Heterocyclizations of functionalized heterocumulenes with C,N-, C,O-, and C,S-binucleophiles: XII. Synthesis of alkyl 3-aryl-1,5-dioxo-2,3,5,6-tetrahydro- 1H-pyrimido-[1,6-a]quinoxaline-4-carboxylates

Article abstract of DOI:10.1134/S1070428010060187

Alkyl 3-oxo-1,2,3,4-tetrahydroquinoxalin-2-ylideneacetates reacted with α-chlorobenzyl isocyanates to give alkyl 3-aryl-1,5-dioxo-2,3,5,6- tetrahydro-1H-pyrimido[1,6-a]quinoxaline-4-carboxylates.

Full text of DOI:10.1134/S1070428010060187

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2010, Vol. 46, No. 6, pp. 890–893. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © O.V. Kushnir, M.V. Vovk, 2010, published in Zhurnal Organicheskoi Khimii, 2010, Vol. 46, No. 6, pp. 894–897.
Heterocyclizations of Functionalized Heterocumulenes
with C,N-, C,O-, and C,S-Binucleophiles: XII.* Synthesis
of Alkyl 3-Aryl-1,5-dioxo-2,3,5,6-tetrahydro-1H-pyrimido-
[1,6-a]quinoxaline-4-carboxylates
O. V. Kushnira and M. V. Vovkb
a Fed’kovich Chernovtsy National University, Chernovtsy, Ukraine
b Institute of Organic Chemistry, National Academy of Sciences of Ukraine,
ul. Murmanskaya 5, Kiev, 02660 Ukraine
e-mail: mvovk@i.com.ua
Received June 9, 2009
Abstract—Alkyl 3-oxo-1,2,3,4-tetrahydroquinoxalin-2-ylideneacetates reacted with α-chlorobenzyl isocy-
anates to give alkyl 3-aryl-1,5-dioxo-2,3,5,6-tetrahydro-1H-pyrimido[1,6-a]quinoxaline-4-carboxylates.
DOI: 10.1134/S1070428010060187
Alkyl 3-oxo-1,2,3,4-tetrahydroquinoxalin-2-ylidene-
acetates Ia and Ib are preparatively accessible poly-
functionalized compounds [2, 3] and are important as
building blocks in heterocyclic chemistry. The en-
amino fragment therein was successfully involved in
both functionalization of the quinoxaline ring [4–6]
and synthesis of fused quinoxaline derivatives. Syn-
thetic approaches to the latter are based on reactions
with mono- and difunctional electrophilic reagents,
which make it possible to obtain furo[2,3-b]quinoxa-
line [4, 7], pyrrolo[1,2-a]quinoxaline [8, 9], and pyrido-
[1,2-a]quinoxaline derivatives [3, 10]; many of these
compounds exhibited pronounced pharmacological
activity [10–14]. On the other hand, structurally related
pyrimido[1,6-a]quinoxaline heterocyclic system re-
mains so far poorly studied. We have found only one
publication on the synthesis of 1H-pyrimido[1,6-a]-
quinoxaline-1,3(2H)-dione 3-oxime via Curtius rear-
rangement of 2-(hydroxyimino)-3-(quinoxalin-2-yl)-
propanoyl azide [15]. Taking into account previously
revealed general relations holding in the formation of
partly hydrogenated pyrimidine ring by condensation
of deactivated enamines with α-chlorobenzyl isocy-
anates [16, 17], in the present work we made an at-
tempt to use the latter for the preparation of polyfunc-
tional pyrimido[1,6-a]quinoxaline derivatives.
ylene chloride to give alkyl 3-aryl-1,5-dioxo-2,3,5,6-
tetrahydro-1H-pyrimido[1,6-a]quinoxaline-4-carbox-
ylates ІІІa–IIIi in 51–73% yield. Most probably, the
reaction involves benzylidenecarbamic chloride form
[18] of α-chlorobenzyl isocyanates ІІ, which adds at
the exocyclic carbon atom in quinoxaline I with forma-
tion of intermediate A. The latter undergo intramolec-
ular cyclization as a result of attack by the chloro-
carbamoyl group on the enamino nitrogen atom
(Scheme 1). The reaction in toluene at room tempera-
ture in the presence of an organic base was less effec-
tive. The yield of the target products was sharply
reduced due to considerable tarring. Presumably, the
reaction under these conditions was accompanied by
side condensation with participation of the NHC(O)
fragment in the quinoxaline ring. Compound Іa is
known to react with common alkyl isocyanates to give
products of C-carbamoylation of the methoxycarbonyl-
methylene fragment, which are then converted into
3-carbamoylfuro[2,3-b]quinoxalines via intramolecular
condensation of the 3-methoxycarbonylmethylene
fragment with the carbonyl group in position 2 of the
heteroring [19].
The structure of compounds ІІІa–IIIi was con-
1
firmed by the IR and H and 13C NMR spectra, and
their purity was checked by GC–MS. In the IR spectra
of ІІІa–IIIi we observed absorption bands typical of
stretching vibrations of amide (1635–1650 cm–1),
ureide (1695–1705 cm–1), and ester carbonyl groups
Quinoxalinones Ia and Ib reacted with α-chloro-
benzyl isocyanates ІІa–IIe on heating in boiling meth-
* For communication XI, see [1].
890

HETEROCYCLIZATIONS OF FUNCTIONALIZED HETEROCUMULENES ... XII.
891
Scheme 1.
H
N
O
Cl
Cl
O
O
+
·
Ar
N
Ar
N
O
N
H
OAlk
Ia, Ib
IIa–IIe
H
H
N
O
N
O
O
O
N
H
OAlk
N
OAlk
H
–HCl
O
N
H
Ar
O
N
Ar
H
Cl
A
IIIa–IIIi
І, Alk = Me (a), Et (b); ІІ, Ar = Ph (a), 2-FC6H4 (b), 3-BrC6H4 (c), 4-O2NC6H4 (d), 3,4-Cl2C6H3 (e); ІІІ, Alk = Me, Ar = Ph (a),
2-FC6H4 (b), 3-BrC6H4 (c), 4-O2NC6H4 (d), 3,4-Cl2C6H3 (e); Alk = Et, Ar = Ph (f), 2-FC6H4 (g), 3-BrC6H4 (h), 3,4-Cl2C6H3 (i).
(1735–1750 cm–1), as well as of N–H groups (3220–
J = 2.0 Hz), 7.03–7.10 m (3H, Harom), 7.31–7.43 m
(5H, Harom), 7.81 d (1H, Harom, J = 6.5 Hz), 8.59 d (1H,
2-H, J = 2.0 Hz), 11.22 s (1H, 6-H). 13C NMR spec-
trum, δC, ppm: 52.29 (CH3), 54.29 (C3), 115.86 (C4),
116.91, 120.88, 122.56, 123.25, 124.08, 125.93, 126.77,
128.19, 128.31, 128.86 (Carom), 139.86 (C4a), 151.24
(C1), 155.97 (C5), 168.98 (4-C=O). Mass spectrum:
m/z 350 [M + 1]+. Found, %: C 65.81; H 4.18; N 11.89.
C19H15N3O4. Calculated, %: C 65.32; H 4.33; N 12.03.
M 349.3.
1
3245 cm–1). The H NMR spectra of ІІІa–IIIi con-
tained doublets from the 3-H and 2-H protons in the
regions δ 5.13–5.37 and 8.51–8.81 ppm, respectively,
3
the coupling constant J2,3 being equal to 2.0–4.5 Hz.
13
The C3 signal appeared in the C NMR spectra in the
region δC 52–61 ppm, which is typical of 3,4-dihydro-
pyrimidinones [17].
EXPERIMENTAL
Methyl 3-(2-fluorophenyl)-1,5-dioxo-2,3,5,6-
tetrahydro-1H-pyrimido[1,6-a]quinoxaline-4-car-
boxylate (IIІb). Yield 51%, mp 268–270°C. IR spec-
trum, ν, cm–1: 3230 (NH); 1745, 1705, 1640 (C=O).
1H NMR spectrum, δ, ppm: 3.63 s (3H, CH3), 5.37 d
(1H, 3-H, J = 3.6 Hz), 7.02–7.36 m (7H, Harom), 7.86 d
(1H, Harom, J = 6.9 Hz), 8.51 d (1H, 2-H, J = 3.6 Hz),
11.23 s (1H, 6-H). 13C NMR spectrum, δC, ppm: 49.82
(CH3), 52.28 (C3), 115.23 (C4), 115.88, 120.82, 122.64,
123.30, 124.08, 125.09, 126.69, 126.84, 127.80, 128.54,
130.48 (Carom), 130.54 (C4a), 151.17 (C1), 155.85 (C5),
159.35 d (C–F, J = 246.5 Hz), 166.65 (4-C=O). Mass
spectrum: m/z 368 [M + 1]+. Found, %: C 61.81;
H 3.68; N 11.57. C19H14FN3O4. Calculated, %:
C 62.12; H 3.84; N 11.44. M 367.3.
The IR specta were recorded in KBr on a UR-20
1
spectrometer. The H and 13C NMR spectra were
measured from solutions in DMSO-d6 on a Bruker
Avance DRX-500 spectrometer (500.13 and
125.75 MHz, respectively) using tetramethylsilane as
internal reference. The mass spectra were obtained on
an Agilent 1100/DAD/HSD/VLG 119562 instrument.
Initial α-chlorobenzyl isocyanates ІIa–IIe were syn-
thesized according to the procedure described in [17] .
Alkyl 3-aryl-1,5-dioxo-2,3,5,6-tetrahydro-1H-
pyrimido[1,6-a]quinoxaline-4-carboxylates ІІІa–IIIi
(general procedure). α-Chlorobenzyl isocyanate ІІa–
IIe, 2.5 mmol, was added to a solution of 2.5 mmol of
quinoxaline Іa or Ib in 20 ml of methylene chloride,
and the mixture was heated for 3 h under reflux. The
mixture was cooled, and the precipitate was filtered
off, dried, and recrystallized from ethanol.
Methyl 3-(3-bromophenyl)-1,5-dioxo-2,3,5,6-
tetrahydro-1H-pyrimido[1,6-a]quinoxaline-4-car-
boxylate (ІІІc). Yield 63%, mp 285–288°C. IR spec-
trum, ν, cm–1: 3230 (NH); 1750, 1695, 1645 (C=O).
1H NMR spectrum, δ, ppm: 3.70 s (3H, CH3), 5.19 d
(1H, 3-H, J = 2.0 Hz), 6.99–7.05 m (3H, Harom), 7.16–
7.51 m (4H, Harom), 7.79 d (1H, Harom, J = 6.6 Hz),
8.62 d (1H, 2-H, J = 2.0 Hz), 11.21 s (1H, 6-H).
Methyl 1,5-dioxo-3-phenyl-2,3,5,6-tetrahydro-
1H-pyrimido[1,6-a]quinoxaline-4-carboxylate
(ІІІa). Yield 58%, mp 276–278°C. IR spectrum, ν,
1
cm–1: 3220 (NH); 1745, 1700, 1645 (C=O). H NMR
spectrum, δ, ppm: 3.68 s (3H, CH3), 5.14 d (1H, 3-H,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 6 2010

KUSHNIR, VOVK
892
13C NMR spectrum, δ, ppm: 52.34 (CH3), 53.40 (C3),
115.92 (C4), 116.01, 120.92, 121.95, 122.55, 123.10,
124.18, 125.01, 126.84, 128.38, 128.71, 129.09, 131.06
(Carom), 142.55 (C4a), 151.18 (C1), 155.91 (C5), 166.79
(4-C=O). Mass spectrum: m/z 429 [M + 1]+. Found, %:
C 53.03; H 3.38; N 9.89. C19H14Br N3O4. Calculated,
%: C 53.29; H 3.30; N 9.81. M 428.2.
(4-C=O). Mass spectrum: m/z 364 [M + 1]+. Found, %:
C 65.89; H 4.58; N 11.69. C20H17N3O4. Calculated, %:
C 66.11; H 4.72; N 11.56. M 363.4.
Ethyl 3-(2-fluorophenyl)-1,5-dioxo-2,3,5,6-tetra-
hydro-1H-pyrimido[1,6-a]quinoxaline-4-carbox-
ylate (ІІІg). Yield 58%, mp 280–282°C. IR spectrum,
ν, cm–1: 3230 (NH); 1745, 1705, 1645 (C=O). 1H NMR
spectrum, δ, ppm: 1.16 t (3H, CH3, J = 6.5 Hz), 4.12 d
(1H, CH2, J = 6.5 Hz), 5.37 d (1H, 3-H, J = 3.5 Hz),
7.03–7.39 m (7H, Harom), 7.91 d (1H, Harom, J =
7.2 Hz), 8.47 d (1H, 2-H, J = 3.5 Hz), 11.21 s (1H,
6-H). 13C NMR spectrum, δC, ppm: 13.54 (CH3), 49.91
(CH2), 60.87 (C3), 115.38 (C4), 115.84, 120.79, 123.34,
124.04, 125.04, 126.71, 126.89, 127.81, 128.15, 130.45
(Carom), 130.58 (C4a), 151.19 (C1), 155.88 (C5), 159.32 d
(C–F, J = 244.8 Hz), 166.98 (4-C=O). Mass spectrum:
m/z 382 [M + 1]+. Found, %: C 63.21; H 4.28; N 10.87.
C20H16 FN3O4. Calculated, %: C 62.99; H 4.23;
N 11.02. M 381.4.
Methyl 3-(4-nitrophenyl)-1,5-dioxo-2,3,5,6-tetra-
hydro-1H-pyrimido[1,6-a]quinoxaline-4-carbox-
ylate (ІІІd). Yield 60%, mp 295–296°C. IR spectrum,
ν, cm–1: 3225 (NH); 1750, 1705, 1650 (C=O). 1H NMR
spectrum, δ, ppm: 3.70 s (3H, CH3), 5.36 d (1H, 3-H,
J = 4.5 Hz), 6.97–7.02 m (3H, Harom), 7.63–7.81 m
(3H, Harom), 8.16 d (1H, Harom, J = 8.7 Hz), 8.30 s (1H,
Harom), 8.81 d (1H, 2-H, J = 4.5 Hz), 11.29 s (1H, 6-H).
13C NMR spectrum, δC, ppm: 52.10 (CH3), 52.51 (C3),
115.45 (C4), 115.87, 121.05, 123.04, 123.76, 124.08,
128.81, 130.16, 131.22, 135.18, 135.98 (Carom), 140.33
(C4a), 149.87 (C1), 154.05 (C5), 165.62 (4-C=O). Mass
spectrum: m/z 394 [M + 1]+. Found, %: C 58.08;
H 3.41; N 14.00. C19H14N4O4. Calculated, %: C 57.87;
H 3.58; N 14.21. M 394.3.
Ethyl 3-(3-bromophenyl)-1,5-dioxo-2,3,5,6-tetra-
hydro-1H-pyrimido[1,6-a]quinoxaline-4-carbox-
ylate (ІІІh). Yield 65%, mp 294–296°C. IR spectrum,
ν, cm–1: 3240 (NH); 1750, 1700, 1645 (C=O). 1H NMR
spectrum, δ, ppm: 1.22 t (3H, CH3, J = 6.5 Hz), 4.17 d
(1H, CH2, J = 6.5 Hz), 5.21 d (1H, 3-H, J = 3.0 Hz),
7.00–7.06 m (3H, Harom), 7.34 m (1H, Harom), 7.55–
7.60 m (2H, Harom), 7.80 d (1H, Harom, J = 7.6 Hz),
8.66 d (1H, 2-H, J = 3.0 Hz), 11.25 s (1H, 6-H).
13C NMR spectrum, δC, ppm: 13.49 (CH3), 51.74
(CH2), 53.55 (C3), 115.73 (C4), 115.77, 120.90, 121.84,
122.65, 123.18, 124.03, 125.12, 126.69, 128.48, 128.72,
129.03, 131.15 (Carom), 142.54 (C4a), 151.06 (C1),
155.94 (C5), 166.63 (4-C=O). Mass spectrum: m/z 442
[M + 1]+. Found, %: C 54.07; H 3.58; N 9.39.
C20H16BrN3O4. Calculated, %: C 54.32; H 3.65;
N 9.50. M 442.3.
Methyl 3-(3,4-dichlorophenyl)-1,5-dioxo-2,3,5,6-
tetrahydro-1H-pyrimido[1,6-a]quinoxaline-4-car-
boxylate (ІІІe). Yield 73%, mp 287–288°C. IR spec-
trum, ν, cm–1: 3240 (NH); 1735, 1700, 1640 (C=O).
1H NMR spectrum, δ, ppm: 3.68 s (3H, CH3), 5.19 d
(1H, 3-H, J = 4.2 Hz), 6.97–7.03 m (3H, Harom), 7.32 d
(1H, Harom, J = 7.2 Hz), 7.55–7.61 m (2H, Harom),
7.76 d (1H, Harom, J = 7.5 Hz), 8.68 d (1H, 2-H, J =
4.2 Hz), 11.26 s (1H, 6-H). 13C NMR spectrum, δC,
ppm: 52.85 (CH3), 53.08 (C3), 115.63 (C4), 115.93,
121.12, 121.87, 122.58, 123.90, 124.64, 125.31, 127.29,
128.43, 128.80, 129.66, 131.92 (Carom), 141.85 (C4a),
151.44 (C1), 155.77 (C5), 166.35 (4-C=O). Mass spec-
trum: m/z 418 [M + 1]+. Found, %: C 54.79; H 3.18;
N 9.91. C19H13Cl2N3O4. Calculated, %: C 54.56;
H 3.13; N 10.05. M 418.2.
Ethyl 3-(3,4-dichlorophenyl)-1,5-dioxo-2,3,5,6-
tetrahydro-1H-pyrimido[1,6-a]quinoxaline-4-car-
boxylate (ІІІi). Yield 68%, mp 284–286°C. IR spec-
trum, ν, cm–1: 3245 (NH); 1740, 1700, 1635 (C=O).
1H NMR spectrum, δ, ppm: 1.22 t (3H, CH3, J =
6.5 Hz), 4.17 d (1H, CH2, J = 6.5 Hz), 5.21 d (1H, 3-H,
J = 3.0 Hz), 7.00–7.06 m (3H, Harom), 7.34 m (1H,
Ethyl 1,5-dioxo-3-phenyl-2,3,5,6-tetrahydro-1H-
pyrimido[1,6-a]quinoxaline-4-carboxylate (ІІІf).
Yield 55%, mp 298–300°C. IR spectrum, ν, cm–1: 3220
1
(NH); 1750, 1700, 1645 (C=O). H NMR spectrum, δ,
ppm: 1.19 t (3H, CH3, J = 6.5 Hz), 4.14 d (1H, CH2,
J = 6.5 Hz), 5.13 d (1H, 3-H, J = 2.5 Hz), 6.99–7.03 m
Harom), 7.55–7.60 m (2H, Harom), 7.80 d (2H, Harom, J =
(3H, Harom), 7.31–7.39 m (5H, Harom), 7.80 d (1H, Harom
,
7.6 Hz), 8.66 d (1H, 2-H, J = 3.0 Hz), 11.25 s (1H,
6-H). 13C NMR spectrum, δC, ppm: 13.40 (CH3), 51.67
(CH2), 53.18 (C3), 115.65 (C4), 115.98, 121.10, 121.67,
122.58, 123.96, 124.69, 125.21, 127.30, 128.48, 128.81,
129.70, 131.96 (Carom), 141.88 (C4a), 151.45 (C1),
155.72 (C5), 166.44 (4-C=O). Mass spectrum: m/z 433
J = 7.0 Hz), 8.57 d (1H, 2-H, J = 2.5 Hz), 11.21 s (1H,
6-H). 13C NMR spectrum, δC, ppm: 13.61 (CH3), 54.44
(CH2), 60.91 (C3), 115.82 (C4), 117.34, 120.86, 122.55,
123.29, 124.05, 125.93, 126.79, 127.97, 128.18, 128.82
(Carom), 139.85 (C4a), 151.27 (C1), 155.98 (C5), 166.38
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 6 2010

HETEROCYCLIZATIONS OF FUNCTIONALIZED HETEROCUMULENES ... XII.
893
[M + 1]+. Found, %: C 55.69; H 3.63; N 9.51.
C19H13Cl2N3O4. Calculated, %: C 55.57; H 3.50;
N 9.72. M 432.3.
10. Trapani, G., Latrofa, A., Franko, M., and Liso, G.,
Farmaco, 1990, vol. 45, p. 589.
11. Ager, J.R., Barnes, A.C., Danswan, G.W., Hair-
sine, D.W., Kay, D.P., Kennewell, P.D., Matharu, S.S.,
Miller, P., Robson, P., Rowlands, D.A., Tully, W.R., and
Westwood, R., J. Med. Chem., 1988, vol. 31, p. 1098.
REFERENCES
1. Vovk, M.V., Kushnir, O.V., Sukach, V.A., and Tsym-
bal, I.F., Russ. J. Org. Chem., 2010, vol. 46, p. 709.
2. Kawahara, N., Nakajima, T., Itoh, T., and Ogura, H.,
12. Mashevskaya, I.V., Makhmudov, R.R., Aleksandro-
va, G.A., Kudinova, O.S., Kol’tsova, S.V., Golene-
va, A.F., and Maslivets, A.N., Khim.-Farm. Zh., 2000,
vol. 34, p. 13.
Heterocycles, 1983, vol. 20, p. 1721.
13. Mashevskaya, I.V., Makhmudov, R.R., Aleksandro-
va, G.A., Duvalov, A.V., and Maslivets, A.I., Khim.-
Farm. Zh., 2001, vol. 35, p. 11.
3. Kawahara, N., Shimamori, T., Itoh, T., Takayanagi, H.,
and Ogura, H., Chem. Pharm. Bull., 1987, vol. 35, p. 457.
4. Kurasawa, Y., Moritaki, Y., Ebukuro, T., and Takada, A.,
14. Mashevskaya, I.V., Makhmudov, R.R., Aleksandro-
va, G.A., Golovnina, O.V., Duvalov, A.V., and Masli-
vets, A.I., Khim.-Farm. Zh., 2001, vol. 35, p. 20.
Chem. Pharm. Bull., 1983, vol. 31, p. 3897.
5. Kurasawa, Y., Muramatsu, M., Hotehama, K., Okamo-
to, K., and Takada, A., J. Heterocycl. Chem., 1985,
vol. 22, p. 1711.
15. Golankewicz, K., Bull. Acad. Pol. Sci., 1964, vol. 12,
p. 459.
6. Arai, K., Okamoto, Y., and Takada, A., J. Heterocycl.
Chem., 1987, vol. 24, p. 1229.
16. Vovk, M.V. and Sukach, V.A., Russ. J. Org. Chem.,
2005, vol. 41, p. 1240.
7. Kurasawa, Y. and Takada, A., Chem. Pharm. Bull., 1981,
17. Sukach, V.A., Bol’but, A.V., Sinitsa, A.D., and
vol. 29, p. 2871.
Vovk, M.V., Synlett, 2006, p. 375.
8. Maslivets, A.N., Golovnina, O.V., Krasnykh, O.P., and
18. Gorbatenko, V.I. and Samarai, L.I., Synthesis, 1980,
Aliev, Z.G., Khim. Geterotsikl. Soedin., 2000, p. 113.
p. 85.
9. Maslivets, A.N., Aliev, Z.G., Krasnykh, O.P., Golovni-
na, O.V., and Atovmyan, L.O., Khim. Geterotsikl.
Soedin., 2004, p. 1501.
19. Okawara, T., Matsumoto, S., Eto, M., Harano, K., and
Furukura, M., Heterocycles, 1995, vol. 41, p. 1951.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 6 2010