An efficient synthesis of chromeno[2,3-d]pyrimidine-2,4-diones with a nitroketene-aminal moiety at C(5) by a one-pot four-component reaction

Article abstract of DOI:10.1002/hlca.201400276

Abstract An efficient and novel synthesis of chromeno[2,3-d]pyrimidine-2,4-dione derivatives with a nitroketene-aminal moiety at C(5) via four-component reaction of salicylaldehydes, barbituric acid, diamines, and 1,1-bis(methylsulfanyl)-2-nitroethene in EtOH and in the presence of AcOH is reported. Easy performance, good yields, and easy purification are the main advantages of this method. All structures were confirmed by IR, MS, and ¹H- and ¹³C-NMR, and by X-ray crystal-structure analyses. A plausible mechanism for this type of reaction is proposed (Scheme).

Full text of DOI:10.1002/hlca.201400276

Helvetica Chimica Acta – Vol. 98 (2015)
663
An Efficient Synthesis of Chromeno[2,3-d]pyrimidine-2,4-diones with a
Nitroketene-Aminal Moiety at C(5) by a One-Pot Four-Component Reaction
by Abdolali Alizadeh*a), Rashid Ghanbaripoura), and Seik Weng Ngb)
a) Department of Chemistry, Tarbiat Modares University, P.O. Box 14115-175, Tehran, Iran
(phone: þ 98-21-88006631; fax: þ 98-21-88006544; e-mail: aalizadeh@modares.ac.ir,
abdol_alizad@yahoo.com)
b) Department of Chemistry, University of Malaya, 50603 Kuala Lumpur, Malaysia
An efficient and novel synthesis of chromeno[2,3-d]pyrimidine-2,4-dione derivatives with a
nitroketene-aminal moiety at C(5) via four-component reaction of salicylaldehydes, barbituric acid,
diamines, and 1,1-bis(methylsulfanyl)-2-nitroethene in EtOH and in the presence of AcOH is reported.
Easy performance, good yields, and easy purification are the main advantages of this method. All
structures were confirmed by IR, MS, and 1H- and 13C-NMR, and by X-ray crystal-structure analyses. A
plausible mechanism for this type of reaction is proposed (Scheme).
Introduction. – Chromeno[2,3-d]pyrimidine-2,4-diones (ꢀoxadeazaflavinsꢁ) are
interesting organic compounds with various biological properties [1]. They are also
biomimetic models of the deazaflavine coenzyme and have been shown to possess
strong redox properties in the conversion of alcohols to aldehydes or ketones [2]. Due
to the importance of oxadeazaflavins, various methods have been reported for their
synthesis [3].
Heterocyclic ketene aminals are powerful and versatile intermediates in hetero-
cyclic synthesis. Reactions of cyclic methylidene-aminals with a number of electrophilic
reagents have been successfully used to synthesize five- and six-membered and fused
heterocycles in recent years. These fused heterocyclic structures are frequently found in
pharmacophores and play important roles in drug discovery. They are also used as
pesticides, herbicides [4], antileishmanial agents [5], antianxiety agents [6], and
antibacterial drugs [7].
As part of our ongoing efforts to explore new routes for the synthesis of a variety of
biologically active fused polycyclic N-heterocycles via one-pot synthesis and reaction of
aminals [8], we decided to study the synthesis of new ꢀoxadeazaflavinꢁ derivatives by
nitroketene aminal intermediates.
Results and Discussion. – Due to the importance of ꢀoxadeazaflavinsꢁ and in
continuation of our studies on the synthesis of new chromene derivatives [9], herein we
report the synthesis of ꢀoxadeazaflavinꢁ-bearing nitroketene aminal derivatives by
reaction of salicylaldehydes 1, barbituric acid, diamines 2, and 1,1-bis(methylsulfanyl)-
2-nitroethene in the presence of AcOH. The reactions of salicylaldehydes 1, barbituric
acid, diamines 2, and 1,1-bis(methylsulfanyl)-2-nitroethene were performed within 6 h
ꢂ 2015 Verlag Helvetica Chimica Acta AG, Zürich

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Table. Prepared Nitroketene-Aminal Moiety-Bearing Chromeno[2,3-d]pyrimidine-2,4-diones
Entry
1
R
H
Diamine 2
Product
Yield [%]
75
3a
2
MeO
80
3b
3
4
MeO
MeO
70
72
3c
3d
in EtOH/H2O 1:1 in the presence of 1 equiv. of AcOH to produce the target
derivatives, 3a – 3d, in excellent yields (Table).
The structures of 3a – 3d were deduced from their elemental analysis, IR, and high-
1
field H- and 13C-NMR spectra, and X-ray crystal-structure analysis of 3b. The mass
spectrum of 3b displayed a fragment-ion peak at m/z 321, which corresponds to the
ꢀoxadeazaflavinꢁ part in agreement with the proposed structure. The IR spectrum of
this compound showed absorption bands due to NH stretching frequencies at 3409,
3255, and 3087 cmÀ1. Further absorption bands at 1702, 1652, 1591, and 1474 cmÀ1 were
attributed to C¼O, C¼C, and aromatic groups. Absorption bands at 1522, 1370, 1266,
1207, 1117, and 1076 cmÀ1 were assigned to the NO2, CÀO, and CÀN groups. The
1H-NMR spectrum of 3b showed one multiplet (d(H) 3.70 – 3.74) for two CH2 groups,
five singlets (3.83, 4.83, 8.76, 10.91, and 11.75) corresponding to MeO, CH, and four NH
groups, respectively, and also two doublets (6.64 (J ¼ 7.6) and 6.94 (J ¼ 7.6)), as well as
one triplet (7.03 (J ¼ 7.6)) for aromatic H-atoms. The 1H-decoupled 13C-NMR spectrum
of 3b showed 15 distinct resonances in agreement with the suggested structure. Final
confirmation for the formation of the reaction products was derived from recrystal-
lization of 3b in MeOH and X-ray analysis. The ORTEP diagram of 3b with the
inclusion of MeOH and H2O is shown in the Figure.
A plausible mechanism for the synthesis of products 3a – 3d is proposed in the
Scheme.
Initial addition of 1,n-diamine to 1,1-bis(methylsulfanyl)-2-nitroethene leads to
ketene aminal 4. Then, Knoevenagel condensation and cyclization between salicylal-

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665
Figure. ORTEP Diagram of 3b
Scheme. A Plausible Mechanism for the Formation of 3a
dehyde 1 and barbituric acid, in the presence of AcOH, affords ꢀoxadeazaflavinꢁ 5.
Finally, Michael addition of 4 and 5 gives 3. To investigate the proposed mechanism,
compound 5 was synthesized as described in [3b], and, when added to ketene aminal
solution, the same product was obtained.
In summary, we have reported a concise synthesis of new ꢀoxadeazaflavinꢁ
derivatives by one-pot reaction of salicylaldehyde, barbituric acid, diamine, and 1,1-
bis(methylsulfanyl)-2-nitroethene. Simple purification, easy performance, simple and
inexpensive starting materials, and excellent yields characterize this method. The
simplicity of the present procedure makes it an interesting alternative to complex

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multistep approaches of this type of heterocycles. Due to the importance of both
oxadeazaflavin and ketene aminal moieties, synthesis of these compounds can be
considered for biological applications in the near future.
Financial support of this research from Tarbiat Modares University, Iran, is gratefully acknowledged.
Experimental Part
General. All starting materials were obtained from Merck (Germany) and Fluka (Switzerland), and
were used without further purification. M.p.: Electrothermal 9100 apparatus. IR Spectra: Shimadzu IR-
460 spectrometer; KBr; n˜ in cmÀ1. 1H- and 13C-NMR spectra: BRUKER DRX 400-AVANCE FT-NMR
instrument (400 and 100 MHz, resp.); in CDCl3; d in ppm rel. to Me4Si as internal standard, J in Hz. MS:
Finnigan-MAT 8430 mass spectrometer (EI, 70 eV); in m/z (rel. %). Elemental analyses: Heraeus CHN-
O-Rapid analyzer.
General Procedure (exemplified for 3a). A soln. of ethane-1,2-diamine (0.074 g, 1 mmol) and 1,1-
bis(methylsulfanyl)-2-nitroethene (0.165 g, 1 mmol) in EtOH (3 ml) was magnetically stirred for 3 h
under reflux. Then, salicyclaldehyde (0.122 g, 1 mmol) and AcOH (0.060 g, 1 mmol) were added,
followed by dropwise addition of a soln. of barbituric acid (0.128 g, 1 mmol) in H2O (3 ml) within 10 min.
After 3 h, the hot mixture was filtered, and the precipitate was washed with EtOH to afford pure product
3a.
1,10a-Dihydro-5-[(imidazolidin-2-ylidene)(nitro)methyl]-2H-[1]benzopyrano[2,3-d]pyrimidine-
2,4(3H)-dione (3a). Yield: 257 mg (75%). White powder. M.p. 2528 (dec.). IR: 3321, 3160 (4 NH); 1710
(2 C¼O), 1663 (C¼C); 1600, 1407 (Ar), 1526, 1349 (NO2); 1309, 1262, 1181 (CÀO); 1089 (CÀN).
1H-NMR: 3.71 – 3.75 (m, 2 CH2); 4.85 (s, CH); 7.00 (d, J ¼ 7.6, 1 arom. H); 7.09 – 7.10 (m, 2 arom. H);
7.20 – 7.25 (m, 1 arom. H); 8.79 (s, 2 NH); 10.95 (s, NH); 11.78 (s, NH). 13C-NMR: 30.4; 43.5; 95.6; 110.1;
115.1; 122.6; 124.5; 127.7; 128.3; 149.6; 150.1; 155.4; 160.6; 163.4. MS: 214 (44), 171 (83), 143 (100), 129
(72), 115 (88), 88 (51), 54 (37). Anal. calc. for C15H13N5O5 (343.30): C 52.48, H 3.82, N 20.40; found: C
58.39, H 3.85, N 20.23.
1,10a-Dihydro-5-[imidazolidin-2-ylidene](nitromethyl-9-methoxy-2H-[1]benzopyrano[2,3-d]pyrimi-
dine-2,4(3H)-dione (3b). Yield: 299 mg (80%). Beige powder. M.p. 2618 (dec.). IR: 3284 (br., 4 NH),
1698 (2 C¼O); 1652 (C¼C); 1591, 1474 (Ar); 1522, 1370 (NO2); 1266, 1207, 1117 (CÀO); 1076 (CÀN).
1H-NMR: 3.70 – 3.74 (m, 2 CH2); 3.83 (s, MeO); 4.83 (s, CH); 6.64 (d, J ¼ 7.6, 1 arom. H); 6.94 (d, J ¼ 7.6,
1 arom. H); 7.03 (t, J ¼ 7.6, 1 arom. H); 8.76 (s, 2NH); 10.91 (s, NH); 11.75 (s, NH). 13C-NMR: 30.5; 43.5;
55.6; 84.7; 110.0; 110.6; 119.5; 123.3; 124.2; 139.6; 146.4; 149.5; 152.7; 160.6; 163.4. MS: 246 (52), 214 (9),
202 (57), 187 (19), 175 (57), 158 (40), 143 (60), 130 (53), 114 (37), 102 (81), 89 (44), 76 (100), 63 (70), 51
(77). Anal. calc. for C16H15N5O6 (373.33): C 51.48, H 4.05, N 18.76; found: C 51.52, H 4.13, N 18.81.
Crystal Data of 3b1). C16H15N5O6 · MeOH · H2O; Mr 423.38; MoKa (l ¼ 0.71073 Š); Z ¼ 2; a ¼
8.0090(6), b ¼ 11.2369(12), c ¼ 11.6759(13) Š; a ¼ 62.452(11), b ¼ 86.673(8), g ¼ 76.093(8)8; V ¼
902.62(15) Š3; Dx (calc.) ¼ 1.558 mg mÀ3; F(000) ¼ 444; 3.3780 ꢀ 2q ꢀ 27.2230; intensity data were
collected at 100(2) K with an Agilent Technologies SuperNova dual diffractometer with Atlas detector,
and employing w/2q scanning technique, in the range of À 10 ꢀ h ꢀ 10, À 14 ꢀ k ꢀ 14, À 15 ꢀ l ꢀ 14; the
structure was solved by a direct method, all non-H-atoms were positioned, and anisotropic thermal
parameters refined from 4166 observed reflections with Rint ¼ 0.0537 by a full-matrix least-squares
technique converged to R1 ¼ 0.0676 and wR2 ¼ 0.1430 (I > 2s(I)).
1,10a-Dihydro-9-methoxy-5-[(nitro)(tetrahydropyrimidin-2(1H)-ylidene)methyl]-2H-[1]benzopyra-
no[2,3-d]pyrimidine-2,4(3H)-dione (3c). Yield: 271 mg (70%). Yellow powder. M.p. 2588 (dec.). IR:
3406, 3255, 3087 (4 NH); 1702 (2 C¼O); 1650 (C¼C); 1591, 1469 (Ar); 1522, 1389 (NO2); 1295, 1267,
1211, 1126 (CÀO); 1072 (CÀN). 1H-NMR: 1.87 – 1.88 (m, CH2); 3.42 – 3.43 (m, 2 CH2N); 3.82 (s, MeO);
4.91 (s, CH); 6.60 (d, J ¼ 7.6, 1 arom. H); 6.93 (d, J ¼ 7.6, 1 arom. H); 7.01 (t, J ¼ 7.6, 1 arom. H); 9.69 (s,
1
)
CCDC-1015214 contains the supplementary crystallographic data for this article. These data can be
obtained free of charge via www.ccdc.cam.ac.uk.

Helvetica Chimica Acta – Vol. 98 (2015)
667
2NH); 10.95 (s, NH); 11.81 (s, NH). 13C-NMR: 18.9; 29.3; 38.5; 55.6; 84.7; 110.6; 111.9; 119.4; 123.2;
124.0; 139.9; 146.3; 149.4; 154.7; 155.6; 163.8. MS: 260 (7), 246 (72), 214 (7), 202 (78), 187 (27), 173 (80),
158 (54), 143 (100), 130 (58), 113 (66), 97 (74), 76 (40), 56 (85). Anal. calc. for C17H17N5O6 (387.35): C
52.71, H 4.42, N 18.08; found: C 52.85, H 4.44, N 17.95.
1,10a-Dihydro-9-methoxy-5-[(nitro)(tetrahydro-5,5-dimethylpyrimidin-2(1H)-ylidene)methyl]-2H-
[1]benzopyrano[2,3-d]pyrimidine-2,4(3H)-dione (3d). Yield: 299 mg (72%). Pale-yellow powder. M.p.
2338 (dec.). IR: 3366, 3269, 3164 (4 NH); 1706 (2 C¼O); 1666 (C¼C); 1614, 1470 (Ar); 1528, 1393 (NO2);
1
1296, 1204, 1121 (CÀO); 1077 (CÀN). H-NMR: 1.04 (s, 2 Me); 3.11 – 3.12 (m, 2 CH2); 3.83 (s, MeO);
4.96 (s, 1 arom. H); 6.58 (d, J ¼ 7.6, 1 arom. H); 6.93 (d, J ¼ 7.6, 1 arom. H); 7.03 (t, J ¼ 7.6, 1 arom. H); 9.77
(s, 2 NH); 10.94 (s, NH); 11.80 (s, NH). 13C-NMR: 23.5 (2Me); 25.6; 29.3; 49.7; 55.6; 84.7; 110.6; 111.8;
119.3; 123.2; 124.0; 139.8; 146.3; 149.4; 153.9; 155.5; 163.7. MS: 244 (59), 201 (65), 171 (81), 158 (46), 141
(36), 125 (100), 110 (23), 96 (74), 84 (83), 70 (64), 56 (82). Anal. calc. for C19H21N5O6 (415.41): C 54.94,
H 5.10, N 16.86; found: C 55.09, H 5.21, N 16.77.
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Received August 25, 2014