Synthesis of hexa- and octahydropyrido[3′2′:4,5]thieno[3,2-d]pyrimidines

Article abstract of DOI:10.1023/A:1023033027915

The reaction of N-methylmorpholinium 4-(2-chlorophenyl)-5-cyano-2-oxo-1,2,3,4-tetrahydropyridine-6-thiolate with chloroacetamide in DMF in the presence of an excess of KOH gave 3-amino-2-carbamoyl-4-(2-chlorophenyl)-6-oxo-4,5,6,7-tetrahydrothieno[2, 3-b]pyridine. Refluxing the latter with acyl chlorides in AcOH or heating in formic acid gave hexahydropyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine derivatives and reaction with cyclohexanone gave a spiro-linked octahydropyrido[3′2′:4,5]thieno[3,2-d]pyrimidine.

Full text of DOI:10.1023/A:1023033027915

Chemistry of Heterocyclic Compounds, Vol. 39, No. 1, 2003
SYNTHESIS OF HEXA- AND OCTAHYDRO-
d
PYRIDO[3'2':4,5]THIENO[3,2- ]PYRIMIDINES*
V. V. Dotsenko1, S. G. Krivokolysko1, and V. P. Litvinov2
The reaction of N-methylmorpholinium 4-(2-chlorophenyl)-5-cyano-2-oxo-1,2,3,4-tetrahydropyridine-6-
thiolate with chloroacetamide in DMF in the presence of an excess of KOH gave 3-amino-2-carbamoyl-
4-(2-chlorophenyl)-6-oxo-4,5,6,7-tetrahydrothieno[2,3-b]pyridine. Refluxing the latter with acyl
chlorides in AcOH or heating in formic acid gave hexahydropyrido[3',2':4,5]thieno[3,2-d]pyrimidine
derivatives and reaction with cyclohexanone gave a spiro-linked octahydropyrido[3',2':4,5]thieno-
[3,2-d]pyrimidine.
Keywords: tetrahydropyridinethiolate, thienopyridine, partially hydrogenated pyridothienopyrimidines,
cyclization.
Substituted 4,7-dihydrothieno[2,3-b]pyridines and their dehydrogenated analogs have been successfully
used previously as starting reagents in the synthesis of polycondensed heterocycles, including
pyrido[3',2':4,5]thieno[3,2-d]pyrimidines [1-3]. Amongst compounds with a similar structure there have been
discovered substances with antianaphylactic [4, 5] and antimicrobial [6] activity. With this in mind, the
development of convenient methods for the synthesis of such compounds seems timely and promising.
In continuation of our study of the chemical properties of tetrahydropyridones [7, 8] and based on the
tetrahydropyridinethiolate 1 we have carried out the synthesis of the substituted tetrahydrothieno[2,3-b]pyridine
2. By further reaction it is transformed to the previously unknown partially hydrogenated
pyrido[3',2':4,5]thieno[3,2-d]pyrimidines.
Hence the reaction of salt 1 with chloroacetamide in the presence of an excess of 10% KOH solution in
DMF gives a 91% yield of the target product 2. The latter reacts with excess acetyl chloride or chloroacetyl
chloride when refluxed in glacial AcOH to form the condensed structures 3a,b. The reaction of compound 2
with cyclohexanone gives a 65.5% yield of octahydropyrido[3',2':4,5]thieno[3,2-d]pyrimidine 4. Reaction of the
thienopyridone 2 with 99% formic acid leads to the formation of compound 3c via a sequence of N-formylation
and cyclization processes.
The IR spectra of the synthesized compounds show absorption bands for the stretching vibrations of the
amino (for 2) and imino groups (for 2-4) in the range 3550-3150 cm-1. The signals for the carbonyl groups are
1
seen in the range 1655-1680 cm-1. The H NMR spectra of all of the synthesized samples show characteristic
bands for the CH(Ar)–CH2 fragment of the tetrahydropyridine ring [7, 9] as three double doublets for CH2
(δ 2.59-2.64 and 3.05-3.17 ppm) and CH (δ 4.54-4.87 ppm). In a number of examples the signals for the
_______
* Dedicated to Professor Salo Gronowitz on the occasion of his anniversary.
__________________________________________________________________________________________
1 East-Ukrainian National University, Lugansk 91034, Ukraine; e-mail: ksg@lep.lg.ua. 2 N. D. Zelinsky
Institute of Organic Chemistry, Russian Academy of Sciences, Moscow 117913, Russia; e-mail: vpl@ioc.ac.ru.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 117-119, January, 2003. Original article
submitted November 4, 2002.
110
0009-3122/03/3901-0110$25.00©2003 Plenum Publishing Corporation

indicated protons appear as broadened pseudo doublets. From a number of signals confirming the
pyridothienopyrimidine structure in compounds 3a-c the most diagnostic are the singlet for the N(3)H group
proton (δ 12.24-12.67 ppm) and the corresponding signals for the other substituents. The presence of the
pyrimidine fragment in the structure of compound 4 is confirmed by the multiplet in the range δ 1.11-1.87 ppm
((CH2)5) and the singlets for the NH groups (δ 10.81, 7.15, and 6.16 ppm).
Cl
Cl
NH2
NH2
CN
ClCH2C(O)NH2
_
CH3
NH
O
N
H
2
KOH, DMF
S
O
N
H
S
+
O
1
AcOH,
O
RC(O)Cl
AcOH,
∆
∆
O
Cl
Cl
N
R
H
N
NH
O
N
H
S
NH
O
N
S
H
O
3a–c
O
HCOOH
4
2
∆
3 a R = Me; b R = CH2Cl; c R = H
EXPERIMENTAL
1H NMR spectra were taken on a Gemini 200 instrument (200 MHz) using DMSO-d6 and TMS as
internal standard. IR spectra were obtained on an IKS-29 spectrophotometer and elemental analysis was
performed on a Perkin-Elmer C,H,N analyser. The course of the reaction and purity of the materials were
monitored using TLC on Silufol UV-254 with acetone–heptane (1:1) as eluent. Melting points were measured
on Koffler stage.
b
3-Amino-2-carbamoyl-4-(2-chlorophenyl)-6-oxo-4,5,6,7-tetrahydrothieno[2,3- ]pyridine (2).
Aqueous KOH solution (10%, 23 ml, 41 mmol) was added to a solution of the thiolate 1 (15 g, 41 mmol) in
DMF (60 ml). The mixture was taken to reflux and passed through filter paper into a solution of
chloroacetamide (4 g, 43 mmol) in DMF (20 ml). The reaction mass was stirred for 12 h, a further 23 ml of the
10% KOH was added, the stirring was continued at reflux for 10 min, and after 48 h it was diluted with water to
a volume of 230 ml and held for 7 days. The precipitate was filtered off and washed with water and ethanol.
Yield 12 g (91%); mp 259-261°C (EtOH) as a white, finely crystalline powder. IR spectrum, ν, cm-1: 1670
1
(C=O); 3450, 3265, 3150 (NH2 and CONH2). H NMR spectrum, δ, ppm (J, Hz): 10.71 (1H, s, NH); 6.75-7.44
(4H, m, Ar); 6.47 (2H, br. s, CONH2); 6.16 (2H, br. s, NH2); 4.54 (1H, br. pseudo-d, C(4)H); 3.07 (1H, m, C(5)H);
2.64 (1H, br. pseudo-d, 2J = 15.7, C(5)H). Found, %: C 53.00; H 3.72; N 12.98. C14H12ClN3O2S. Calculated, %:
C 52.26; H 3.76; N 13.06.
d
9-(2-Chlorophenyl)-2-methyl-4,7-dioxo-3,4,6,7,8,9-hexahydropyrido[3',2':4,5]thieno[3,2- ]pyrimidine
(3a). Acetyl chloride (0.44 ml, 6.2 mmol) was added to a suspension of the thienopyridine 2 (1 g, 3.1 mmol) in
AcOH (10 ml) and the mixture was refluxed for 6 h. The precipitate formed was filtered off and washed with
111

ethanol. Yield 0.81 g (75%); mp >300°C as a white, finely crystalline powder. IR spectrum, ν, cm-1: 1660, 1680
(2 C=O); 3420, 3465 (2 NH). 1H NMR spectrum, δ, ppm (J, Hz): 12.24 (1H, br. s, N(3)H); 11.03 (1H, s, N(6)H);
2
6.64-7.46 (4H, m, Ar); 4.80 (1H, br. pseudo-d, C(9)H); 3.15 (1H, m, C(8)H); 2.59 (1H, br. pseudo-d, J = 16.2,
C(8)H); 2.24 (3H, s, Me). Found, %: C 56.50; H 3.60; N 12.12. C16H12ClN3O2S. Calculated, %: C 55.57; H 3.58;
N 12.15.
d
4,7-Dioxo-2-chloromethyl-9-(2-chlorophenyl)-3,4,6,7,8,9-hexahydropyrido[3',2':4,5]thieno[3,2- ]-
pyrimidine (3b) was obtained similarly to product 3a using chloroacetyl chloride (0.49 ml, 6.2 mmol).
Yield 0.98 g (83%); mp >300°C as a white, finely crystalline powder. IR spectrum, ν, cm-1: 1660, 1675
(2 C=O); 3390, 3470 (2 NH). 1H NMR spectrum, δ, ppm (J, Hz): 12.67 (1H, br. s, N(3)H); 11.12 (1H, s, N(6)H);
2
3
6.68-7.48 (4H, m, Ar); 4.86 (1H, br. pseudo-d, C(9)H); 4.38 (2H, s, CH2Cl); 3.17 (1H, dd, J = 16.3, J = 8.1,
2
C(8)H); 2.59 (1H, br. pseudo-d, J = 16.3, C(8)H). Found, %: C 50.98; H 2.93; N 11.01. C16H11Cl2N3O2S.
Calculated, %: C 50.54; H 2.92; N 11.05.
d
4,7-Dioxo-9-(2-chlorophenyl)-3,4,6,7,8,9-hexahydropyrido[3',2':4,5]thieno[3,2- ]pyrimidine (3c).
A solution of the thienopyridine 2 (1 g, 3.1 mmol) in 99% formic acid (10 ml) was refluxed for 20 h and the
mixture was then diluted with water (15 ml). The precipitate formed was filtered off and recrystallized from
AcOH (50 ml). Yield 0.80 g (78%); mp >300°C as a white, finely crystalline powder. IR spectrum, ν, cm-1:
1650, 1665 (2 C=O); 3425, 3480 (2 NH). 1H NMR spectrum, δ, ppm (J, Hz): 12.67 (1H, br. s, N(3)H); 11.07 (1H,
br. s, N(6)H); 7.86 (1H, br. s, C(2)H); 6.67-7.45 (4H, m, Ar); 4.87 (1H, br. pseudo-d, C(9)H); 3.10 (1H, m, C(8)H);
2.61 (1H, br. pseudo-d, 2J = 16.0, C(8)H). Found, %: C 54.91; H 3.01; N 12.60. C15H10ClN3O2S. Calculated, %:
C 54.30; H 3.04; N 12.66.
4,7-Dioxo-9-(2-chlorophenyl)-2-(1'-cyclohexanespiro)-1,2,3,4,6,7,8,9-octahydropyrido[3',2':4,5]-
d
was obtained similarly to pyrimidine
thieno[3,2- ]pyrimidine (4)
3a
using cyclohexanone (1.93 ml,
18.6 mmol) and reflux time of 12 h. Yield 0.78 g (65.5%); mp >300°C as colorless crystals. IR spectrum,
ν, cm-1: 1665, 1680 (2 C=O); 3465, 3435, 3400, 3250 (3 NH). 1H NMR spectrum, δ, ppm (J, Hz): 10.81 (1H, s,
N(6)H); 6.71-7.48 (4H, m, Ar); 7.15 (1H, s, N(3)H); 6.16 (1H, s, N(1)H); 4.61 (1H, br. pseudo-d, C(9)H); 3.05 (1H,
dd, 2J = 16.5, 3J = 7.7, C(8)H); 2.64 (1H, br. pseudo-d, 2J = 16.5, C(8)H); 1.11-1.87 (10H, m, (CH2)5). Found, %:
C 60.09; H 4.97; N 10.41. C20H20ClN3O2. Calculated, %: C 59.77; H 5.02; N 10.45.
This work was carried out with the financial support of the Russian fund for basic research (project
No. 02-03-32063).
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