PAPER
New Facile Synthesis of exo-Methylene 3,1-Benzothiazines
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IR (KBr): 3449 (m, NH), 3364 (m, NH), 3100 (w), 3020 (w), 2921
(w), 2854 (w), 2194 (s, C≡C), 1620 (m), 1593 (s), 1510 (s), 1340 (s),
1312 (m), 1255 (m), 1177 (w), 1106 (m), 856 (m), 817 (m), 748 (m)
cm–1.
1H NMR (200 MHz, CDCl3): = 2.24 (s, 3 H), 4.17 (br s, 2 H, NH2),
6.64 (d, 3J = 8.3 Hz, 1 H), 6.99 (dd, 3J = 8.1 Hz, 1 H), 7.19 (s, 1 H,
ArH), 7.61 (d, 3J = 8.8 Hz, 2 H), 8.19 (d, 3J = 8.8 Hz, 2 H).
(4Z)-4-Benzylidene-N-(4-methoxyphenyl)-6-methyl-4H-3,1-
benzothiazin-2-amine (3c)
Yield: 43%; white solid; mp 134–135 °C.
IR (KBr): 3014 (w), 2909 (w), 1629 (s), 1578 (s), 1500 (s), 1336
(m), 1296 (w), 1238 (s), 1199 (m), 1102 (w), 1033 (w), 912 (w), 857
(w), 836 (m), 821 (m), 756 (m), 696 (m), 591 (m) cm–1.
1H NMR (200 MHz, CDCl3): = 2.41 (s, 3 H), 3.79 (s, 3 H), 6.84
(d, 3J = 8.0 Hz, 2 H), 6.98 (br s, NH, 1 H), 7.08–7.48 (m, ArH, CH,
11 H).
13C NMR (50 MHz, CDCl3): = 20.2, 91.9, 92.7, 106.5, 114.7,
123.6, 127.3, 130.3, 131.8, 132.3, 132.4, 145.8, 146.6.
Anal. Calcd for C15H13N2O2: C, 71.42; H, 4.79; N, 11.10. Found: C,
71.18; H, 4.68; N, 10.95.
13C NMR (50 MHz, CDCl3): = 21.0, 55.4, 114.0, 121.2, 122.7,
124.9, 126.3, 126.4, 126.8, 127.4, 128.1, 129.2, 130.4, 133.1, 133.8,
135.7, 140.7, 148.4, 155.9.
Exo-Methylene Benzothiazines; General Procedure
ESI–MS: m/z calcd for C23H21N2OS+: 373.1; found: 373.2; correct
isotopic splitting.
Compound 1a (296 mg, 1.43 m mol) and 2,6-dimethylphenyl
isothiocyanate (2a) (236 mg, 1.44 mmol) were heated to reflux in
EtOH (10 mL) in presence of catalytic amounts of N,N-dimethyl-
aminopyridine (DMAP) for 2 d. Upon cooling yellow crystals were
formed (269 mg, 726 mol) that were identified as 4-benzylidene -
2-(2, 6-dimethylphenyl)-amino-6-methyl-3,1-benzothiazine (3a).
Anal. Calcd for C23H20N2OS: C, 74.16; H, 5.41; N, 7.52; S, 8.61.
Found: C, 73.90; H, 5.48; N, 7.50; S, 8.53.
(4Z)-4-Benzylidene-N-ethyl-6-methyl-4H-3,1-benzothiazin-2-
amine (3d)
Yield: 91%; yellow oil.
CPC Systems (Cellular Process Chemistry Systems) Reactor:
General Procedure
IR (neat): 3398 (s, NH), 3243 (m, NH), 3054 (m), 3021 (m), 2972
(m), 2927 (m), 2872 (m), 1621 (s), 1579 (s), 1484 (s), 1444 (m),
1378 (w), 1353 (w), 1265 (m), 1194 (s), 1121 (m), 1030 (w), 909
(m), 850 (m), 825 (s), 754 (s), 736 (s), 695 (s) cm–1.
1H NMR (250 MHz, CDCl3): = 1.19 (t, 3J = 7.2 Hz, 3 H), 2.42 (s,
3 H), 3.51 (q, 3J = 7.2 Hz, 2 H), 4.56 (br s, 1 H, NH), 7.15–7.21 (m,
3 H, ArH), 7.30–7.50 (m, 6 H, ArH, =CH).
13C NMR (63 MHz, CDCl3): = 14.6, 20.9, 37.1, 121.0, 124.8,
125.5, 125.8, 127.2, 127.4, 127.9, 129.2, 130.3, 133.1, 135.9, 142.2,
150.2.
The ortho alkynylated aniline 1a (200 mg, 48.3 mM in 1-butanol)
and propyl isothiocyanate 2b (122 mg, 60.3 mM in 1-butanol) in
presence of catalytic amounts of N,N-dimethylaminopyridine
(DMAP) were allowed to react in a CPC CytosTM reactor at 101 °C
(1.8 mL/min flow rate). 1-Butanol was removed under vacuum and
after column chromatography (silica gel, 5% Et2O in hexane) 3e
(220 mg) was afforded in 74% yield.
(4Z)-4-Benzylidene-N-(2,6-dimethylphenyl)-6-methyl-4H-3,1-
benzothiazin-2-amine (3a)
Yield: 51%; yellow solid; mp 208–210 °C.
ESI-MS: m/z calcd for C18H19N2S+: 295.1; found: 295.1; correct iso-
topic splitting.
IR (KBr): 3140 (w), 3024 (m), 2917 (m), 2849 (m), 1634 (s), 1574
(s), 1504 (s), 1443 (m), 1404 (w), 1343 (m), 1225 (m), 1188 (m),
1090 (w), 1030 (w), 911 (w), 858 (w), 814 (m), 772 (m), 696 (m)
cm–1.
(4Z)-4-Benzylidene-6-methyl-N-propyl-4H-3,1-benzothiazin-2-
amine (3e)
Yield: 67%; yellow oil.
1H NMR (250 MHz, CDCl3): = 2.21 (s, 6 H), 2.35 (s, 3 H), 6.76
(d, 3J = 8.1 Hz, 1 H), 7.03 (dd, 3J = 8.1 Hz, 4J = 1.5 Hz, 1 H), 7.07–
7.08 (m, 4 H, 10-H, ArH), 7.20–7.41 (m, 6 H, ArH, =CH).
13C NMR (63 MHz, CDCl3): = 18.3, 18.4, 20.9, 121.0, 124.9,
125.7, 126.3, 126.4, 127.3, 128.1, 128.2, 128.6, 129.2, 130.4, 132.8,
133.7, 135.7, 138.9, 139.2, 151.3.
MS (EI, 70 eV): m/z (%) = 370 [M+] (63), 355 (25) [M – CH3], 337
[M – SH] (100), 322 [M – SH – CH3] (11), 239 [M – C8H9NC] (29),
206 [– SH] (25), 91 (29), 77 (36).
IR (neat): 3434 (w, NH), 3019 (m), 2965 (m), 2933 (m), 2875 (m),
2400 (w), 1622 (s) 1582 (s), 1484 (s), 1444 (w), 1382 (w), 1216 (s),
1187 (s), 1122 (w), 1036 (w), 929 (w), 912 (w), 827 (m), 758 (s),
696 (m), 669(s) cm–1.
1H NMR (200 MHz, CDCl3): = 0.96 (t, J = 7.3 Hz, 3 H), 1.54
3
(sextet, 3J = 7.3 Hz, 2 H), 2.41 (s, 3 H), 3.44 (t, 3J = 7.3 Hz, 2 H),
4.57 (br s, 1 H, NH), 7.17 (br s, 3 H, ArH), 7.29–7.50 (m, 6 H, ArH,
CH).
13C NMR (50 MHz, CDCl3): = 11.3, 20.9, 22.6, 44.0, 121.0, 124.8,
125.4, 125.8, 127.2, 127.4, 128.0, 129.2, 130.3, 133.0, 135.9, 142.2,
150.4.
Anal. Calcd for C24H22N2S: C, 77.80; H, 5.98; N, 7.56; S, 8.65.
Found: C, 77.62; H, 6.13; N, 7.55; S, 8.56.
ESI-MS: m/z calcd for C19H21N2S+: 309.1; found: 309.2; correct iso-
topic splitting.
(4Z)-4-Benzylidene-6-methyl-N-phenyl-4H-3,1-benzothiazin-2-
amine (3b)
Yield: 38%; white solid; mp 212–213 °C.
(4Z)-4-Benzylidene-N-cyclohexyl-6-methyl-4H-3,1-benzothiaz-
in-2-amine (3f)
Yellow oil.
IR (KBr): 3024 (w), 2850 (w), 1636 (s), 1581 (s), 1498 (m), 1445
(w), 1401 (w), 1340 (m), 1239 (m), 1195 (m), 1166 (w), 1023 (w),
917 (w), 869 (w), 817 (m), 786 (w), 765 (m), 696 (m) cm–1.
IR (neat): 3387 (m, NH), 3247 (w, NH), 3055 (w), 3021 (m), 2930
(s), 2853 (s), 1621 (s), 1578 (s), 1483 (s), 1445 (m), 1368 (w), 1348
(w), 1248 (m), 1195 (m), 1175 (s), 1123 (m), 1076 (w), 909 (s), 846
(m), 826 (s), 754 (m), 733 (s), 695 (s) cm–1.
1H NMR (600 MHz, CDCl3): = 1.13–1.23 (m, 3 H), 1.36–1.44 (m,
2 H), 1.60–1.64 (m, 1 H), 1.70–1.73 (m, 2 H), 2.03–2.06 (m, 2 H),
2.38 (s, 3 H), 3.99 (br s, 1 H), 4.35 (br s, 1 H, NH), 7.09 (d, 3J = 8.1
Hz, 1 H), 7.13 (s, 1 H, CH), 7.14 (dd, 3J = 8.1 Hz, 4J = 1.8 Hz, 1 H),
1H NMR (200 MHz, CD2Cl2): = 2.38 (s, 3 H), 6.46 (br s, 1 H, NH),
7.01–7.44 (m, 12 H, Ar–H, CH), 7.56 (d, 3J = 8.3 Hz, 2 H).
13C NMR (50 MHz, DMSO-d6): = 21.6, 120.3, 121.2, 122.8,
123.3, 126.0, 126.7, 127.4, 128.4, 129.2, 129.6, 130.2, 131.5, 134.8,
136.6, 141.5, 142.0, 147.0.
ESI-MS: m/z calcd for C22H19N2S+: 343.1; found: 343.1; correct iso-
topic splitting.
Synthesis 2004, No. 3, 415–418 © Thieme Stuttgart · New York