Synthesis of thiopyrano[4″,3″:4′,5′]pyrido[3′,2′:4,5]furo[3,2-d]pyrimidines

Article abstract of DOI:10.1016/j.cclet.2009.12.010

Reactions of the 6-hydroxy-thiopyrano[3,4-c]pyridine-5-carbonitrile derivative 1 with α-halo-carbonyl compounds gave the ortho-substituted intermediates 2a-c which were converted into furo[2,3-b]thiopyrano[4,3-d]pyridines 3a-c by fusion of a furan moiety

Full text of DOI:10.1016/j.cclet.2009.12.010

Available online at www.sciencedirect.com
Chinese Chemical Letters 21 (2010) 669–673
www.elsevier.com/locate/cclet
Synthesis of thiopyrano[400,300:40,50]pyrido[30,20:4,
5]furo[3,2-d]pyrimidines
*
Essam Kh. Ahmed, Mohamed A. Ameen
Chemistry Department, Faculty of Science, El Minia University, El Minia 61519, Egypt
Received 23 September 2009
Abstract
Reactions of the 6-hydroxy-thiopyrano[3,4-c]pyridine-5-carbonitrile derivative 1 with a-halo-carbonyl compounds gave the
ortho-substituted intermediates 2a–c which were converted into furo[2,3-b]thiopyrano[4,3-d]pyridines 3a–c by fusion of a furan
moiety under basic conditions. Further cyclization of 3a–c led to a fusion of a pyrimidine ring, yielding the tetracyclic products 6, 7
and 8. In addition, condensation of 6 with various aromatic aldehydes afforded the corresponding imines 9a,b. Mannich reaction of
7 gave products 10a,b.
# 2009 Mohamed A. Ameen. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: S,N-Heterocycles; S,N,O-Heterocyles; Furo[2,3-b]thiopyrano[4,3-d]pyridine; Thiopyranopyridofuropyrimidines
Nitrogen, oxygen, and sulphur containing heterocyclic compounds have received considerable attention due to
their wide range of pharmacological activities. The furopyrimidine derivatives are important class of such heterocyclic
compounds in pharmaceutical discovery research. Antifungal [1], antifolate [2–4], antibacterial [5], antitumor [3,6],
antiviral [7,8], and anti-HCMV (human cytomegalovirus) [9] activities have been described for these compounds.
Recently, some furopyrimidines were shown to be potent VEGFR2 (vascular endothelial growth factor receptor 2)
and EGFR (epidermal growth factor receptor) inhibitors [10].
Akt, a serine/threonine protein kinase as a viral oncogene, is a critical regulator of PI3K-mediated cell proliferation
and survival [11–13]. Since the discovery of human Akt1 (PKB), two additional mammalian Akt isoforms, Akt2 and
Akt3, have been identified [14]. One of the intracellular signaling pathways that frequently are activated in cancer cells
is the PI3K/Akt kinase pathway [15]. On translocation, Akt is phosphorylated and activated, ultimately resulting in
stimulation of cell growth and survival. As an attractive target for the potential treatment of cancer, furo[2,3-
d]pyrimidines have been investigated as Akt1 kinase inhibitors [16,17] with positive results. As a part of our program
toward these small molecule compounds and because of this successive finding we are prompted to synthesize a series
of fused furo[3,2-d]pyrimidines starting from 3,4-dihydro-6-hydroxy-8-methoxy-1H-thiopyrano[3,4-c]pyridine-5-
carbonitrile.
Reaction of 4-oxo-tetrahydrothiopyran-3-carboxylic acid methyl ester [18] with malononitrile in methanol-
benzene containing ammonium acetate and acetic acid would be predicted to afford 3,4-dihydro-6-hydroxy-8-
* Corresponding author.
E-mail address: m_ameen10@yahoo.com (M.A. Ameen).
1001-8417/$ – see front matter # 2009 Mohamed A. Ameen. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2009.12.010

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E. Kh Ahmed, M.A. Ameen / Chinese Chemical Letters 21 (2010) 669–673
Scheme 1.
methoxy-1H-thiopyrano[3,4-c]pyridine-5-carbonitrile [19] (1), obviously via a mechanism described by Van der Baan
and Bichelhaupt [20] for structurally related cyclohexane derivatives. Alkylation of the tautomeric hydroxyl group in
such lactams by a-haloester, a-haloamide or a-halonitrile yielded the corresponding a-acidic-3,4-dihydro-6-alkoxy-
8-methoxy-1H-thiopyrano[3,4-c]pyridine-5-carbonitriles 2a–c which are prone to undergo one or more cyclization. In
the presence of sodium ethoxide solution, the target systems 3a–c, i.e. the corresponding 1-amino-9,8-dihydro-5-
methoxy-6H-furo[2,3-b]thiopyrano[4,3-d]pyridines, were obtained in a good yields. Treatment of 3a with hydrazine
hydrate afforded 1-amino-8,9-dihydro-5-methoxy-6H-furo[2,3-b]thiopyrano[4,3-d]pyridine-2-carboxylic acid hydra-
zide (5) which could be alternatively obtained from 2a by initial conversion to the corresponding hydrazide 4 using
hydrazine hydrate followed by cyclization in sodium ethoxide solution (Scheme 1).
As illustrated in Scheme 2 compounds 3a-c were also advantageously used for further cyclization. Treatment of o-
aminohydrazide 5 with ethyl orthoformate built the pyrimido moiety in compound 6. Deamination of compound 6 by
nitrous acid formed 1,4-dihydro-5-methoxy-2H-thiopyrano[400,300:40,50]pyrido[30,20:4,5]furo[3,2-d]pyrimidine-
8(9H)-one (7), which is identical with product obtained in good yield by treatment of 3b with triethyl orthoformate.
Whereas cyclocondensation of 3c with formamide afforded 4-amino-1,4-dihydro-5-methoxy-2H-thio-
pyrano[400,300:40,50]pyrido[30,20:4,5]furo[3,2-d]pyrimidine (8).
Condensation of 6 with various aromatic aldehydes produced the corresponding imines 9a,b in good yields.
Reaction of compound 7 with formaldehyde and secondary amines (ambient temperature) yielded the corresponding
Mannich-type bases 10a,b in 77–95% yields.
Scheme 2.

E. Kh Ahmed, M.A. Ameen / Chinese Chemical Letters 21 (2010) 669–673
671
In conclusion, an efficient synthesis of furo[3,2-d]pyrimidines have been developed, having several merits over
hitherto known methods, i.e. fewer reaction steps, mild reaction conditions and higher yields. A number of the
obtained products are presently under pharmacological screening.
1. Experimental
Mps have been determined using open glass capillaries on a Gallenkamp melting point apparatus and are
uncorrected. The IR spectra were recorded with a Shimadzu 408 instrument using potassium bromide pellets. The 1H
NMR (400 MHz) and 13C NMR (100 MHz) spectra were measured in DMSO-6 using a Bruker AM 400 with TMS as
an internal standard.
1.1. Synthesis of 2a–c
1.1.1. General procedures
A mixture of compound 1 (2.2 g, 0.01 mol) and a-haloester, a-haloamide or a-halonitrile (0.01 mol) in DMF
(30 mL) was refluxed for 1 h in the presence of anhydrous potassium carbonate (0.01 mol). The reaction mixture was
cooled, poured into cold water and stirred for 1 h at room temperature. The product was filtered off and recrystallized
from an appropriate solvent.
1.1.1.1. 3,4-Dihyro-6-(cyano-methyl)oxy-8-methoxy-1H-thiopyrano[3,4-c]pyridine-5-carbonitrile (2c). Colorless
crystals from ethanol; Yield (1.98 g, 77%); Mp: 100–101 8C; IR (KBr) y (cmꢀ1): 2990, 2980, 2210, 1580, 1560;
1H NMR (CDCl3): d 2.82 (t, 2H, J = 5.6 Hz, H-4), 3.20 (t, 2H, J = 5.6 Hz, H-3), 3.34 (s, 2H, H-1), 4.10 (s, 3H, OCH3),
5.37 (s, 2H, OCH3), Calcd. (%) for C12H11N3O2S (261.29): C; 55.15, H; 4.24, N; 16.08. Found: C; 54.90, H; 4.10, N;
15.92.
1.2. Synthesis of 3a–c
1.2.1. General procedures
To a stirred suspension of compound 2a, 2b or 2c (0.01 mol) in absolute ethanol (20 mL), sodium ethoxide
(0.01 mol) was added. Stirring was continued for 15 min and then the reaction mixture was refluxed for another
30 min. The separated solid product was filtered off and recrystallized from an appropriate solvent.
1.2.1.1. 1-Amino-8,9-dihyro-5-methoxy-6H-furo[2,3-b]thiopyrano[4,3-d]pyridine-2-carboxamide
(3b). Yellow
crystals from ethanol; Yield (1.8 g, 65%); Mp: 174–175 8C; IR (KBr) y (cmꢀ1): 3300, 2990, 1655, 1620; H
NMR 1H NMR (DMSO-d6): d 2.90 (t, 2H, J = 5.6 Hz, H-9), 3.40 (t, 2H, J = 5.6 Hz, H-8), 3.60 (s, 2H, H-6), 3.85 (s,
3H, OCH3), 5.00 (s, 2H, NH2), 6.70 (s, 2H, CONH2); Calcd. (%) for C12H13N3O3S (279.30): C; 51.60, H; 4.69, N;
15.04. Found: C; 51.18, H; 4.33, N; 14.80.
1
1.2.1.2. 3,4-Dihydro-6-(hydrazinocarbonylmethyl)-oxy-8-methoxy-1H-thiopyrano[3,4-c]pyridine-5-carbonitrile
(4). A mixture of 2a (1 g, 0.015 mol) and hydrazine hydrate (2 mL) in ethanol (20 mL) was refluxed for 15 min. The
reaction mixture was cooled at room temperature. The product was collected by filtration, recrystallized from ethanol
to give (0.64 g, 68%) of 4 as colorless crystals. Mp: 193–194 8C; IR (KBr) y (cmꢀ1): 3300, 2990, 2200, 1680, 1580; 1H
NMR (CDCl3): d 2.85 (t, 2H, J = 5.6 Hz, H-4), 3.10 (t, 2H, J = 5.6 Hz, H-3), 3.60 (s, 2H, H-1), 3.65 (s, 3H, OCH3),
4.29 (s, 2H, NH2), 4.65 (s, 2H, OCH2), 9.40 (s, 1H, NH2); 13C NMR (CDCl3): d 22.99 (t, C-4), 23.57 (t, C-3), 29.08 (s,
C-1), 54.18 (OCH3), 68.54 (OCH2), 86.69 (s, C-5), 110.69 (C-8a), 114.55 (s, CN), 152.74 (C-4a), 160.78 (C-8), 161.18
(C-6), 162.92 (s, C O); Calcd. (%) for C12H14N4O3S (294.33): C; 48.96, H; 4.79, N; 19.03. Found: C; 48.80, H; 4.57,
N; 18.90.
1.2.1.3. 1-Amino-8,9-dihyro-5-methoxy-6H-furo[2,3-b]thiopyrano[4,3-d]pyridine-2-carboxylic acid hydrazide
(5). Method A: A mixture of 2a (0.3 g, 0.001 mol) and hydrazine hydrate (2 mL, 80%) was refluxed in ethanol
(5 mL) for 2 h. After cooling the separated solid product filtered off washed with ethanol to give (0.24 g, 82.7%) of 5.
Mp: 248-250 8C; IR (KBr) y (cmꢀ1): 3400, 3300, 2980, 1660, 1620; 1H NMR (DMSO-d6): d 2.90 (t, 2H, J = 5.6 Hz,

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H-9), 3.30 (t, 2H, J = 5.6 Hz, H-8), 3.60 (s, 2H, H-6), 3.85 (s, 3H, OCH3), 4.30 (s, 2H, NH2), 5.70 (s, 2H, CONH2), 9.20
(s, 1H, NH); 13C NMR (DMSO-d6): d 22.96 (t, C-9), 23.69 (t, C-8), 27.02 (s, C-6), 54.12 (OCH3), 106.39 (C-1), 112.46
(s, C-5a), 123.70 (C-9b), 136.26 (s, C-9a), 143.96 (s, C-2), 155.28 (s, C-3a), 159.83 (s, C-5), 161.08 (s, C O); Calcd.
(%) for C12H14N4O3S (294.32): C; 48.96, H; 4.79, N; 19.03. Found: C; 48.80, H; 4.67, N; 18.90.
Method B: Compound 5 obtained from 4 in 85% yield, was spectroscopic ally equivalent with the material
separated in method A.
1.2.1.4. 9-Amino-1,4-dihyro-5-methoxy-2H-thiopyrano[400,300:40,50]pyrido[30,20:4,5]furo[3,2-d]pyrimidine-8(9H)-
one (6). A mixture of 5 (0.3 g, 0.001 mol) and ethyl orthoformate (0.2 g, 0.0017 mol) was heated at 180 8C. The
initial melt solidified, triturating and recrystallization of the solid product from aqueous DMF yielded 0.22 g (72.4%)
of compound 6. Mp: 290–291 (Lit. [19], Mp: 294–296).
1.2.1.5. 1,4-Dihyro-5-methoxy-2H-thiopyrano[400,300:40,50]pyrido[30,20:4,5]furo[3,2-d]pyrimidine-8(9H)-one
(7). Method A: A suspension of compound 6 (0.29 g, 0.001 mol) in 50% aqueous acetic acid (5 mL) was warmed to
45–50 8C and then treated with sodium nitrite (0.14 g, 0.002 mol) in portions. The mixture was heated at 45–50 8C
until the evolution of all nitrogen gases ceased. The resulting solution was cooled and diluted with water. The solid
product was purified by dissolving in 10% sodium hydroxide solution (3 mL), precipitated by HCl followed and
recrystallized from aqueous DMF to give colorless crystals of compound 7. Yield (0.17 g, 59%). Mp: 310 8C
(decomp.); IR (KBr) y (cmꢀ1): 2980, 1680, 1640, 1600, 1580; 1H NMR (DMSO-d6): d 2.90 (t, 2H, J = 5.6 Hz, H-1),
3.40 (t, 2H, J = 5.6 Hz, H-2), 3.60 (s, 2H, H-4), 4.10 (s, 3H, OCH3), 8.10 (s, 1H, NH), 12.80 (s, 1H, H-10); Calcd. (%)
for C13H11N3O3S (289.31): C; 53.96, H; 3.83, N; 14.52. Found: C; 53.80, H; 3.68, N; 14.29.
Method B: Compound 7 separated from 3b in 86% yield is identical in all aspects with that obtained above.
1.2.1.6. 8-Amino-1,4-dihyro-5-methoxy-2H-thiopyrano[400,300:40,50]pyrido[30,20:4,5]furo[3,2-d]pyrimidine (8). A
mixture of 3c (0.6 g, 0.0023 mol) formamide (5 mL) and formic acid (3 ml) in DMF (5 mL) was refluxed for 8 h
then cooled at room temperature. The resulting solid product was collected by filtration and recrystallized from
methanol to yield 0.5 g (86.3%) of 8 as brown crystals. Mp: 318 8C (decomp.); IR (KBr) y (cmꢀ1): 3300, 2980, 1680,
1640, 1600; 1H NMR (DMSO-d6): d 2.90 (t, 2H, J = 5.6 Hz, H-1), 3.30 (t, 2H, J = 5.6 Hz, H-2), 3.55 (s, 2H, H-4), 4.10
(s, 3H, OCH3), 6.80 (bs, 2H, NH2), 8.40 (s, 1H, H-10); Calcd. (%) for C13H12N4O2S (288.33): C; 54.15, H; 4.20, N;
19.43. Found: C; 54.02, H; 4.06, N; 19.29.
1.2.1.7. Arylideneamino-1,4-dihyro-5-methoxy-2H-thiopyrano[400,300:40,50]pyrido[30,20:4,5]furo[3,2-d]pyrimidine-
8(9H)-one (9a,b). A mixture of 6 (0.3 g, 0.001 mol) and aromatic aldehydes (0.001 mol) in ethanol (10 mL) in
presence of catalytic amount of piperidine was refluxed for 30 min. The reaction mixture was concentrated to one-half
of its volume then cooled. The solid crystals collected and recrystallized from appropriate solvent.
1.2.1.8. 9-Benzylideneamino-1,4-dihyro-5-methoxy-2H-thiopyrano[400,300:40,50]pyrido[30,20:4,5]furo[3,2-d]-pyrimi-
dine-8(9H)-one (9a). Yellow crystals from methanol; Yield (0.28 g, 70%); Mp: 194–196 8C; IR (KBr) y (cmꢀ1):
3000, 2980, 1700, 1600, 1580; 1H NMR (DMSO-d6): d 2.83 (t, 2H, J = 5.6 Hz, H-1), 3.20 (t, 2H, J = 5.6 Hz, H-2), 3.50
(s, 2H, H-4), 4.20 (s, 3H, OCH3), 7.60–7.80 (m, 5H, Ar-H), 8.40 (s, 1H, H-10), 9.30 (s, 1H, CH N); Calcd. (%) for
C20H16N4O3S (392.44): C, 61.21, H; 4.11, N; 14.28. Found: C; 61.04, H; 3.95, N; 14.12.
1.2.1.9. 9-Substituted-aminomethyl-1,4-dihyro-5-methoxy-2H-thiopyrano[400,300:40,50]pyrido[30,20:4,5]furo[3,2-d]-
pyrimidine (10a,b). To a mixture of 7 (0.3 g, 0.001 mol), and secondary amine (0.001 mol), formaldehyde (5 mL)
was added. The reaction mixture was stirred at 10–15 8C for 30 min. The separated solid product was filtered off,
washed with petroleum ether and recrystallized from methanol.
1.2.1.10. 9-Piperidine-aminomethyl-1,4-dihyro-5-methoxy-2H-thiopyrano[400,300:40,50]pyrido[30,20:4,5]furo[3,2-d]-
pyrimidine (10a). Pale yellow crystals; Yield (0.3 g, 80%); Mp: 124–126 8C; IR (KBr) y (cmꢀ1): 2985, 1690, 1610,
1580; H NMR (DMSO-d6): d 1.65–1.85 (m, 6H), 2.7-2.85 (m, 4H), 2.95 (t, 2H, J = 5.6 Hz, H-1), 3.30 (t, 2H,
1
J = 5.6 Hz, H-2), 3.55 (s, 2H, H-4), 4.10 (s, 3H, OCH3), 5.15 (s, 2H, CH2), 8.40 (s, 1H, H-10); Calcd. (%) for
C19H22N4O3S (386.48): C; 59.05, H; 5.74, N; 14.50. Found: C; 58.88, H; 5.53, N; 14.32.

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