Three-component synthesis of dimethyl 7-aryl-8-(3-arylquinoxalin-2-yl)-2- (R-imino)-9-oxo-1,6-dioxa-spiro[4.4]nona-3,7-diene-3,4-dicarboxylates

Article abstract of DOI:10.1007/s10593-014-1439-x

We have developed a method for the synthesis of dimethyl 7-aryl-8-(3-arylquinoxalin-2-yl)-2-(R-imino)-9-oxo-1,6-dioxaspiro[4.4]nona-3, 7-diene-3,4-dicarboxylates, based on a three-component reaction of 5-aryl-4-(quinoxalin-2-yl)furan-2,3-diones, 1-adamantylisocyanide or o-methylphenylisocyanide, and dimethyl acetylenedicarboxylate.

Full text of DOI:10.1007/s10593-014-1439-x

Chemistry of Heterocyclic Compounds, Vol. 50, No. 1, April, 2014 (Russian Original Vol. 50, No. 1, January, 2014)
THREE-COMPONENT SYNTHESIS OF DIMETHYL 7-ARYL-
8-(3-ARYLQUINOXALIN-2-YL)-2-(R-IMINO)-9-OXO-1,6-DIOXA-
SPIRO[4.4]NONA-3,7-DIENE-3,4-DICARBOXYLATES
1
1
*
N. Yu. Lisovenko and A. V. Dryahlov
We have developed a method for the synthesis of dimethyl 7-aryl-8-(3-arylquinoxalin-2-yl)-2-(R-imino)-
9-oxo-1,6-dioxaspiro[4.4]nona-3,7-diene-3,4-dicarboxylates, based on a three-component reaction of
5-aryl-4-(quinoxalin-2-yl)furan-2,3-diones, 1-adamantylisocyanide or о-methylphenylisocyanide, and
dimethyl acetylenedicarboxylate.
Keywords: 5-aryl-4-(quinoxalin-2-yl)furan-2,3-diones, dimethyl acetylenedicarboxylate, dimethyl 7-aryl-
8-(3-arylquinoxalin-2-yl)-2-(R-imino)-9-oxo-1,6-dioxaspiro[4.4]nona-3,7-diene-3,4-dicarboxylates,
isocyanides, methyl 2-[5-aryl-4-(quinoxalin-2-yl)-3-oxo-2(3H)-furanylidene]acetate, γ-spiroiminolactones,
multicomponent reaction.
Multicomponent reactions (MCRs) are effective and accessible methods for the synthesis of organic
compounds. The main advantage of this type of reactions is the large number of products that can be
prepared in one stage from simple and easily available starting materials [1]. MCRs are widely used for many
different practical applications: the discovery of biologically active compounds, catalysts, novel materials,
etc. Such reactions generally provide good yields, are fast, and in most cases proceed under mild conditions.
Major advances in this field have been achieved by using isocyanides, the unique properties of which have
enabled the development of remarkably effective approaches to the synthesis of complex organic compounds
[2-4]. A three-component synthesis based on isocyanides, carbonyl compounds, and acetylenedicarboxylic
esters is an example of successful MCR, which has been recently used for the synthesis of diverse
heterocyclic compounds [5]. This reaction has provided access to substituted furans [6-7], pyrroles [8],
pyrans [9-10], and other heterocyclic systems, which were difficult or impossible to prepare by other
methods. Only one case has been reported in the literature, where a similar reaction was performed with
furan-2,3-diones in the role of the carbonyl component [11].
We used a three-component reaction of 5-aryl-4-(quinoxalin-2-yl)furan-2,3-diones 1a-c [12],
dimethyl acetylenedicarboxylate, and 1-adamantylisocyanide or о-methylphenylisocyanide [13] to obtain high
yields of the dimethyl 7-aryl-8-(3-arylquinoxalin-2-yl)-2-(R-imino)-9-oxo-1,6-dioxaspiro[4.4]nona-3,7-diene-
3,4-dicarboxylates 2a-f as the only products (Table 1).
The spirocompounds 2a-f are yellow or colorless crystals with high melting points, readily soluble in
chloroform, poorly soluble in acetonitrile and alcohol, insoluble in water and alkanes.
_______
*To whom correspondence should be addressed, e-mail: lisovn@mail.ru.
1Perm State National Research University, 15 Bukireva St., Perm 614990, Russia.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 5-10, 2014. Original article
submitted July 17, 2013; revision submitted December 18, 2013.
0009-3122/14/5001-0001©2014 Springer Science+Business Media New York
1

TABLE 1. Physicochemical Characteristics of the Synthesized
Compounds 2a-f and 3a-c
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Mp, С
Yield, %
С
H
N
C41H35N3O7
72.36
72.23
5.24
5.17
6.26
6.16
269-270
286-287
203-205
145-147
190-191
167-169
187-189
193-195
152-154
87
85
89
84
86
93
71
67
88
2а
2b
2c
2d
2e
2f
C43H39N3O7
C45H43N3O7
C38H27N3O7
C40H31N3O7
C42H35N3O7
C27H18N2O4
C29H22N2O4
C31H26N2O4
72.63
5.41
5.99
72.76
5.54
5.92
73.32
73.25
5.77
5.87
5.79
5.69
71.50
4.35
6.66
71.58
4.27
6.59
72.21
72.17
4.78
4.69
6.23
6.31
72.79
5.15
6.12
72.71
5.09
6.06
74.58
74.65
4.23
4.18
6.40
6.45
3a
3b
3c
75.33
4.86
6.14
75.31
4.79
6.06
75.97
75.90
5.33
5.34
5.76
5.71
N
N
Ar
O
R
N+
COOMe
COOMe
COOMe
+
N
R
C
+
+
O
–
COOMe
O
1a–c
Ar
A
ClCH2CH2Cl then room temp.,
1–4 h
–10°C
N
Ar
O
N
Ar
R
N+
O
N
O
O
N
N
R
O
O
Ar
Ar
COOMe
COOMe
MeOOC
MeOOC
B
2a–f
1a, 2a,d Ar = Ph, 1b, 2b,e Ar = 4-MeC6H4, 1c, 2c,f Ar = 4-EtC6H4;
2a–c R = 1-adamantyl, 2d–f R = 2-MeC6H4
The spectral characteristics of compounds 2a-f matched those of the model compounds with structures
confirmed by X-ray structural analysis [14] (Table 2).
Compounds 2a-f apparently were formed through the zwitterionic intermediate А, which attacked the
lactone carbonyl of the furan-2,3-diones 1a-c leading to the intermediate compound В, which further cyclized to
the respective spiro compounds 2a-f.
In order to evaluate the possibility of an alternate pathway for this reaction (addition to the ketone
carbonyl of the furan ring) we performed a reaction of the 5-aryl-4-(quinoxalin-2-yl)furan-2,3-diones 1a-c with
(methoxycarbonylmethylene)triphenylphosphorane and obtained new examples of substituted furan-3-ones: the
5-aryl-4-(quinoxalin-2-yl)furan-3-ones 3a-c.
Compounds 3a-c are yellow crystals with high melting points, readily soluble in chloroform, poorly
soluble in acetonitrile, insoluble in water and hexane (Table 1).
2

Ar
N
N
Ar
N
N
PPh3
O
O
COOMe
O
O
1a–c
+
PPh3
PhMe
room temp.
1–2 h
PPh3
O
O
Ar
Ar
MeOOC
COOMe
D
C
R
N
N
N
Ar
R
N+
C
COOMe
N
N
Ar
O
O
MeOOC
COOMe
–Ph3PO
ClCH2CH2Cl
COOMe
COOMe
O
COOMe
Ar
3a–c
O
Ar
3 a Ar = Ph, b Ar = 4-MeC6H4, c Ar = 4-EtC6H4
TABLE 2. Spectral Characteristics of the Synthesized Compounds 2a-f and 3a-c
Com-
pound
IR spectra, ν, cm-1
1H NMR spectra, δ, ppm (J, Hz)
2a
1762 (CO2Me),
1.66-2.06 (15H, m, H Ad); 3.78 (3H, s, COOCH3);
3.89 (3H, s, COOCH3); 7.33-7.99 (12H, m, H Ar, H Ph);
8.16 (1H, d, J = 8.1, H Ar); 8.21 (1H, d, J = 7.8, H Ar)
1740 (CO2Me),
1723 (C=O), 1691 (C=N)
2b
2c
1752 (CO2Me),
2.29 (3H, s, ArCH3); 2.32 (3H, s, ArCH3);
1736 (CO2Me),
1.67-2.07 (15H, m, H Ad); 3.78 (3H, s, COOCH3);
3.89 (3H, s, COOCH3); 7.16 (2Н, d, J = 8.1, H Ar);
7.23 (2H, d, J = 8.1, H Ar); 7.38 (2H, d, J = 7.8, H Ar);
7.46 (2H, d, J = 7.8, H Ar); 7.89-7.98 (2H, m, H Ar);
8.17 (1H, d, J = 8.1, H Ar); 8.19 (1H, d, J = 7.8, H Ar)
1720 (C=O), 1704 (C=N)
1760 (CO2Me),
1735 (CO2Me),
1721 (C=O), 1705 (C=N)
1.10-1.18 (6H, m, 2CH2CH3); 1.68-2.07 (15H, m, H Ad);
2.53-2.64 (4H, m, 2CH2CH3); 3.79 (3H, s, COOCH3);
3.89 (3H, s, COOCH3); 7.15 (2Н, d, J = 8.1, H Ar);
7.23 (2H, d, J = 8.1, H Ar) 7.32 (2H, d, J = 7.8, H Ar);
7.43 (2H, d, J = 7.8, H Ar); 7.88-7.98 (2H, m, H Ar);
8.16 (1H, d, J = 8.1, H Ar); 8.19 (1H, d, J = 7.8, H Ar)
2d
2e
1752 (CO2Me),
2.13 (3H, s, ArCH3); 3.85 (3H, s, COOCH3);
1736 (CO2Me),
3.99 (3H, s, COOCH3); 7.05-8.22 (18H, m, H Ar, H Ph)
1723 (C=O), 1687 (C=N)
1751 (CO2Me),
2.15 (3H, s, ArCH3); 2.31 (3H, s, ArCH3);
1736 (CO2Me),
2.51 (3H, s, ArCH3); 3.83 (3H, s, COOCH3);
3.99 (3H, s, COOCH3); 6.94-7.59 (14H, m, H Ar);
7.95 (1H, d, J = 8.1, H Ar); 8.19 (1H, d, J = 7.8, H Ar)
1721 (C=O), 1692 (C=N)
2f
1756 (CO2Me),
1.10-1.15 (6H, m, 2CH2CH3); 2.16 (3H, s, ArCH3);
2.56-2.72 (4H, m, 2CH2CH3); 3.84 (3H, s, COOCH3);
3.99 (3H, s, COOCH3); 6.92-7.57 (14H, m, H Ar);
7.94 (1H, d, J = 8.1, H Ar); 8.18 (1H, d, J = 7.8, H Ar)
1737 (CO2Me),
1726 (C=O), 1690 (C=N)
3a
3b
1728 (CO2Me), 1703 (C=O)
1725 (CO2Me), 1709 (C=O)
3.80 (3H, s, COOCH3); 6.09 (1H, s, =CHCOOMe);
7.36-7.98 (12H, m, H Ar, H Ph);
8.15 (1H, d, J = 8.1, H Ar); 8.23 (1H, d, J = 7.8, H Ar)
2.33 (3H, s, ArCH3); 2.38 (3H, s, ArCH3);
3.88 (3H, s, COOCH3); 6.09 (1H, s, =CHCOOMe);
7.10 (2Н, d, J = 8.1, H Ar); 7.36 (2H, d, J = 8.1, H Ar);
7.43 (2H, d, J = 7.8, H Ar); 7.51 (2H, d, J = 7.8, H Ar);
8.12-8.15 (2H, m, H Ar); 8.21 (1H, d, J = 8.1, H Ar);
8.22 (1H, d, J = 7.8, H Ar)
3c
1723 (CO2Me), 1701 (C=O)
1.12-1.18 (6H, m, 2CH2CH3);
2.54-2.67 (4H, m, 2CH2CH3); 3.80 (3H, s, COOCH3);
6.06 (1H, s, =CHCOOMe); 7.18 (2Н, d, J = 8.1, H Ar);
7.32 (2H, d, J = 8.1, H Ar) 7.39 (2H, d, J = 7.8, H Ar);
7.49 (2H, d, J = 7.8, H Ar); 7.89-7.99 (2H, m, H Ar);
8.14 (1H, d, J = 8.1, H Ar); 8.20 (1H, d, J = 7.8, H Ar)
3

The reaction was apparently initiated by a nucleophilic attack of (methoxycarbonylmethylеne)-
triphenylphosphorane at the lactone carbonyl of the furandione ring, leading to the formation of an intermediate
betaine C, which further rearranged to the oxoazophosphetidine D, which transformed to compounds
3а-с by elimination of triphenylphosphine oxide. A Wittig reaction of (methoxycarbonylmethylene)-
triphenylphosphorane with substituted furan-2,3-diones was described previously, giving the product resulting
from an addition at the lactone carbonyl group [15].
The attempts at three-component reactions of compounds 3a-c with dimethyl acetylenedicarboxylate
and isocyanide were not successful: separation of the reaction mixtures gave only the starting furan-3-ones 3a-c.
The reason for such a behavior of compounds 3a-c was apparently in the sterically hindered approach to the ketone
carbonyl of the furan ring, and the low reactivity of ester carbonyl groups.
Thus, we have established that the interaction of 5-aryl-4-(quinoxalin-2-yl)furan-2,3-diones, dimethyl
acetylenedicarboxylate, and isocyanides gives single products from a reaction at the lactone carbonyl of the
furan-2,3-diones, namely, dimethyl 7-aryl-8-(3-arylquinoxalin-2-yl)-2-(R-imino)-9-oxo-1,6-dioxaspiro[4.4]nona-
3,7-diene-3,4-dicarboxylates.
EXPERIMENTAL
1
IR spectra were recorded on an FSM 1202 spectrometer in Nujol. The H NMR spectra were acquired
on a Mercury Plus 300 instrument (300 MHz) in DMSO-d6, the internal standard was HMDS (δ 0.05 ppm).
13С NMR spectra were acquired on a Mercury Plus 300 instrument (75 MHz) in СDCl3 (compounds 2a,b), and
on a Bruker 500 instrument (125 MHz) in DMSO-d6 (compounds 2d,e), the internal standard was TMS. Mass
spectra were recorded on a Kratos MS-30 instrument at 200°С temperature, with EI ionization (70 eV).
Elemental analysis was performed on a Leco CHNS-932 analyzer. Melting points were determined on a PTP-2
apparatus. The individuality of the obtained compounds was confirmed by TLC on Sorbfil-TLC-A-UV plates,
the eluents were EtOAc or hexane–EtOAc (5:3 and 5:1), the visualization was with iodine vapor. Dimethyl
acetylenedicarboxylate was purchased from Sigma-Aldrich. Isocyanides used in this work were synthesized by
known methods [16, 17].
Preparation of Compounds 2a-f (General Method). A solution of 5-aryl-4-(quinoxalin-2-yl)furan-
2,3-dione 1a-c (1.0 mmol) and dimethyl acetylenedicarboxylate (1.1 mmol) in anhydrous 1,2-dichloroethane
(10 ml) was cooled to -10°С and added dropwise to a cold (-10°С) solution of the corresponding isocyanide
(1.1 mmol) in anhydrous 1,2-dichloroethane (10 ml). The mixture was stirred at room temperature for 1-4 h.
The solvent was removed, and the residue was crystallized by trituration with EtOH. The synthesized
compounds were recrystallized from EtOH.
Dimethyl 2-(1-adamantylimino)-9-oxo-7-phenyl-8-(3-phenylquinoxalin-2-yl)-1,6-dioxaspiro[4.4]nona-
3,7-diene-3,4-dicarboxylate (2a) was synthesized from 1-adamantylisocyanide and furan-2,3-dione 1а.
Colorless crystals. 13C NMR spectrum, δ, ppm: 29.5, 36.3, 42.1 (С adamantane); 53.0 (ОСН3); 53.1 (ОСН3);
57.0 (С adamantane); 104.2 (С spiro); 114.0; 126.1; 128.1; 128.5; 128.7; 129.3; 129.8; 129.9; 130.0; 130.5;
130.6; 130.7; 131.4; 133.3; 134.6; 138.2; 138.6; 139.6; 141.5; 141.9; 144.5; 145.4; 147.8; 150.5; 154.7 (C=N);
159.4, 161.3, 190.0 (3С=О).
Dimethyl 2-(1-adamantylimino)-7-(4-methylphenyl)-8-[3-(4-methylphenyl)quinoxalin-2-yl]-9-oxo-
1,6-dioxaspiro[4.4]nona-3,7-diene-3,4-dicarboxylate (2b) was synthesized from 1-adamantylisocyanide and
furan-2,3-dione 1b. Colorless crystals. 13C NMR spectrum, δ, ppm: 21.2 (CH3); 21.7 (CH3); 29.5, 36.3,
42.1 (С adamantane); 53.0 (ОСН3); 53.1 (ОСН3); 56.9 (С adamantane); 104.1 (С spiro); 113.7; 125.3; 128.1;
128.6; 128.7; 129.1; 129.2; 129.3; 129.7; 130.5; 130.6; 131.2; 133.2; 134.4; 138.3; 138.8; 139.6; 141.6; 141.9;
144.5; 145.6; 147.8; 148.0; 150.5; 154.8 (C=N); 159.6, 161.3, 190.1 (3С=О).
4

Dimethyl 2-(1-adamantylimino)-7-(4-ethylphenyl)-8-[3-(4-ethylphenyl)quinoxalin-2-yl]-9-oxo-1,6-dioxa-
spiro[4.4]nona-3,7-diene-3,4-dicarboxylate (2c) was synthesized from 1-adamantylisocyanide and furan-
2,3-dione 1c. Colorless crystals.
Dimethyl 2-[(2-methylphenyl)imino]-9-oxo-7-phenyl-8-(3-phenylquinoxalin-2-yl)-1,6-dioxaspiro-
[4.4]nona-3,7-diene-3,4-dicarboxylate (2d) was synthesized from о-methylphenylisocyanide and furan-2,3-dione
13
1а. Yellow crystals. C NMR spectrum, δ, ppm: 17.4 (СН3); 53.8 (ОСН3); 54.0 (ОСН3); 104.8 (С spiro); 113.4;
121.2; 124.1; 126.1; 126.2; 126.3; 126.4; 126.7; 128.0; 128.2; 128.3; 128.4; 128.8; 128.9; 129.0; 129.1; 129.2;
130.5; 130.8; 131.5; 134.3; 136.2; 137.3; 139.6; 140.7; 141.1; 141.9; 143.5; 145.4; 150.5; 154.0 (C=N); 158.6,
160.1, 190.9 (3С=О). Mass spectrum, m/z (Irel, %): 637 [М]+ (100).
Dimethyl 7-(4-methylphenyl)-2-[(2-methylphenyl)imino]-8-[3-(4-methylphenyl)quinoxalin-2-yl]-
9-oxo-1,6-dioxaspiro[4.4]nona-3,7-diene-3,4-dicarboxylate (2e) was synthesized from о-methylphenyliso-
cyanide and furan-2,3-dione 1b. Colorless crystals. 13C NMR spectrum, δ, ppm: 17.3 (СН3); 20.8 (CH3); 21.2
(CH3); 53.8 (ОСН3); 53.9 (ОСН3); 104.8 (С spiro); 113.0; 121.3; 124.0; 126.1; 126.4; 126.9; 128.3; 128.4;
128.6; 128.8; 128.9; 129.0; 129.1; 129.8; 129.9; 130.5; 130.6; 131.4; 134.6; 136.2; 137.4; 138.6; 139.6; 140.6;
141.1; 141.8; 143.5; 145.3; 145.5; 150.5; 153.9 (C=N); 158.6, 160.1, 190.0 (3С=О).
Dimethyl 7-(4-ethylphenyl)-8-[3-(4-ethylphenyl)quinoxalin-2-yl]-2-[(2-methylphenyl)imino]-9-oxo-
1,6-dioxaspiro[4.4]nona-3,7-diene-3,4-dicarboxylate (2f) was synthesized from о-methylphenylisocyanide
and furan-2,3-dione 1c. Yellow crystals.
Preparation of Compounds 3a-c (General Method). A solution of the corresponding 5-aryl-
4-(quinoxalin-2-yl)furan-2,3-dione 1a-c (1 mmol) in anhydrous toluene (5 ml) was stirred for 10 min, then a
solution of (methoxycarbonylmethylene)triphenylphosphorane (1 mmol) in anhydrous toluene (5 ml) was added
dropwise. The mixture was stirred at room temperature for 1-2 h. The solvent was evaporated (except in the case
of compound 3b, which precipitated without removal of the solvent); the residue was crystallized by trituration
with MeCN. The synthesized compounds were recrystallized from MeCN.
Methyl 2-[3-oxo-5-phenyl-4-(3-phenylquinoxalin-2-yl)-2(3H)-furanylidene]acetate (3a) was
synthesized from furan-2,3-dione 1a. Yellow crystals. Mass spectrum, m/z (Irel, %): 434 [М]+ (84).
Methyl 2-{5-(4-methylphenyl)-4-[3-(4-methylphenyl)quinoxalin-2-yl]-3-oxo-2(3H)-furanylidene}-
acetate (3b) was synthesized from furan-2,3-dione 1b. Yellow crystals. Mass spectrum, m/z (Irel, %): 462 [М]+
(100).
Methyl 2-{5-(4-ethylphenyl)-4-[3-(4-ethylphenyl)quinoxalin-2-yl-3-oxo]-2(3H)-furanylidene}acetate
(3c) was synthesized from furan-2,3-dione 1c. Yellow crystals. Mass spectrum, m/z (Irel, %): 490 [М]+ (21).
This work received financial support from the Ministry of Education of the Perm region (project MIG)
and the Russian Foundation for Basic Research (grants 13-03-96024-r_ural_a and 14-03-96012-r_ural_а).
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