S.-O. Lawesson, Tetrahedron 1979, 35, 2433; A. A. El-Barbary, K. Clausen, S.-O. Lawesson,
Tetrahedron 1980, 36, 3309; A. A. El-Barbary, S.-O. Lawesson, Tetrahedron 1981, 37, 2641; S. Sheibye, S.-O.
Lawesson, C. Romming, Acta Chem. Scand., Ser. B 1981, 35, 239; S. Sheibye, R. Shabana, S.-O. Lawesson,
Tetrahedron 1982, 38, 993; R. Shabana, F. Osman, S. S. Atres, Tetrahedron 1994, 50, 6975; N. Duban-
Assibat, A. Baceiredo, G. Betrand, J. Org. Chem. 1995, 60, 3904; R. N. Butler, E. C. Makenna, D. Grogen,
Chem. Commun. 1997, 2149; Y. A. Ibrahim, A. M. Kadry, M. R. Ibrahim, J. N. Lisgarten, B. S. Potter, R. A.
Palmer, Tetrahedron 1999, 55, 13457; S.-L. Deng, D.-Z. Liu, Synthesis 2001, 2445.
[5] T. Nishio, J. Chem. Soc., Chem. Commun. 1989, 205; J. Chem. Soc., Perkin Trans. 1 1993, 1113.
[6] C. Djerassi, C. T. Scholz, J. Org. Chem. 1950, 15, 694.
[7] R. Kuhn, F. Heidelberg, Liebigs Ann. Chem. 1954, 590, 55.
[8] P. A. S. Smith, J. M. Sullivan, J. Org. Chem. 1961, 26, 1132.
[9] A. K. Bose, M. S. Manhas, J. S. Chib, H. P. S. Chawanda, B. Dayal, J. Org. Chem. 1974, 39, 2877.
[10] B. George, E. P. Papadopoulos, J. Org. Chem. 1977, 42, 441.
[11] R. Vivadi, H. J. M. Dou, G. Vernin, J. Metzger, Bull. Soc. Chim. Fr. 1969, 11, 4041.
Received October 5, 2004