Synthesis of a novel heterocyclic system - Pyrimido[5′, 4′:5, 6]thiopyrano [2, 3-b]indole

Article abstract of DOI:10.2174/157017809789869492

An efficient protocol for the synthesis of pyrimido[5′, 4′:5, 6]thiopyrano[2, 3-b]indoles by the cyclocondensation of 1, 3-dihydro-2H-indole- 2-thione with 6-chloropyrimidine-5-carbaldehydes has been developed. 4-Chloro-2-methylthiopyrimido[5′, 4′:5, 6]th

Full text of DOI:10.2174/157017809789869492

526
Letters in Organic Chemistry, 2009, 6, 526-528
Synthesis of a Novel Heterocyclic System - Pyrimido[5ꢀ,4ꢀ:5,6]thiopyrano
[2,3-b]indole
Jurgis Sudzius and Sigitas Tumkevicius*
Vilnius University, Department of Organic Chemistry, Naugarduko 24, LT-03225 Vilnius, Lithuania
Received April 21, 2009: Revised July 07, 2009: Accepted September 08, 2009
Abstract: An efficient protocol for the synthesis of pyrimido[5ꢀ,4ꢀ:5,6]thiopyrano[2,3-b]indoles by the cyclocondensation
of 1,3-dihydro-2H-indole-2-thione with 6-chloropyrimidine-5-carbaldehydes has been developed. 4-Chloro-2-
methylthiopyrimido[5ꢀ,4ꢀ:5,6]thiopyrano[2,3-b]indole was found to undergo smooth nucleophilic substitution with various
nucleophiles to give 4-substituted pyrimido[5ꢀ,4ꢀ:5,6]thiopyrano[2,3-b]indoles.
Keywords: indoline-2-thione, pyrimidine-5-carbaldehydes, cyclocondensation, nucleophilic substitution, pyrimido[5ꢀ,4ꢀ:5,6]
thiopyrano[2,3-b]indoles.
INTRODUCTION
with anticipated biological activity [8] we report herein on a
simple and efficient synthesis of a novel heterocyclic system
- pyrimido[5ꢀ,4ꢀ:5,6]thiopyrano[2,3-b]indole.
The indole nucleus is a prominent structural motif found
in numerous natural products and synthetic compounds with
important biological activities [1] and thus considerable
attention has been directed towards general, flexible and
simple methods for the synthesis of highly functionalized
indole derivatives and heterocycles containing indole moiety
[2]. Several natural products having specific biological
activity contain the indole-2-thiol fragment. For example,
phytoalexins, such as brassilexin, sinalexin, and cyclo-
brassinin occurring in plants, have a broad antimicrobial
activity, playing crucial roles in their resistance to pathogen
invasion [3]. 3-Arylidene-1,3-dihydroindole-2-thiones as
well as their oxidation products - 2,2ꢀ-dithiobisindoles have
been demonstrated as useful tyrosine kinase inhibitors [4].
3,3-Disubstituted indole-2-thiones were found to be
progesterone receptor antagonists [5].
RESULTS AND DISCUSSION
We have found that performing condensation reaction of
1,3-dihydroindole-2-thione (1) with pyrimidine-5-carbalde-
hydes 2a [9] or b in benzene at room temperature in the
presence of anhydrous potassium carbonate under argon
atmosphere led to formation of tetracyclic heterocycle
derivatives
-
pyrimido[5ꢀ,4ꢀ:5,6]thiopyrano[2,3-b]indoles
3a,b (Scheme 1) [10]. The structure of 3a,b was assigned on
the basis of their spectral and elemental analysis data. In
their IR spectra there is no absorption of the C=O and NH
groups. In the 1H NMR spectra along with signals of
aromatic protons in a region 7.4-8.0 ppm and methylthio
group at 2.72 ppm and 2.67 ppm, respectively, a singlet at
8.62 ppm and 8.55 ppm appeared due to C(5)-H resonance of
compounds 3a,b. 13C NMR spectra of compounds 3a,b as
well as elemental analysis data are consistent with the
proposed structures. In order to isolate possible reaction
intermediates – corresponding S-alkylated indole or 3-(5-
pyrimidinyl-methylidene)indole derivatives we performed
several experiments under different conditions. However
they were not successful. For example, performing the
reaction of 1 with carbaldehydes 2a,b in 2-propanol or
ethanol in the presence of triethylamine or piperidine, i.e.
under conditions usually leading to the corresponding 3-
arylideneindole-2-thiones [4c, 7], resulted in a formation of
inseparable multicomponent mixture of products.
1,3-Dihydroindole-2-thiones have been used as diverse
initial materials for the synthesis of fused indole heterocycles
including some natural products and their analogues. For
example, the Vilsmeier formylation of 1,3-dihydroindole-2-
thione and following work up of the obtained intermediates
with ammonia or carbon disulphide led to the efficient
synthesis of natural phytoalexins - brassilexin, sinalexin and
thiopyrano[2,3-b:6,5-bꢀ]diindole [3a,b]. Condensation of
indoline-2-thiones with cyclohexyl isocyanide furnished
useful intermediates for the synthesis of thieno[2,3-b]indoles
[6]. Reaction of 1,3-dihydroindole-2-thiones with aromatic
aldehydes yielded the corresponding 3-arylideneindole-2-
thiones [4c, 7], some of which as diene components easily
reacted in the hetero-Diels-Alder reaction to give
thiopyrano[2,3-b]indole derivatives [7]. Nevertheless,
reactions of 1,3-dihydroindole-2-thiones with heteroaromatic
aldehydes bearing other reactive functional groups are
studied insufficiently. In this context and in the course of our
studies on the synthesis of fused pyrimidine heterocycles
Chloro group in 3a appeared to be rather reactive towards
various nucleophiles. Compound 3a reacted with selected
N-, O- and S-nucleophiles to give the corresponding 4-
substituted 2-methylthiopyrimido[5ꢀ,4ꢀ:5,6]-thiopyrano[2,3-
b]indoles (3b-h) (Scheme 2) [11]. For example,
displacement of chloro group in compound 3a with methanol
or ethanol to give compounds 3b,c occured at room
temperature in the presence of potassium carbonate.
Treatment of 3a with equivalent amount of aniline,
*Address correspondence to this author at the Vilnius University,
Department of Organic Chemistry, Naugarduko 24, LT-03225 Vilnius,
Lithuania; E-mail: sigitas.tumkevicius@chf.vu.lt
1570-1786/09 $55.00+.00
© 2009 Bentham Science Publishers Ltd.

Synthesis of a Novel Heterocyclic System
Letters in Organic Chemistry, 2009, Vol. 6, No. 7
527
7
6
R
4
R
5
8
CHO
Cl
3
N
N
C6H6, K2CO3
r.t., 24h
S
+
9
N
10
N
1
SMe
2
N
S
MeS
N
11
H
3a,b
2a,b
1
R = Cl (a); OMe (b)
Scheme 1.
Nu
Cl
N
N
NuH
N
r.t., K2CO3
(45-80%)
N
S
N
SMe
S
N
SMe
3b-h
3a
Nu = OMe (b), OEt (c), NH2 (d), NHPh (e), N(CH2)4O (f), NHCH2CO2Me (g), SCH2CO2Et (h)
Scheme 2.
[8]
(a) Brukstus, A.; Melamedaite, D.; Tumkevicius, S. Synth.
Commun., 2000, 30, 3719; (b) Tumkevicius, S.; Dailide, M.;
Kaminskas, A. J. Heterocycl. Chem., 2006, 43, 1629; (c)
Tumkevicius, S.; Dailide, M. J. Heterocycl. Chem., 2005, 42, 1305;
(d) Tumkevicius, S.; Masevicius, V. Synlett, 2004, 2327.
Santilli, A. A.; Kim, D. H.; Wanser, S. V. J. Heterocycl. Chem.,
1971, 8, 445.
morpholine, methyl aminoacetate or ethyl mercaptoacetate in
tetrahydrofuran in the presence of potassium carbonate
furnished the corresponding 4-substituted 2-methyl-
thiopyrimido[5ꢀ,4ꢀ:5,6]thiopyrano[2,3-b]indoles (3d-h) in 45-
80% yields.
[9]
In summary, we have developed a simple and efficient
synthesis of a novel tetracyclic heterocyclic system -
pyrimido[5ꢀ,4ꢀ:5,6]thiopyrano[2,3-b]indoles, containing str-
uctural units of indole, thiopyrane and pyrimidine, that
makes these compounds readily available for further
chemical and biological study.
[10]
Synthetic procedure for 4-chloro-2-methylthiopyrimido[5ꢀ,4ꢀ:5,
6]thiopyrano[2,3-b]indole (3a). A solution of 0.15 g (1 mmol) 1,3-
dihydro-indole-2-thione in 10 ml of dry benzene was flushed with
argon. Then 0.22 g (1 mmol) 4,6-dichloro-2-methylthiopyrimidine-
5-carbaldehyde [9] and 0.15 g (1.1 mmol) of potassium carbonate
was added. The reaction mixture was stirred at room temperature
for 24 h and filtered. Filtrate was concentrated under reduced
pressure to dryness and the resulting solid was recrystallized to
give 0.21 g (66%) of compound 3a as orange red needle crystals,
m.p. 183 ºC (dec.) (from chloroform). 1H-NMR (300 MHz, CDCl3)
ꢁ, ppm: 2.72 (s, 3H, SCH3), 7.43 (td, 1H, J = 7.3 Hz, J = 1.0 Hz,
C7-H), 7.63 (td, 1H, J = 8.0 Hz, J = 1.0 Hz, C8-H), 7.79 (d, 1H, J =
8.0 Hz, C9-H), 8.09 (d, 1H, J = 7.1 Hz, C6-H) 8.62 (s, 1H, C5-H).
13C-NMR (75 MHz, DMSO-d6) ꢁ, ppm: 14.7, 115.3, 119.2, 121.6,
123.9, 124.1, 125.5, 130.6, 132.2, 154.9, 160.4, 160.7, 165.0,
171.9. Anal. Calcd. for C15H8N3S2Cl: C, 52.91; H, 2.54; N, 13,22.
Found: C, 53.29; H, 2.49; N, 13.04.
REFERENCES AND NOTES
[1]
(a) Sundberg, R. J. Indoles; Academic Press: London, 1996; (b)
Sundberg, R. J. In Comprehensive Heterocyclic Chemistry II;
Katritzky, A. R.; Ress, C. W.; Scriven, E. F. V.; Bird, C. W.; Eds.;
Pergamon Press: Oxford, 1996; Vol. 2, p. 119; (c) Gribble, G. W.
Comprehensive Heterocyclic Chemistry II; Katritzky, A. R.; Ress,
C. W.; Scriven, E. F. V.; Bird, C. W., Eds.; Pergamon Press:
Oxford, 1996; Vol. 2, p. 207.
[11]
Spectral and physical data of compounds 3b-h. Compound 3b:
Yield 63%, m.p. 220-222 ºC (form ethyl acetate). IR, cm-1: 1549,
1502, 1427. 1H-NMR (300 MHz, CDCl3) ꢁ, ppm.: 2.67 (s, 3H,
SCH3), 4.23 (s, 3H, OCH3) 7.36 (td, 1H, J = 7.5 Hz, J = 0.9 Hz,
C7-H), 7.56 (td, 1H, J = 7.7 Hz, J = 1.0 Hz, C8-H), 7.76 (d, 1H, J =
7.8 Hz, C9-H), 8.01 (d, 1H, J = 7.5 Hz, C6-H) 8.55 (s, 1H, C5-H).
13C-NMR (75 MHz, DMSO-d6) ꢁ, ppm: 14.7, 55.4, 106.4, 119.1,
121.0, 123.4, 123.5, 125.9, 129.8, 130.0, 154.9, 161.1, 164.0,
[2]
[3]
(a) Humphrey, G. R.; Kuethe, J. T. Chem. Rev., 2006, 106, 2875;
(b) Cacchi, S.; Fabrizi, G. Chem. Rev., 2005, 105, 2873; (c)
Gribble, G. W. J. Chem. Soc. Perkin Trans. I, 2000, 1045.
(a) Pedras, M. S. C.; Jha, M. J. Org. Chem., 2005, 70, 1828; (b)
Pedras, M. S. C.; Zaharia, I. L. Org. Lett., 2001, 3, 1213; (c)
Pedras, M. S. C.; Okanga, F. I. J. Agric. Food Chem., 1999, 47,
1196; (d) Pedras, M. S. C.; Khan, A. Q. J. Agric. Food Chem.,
1996, 44, 3403.
o
165.7, 172.3. Compound 3c: Yield 73%, m.p. 226.5-227 C (from
ethyl acetate): 1H-NMR (300 MHz, CDCl3) ꢁ, ppm: 1.60 (t, 3H, J =
7.1 Hz, CH3), 2.68 (s, 3H, SCH3), 4.71 (q, 2H, J = 7.1 Hz, OCH2)
7.38 (t, 1H, J = 7.5 Hz, C7-H), 7.59 (t, 1H, J = 7.9 Hz, C8-H), 7.79
(d, 1H, J = 7.9 Hz, C9-H), 8.08 (d, 1H, J = 7.5 Hz, C6-H), 8.61 (s,
1H, C5-H). 13C-NMR (75 MHz, CDCl3) ꢁ, ppm: 14.6, 14.7, 64.6,
106.4, 119.3, 121.4, 123.3, 123.5, 126.4, 129.7, 130.3, 155.3,
161.6, 164.4, 165.5, 172.2. Compound 3d: Yield 80%, m.p. 320 oC
(dec.): IR, cm-1: 3322, 3160 (NH). 1H-NMR (300 MHz, DMSO-d6)
ꢁ, ppm: 2.54 (s, 3H, SCH3), 7.36 (t, 1H, J = 7.5 Hz, C7-H), 7.51 (t,
1H, J = 7.8 Hz, C8-H), 7.66 (d, 1H, J = 7.8 Hz, C9-H), 8.01 (d, 1H,
J = 7.5 Hz, C6-H), 8.01 (s, 2H, NH2), 9.09 (s, 1H, C5-H). 13C-NMR
(75 MHz, DMSO-d6) ꢁ, ppm: 14.3, 103.3, 119.0, 121.2, 123.4,
126.8, 126.9, 127.8, 129.2, 154.6, 160.1, 161.7, 163.6, 171.8.
Compound 3e: Yield 64%, m.p. 141-142 oC (from chloroform): IR,
cm-1: 3436 (NH). 1H-NMR (300 MHz, DMSO-d6) ꢁ, ppm: 2.50 (s,
3H, SCH3), 7.25 (t, 1H, J = 7.4 Hz, C4ꢀ-H), 7.43 (t, 1H, J = 7.4 Hz,
[4]
(a) Olgen, S.; Akaho, E.; Nebioglu, D. Farmaco, 2005, 60, 497; (b)
Olgen, S. Arch. Pharm. Res., 2006, 29, 1006; (c) Olgen, S.; Gotz,
C.; Jose, J. Biol. Pharm. Bull., 2007, 30, 715; (d) Rewcastle, G. W.;
Palmer, B. D.; Dobrusin, E. M.; Fry, D. W.; Kraker, A. J.; Denny,
W. A. J. Med. Chem., 1994, 37, 2033. (e) Palmer, B. D.;
Rewcastle, G. W.; Thompson, A. M.; Boyd, M.; Showalter, H. D.
H.; Sercel, A. D.; Fry, D. W.; Kraker, A. J.; Denny, W. A. J. Med.
Chem., 1995, 38, 58.
Fensome, A.; Koko, M.; Wrobel, J.; Zhang, P.; Zhang, Z.; Cohen,
J.; Lundeen, S.; Rudnick, K.; Zhu, Y.; Winneker, R. Bioorg. Med.
Chem. Lett., 2003, 13, 1317.
Moghaddam, F. M.; Saeidian, H.; Mirjafary, Z.; Taheri, S.;
Kheirjou, S. Synlett, 2009, 1047.
[5]
[6]
[7]
(a) Thompson, A. M.; Boyd, M.; Denny, W. A. J. Chem. Soc.
Perkin Trans. 1, 1993, 1835; (b) Kamila, S.; Biehl, E.
Heterocycles, 2004, 63, 2785.

528 Letters in Organic Chemistry, 2009, Vol. 6, No. 7
Sudzius and Tumkevicius
C7-H), 7.48 (t, 2H, J = 7.5 Hz, C3ꢀ,5ꢀ-H), 7.57 (t, 1H, J = 7.4 Hz,
C8-H), 7.70(d, 1H, J = 7.4 Hz, C9-H), 7.73 (d, 2H, J = 7.5 Hz,
C2ꢀ,4ꢀ-H), 8.14 (d, 1H, J = 7.4 Hz, C6-H), 9.48 (s, 1H, C5-H),
Hz, C8-H), 7.66 (d, 1H, J = 7.9 Hz, C9-H), 8.01 (d, 1H, J = 7.2 Hz,
C6-H), 9.08 (s, 1H, C5-H), 9.22 (t, 1H, J = 5.4 Hz, NH). 13C NMR
(75 MHz, CDCl3) ꢁ, ppm: 14.2, 43.5, 52.7, 103.7, 119.2, 121.2,
123.5, 125.4, 126.8, 128.3, 129.4, 155.0, 159.3, 160.0, 163.1,
170.8, 171.4. Compound 3h: Yield 60%, m.p. 193-194 ºC (from
ethyl acetate). IR (KBr), cm-1: 1732 (CO). 1H NMR (300 MHz,
CDCl3) ꢁ, ppm: 1.36 (t, 3H, J = 7.1 Hz, CH3), 2.63 (s, 3H, SCH3),
4.13 (s, 2H, SCH2), 4.29 (q, 2H, J = 7.0 Hz, OCH2), 7.35 (t, 1H, J =
7.2 Hz, C7-H), 7.55 (t, 1H, J = 7.4 Hz, C8-H), 7.72 (d, 1H, J = 7.9
o
10.33 (s, 1H, NH). Compound 3f: Yield 45%, m.p. 184.5-185 C
1
(from acetone): H-NMR (300 MHz, CDCl3) ꢁ, ppm: 2.65 (s, 3H,
SCH3), 3.80 – 3.96 [m, 8H, N(CH2)4O], 7.36 (t, 1H, J = 7.5 Hz, C7-
H), 7.57 (t, 1H, J = 7.5 Hz, C8-H), 7.78(d, 1H, J = 7.5 Hz, C9-H),
7.99 (d, 1H, J = 7.5 Hz, C6-H), 8.24 (s, 1H, C5-H); 13C-NMR (75
MHz, CDCl3) ꢁ, ppm: 14.7, 50.95, 66.9, 94.9, 119.4, 120.5, 123.2,
124.9, 126.2, 126.5, 129.7, 154.7, 162.5, 163.3, 165.8, 172.1.
Compound 3g: Yield 55%, m.p. 201-202 ºC (from benzene): IR
(Nujol), cm-1: 3520 (NH), 1746 (CO). 1H-NMR (300 MHz, CDCl3)
ꢁ, ppm: 2.48 (s, 3H, SCH3), 3.71 (s, 3H, OCH3), 4.31 (d, 2H, J =
5.5 Hz, NCH2), 7.38 (t, 1H, J = 7.7 Hz, C7-H), 7.52 (t, 1H, J = 7.4
Hz, C9-H), 7.99 (d, 1H, J = 7.5 Hz, C6-H), 8.33 (s, 1H, C5-H). 13
C
NMR (75 MHz, CDCl3) ꢁ, ppm: 14.5, 14.7, 32.9, 62.5, 114.5,
119.4, 121.4, 122.8, 123.6, 125.8, 130.3, 130.9, 155,4, 161.0,
162.8, 168.4, 170.7.