A novel, one-pot four-component route to 2′-thioxo-2′,3′- dihydrospiro[indole-3,6′-[1,3]thiazin]-2-one derivatives

Article abstract of DOI:10.1002/hlca.201000419

An efficient route to 2′,3′-dihydro-2′- thioxospiro[indole-3,6′-[1,3]thiazin]-2(1H)-one derivatives is described. It involves the reaction of isatine, 1-phenyl-2-(1,1,1-triphenyl- λ⁵-phosphanylidene)ethan-1-one, and different amines in the presence of CS₂ in dry MeOH at reflux (Scheme 1). The alkyl carbamodithioate, which results from the addition of the amine to CS ₂, is added to the α,β-unsaturated ketone, resulting from the reaction between 1-phenyl-2-(1,1,1-triphenyl-λ⁵- phosphanylidene)ethan-1-one and isatine, to produce the 3′-alkyl-2′, 3′-dihydro-4′-phenyl-2′-thioxospiro[indole-3,6′-[1,3] thiazin]-2(1H)-one derivatives in excellent yields (Scheme 2). Their structures were corroborated spectroscopically (IR, ¹H- and ¹³C-NMR, and EI-MS) and by elemental analyses. Copyright

Full text of DOI:10.1002/hlca.201000419

Helvetica Chimica Acta – Vol. 94 (2011)
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A Novel, One-Pot Four-Component Route to 2’-Thioxo-2’,3’-
dihydrospiro[indole-3,6’-[1,3]thiazin]-2-one Derivatives
by Abdolali Alizadeh* and Javad Mokhtari
Department of Chemistry, Tarbiat Modares University, P.O. Box 14115 – 175, Tehran, Iran
(phone: þ 98-21-88006631; fax: þ 98-21-88006544; e-mail: abdol_alizad@yahoo.com,
aalizadeh@Modares.ac.ir)
An efficient route to 2’,3’-dihydro-2’-thioxospiro[indole-3,6’-[1,3]thiazin]-2(1H)-one derivatives is
described. It involves the reaction of isatine, 1-phenyl-2-(1,1,1-triphenyl-l5-phosphanylidene)ethan-1-
one, and different amines in the presence of CS2 in dry MeOH at reflux (Scheme 1). The alkyl
carbamodithioate, which results from the addition of the amine to CS2, is added to the a,b-unsaturated
ketone, resulting from the reaction between 1-phenyl-2-(1,1,1-triphenyl-l5-phosphanylidene)ethan-1-one
and isatine, to produce the 3’-alkyl-2’,3’-dihydro-4’-phenyl-2’-thioxospiro[indole-3,6’-[1,3]thiazin]-2(1H)-
one derivatives in excellent yields (Scheme 2). Their structures were corroborated spectroscopically (IR,
1H- and 13C-NMR, and EI-MS) and by elemental analyses.
Introduction. – A wide range of advantages offered by multicomponent reactions
(MCRs), such as high degree of atom economy, convergence, ease of execution, and
access to complex molecules, has been recognized in the past decade. The utility of
MCRs in preparing libraries to screen for biologically active compounds and potent
drug candidates is well-appreciated [1]. Thus, the search and discovery of new MCRs is
still of considerable current interest.
The indole ring system is probably the most ubiquitous heterocycle in nature.
Because of the great structural diversity of biologically active indoles, it is not surprising
that the indole ring system has become an important structural component in many
pharmaceutical agents [2].
Furthermore, it has been reported that sharing C(3) of indoles in the formation of
spiro-indole derivatives can highly enhance their biological activity [3]. The spiro-
oxindole system is the core structure of several pharmacological agents and natural
alkaloids [4]. For example, spirotryprostatin A and B, two natural alkaloids isolated
from the fermentation broth of Aspergillus fumigatus, have been identified as novel
inhibitors of microtubule assembly [4d], and pteropodine and isopteropodine have
been shown to modulate the function of muscarinic serotonin receptors [4a] (Fig. 1).
The dithiocarbamates and their cyclic derivatives show antibacterial [5], anthel-
mintic [6], fungicidal [7], herbicidal [8], antifouling [9], growth depressant [10], and
algicidal activities [11]. They are also effective catalysts for photopolymerization [12]
and vulcanization [13] (Fig. 2).
Considering the above reports, and as part of our program aimed at developing new
methodologies for the preparation of heterocyclic compounds [14], here, we report the
ꢀ 2011 Verlag Helvetica Chimica Acta AG, Zꢁrich

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Helvetica Chimica Acta – Vol. 94 (2011)
Fig. 1. Representatives of important spiro-oxindoles
Fig. 2. Representatives of substituted dithiocarbamates
synthesis of 2’,3’-dihydro-2’-thioxospiro[indole-3,6’-[1,3]thiazin]-2(1H)-one deriva-
tives through a condensation reaction in MeOH.
Results and Discussion. – Our new method leading to the formation of the title
compounds is depicted in Scheme 1. Reaction between an isatine 2, 1-phenyl-2-(1,1,1-
triphenyl-l5-phosphanylidene)ethan-1-one, and different benzyl and alkyl amines 1 in
the presence of CS2 in dry MeOH at reflux afforded the 3’-alkyl-2’,3’-dihydro-4’-phenyl-
2’-thioxospiro[indoline-3,6’-[1,3]thiazin]-2(1H)-one derivatives 3 in 72 – 87% yields
(Scheme 1).
Scheme 1

Helvetica Chimica Acta – Vol. 94 (2011)
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The structures of compounds 3a – 3g were deduced from their elemental analysis,
1
and IR, and H- and 13C-NMR spectra. The mass spectrum of 3a displayed the
molecular-ion peak at m/z 414, which is in agreement with the proposed structure. The
IR spectrum of 3a showed absorption bands due to the NH group at 3170, the CO
1
group at 1689, and CS group at 1175 cmꢀ1. The H-NMR spectrum of 3a showed two
sharp singlets for CH and NH groups (d(H) 8.86 and 10.94 ppm), two doublets at d(H)
4.65, and 4.89 (2J ¼ 15.0) for the CH2ꢀN, and the Ar moieties gave rise to multiplets in
1
the aromatic region of the spectrum (6.71 – 7.61 ppm). The H-decoupled 13C-NMR
spectrum of 3a showed 20 distinct resonances in agreement with the suggested
structure.
Although we have not established the mechanism of the reaction experimentally, a
possible explanation is proposed in Scheme 2. Compound 3 could be resulted from the
initial addition of the amine to CS2 and subsequent attack of the resulting reactive alkyl
carbamodithioate 5 on compound 4 to yield intermediate 6. Cyclization of the
intermediate 6 and subsequent loss of H2O lead to compound 3.
Scheme 2. Proposed Mechanism of the Formation of 3
In conclusion, an efficient method for the preparation of 2’,3’-dihydro-2’-
thioxospiro[indole-3,6’-[1,3]thiazin]-2(1H)-one derivatives using readily available
starting materials is reported. These types of heterocycles contain a number of
functional groups with possible biological activities. Prominent among the advantages
of this new method are operational simplicity and high product yields.
Experimental Part
General. The reagents, including 5-bromoisatine, and solvents were obtained from Fluka (Buchs)
and used without further purification. M.p.: Electrothermal 9100 apparatus. IR Spectra (KBr): Shimadzu
1
IR-460 spectrometer. H- and 13C-NMR spectra were recorded at 500 and 125 MHz, respectively, on a
BRUKER DRX 500-AVANCE FT-NMR instrument with (D6)DMSO as solvent. MS: FINNIGAN-MAT
8430 mass spectrometer operating at an ionization potential of 70 eV. Elemental analyses for C, H, and
N: Heraeus CHN-O-Rapid analyzer.
General Procedure. Formation of 3a. A soln. of 1-phenyl-2-(1,1,1-triphenyl-l5-phosphanylidene)-
ethan-1-one (0.38 g, 1 mmol) and isatin (0.15 g, 1 mmol) was magnetically stirred in MeOH (3 ml) for

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20 min. Then, BnNH2 (0.11 g, 1 mmol) and CS2 (1.2 mmol) were added simultaneously. The mixture was
stirred for 6 h at reflux temp. The progress of the reaction was followed by means of TLC. After
completion, the solvent was removed under reduced pressure, and the residue was purified by CC
(hexane/AcOEt, 4 :1).
3’-Benzyl-2’,3’-dihydro-4’-phenyl-2’-thioxospiro[indole-3,6’-[1,3]thiazin]-2(1H)-one (3a). Yield:
0.32 g (78%). Yellow crystals. M.p. 2128 (dec.). IR: 3170 (NH), 1689 (NCO), 1462, 1447 (Ar), 1175
(C¼S). 1H-NMR: 4.65 (d, J ¼ 15.0, 1 H); 4.89 (d, J ¼ 15.0, 1 H); 6.71 (t, J ¼ 7.0, 1 H); 6.78 (d, J ¼ 7.7, 1 H ) ;
7.05 – 7.10 (m, 6 H); 7.22 (t, J ¼ 7.6, 1 H); 7.28 (t, J ¼ 7.5, 2 H); 7.53 (d, J ¼ 7.8, 1 H); 7.61 (d, J ¼ 7.4, 2 H);
8.86 (s, 1 H); 10.94 (s, 1 H). 13C-NMR: 47.9; 102.0; 110.2; 118.6; 119.8; 121.4; 126.4; 126.4; 127.0; 127.8;
128.0; 128.9; 129.7; 129.8; 136.2; 137.9; 142.1; 150.0; 168.5; 190.9. EI-MS (70 eV): 415 (10, [M þ 1]þ), 341
(9), 327 (17), 281 (57), 207 (27), 147 (36), 73 (76), 43 (100). Anal. calc. for C24H18N2OS2 (414.54): C
69.54, H 4.38, N 6.76; found: C 69.49, H 4.30, N 6.65.
3’-(2-Chlorobenzyl)-2’,3’-dihydro-4’-phenyl-2’-thioxospiro[indole-3,6’-[1,3]thiazin]-2(1H)-one (3b).
Yield: 0.38 g (86 %). Yellow crystals. M.p. 2208 (dec.). IR: 3211 (NH), 1690 (NCO), 1595, 1462 (Ar),
1171 (C¼S). 1H-NMR: 4.73 (d, J ¼ 16.1, 1 H); 4.96 (d, J ¼ 16.1, 1 H); 6.69 (t, J ¼ 7.2, 1 H); 6.79 (t, J ¼ 7.3,
2 H); 6.97 – 7.29 (m, 7 H); 7.45 (d, J ¼ 7.8, 1 H); 7.60 (d, J ¼ 9.1, 2 H); 8.95 (s, 1 H); 10.98 (s, 1 H).
13C-NMR: 45.3; 101.7; 110.3; 119.8; 120.8; 121.5; 126.0; 126.4; 126.8; 128.0; 128.2; 129.0; 129.5; 129.8;
131.4; 132.6; 137.6; 142.2; 149.4; 168.5; 191.5. EI-MS (70 eV): 448 (1, Mþ), 429 (40), 355 (28), 281 (21),
221 (28), 147 (38), 73 (100), 43 (17). Anal. calc. for C24H17ClN2OS2 (448.98): C 64.20, H 3.82, N 6.24;
found: C 64.14, H 3.75, N 6.18.
3’-(4-Chlorobenzyl)-2’,3’-dihydro-4’-phenyl-2’-thioxo-spiro[indole-3,6’-[1,3]thiazin]-2(1H)-one (3c).
Yield: 0.35 g (79%). Yellow crystals. M.p. 2408 (dec.). IR: 3205 (NH), 1691 (NCO), 1463 (Ar), 1171
(C¼S). 1H-NMR: 4.66 (d, J ¼ 16.1, 1 H); 4.88 (d, J ¼ 16.1, 1 H); 6.71 (t, J ¼ 8.1, 1 H); 6.78 (d, J ¼ 8.7, 1 H);
7.06 – 7.09 (m, 3 H); 7.15 (d, J ¼ 8.4, 2 H); 7.24 (t, J ¼ 6.0, 1 H); 7.29 (t, J ¼ 7.9, 2 H); 7.52 (d, J ¼ 8.0, 1 H);
7.60 (d, J ¼ 7.5, 2 H); 8.89 (s, 1 H); 10.95 (s, 1 H). 13C-NMR: 47.2; 101.9; 110.2; 118.7; 119.8; 121.4; 126.4;
126.4; 128.0; 129.0; 129.7; 129.8; 131.6; 135.3; 137.8; 142.1; 149.8; 168.5; 191.0. EI-MS (70 eV): 448 (1,
Mþ), 207 (9), 182 (8), 125 (100), 116 (9), 89 (20), 73 (5), 43 (32). Anal. calc. for C24H17ClN2OS2 (448.98):
C 64.20, H 3.82, N 6.24; found: C 64.16, H 3.77, N 6.19.
2’,3’-Dihydro-3’-(4-methylbenzyl)-4’-phenyl-2’-thioxospiro[indole-3,6’-[1,3]thiazin]-2(1H)-one (3d).
Yield: 0.35 g (81%). Yellow crystals. M.p. 2328 (dec.). IR: 3188 (NH), 1683 (NCO), 1455 (Ar), 1175
(C¼S). 1H-NMR: 2.17 (s, 3 H); 4.54 (d, J ¼ 16.0, 1 H); 4.85 (d, J ¼ 16.0, 1 H); 6.71 (t, J ¼ 7.3, 1 H); 6.78 (d,
J ¼ 8.0, 1 H); 6.91 (d, J ¼ 7.8, H); 6.95 (d, J ¼ 7.8, 2 H); 7.08 (t, J ¼ 7.3, 1 H); 7.25 (t, J ¼ 7.6, 1 H); 7.31 (t, J ¼
7.4, 2 H); 7.54 (d, J ¼ 8.0, 1 H); 7.61 (d, J ¼ 7.5, 2 H); 8.85 (s, 1 H); 10.94 (s, 1 H). 13C-NMR: 20.5; 47.2;
101.5; 109.7; 118.0; 119.4; 120.9; 125.9; 125.9; 127.5; 128.1; 128.5; 129.1; 129.3; 132.7; 135.5; 137.4; 141.6;
149.6; 168.0; 190.2. EI-MS (70 eV): 429 (1, [M þ 1]þ), 207 (12), 162 (8), 116 (4), 105 (100), 91 (8), 73
(16), 43 (28). Anal. calc. for C25H20N2OS2 (428.56): C 70.07, H 4.70, N 6.54; found: C 70.01, H 4.66, N 6.52.
2’,3’-Dihydro-3’-(4-methoxybenzyl)-4’-phenyl-2’-thioxospiro[indole-3,6’-[1,3]thiazin]-2(1H)-one
(3e). Yield: 0.33 g (74%). Yellow crystals. M.p. 1848. IR: 3215 (NH), 1677 (NCO), 1542, 1444 (Ar), 1237
(C¼S). 1H-NMR: 3.71 (s, 3 H); 4.56 (d, J ¼ 15.2, 1 H); 4.82 (d, J ¼ 15.2, 1 H); 6.72 (t, J ¼ 7.8, 1 H); 6.78 (d,
J ¼ 7.7, 1 H); 6.86 (d, J ¼ 7.7, 2 H); 7.08 (t, J ¼ 7.7, 1 H); 7.19 (d, J ¼ 8.1, 2 H); 7.25 (t, J ¼ 6.6, 1 H); 7.30 (t,
J ¼ 7.7, 2 H); 7.56 (d, J ¼ 7.8, 1 H); 7.62 (d, J ¼ 8.12, 2 H); 8.81 (s, 1 H); 10.92 (s, 1 H). 13C-NMR: 47.4; 55.4;
102.0; 110.2; 113.6; 114.1; 118.5; 119.8; 121.4; 126.4; 128.3; 129.0; 129.7; 129.8; 137.9; 142.0; 150.2; 158.7;
168.5; 190.6. EI-MS (70 eV): 444 (1, [M þ 1]þ), 179 (4), 121 (100), 91 (5), 77 (10), 63 (2), 51 (4), 57 (14).
Anal. calc. for C25H20N2O2S2 (444.56): C 67.54, H 4.53, N 6.30; found: C 67.50, H 4.48, N 6.28.
5-Bromo-3’-(4-chlorobenzyl)-2’,3’-dihydro-4’-phenyl-2’-thioxospiro[indole-3,6’-[1,3]thiazin]-2(1H)-
one (3f). Yield: 0.38 g (72%). Yellow crystals. M.p. 2108 (dec.). IR: 3239 (NH), 1696 (NCO), 1592, 1460
(Ar), 1171 (C¼S). 1H-NMR: 4.68 (d, J ¼ 15.6, 1 H); 4.90 (d, J ¼ 15.6, 1 H); 6.75 (d, J ¼ 8.4, 1 H); 7.07 (d,
J ¼ 8.4, 2 H); 7.15 (d, J ¼ 8.2, 2 H); 7.25 – 7.32 (m, 4 H); 7.58 (d, J ¼ 8.1, 2 H); 7.64 (d, J ¼ 4.6, 1 H); 9.02 (s,
1 H); 11.12 (s, 1 H). 13C-NMR: 54.9; 101.4; 111.6; 112.7; 117.0; 121.0; 125.9; 127.5; 128.1; 128.6; 129.3;
129.6; 131.1; 131.4; 134.7; 136.8; 140.6; 151.8; 167.6; 190.0. EI-MS (70 eV): 527 (2, Mþ), 183 (9), 125
(100), 116 (5), 99 (6), 89 (16), 75 (4), 63 (8), 43 (1). Anal. calc. for C24H16BrClN2OS2 (527.88): C 54.61, H
3.05, N 5.31; found: C 54.58, H 3.02, N 5.28.

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2’,3’-Dihydro-4’-phenyl-3’-(prop-2-en-1-yl)-2’-thioxospiro[indole-3,6’-[1,3]thiazin]-2(1H)-one (3g).
Yield: 0.32 g (87%). Yellow crystals. M.p. 1728. IR: 3153 (NH), 2927 (aliphatic CH), 1640 (C¼C),
1706 (NCO), 1452 (Ar), 1223 (C¼S). 1H-NMR: 4.08 – 4.13 (m, 2 H); 5.23 (d, J ¼ 10.2, 1 H); 5.28 (d, J ¼
10.2, 1 H); 5.85 – 5.89 (m, 1 H); 6.88 (d, J ¼ 7.7, 1 H); 7.02 (t, J ¼ 7.6, 1 H); 7.32 (t, J ¼ 7.6, 2 H); 7.54 (t, J ¼
7.7, 2 H); 7.64 (t, J ¼ 7.2, 1 H); 7.87 (s, 1 H); 8.12 (d, J ¼ 7.6, 2 H); 8.23 (s, 1 H); 8.31 (d, J ¼ 7.8, 1 H).
13C-NMR: 47.0; 110.0; 117.6; 120.7; 122.9; 126.5; 128.0; 128.8; 128.9; 132.7; 133.1; 133.8; 136.7; 137.6;
143.2; 169.3; 191.1. EI-MS (70 eV): 365 (1, [M þ 1]þ), 281 (25), 221 (30), 147 (37), 73 (100), 44 (20).
Anal. calc. for C20H16N2OS2 (364.48): C 65.91, H 4.42, N 7.69; found: C 65.80, H 4.39, N 7.65.
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Received November 12, 2010