Synthesis of N-haloacyl and N-hetarylthioacyl derivatives of 2-amino-5-aryl-6H-1,3,4-thiadiazine

Article abstract of DOI:10.1007/s11172-007-0255-1

Conditions for N-acylation of 2-amino-5-aryl-6H-1,3,4-thiadiazines with trifluoroacetic anhydride and halogen-substituted carboxylic acid halides with retention of the initial heterocyclic system were found. 5-Aryl-2-haloacylamino- 6H-1,3,4-thiadiazines w

Full text of DOI:10.1007/s11172-007-0255-1

Russian Chemical Bulletin, International Edition, Vol. 56, No. 8, pp. 1631—1636, August, 2007
1631
Synthesis of Nꢀhaloacyl and Nꢀhetarylthioacyl derivatives
of 2ꢀaminoꢀ5ꢀarylꢀ6Hꢀ1,3,4ꢀthiadiazine*
L. B. Kulikova,ꢀ G. I. Ezhova, N. E. Kravchenko, O. V. Dorofeeva, A. S. Kulikov, and A. G. Zavozin
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5328. Eꢀmail: azavozin@ioc.ac.ru
Conditions for Nꢀacylation of 2ꢀaminoꢀ5ꢀarylꢀ6Hꢀ1,3,4ꢀthiadiazines with trifluoroacetic
anhydride and halogenꢀsubstituted carboxylic acid halides with retention of the initial heteroꢀ
cyclic system were found. 5ꢀArylꢀ2ꢀhaloacylaminoꢀ6Hꢀ1,3,4ꢀthiadiazines were obtained in
preparative yields. Their reactions with hetarenethiols afforded Nꢀhetarylthioacyl derivatives.
Key words: Nꢀhaloacyl and Nꢀhetarylthioacyl derivatives of 2ꢀaminoꢀ5ꢀarylꢀ6Hꢀ1,3,4ꢀ
thiadiazines, hetarenethiols, acylation, alkylation.
Interest in the synthesis of 6Hꢀ1,3,4ꢀthiadiazine deꢀ
rivatives, which belong to the sixꢀmembered nonaromatic
heterocyclic system, has substantially grown in the last
few decades.1—3 This is largely due to a broad spectrum of
biological (e.g., fungicidal,4 antiviral,5 antiinflammatory,6
vasodilator,7 etc.) activity of such derivatives. In addition,
6Hꢀ1,3,4ꢀthiadiazines show unusual reactivities. An imꢀ
portant feature that largely determines their specific
chemical properties is easy elimination of the S atom
from the sixꢀmembered ring leading to pyrazole derivaꢀ
tives. Such transformations can be initiated thermally
(by heating neat reagents or their solutions in nonpolar
organic solvents8), in reactions with nucleophiles9 and
acylating reagents,10 under the action of UV irradiation,
and other factors. In addition, known intramolecular reꢀ
arrangements of 6Hꢀ1,3,4ꢀthiadiazines result in ring conꢀ
traction leading to thiazole,11 1,2,3ꢀthiadiazole,12 and
1,3,4ꢀthiadiazole derivatives.13 Because of this, the thiaꢀ
diazine ring is often unstable in most chemical reactions.
Such features of its reactivity make it difficult to obtain
novel functional derivatives of this heterocycle and limit
the range of its accessible derivatives.2
Treatment of 6Hꢀ1,3,4ꢀthiadiazine derivatives with
acylating reagents mostly results in ring contraction leadꢀ
ing to fiveꢀmembered heterocycles. For instance, the use
of acetic anhydride gives acylated pyrazole derivatives.10,14
Known examples of acylation of 2ꢀaminoꢀ6Hꢀ1,3,4ꢀ
thiadiazines with retention of the initial heterocyclic sysꢀ
tem are few. Acylation of 5,6ꢀdialkyl(diaryl)ꢀ2ꢀaminoꢀ
6Hꢀ1,3,4ꢀthiadiazines with diketene yields 2ꢀacylamino
derivatives.15 Benzoylation of 5ꢀsubstituted 2ꢀaminoꢀ
thiadiazines in the presence of pyridine can give, dependꢀ
ing on the solvent and the ratio of the starting reagents,
benzoylation products at both the amino group of the side
chain and at the ring N atoms.16,17
The goal of the present work was to study the possibilꢀ
ity of acylating 2ꢀaminoꢀ5ꢀarylꢀ6Hꢀ1,3,4ꢀthiadiazines at
the exocyclic N atom without involving the heterocyclic
ring. We were going to use functionalized acylating reꢀ
agents to obtain acylation products and study some of
their chemical transformations, also occurring with reꢀ
tention of the 6Hꢀ1,3,4ꢀthiadiazine fragment.
The starting 2ꢀaminoꢀ5ꢀphenylꢀ (1a), 2ꢀaminoꢀ5ꢀ
(4ꢀmethylphenyl)ꢀ (1b), and 2ꢀaminoꢀ5ꢀ(4ꢀbromopheꢀ
nyl)ꢀ6Hꢀ1,3,4ꢀthiadiazines (1c) were prepared from apꢀ
propriate αꢀhaloacetophenones and thiosemicarbazide.18
Compounds 1a—c were acylated with trifluoroacetic anꢀ
hydride, chloroacetyl chloride, bromoacetyl bromide,
2ꢀbromobutyryl bromide, and 4ꢀfluorobenzoyl chloride.
As a result, we found the conditions for highꢀyielding
acylation of amines 1a—c at the exocyclic amino group
with retention of the initial cyclic structure.
For instance, treatment of amines 1a—c with an exꢀ
cess of trifluoroacetic anhydride in benzene at room temꢀ
perature gave the corresponding trifluoroacetamides 2a—c
(Scheme 1).
Treatment of amines 1a,b with chloroacetyl chloride
in acetonitrile in the presence of pyridine at room temꢀ
perature afforded chloroacetamides 3a,b. Acylation of
amine 1c under these conditions did not yield the correꢀ
sponding chloroacetamide (TLC data), the starting amine
being mainly recovered unchanged. At the same time, the
action of bromoacetyl bromide on amine 1c under analoꢀ
gous conditions gave acylation product 3c in a virtually
quantitative yield. Products 4a—c were obtained with
* Dedicated to Academician V. A. Tartakovsky on the occasion
of his 75th birthday.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1570—1575, August, 2007.
1066ꢀ5285/07/5608ꢀ1631 © 2007 Springer Science+Business Media, Inc.

1632
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 8, August, 2007
Kulikova et al.
Scheme 1
products can be of interest for a study of their biological
activity. We found that 2ꢀhaloacylaminoꢀ5ꢀarylꢀ6Hꢀ1,3,4ꢀ
thiadiazines 3a—c and 4a—c can alkylate heterocyclic
thiols under mild conditions to give the corresponding
5ꢀarylꢀ2ꢀhetarylthioacetyl(butyryl)aminoꢀ6Hꢀ1,3,4ꢀthiaꢀ
diazines 6—11.
R = H (1a—4a), Me (1b—4b, 5), Br (1c—4c)
Reagent R´X
Product
(CF3CO)2O
2a—c*
3a,b
3c
ClCH2C(O)Cl
BrCH2C(O)Br
Et(Br)CHC(O)Br
4a—c
5
* R´ = CF3CO
2ꢀbromobutyryl bromide as an acylating reagent (see
Scheme 1).
The acylation conditions for the synthesis of comꢀ
pounds 3a—c can be used to obtain other 2ꢀacylaminoꢀ5ꢀ
arylꢀ6Hꢀ1,3,4ꢀthiadiazines. For instance, amine 1b was
easily acylated with 4ꢀfluorobenzoyl chloride under these
conditions to give derivative 5. It should be noted that for
all products 3a—c and 4a—c containing a mobile halogen
1
atom in the acyl substituent, the H NMR spectra were
unsatisfactory. Apparently, the heterocycle in these comꢀ
pounds can break down or undergo 6H → 4H tautoꢀ
merization19 under conditions of spectra recording. The
compounds obtained were identified from mass spectra
and elemental analysis data. When exposed to electron
impact, most of these compounds produce molecular ions.
1
The H NMR spectra of compounds 2a—c and 5 unꢀ
ambiguously indicate that their thiadiazine rings exist only
in the 6Hꢀform. The signals for two protons at the C(6)
atom of the heterocycle appear as a singlet at δ 3.9—4.0,
which agrees with the literature data.13—16 A signal for the
proton at the N(4) atom of the heterocycle, which is
usually shifted downfield (δ 5.6), is absent.18—21
To examine the possibility of using 2ꢀacylaminoꢀ5ꢀ
arylꢀ6Hꢀ1,3,4ꢀthiadiazines 3a—c and 4a—c in the synꢀ
thesis of novel derivatives of this heterocyclic system (tenꢀ
dency toward reactions occurring with retention of the
initial heterocycle) and prove their structures more rigorꢀ
ously, we studied their reactions with heterocyclic thiols.
Alkylation of thiols was chosen because this reaction can
be effected under sufficiently mild conditions22 (room
temperature during the synthesis and isolation of prodꢀ
ucts and the absence of strong bases in the reaction meꢀ
dium). This would prevent any transformation of the
thiadiazine ring. In addition, according to literature data,
most of the thiols employed exhibit biological (e.g.,
antihypoxic23 and bactericidal24) activities and alkylation
R = Me (10), Br (11)
It should be noted that in contrast to acyl derivatives
3a—c and 4a—c, the mass spectra of sulfides 6—11 conꢀ
tain no molecular ion peaks. The most intense peaks are
due to the fragments formed upon cleavage of the S—acyl
bond and to aromatic nitriles.
To sum up, we found mild conditions for acylation of
2ꢀaminoꢀ5ꢀarylꢀ6Hꢀ1,3,4ꢀthiadiazines with retention of
the initial heterocyclic structure. Alkylation of hetareneꢀ
thiols with haloacylaminothiadiazines showed that haloꢀ
gen derivatives can serve as convenient starting mateꢀ
rials for the synthesis of other 2ꢀaminoꢀ5ꢀarylꢀ6Hꢀ
1,3,4ꢀthiadiazine derivatives containing pharmacophore
groups.
The yields and selected physicochemical characterꢀ
istics of the products obtained are given in Table 1.
Their spectroscopic characteristics are summarized in
Tables 2 and 3.

Acylamino derivatives of thiadiazine
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 8, August, 2007
1633
Table 1. Yields and selected physicochemical characteristics of 2ꢀaminoꢀ5ꢀarylꢀ6Hꢀ1,3,4ꢀthiadiazines 2—11
Comꢀ
pound
Yield
(%)
M.p.
/°C
Rf
Found
Calculated
Molecular
formula
(%)
(eluent)*
С
H
N
Hal
2а
2b
2c
3a
3b
3c
4a
4b
4c
5
79
82
76
84
81
90
69
88
98
82
74
85
77
82
79
72
166—167
197—198
182—183
173—175
191—193
173—175
133—135
128—130
154—157
206—207
161—163
175—177
182—184
167—169
197—198
184—186
0.74 (A)
0.88 (B)
0.67 (A)
0.63 (B)
0.61 (B)
0.69 (A)
0.78 (B)
0.74 (B)
0.73 (B)
0.64 (B)
0.35 (B)
0.55 (B)
0.25 (B)
0.64 (B)
0.11 (B)
0.44 (B)
45.65
45.99
48.15
47.84
36.28
36.08
49.02
49.35
51.71
51.15
33.12
33.78
46.12
45.89
47.66
47.47
37.17
37.25
61.58
62.37
48.14
48.54
57.98
57,65
47.67
47.91
56.66
57.12
46.01
46.20
39.18
39.77
2.76
2.81
3.52
3.35
2.05
1.93
3.98
3.76
4.47
4.29
2.27
2.32
4.00
4.15
4.62
4.55
3.09
3.13
4.04
4.31
4.02
4.07
4.74
4.38
3.18
3.06
5.12
5.30
4.22
4.49
3.80
3.34
14.33
14.63
14.02
13.95
11.24
11.48
15.31
15.69
15.01
14.91
10.44
10.74
12.16
12.35
11.54
11.86
10.20
10.03
12.46
12.84
24.64
24.26
15.70
16.01
15.02
15.18
18.00
17.53
18.88
18.73
15.85
16.37
—
—
—
—
—
С11H8F3N3OS
С12H10F3N3OS
С11H7BrF3N3OS
С11H10ClN3OS
С12H12ClN3OS
С11H9Br2N3OS
С13H14BrN3OS
С14H16BrN3OS
С13H13Br2N3OS
С17H14FN3OS
С14H14N6OS2
—
13.04
13.24
12.77
12.58
39.78
40.86
23.33
23.48
22.19
22.55
38.72
38.13
—
—
—
—
—
6
7
С21H19N5O2S2
С21H16BrN7OS2
С19H21N5OS2
—
8
18.06
18.62
—
—
—
—
15.22
15.56
9
10
11
С18H20N6O2S3
С17H17BrN6O2S3
* The eluent was benzene—ethyl acetate (5 : 1) (A) and (3 : 1) (B).
1
Table 2. H NMR, IR, and mass spectra of 2ꢀaminoꢀ5ꢀarylꢀ6Hꢀ1,3,4ꢀthiadiazines 2a—c and 5—11
Comꢀ
pound
IR,
ν/cm–1
1H NMR (DMSOꢀd6)
MS, m/z (Irel (%))
δ, J/Hz
2a
2b
3214, 1646, 1612, 1560,
1488, 1446, 1368, 1346,
1292, 1214, 1150, 1086,
1010, 922, 880, 810,
792, 766, 722
3220, 1648, 1604, 1568,
1484, 1436, 1372, 1344,
1288, 1212, 1152, 1092,
1008, 928, 872, 812,
784, 736
4.00 (s, 2 H, С(6)Н2);
7.65 (m, 5 H, Ph);
13.45 (s, 1 H, NH)
287 [M]+ (36), 218 [M – CF3]+ (100),
191 [M – COCF3]+ (26), 69 [CF3]+ (68)
2.32 (s, Me);
4.05 (s, 2 H, С(6)Н2);
7.36, 7.86 (АА´BB´, 4 H, Ar, 3J = 7.5);
13.55 (s, 1 H, NH)
301 [M]+ (54), 232 [M – CF3]+ (100),
205 [M – COCF3]+ (11), 91 [CH2Ph]+ (32),
69 [CF3]+ (89)
(to be continued)

1634
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 8, August, 2007
Kulikova et al.
Table 2 (continued)
Comꢀ
pound
IR,
ν/cm–1
1H NMR (DMSOꢀd6)
MS, m/z (Irel (%))
δ, J/Hz
2c
3210, 1642, 1614, 1554,
1480, 1446, 1368, 1346,
1210, 1146, 1082, 1022,
926, 874, 802, 786,
762, 720
4.05 (s, 2 H, С(6)Н2);
7.76, 7.90 (АА´BB´, 4 H, Ar,
3J = 7.4); 13.70 (s, 1 H, NH)
367 [M (81Br)]+ (11), 365 [M (79Br)]+ (13),
298 [M (81Br) – CF3]+ (92),
296 [M (79Br) – CF3]+ (100),
270 [M (81Br) – COCF3]+ (24),
268 [M (79Br) – COCF3]+ (28),
157 [81BrC6H4]+ (30),
155 [79BrC6H4]+ (34), 69 [CF3]+ (68)
327 [M]+ (11), 205 [starting amine]+ (42),
123 [4ꢀCOC6H4F] (72),
5
6
3280, 2932, 1698, 1640,
1568, 1502, 1454, 1402,
1346, 1280, 1202, 1164,
1122, 1088, 1060, 1014,
990, 934, 886, 824, 748
3180, 3128, 2854, 1700,
1648, 1620, 1572, 1544,
1516, 1468, 1448, 1408,
1368, 1324, 1272, 1196,
1180, 1164, 1112, 1012,
1004, 952, 912, 884, 852,
828, 800, 772, 740, 708
3208, 2972, 2912, 1708,
1700, 1608, 1496, 1480,
1456, 1432, 1376, 1320,
1300, 1260, 1188, 1148,
1104, 1044, 1012, 984,
944, 916, 856, 820, 780,
760, 752, 740, 712
3380, 3060, 2932, 1676,
1616, 1580, 1492, 1476,
1412, 1384, 1356, 1320,
1272, 1196, 1176, 1164,
1108, 1100, 1072, 1004,
992, 940, 872, 812,
748, 724
3162, 3112, 2894, 1680,
1642, 1572, 1536, 1512,
2.40 (s, 3 H, Me); 3.88 (s, 2 H,
С(6)Н2); 7.36 (m, 4 H, Ar);
7.82, 7.20 (both m, 2 H each, Ar);
12.65 (s, 1 H, NH)
95 [C6H4F] (34),
117 [4ꢀMeC6H4CN]+ (27),
91 [CH2Ph]+ (100)
3.62 (s, 3 H, Me); 3.74 (s, 2 H, СН2CO);
4.15 (s, 2 H, С(6)Н2); 7.50 (m, 3 H, Ph);
7.95 (m, 2 H, Ph);
8.55 (s, 1 H, СН triaz. ring);
12.30 (s, 1 H, NH)
231 [M – starting thiol]+ (28),
191 [starting amine]+ (15),
115 [starting thiol]+ (100),
103 [PhCN]+ (88), 77 [Ph]+ (68)
7
8
9
2.30 (s, 3 H, СН3Ar); 2.82 (s, 3 H, MeCO);
3.72 (s, 2 H, С(6)Н2);
4.28 (s, 2 H, СН2CO); 7.35 (m, 4 H, Ar);
7.60 (d, 1 H, С(4)Н benzimidazole, 3J = 6.6);
7.84 (m, 3 H, Ar); 12.20 (s, 1 H, NH)
245 [M – starting thiol]+ (18),
205 [starting amine]+ (38),
162 [starting amine – СОMe]+ (24),
117 [4ꢀМеС6Н4СN]+ (100),
91 [4ꢀМеС6Н4]+ (56)
3.70 (s, 2 H, С(6)Н2); 3.84 (s, NMe);
4.36 (s, 2 H, СН2CO);
7.44—8.35 (m, 8 H, 4 H Ar, 4 Н Het);
12.30 (s, 1 H, NH)
311 [M (81Br) – starting thiol]+ (5),
309 [M (79Br) – starting thiol]+ (5),
257 [starting thiol + CH2CO]+ (42),
216 [starting thiol]+ (100),
201 [starting thiol – Me]+ (7),
184 [4ꢀ81BrC6H4CN+1]+ (12),
182 [4ꢀ79BrC6H4CN+1]+ (12)
399 [M]+ (4), 259 [M – starting thiol]+ (42),
191 [starting amine]+ (40),
1.05 (t, 3 H, MeCH2, 3J = 10.2);
2.00 (m, 2 H, MeCH2 3J = 10.2);
140 [starting thiol]+ (78),
1450, 1412, 1352, 1326,
1272, 1206, 1164, 1006,
990, 962, 922, 874, 838,
794, 770, 730, 714
2.34 (s, 6 H, 2 СН3 Het); 4.05 (s, 2 H, С(6)Н2); 103 [PhCN]+ (100), 77 [Ph]+ (46)
4.62 (t, 1 H, CHCH2, 3J = 8.2); 7.00 (s, 1 H,
С(4)Н pyrimidine); 7.52 (m, 3 H, Ph);
7.96 (m, 2 H, Ph); 12.10 (s, 1 H, NH)
10
11
3156, 3032, 2872, 1688,
1560, 1412, 1344, 1312,
1276, 12561164, 1088,
1052, 1000, 960, 912,
884, 808, 724, 704
1.10 (t, 3 H, MeCH2, 3J = 10.4); 1.96 (q, 2 H,
MeCH2, 3J = 10.4); 2.22 (s, 3 H, СН3Ar);
2.88 (s, 3 H, MeCO); 3.78 (s, 2 H, 3 С(6)Н2);
4.26 (t, 1 H, CHCH2 3J = 8.2);
273 [M – starting thiol]+ (4),
205 [starting amine]+ (36),
162 [starting amine – COMe]+ (5),
117 [4ꢀMeC6H4CN]+ (100),
91 [4ꢀMeC6H4]+ (33)
7.32, 7.82 (АА´BB´, 4 H, Ar, 3J = 8.4);
12.35, 12.55 (both s, 1 H each, NH)
1.00 (t, 3 H, MeCH2, 3J = 9.8); 1.98 (q, 2 H,
MeCH2, 3J = 9.8); 2.70 (s, 3 H, MeCO);
3.82 (s, 2 H, С(6)Н2);
3186, 3134, 2872, 1688,
1640, 1612, 1534, 1512,
1474, 1438, 1420, 1366,
1334, 1254, 1176, 1164,
339 [M (81Br) – starting thiol]+ (7),
337 [M (79Br) – starting thiol]+ (8),
244 [starting thiol + CH(Et)CO]+ (62),
201 [starting thiol + CH(Et)CO –
— MeCO]+ (36),
3
4.40 (t, 1 H, CHCH2, J = 7.6);
1012, 1000, 966, 914,
888, 828, 810, 776, 732
7.66, 7.94 (АА´BB´, 4 H, Ar, 3J = 8.2);
12.45, 12.65 (both s, 1 H each, NH)
175 [starting thiol]+ (100),
184 [4ꢀ81BrC6H4CN+1]+ (16),
182 [4ꢀ79BrC6H4CN+1]+ (18),
133 [5ꢀaminoꢀ1,3,4ꢀthiadiazoleꢀ2ꢀthiol]+ (74)

Acylamino derivatives of thiadiazine
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 8, August, 2007
1635
Table 3. IR and mass spectra of 2ꢀaminoꢀ5ꢀarylꢀ6Hꢀ1,3,4ꢀthiadiazines 3a—c and 4a—c
Comꢀ
pound
IR, ν/cm–1
MS, m/z (Irel (%))
3a
3b
3c
2884, 1696, 1636, 1612, 1580, 1544,
1420, 1332, 1208, 1112, 1096, 1012,
952, 916, 864, 800, 780, 760, 744, 708
2882, 1692, 1640, 1576, 1544, 1416,
1336, 1208, 1104, 1012, 956, 916,
868, 836, 812, 788, 748, 720
2960, 2892, 1728, 1636, 1616, 1572,
1454, 1420, 1412, 1328, 1196, 1108,
1076, 1004, 952, 840, 756, 712
269 [M (37Cl)]+ (4), 267 [M (35Cl)]+ (10), 231 [M – HCl]+ (32),
218 [M – CH2Cl]+ (76), 103 [C6H5CN]+ (80), 91 [CH2Ph]+ (26),
79 [CH2CO(37Cl)]+ (30), 77 [CH2CO(35Cl)]+ (100)
283 [M (37Cl)]+ (8), 281 [M (35Cl)]+ (23), 245 [M – HCl]+ (7),
232 [M – CH2Cl]+ (100), 117 [4ꢀMeC6H4CN]+ (42),
91 [CH2Ph]+ (26), 79 [CH2CO(37Cl)]+ (4), 77 [CH2CO(35Cl)]+ (15)
393 [M (81Br + 81Br)]+ (8), 391 [M (79Br + 81Br)]+ (15),
389 [M (79Br + 79Br)]+ (8), 311 [393 – H81Br, 391 – H79Br]+ (36),
309 [391 – H81Br, 389 – H79Br]+ (32), 298 [311 – СН2]+ (100),
296 [309 – СН2]+ (92), 271 [starting amine (81Br)]+ (34),
269 [starting amine (79Br)]+ (36), 183 [4ꢀ81BrC6H4CN]+ (76),
181 [4ꢀ79BrC6H4CN]+ (60), 102 [C6H4CN]+ (68)
4a
4b
3112, 2970, 2870, 1674, 1612, 1562,
1492, 1460, 1376, 1328, 1276, 1180,
1074, 1016, 816, 770, 712
3104, 2968, 2876, 1672, 1604, 1564,
1492, 1456, 1380, 1324, 1276, 1248,
1184, 1116, 1072, 1052, 1020, 820,
764, 712
341 [M (81Br)]+ (6), 339 [M (79Br)]+ (6), 309 [M (81Br) – S]+ (14),
308 [M (81Br) – SH]+ (22), 307 [M (81Br) – H2S, M (79Br) – S]+ (100),
218 [M – EtCHBr]+ (15), 134 [4ꢀPhC(Me)=NNH2] (24), 103 [PhCN]+ (55)
323 [M (81Br) – S]+ (8), 322 [M (81Br) – SH]+ (22),
321 [M (81Br) – H2S, M (79Br) – S]+ (100),
232 [M – EtCHBr]+ (26), 148 [4ꢀMeC6H4C(Me)=NNH2] (9),
117 [4ꢀMeC6H4CN]+ (22), 91 [CH2Ph]+ (53)
4c
3152, 2968, 2904, 1704, 1688, 1632,
1588, 1560, 1492, 1392, 1324, 1272,
1208, 1160, 1076, 960, 924, 900,
820, 804, 752, 704, 660
340 [M (81Br + 81Br) – 81Br]+ (7), 339 [M (81Br + 81Br) – H81Br]+ (9),
338 [M (81Br + 79Br) – 81Br, M (81Br + 79Br) – 79Br]+ (7),
337 [M (81Br + 79Br) – H81Br, M (81Br + 79Br) – H79Br]+ (6),
298 [M (81Br + 81Br) – EtСН281Br, M (81Br + 79Br) – EtСН279Br]+ (96),
296 [M (81Br + 79Br) – EtСН281Br, M (79Br + 79Br) – EtСН279Br]+ (90),
271 [starting amine (81Br)]+ (17), 269 [starting amine (79Br)]+ (19),
183 [4ꢀ81BrC6H4CN]+ (48), 181 [4ꢀ79BrC6H4CN]+ (49), 102 [C6H4CN]+ (100)
Nꢀ(5ꢀArylꢀ6Hꢀ1,3,4ꢀthiadiazinꢀ2ꢀyl)ꢀ2ꢀbromobutyramides
4a—c (general procedure). Dry pyridine (0.95 g, 12 mmol) was
Experimental
IR spectra were recorded on a URꢀ20 spectrometer (KBr
pellets). H NMR spectra were recorded on a Bruker WMꢀ250
added at 0—5 °C (cooling with ice) to a suspension of the startꢀ
ing amine 1a—c (10 mmol) in dry acetonitrile (50 mL). Then
2ꢀbromobutyryl bromide (2.76 g, 12 mmol) was added dropwise.
The reaction mixture was stirred at room temperature for 4—5 h
and poured into water (150 mL). The precipitate that formed
was filtered off, washed with water, and dried in air. The dry
product was washed with ether.
1
spectrometer (250 MHz). Mass spectra were recorded on a
Finnigan MAT INCOSꢀ50 spectrometer (EI, 70 eV). Melting
points were determined on a Boetius PHMK 05 instrument.
Thinꢀlayer chromatography was carried out on Silufol UVꢀ254
plates (spot visualization under UV light).
Nꢀ(5ꢀArylꢀ6Hꢀ1,3,4ꢀthiadiazinꢀ2ꢀyl)trifluoroacetamides
2a—c (general procedure). Trifluoroacetic anhydride (5.25 g,
25 mmol) was added dropwise at 0—5 °C (cooling with ice) to a
suspension of the starting amine 1a—c (10 mmol) in dry benꢀ
zene (30 mL). The reaction mixture was kept at room temperaꢀ
ture for 4—5 h and concentrated under reduced pressure. The
residue was treated with ether, filtered off, and recrystallized
from ethanol.
Nꢀ(5ꢀArylꢀ6Hꢀ1,3,4ꢀthiadiazinꢀ2ꢀyl)haloacetamides 3a—c
(general procedure). Dry pyridine (0.95 g, 12 mmol) was added
at 0—5 °C (cooling with ice) to a suspension of the starting
amine 1a—c (10 mmol) in dry acetonitrile (50 mL). Then
chloroacetyl chloride (1.36 g, 12 mmol) (for amine 1c, bromoꢀ
acetyl bromide (2.42 g, 12 mmol)) was added dropwise. The
reaction mixture was stirred at room temperature for 20 h and
poured into water (150 mL). The precipitate that formed was
filtered off, washed with water, and dried in air. The dry product
was washed with acetone and ether.
Nꢀ[5ꢀ(4ꢀTolyl)ꢀ6Hꢀ1,3,4ꢀthiadiazinꢀ2ꢀyl]ꢀ4ꢀfluorobenzamide
(5). Dry pyridine (0.95 g, 12 mmol) was added at 0—5 °C (coolꢀ
ing with ice) to a suspension of 2ꢀaminoꢀ5ꢀ(4ꢀtolyl)ꢀ6Hꢀ1,3,4ꢀ
thiadiazine (1b) (2.05 g, 10 mmol) in dry acetonitrile (50 mL).
Then 4ꢀfluorobenzoyl chloride (1.90 g, 12 mmol) was added
dropwise. The reaction mixture was stirred at room temperature
for 4—5 h and poured into water (150 mL). The precipitate that
formed was filtered off, washed with water, and dried in air. The
dry product was washed with ether and recrystallized from aqueꢀ
ous DMF.
Nꢀ(5ꢀArylꢀ6Hꢀ1,3,4ꢀthiadiazinꢀ2ꢀyl)ꢀ2ꢀhetarylthioacetꢀ
amides 6—8 and Nꢀ(5ꢀarylꢀ6Hꢀ1,3,4ꢀthiadiazinꢀ2ꢀyl)ꢀ2ꢀhetarylꢀ
thiobutyramides 9—11 (general procedure). A suspension of a
thiol (10.5 mmol) and Na2CO3 (1.27 g, 12 mmol) in DMF
(40 mL) was stirred for 10—15 min and then compound 3a—c or
4a—c (10 mmol) was added. The reaction mixture was stirred at
room temperature for 24 h and poured into water (200 mL). The
precipitate that formed was filtered off, washed with water, and

1636
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 8, August, 2007
Kulikova et al.
dried in air. The dry product was suspended in acetone, stirred
for 10—15 min, filtered off, and washed with acetone and
ether. Nꢀ(5ꢀPhenylꢀ6Hꢀ1,3,4ꢀthiadiazinꢀ2ꢀyl)ꢀ2ꢀ(4,6ꢀdimethylꢀ
pyrimidinꢀ2ꢀylthio)butyramide (9) was washed with ether and
crystallized from ethanol.
12. G. Ege, Ph. Arnold, G. Jooss, and R. Noronha, Liebigs Ann.
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13. A. E. Baydar, G. Boyd, and P. F. Lindley, Chem. Commun.,
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14. H. Beyer, H. Honeck, and Z. Reichelt, Liebigs Ann. Chem.,
1970, 741, 45.
15. N. Yoshida, K. Wachi, and K. Tanaka, Jpn Pat. 74ꢀ110697;
Chem. Abstrs, 1975, 82, 171095.
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Received February 21, 2007;
in revised form April 2, 2007