Short communication
Three-component Synthesis of Novel Highly Functionalized 2,6-dihydropyrimido[2,1-a]isoindole Derivatives
Robabeh Baharfar* and Najmeh Abbasi
Department of Chemistry, University of Mazandaran, P. O. Box 453, Babolsar, Iran
* Corresponding author: E-mail: baharfar@umz.ac.ir Fax: 00981125342350
Received: 24-01-2011
Abstract
Three-component reaction of dialkyl acetylenedicarboxylates, isocyanides and 1,3- diimino isoindoline affords highly functionalized 2,6-dihydropyrimido[2,1-a]isoindole derivatives in good yields under catalyst free and mild reaction conditions.
Keywords: Alkyl isocyanides, dialkyl acetylenedicarboxylates, 1,3-diimino isoindoline, 2,6-dihydropyrimido[2,1-a]isoindole derivatives, three-component reaction.
1. Introduction
Multi-component (MCR) reactions play an important role in the synthesis of various N-containing heterocyclic compounds,1'2 and become a widespread area of research in organic, combinatorial, and medicinal chemistry.3 The MCR strategy offers significant advantages over the conventional linear-type synthesis due to its flexibility, convergence, atom efficient nature and the fast assembly of poly-substituted systems without isolation of unstable intermediates.1, 4
Pyrimidines and fused pyrimidines are important classes of heterocyclic compounds exhibiting a broad spectrum of biological activities.5-8 Among them, pyrimi-do indoles and pyrimido isoindoles are well known for their potential biological and pharmalogical activities,910 such as analgesic, anti-allergy, bactericide, infective, antihypertensive, anti-inflammatory, antitumor, anti-HIV activities as well as their synthetic applications.1112 In recent years, the synthesis and synthetic applications of the pyrimidine derivatives have been widely investigated.13-16 In spite of developments in the chemistry of fused pyrimi-dines, little attention has been paid to the synthesis of pyrimido[2,1-a]isoindoles.17 The development of a new and effective synthetic method for preparation of hete-rocyclic compounds containing pyrimidine ring fragments is therefore, an interesting challenge. Due to the biological activity of fused pyrimidines, and our interest in the
synthesis of heterocyclic compounds,18-22 herein, we report a simple and efficient method for the preparation of novel 2,6-dihydropyrimido[2,1-a]isoindole derivatives.
2. Results and Discussion
Alkyl isocyanides (1), dialkyl acetylenedicarboxyla-tes (2) and 1,3-diimino isoindoline (3) undergo a smooth 1:1:1 or 1: 2:1 additional reaction in THF at room temperature, to produce 2,6- dihydro[2,1-a]isoindole derivatives (4) and (5) in good yields along with N-vinyl isoindoles (6) as by-product (Scheme 1).
The structures of the compounds 4a-e and 5a-e were deduced from their IR and high-field 1H and 13C NMR spectra. The mass spectra of 4a and 5a display the molecular ion (M+) peak at 370 and 512 m/z, respectively, which are consistent with a 1:1:1 or 1:2:1 adduct of ieri-butyl isocyanide, dimethyl acetylene dicarboxylate, and 1,3-dii-mino isoindoline. The 1H NMR spectrum of 4a exhibits four sharp lines arising from tert-butyl (5 = 1.57 ppm), two methoxy (5 = 3.68 and 3.78 ppm) and methine (5 =5.86 ppm) protons which are readily recognized. Furthermore, two broad singlets were observed for the two NH groups, along with characteristic multiplet signals for the aromatic protons. Upon the addition of a drop of D2O to the NMR tube containing CDCl3 solution of 4a the latter signal disappeared. Additionally, the proton decoupled 13C NMR spectrum of 4a shows 17 distinct resonances in agreement
Yield %
4,5,6	K	R1	4	5	6
a	tert- Bu	Me	47	40	5
b	tert- By	Et	47	40	5
c	ttrt- Uu tett	-Dii	45	42	5
>1	Cvclohexyl	Mi	45	40	5
e	Cyclohexyl	Et	45	40	5
Scheme 1
with the proposed structure. The partial assignment of these resonances is provided in the experimental section. The NMR spectrum of the compound 5a is similar to that of 4a, except that one of the NH groups, which was replaced by a N-vinyl group that exhibits three singlets for two met-hoxy groups and a vinylic (5 =5.79 ppm) proton.
The :H and 13C NMR spectra of compounds 4b-e and 5b-e are similar to those of 4a and 5a, respectively, except for the alkylamino and ester moieties, which exhibit their characteristic signals with appropriate chemical shifts (see experimental section).
Although we have not established the mechanism of the reaction between isocyanides and acetylenic esters in the presence of compound 3 in an experimental manner, a plausible mechanism is proposed in Scheme 2. Based on the well stablished chemistry of isocyanides, it is reasonable to assume that the functionalized 2,6- dihydropyri-mido[2,1-a]isoindoles 4 apparently resulted from the initial additions of the isocyanide to the acetylenic ester and subsequent protonation of the 1:1 adduct 7 by compound 3, followed by the conjugate addition of the anion of the NH-acid 8 on the positively charged ion 9 to form keteni-mine 10. The ketenimine intermediate 10 can be cyclized via an intramolecular attack of the NH-acid on the Csp of the ketenimine under the reaction conditions employed to produce the fused ring system 4. The reaction of the product 4 with another molecule of acetylenic ester generates the highly functionalized N-vinyl derivatives of 5.
3. Experimental
Dialkyl acetylene dicarboxylates, tert-butyl isocya-nide, cyclohexyl isocyanide and 1,3-diimino isoindoline were obtained from Fluka (Buchs, Switzerland) and were used without further purification. Melting points were measured on an Electrothermal 9100 apparatus and are uncorrected. 'H, 13C NMR spectra was measured with Bruker DRX-400 Advance spectrometers. Mass spectra were recorded on a Finnigan-Matt 8430 mass spectrometer operating at an ionization potential of 70 eV. IR spectra were recorded on a FT-IR BRUKER VECTOR 22 spectrometer.
General procedure for the synthesis of 2,6-dihydrop-yrimido[2,1-a]isoindole derivatives (4a) and (5a)
To a magnetically stirred solution of 0.28 g of dialkyl acetylenedicarboxylate (2 mmol) and 0.29 g of 1,3-diimino isoindoline (2 mmol) in 10 mL THF was added dropwise a solution of 0.166 g of alkyl isocyanide (2 mmol) in 2 mL THF at room temperature over 10 min. The reaction mixture was stirred for 48 h. The solvent was then removed under reduced pressure and the desired compounds were separated from the resultant residue by silica gel column chromatography (Merck 230-400 mesh) using n-hexane: ethyl acetate mixture as an eluant.
Dimethyl 4-(tert-butylamino)-6-imino-2,6-dihydrop-yrimido[2,1-a]isoindole-2,3-dicarboxylate (4a): Orange powder, m.p. 120-122 °C, yield 47%, IR (KBr) (vmax, cm-1): 3330-3530 (NH), 1620-1750 (C=O); MS, m/z (%): 370 (M+, 3), 353 (18), 311 (100), 255) 92), 223 (39), 57 (14); 1H NMR (400.13 MHz, CDCl3): 5H 1.57 [9H, s, C(CH3)3], 3.68 and 3.78 (6H, 2s, 2 OC3 H3)H, 5.86 (1H, s, NCH ), 7.69-8.01 (4H, m, 4 CH, Ar), 8.73 and 9.23 (2H, 2br s, 2 NH); 13C NMR (100.61 MHz, CDCl3): 5C 30.92 (C (CH3)3), 50.69 and 50.85 (2 OCH3), 52.533 (NCCMe3), 52.82 (NCH), 72.46 (N-C=C), 121.78,123.16, 132.18 and 132.82 (4 CH, Ar),131.32 and 133.11 (2 C, Ar), 155.95 (C=NH), 158.68 (N-C=N), 158.83 (N-C-NH), 168.88 and 171.28(2 C=O).
Diethyl 4-(tert-butylamino)-6-imino-2,6-dihydropyri-mido[2,1-a]isoindole-2,3-dicarboxylate (4b): Orange powder, m.p. 123-125 °C, yield 47%, IR (KBr) (vmax, cm-1): 3300-3500 (NH), 1620-1730 (C=O); 1H NMR (400.13 MHz, CDCl3): 5H 1.24 and 1.35 (6H, 2t, 3JHH=7.2 Hz, 2 CH3), 1.57 [93H, s,HC(CH3)3], 4.08-4.32 (4HH,Hm, 2 OCH2), 5.84 (1H, s, NCH), 7.67-8.00 (4H, m, 4 CH, Ar),8.65 and 9.32 (2H, 2br s, 2 NH); 13C NMR (100.61 MHz, CDCl3): 5C 14.08 and 14.73 (2 CH3), 30.94 (C(CH3)3), 51.00 (NCMe3), 52.74 (NCH), 59.15 and 61.39 (2 OCH2), 72.62 (N-C=C), 121.72, 123.13, 132.12 and 132.72 (4 CH, Ar), 131.86 and 133.15 (2 C, Ar), 155.86 (C=NH), 158.60 (N-C=N), 158.75 (N-C-NH), 168.58 and 170.95 (2 C=O).
Di(tert-butyl) 4-(tert-butylamino)-6-imino-2,6 dihy-dropyrimido[2,1a]isoindole-2,3-dicarboxylate (4c):
Orange powder, m.p. 137-140 °C, yield 45%, IR (KBr) (vmax, cm-1): 3330-3520 (NH), 1620-1730 (C=O); MS, m/z (%): 454(M+, 5), 353 (44), 297 (100), 241) 61), 57 (36); 1H NMR (400.13 MHz, CDCl3): 5H 1.42, 1.56 and 1.57 (27H, 3s, 3C(CH3)3), 5.58 (1H, s, NCH), 7.65-7.98 (4H, m, 4 CH, Ar), 8.56 and 9.17 (2H, 2br s, 2 NH); 13C NMR (100.61 MHz, CDCl3): 5C 28.06, 28.78 and 31.04 (3C(CH3)3), 50.77 (NCMe3), 52.53 (NCH), 74.56 (N-C=C), 79.01 and 81.97 (2 OCMe3), 121.79, 122.96, 131.92 and 132.50 (4 CH, Ar), 130.85 and 133.30 (2 C, Ar), 150.40 (C=NH), 156.11 (N-C=N), 158.44 (N-C-NH), 168.30 and 170.09 (2 C=O).
Dimethyl 4-(cyclohexylamino)-6-imino-2,6-dihydrop-yrimido[2,1a]isoindole-2,3-dicarboxylate (4d): Orange powder, m.p. 176-180 °C, yield 45%, IR (KBr) (vmax, cm-1): 3350-3520 (NH), 1600-1730 (C=O); 1H NMR (400.13 MHz, CDCl3 ): 5H 1.26-2.08 [10H, m, CH(CH2)5], 3.68 and 3.378 (6HH, 2s, 2 OCH3), 4.27-4.34 (1H, m, NHCH), 5.89 (1H, s, NCH), 7.68-8.04 (4H, m, 4 CH, Ar), 8.56 and 9.07 (2H, 2 br s, 2 NH); 13C NMR (100.61 MHz, CDCl3): 5C 24.71, 24.79, 25.70, 33.73 and 34.24 (5 CH2), 49.50 (NHCH), 50.63 and 50.87 (2 OCH3), 52.52 (NCH), 71.82 (N-C=C), 121. 69, 123.34, 132.31
and 132.82 (4 CH, Ar), 131.34 and 133.02 (2 C, Ar), 157.14 (C=NH), 157.36 (N-C=N), 158.81 (N-C-NH), 168.76 and 171.30 (2 C=O).
Diethyl 4-(cyclohexylamino)-6-imino-2,6-dihydropyri-mido[2,1-a]isoindole-2,3-dicarboxylate (4e): Orange powder, m.p. 152-155 °C, yield 45%, IR (KBr) (vmax, cm-1): 3330-3530 (NH), 1600-1720 (C=O); 1H NMR (400.13 MHz, CDCl3): §H 1.23 and 1.35 (6H, 2t, 3JHH=7.2 Hz, 2 CH3), 1.26-2.07 [10H, m, CH(CH2)5], 4.13 (2H, q, 3Jhh=7.2 Hz, OCH2), 4.17-4.23 (1H, m, NHCH), 4.24-4.32 (2H, m, OCH2), 5.82 (1H, s, NCH), 7.69-8.03 (4H, m, 4 CH, Ar), 8.52 and 9.08 (2H, 2 br s, 2 NH); 13C NMR (100.61 MHz, CDCl3): 5C 14.08 and 14.72 (2 CH3), 24.74, 24.82, 25.68, 33.734 aCnd 34.27 (5 CH2), 49.435 (NHCH), 51.04 (NCH), 59.09 and 61.37 (2 OCH2), 71.99 (N-C=C), 121.64, 123.31, 132.05 and 132.73 (4 CH, Ar), 131.51 and 133.07 (2 C, Ar), 157.04 (C=NH), 157.27 (N-C=N), 158.82 (N-C-NH), 168.47 and 170.99 (2 C=O).
Dimethyl 4-(tert-butylamino)-6-{[(E)-3-methoxy-1-(me-thoxycarbonyl)-3-oxo-1-propenyl]imino}-2,6-dihydrop-yrimido[2,1a]isoindole-2,3-dicarboxylate(5a): Red
powder, m.p. 143-146 °C, yield 40%, IR (KBr) (vmax, cm-1): 3380-3450 (NH), 1620-1700 (C=O); MS, m/z (%): 512 (M+, 3), 453 (70), 438 (50), 394) 100), 57 (20); 1H NMR (400.13 MHz, CDCl3 ): §H 1.56 [9H, s, C(CH3)3], 3.66, 3.78, 3.79 and 3.90 (12H, 4s, 4 OCH3), 5.51 (1H, s, NCH), 5.79 (1H, s, CH), 7.67-8.27 (4H, m, 4 CH, Ar), 9.22(1H, br s, NH); 13C NMR (100.61 MHz, CDCl3): 5C 30.92(C(CH3)3), 50.75, 51.14, 51.86 and 52.53 (4 OCH3), 52.90 (N-CMe3), 53.06 (NCH), 72.81 (N-C=C), 104.45 (C=CH), 123.50, 126.33, 132.68 and 133.03 (4 CH, Ar), 128.61 and 134.21 (2 C, Ar), 151.89 (C=CH), 152.96 (C=NH), 155.28 (N-C=N), 158.23 (N-C-NH), 165.12, 165.67, 168.85 and 170.96 (4 C=O).
Diethyl 4-(tert-butylamino)-6-{[(E)-3-ethoxy-1-(et-hoxycarbonyl)-3-oxo-1-propenyl]imino}-2,6-dihy-dropyrimido[2,1-a]isoindole-2,3-dicarboxylate (5b):
Red powder, m.p. 136-139 °C, yield 40%, IR (KBr) (vmax, cm-1): 3400-3500 (NH), 1600-1730 (C=O); MS, m/z (%): 568 (M+, 75) 495 (100), 439 (25), 57(25); 1H NMR (400.13 MHz, CDCl3): §H 1.23, 1.32, 1.34 and 1.35 [12H, 4t, 3Jhh=7.2 Hz, 4 CH3], 1.63 [9H, s, C(CH3)3], 4.05-4.33 (6H, HmH, 3 OCH2), 4.335(2H, q, 3JHH=7.2 Hz3, 3OCH2), 5.48 (1H, s, NCH), 5.79 (1H, s, CH), 77.64-8.27 (4H, m, 4 CH, Ar), 9.32 (1H, br s, NH); 13C NMR (100.61 MHz, CDCl3): 5C 13.93, 14.08, 14.19 and 14.76 (4 CH3), 30.94 (C(CH3)3), 51.27 (NCMe3), 52.81 (NCH), 59.24, 60.68, 61.38 and 62.33(4 OCH2), 73.04 (N-C=C), 104.59 (C=CH) 123.40, 126.36, 132.54 and 132.88 (4 CH, Ar), 128.61 and 134.23 (2 C, Ar),151.86 (C=CH), 153.06 (C=NH), 155.28 (N-C=N), 158.20 (N-C-NH), 164.68, 165.20, 168.56 and 170.62 (4 C=O).
Di(tert-butyl) 6-{[(E)-3-(tert-butoxy)-1-(tert-butoxy-carbonyl)-3-oxo-1-propenyl]imino}-4-(tert-butylami-no)-2,6-dihydropyrimido[2,1-a]isoindole-2,3-dicar-boxylate (5c): Red powder, m.p. 169-173 °C, yield 42%, IR (KBr) (vmax, cm-1): 3380-3520 (NH), 1600-1750 (C=O); 1H NMR (400.13 MHz, CDCl3): §H 1.41, 1.51, 1.52, 1.55 and 1.57 (45H, 5s, 5 C(CH3)3), 5.34 (1H, s, NCH), 5.58 (1H, s, CH), 7.61-8.24 (4H, m, 4 CH, Ar), 9.15 (1H, br s, NH); 13C NMR (100.61 MHz, CDCl3): 5C 27.93, 28.11, 28.22, 28.77 and 31.04 (5 C(CH3)3), 52.17 (NCMe3), 52.55 (NCH), 74.71 (N-C=C), 78.98, 80.65, 81.70 and 83.48 (4 OCMe3), 105.88 (C=CH), 123.08, 126.56, 132.13 and 132.45 (4 CH, Ar), 127.36 and 134.34 (2 C, Ar), 151.86 (C=CH), 152.50 (C=NH), 156.40 (N-C=N), 158.10 ( N-C-NH), 163.47, 164.58, 168.33 and 170.06 (4 C=O).
Dimethyl 4-(cyclohexylamino)-6-{[(E)-3-methoxy-1-(methoxycarbonyl)-3-oxo-1-propenyl]imino}-2,6-dihydropyrimido[2,1-a]isoindole-2,3-dicarboxyla-te(5d): Red powder, m.p. 127-130 °C, yield 40%, IR (KBr) (vmax, cm-1): 3320-3520 (NH),1600-1720 (C=O); MS, m/z (%): 538 (M+, 57), 479(100), 305(13), 252 (10); 1H NMR (400.13 MHz, CDCl3): §H 1.62-2.06 [10H, m, CH(CH2)5], 3.65, 3.78, 3.79 and 3.90 [12H, 4s, 4 OCH3], 4.24-4.31 (1H, m, NHCH), 5.50 (1H, s, NCH), 5.78 (1H, s, CH), 7.65-8.25 (4H, m, 4 CH, Ar), 9.06 (1H, br d, 3Jhh=8 Hz, NH); 13C NMR (100.61 MHz, CDCl3): 5C 24.68, 24.77, 25.63,, 33.68 and 34.26 (5 CH2), 49.59 (NHCH), 50.70, 51.19, 51.86 and 52.51 (4 OCH3), 53.07 (NCH), 72.14 (N-C=C), 104.45 (C=CH), 123.68, 126.29, 132.64 and 133.05 (4 CH, Ar), 128.61 and 134.13 (2 C, Ar), 151.78 (C=CH), 152.91(C=NH), 156.40 (N-C=N), 156.90 (N-C-NH), 165.13, 165.67, 168.72 and 170.98 (4 C=O).
Diethyl 4-(cyclohexylamino)-6-{[(E)-3-ethoxy-1-(etho-xycarbonyl)-3-oxo-1-propenyl]imino}-2,6-dihydrop-yrimido[2,1-a]isoindole-2,3-dicarboxylate (5e): Red
powder, m.p. 125-128 °C, yield 40%, IR (KBr) (vmax, cm-1): 3300-3530 (NH), 1600-1780 (C=O); 1H NMR (400.13 MHz, CDCl3): §H 1.22 [3H, t, 3JHH = 7.2 Hz, CH3], 1.27-1.37 (9H, 3t, 3JHH = 7.2 Hz, 3 CH3), 1.383-2.07 [10H, m, CH(CH2)5]. 4.06-4.33 (4H, m, 2 OCH2), 4.24 and 4.33 (4H, 2q, 3JHH=7.2 Hz 2 OCH2) 4.67 (1H, m, NHCH), 5.48 (1H, s, NCH), 5.78 (1H, s, CH), 7.64-8.27 (4H, m, 4 CH, Ar), 9.07 (1H, br d, 3JHH = 8 Hz NH); 13C NMR (100.61 MHz, CDCl3): HC 13.93, 14.09, 14.19 and 14.76 (4 CH3), 24.72, 24.80, 25.66, 33.69 and 34.31 (5 CH2), 49.57 (NHCH), 51.32 (NCH), 59.18, 60.68, 61.37 and 62.34 (4 OCH2), 72.38 (N-C=C), 104.61 (C=CH),123.58, 126.33, 132.50 and 132.90 (4 CH, Ar),130.28 and 134.15 (2 C, Ar), 151.76 (C=CH), 153.00 (C=NH), 156.41 (N-C=N), 156.87 (N-C-NH), 164.69, 165.20, 168.43 and 170.65 (4 C=O).
Dimethyl (E)-2-[(3-imino-2,3-dihydro-1H-isoindol-1-yliden)amino]-2-butenedioate (6a): Yellow powder, m.p. 165-166 °C, yield 5%, IR (KBr) (vmax, cm-1): 3500-3650 (NH), 1620-1730 (C=O); 1H NMR (400.13 MHz, DMSO-d6): §H 3.64 and 3.74 (6H, 2s, 2 OCH3), 5.85 (1H, s, CH), 7.60 (2H, m, 2 CH, Ar), 7.72 and 7.91 (2H, 2m, 2 CH, Ar), 9.11 (2H, br s, 2 NH); 13C NMR (100.61 MHz, DMSO-d6): 5C 51.71 and 52.52 (2 OCH3), 109.39 (C=CH), 121.88, 122.28, 131.38 and 132.09(4 CH, Ar), 135.45 and 139.92 (2 C, Ar), 155.24 (C=CH), 166.30 and 166.98 (2 C=N), 170.01 and 172.77 (2 C=O).
Diethyl (E)-2-[(3-imino-2,3-dihydro-1H-isoindol-1-yli-den)amino]-2-butenedioate (6b): Yellow powder, m.p. 134-135 °C, yield 5%, IR (KBr) (vmax, cm-1): 3320-3520 (NH), 1600-1730 (C=O); Ms, m/z (%): 315(M+, 75), 270 (33), 243 (91), 196 (50), 170 (54), 129 (100); 1H NMR (400.13 MHz, DMSO-d6): §H 1.20 and 1.24 (6H, 2t, 3Jhh=7.2 Hz, 2 CH3), 4.09 and 4.20 (4H, 2q, 3JHH=7.2 Hz, 2 OCH2), 5.80 (1H, s, CH), 7.57-7.62 (2H, m, 2 CH, Ar), 7.69-7.92 (2H, 2m, 2CH, Ar), 9.05 and 9.17 (2H, 2s, 2 NH); 13C NMR (100.61 MHz, DMSO-d6): 5C 14.23 and 14.60 (2 CH3), 60.19 and 61.20 (2 OCH2), 109.16 (C=CH), 121.83, 122.26, 131.34 and 132.05 (4 CH, Ar), 135.50 and 139.97 (2 C, Ar), 155.34 (C=CH), 165.82 and 166.39 (2 CN), 170.00 and 172.86 (2 C=O).
Di(tert-butyl)(E)-2-[(3-imino-2,3-dihydro-1H-isoindol-1-yliden)amino]-2-butenedioate (6c): Yellow powder, m.p.167-168 °C, yield 5%, IR (KBr) (vmax, cm1): 3350-3520 (NH), 1620-1750 (C=O); 1H NMR (400.13 MHz, DMSO-d6): §H 1.44 and 1.45 (18H, 2s, 2 OCMe3), 5.62(1H, s, CH), 7.60 (2H, m, 2 CH, Ar), 7.72 and 7.91 (2H, 2m, 2 CH, Ar), 8.92 and 9.03 (2H, 2s, 2 NH); 13C NMR (100.61 MHz, DMSO-d6): 5C 28.11 and 28.33 (2 OCMe3), 79.95 and 81.43 (2 O CMe3), 109.77 (C=CH), 121.67, 122.19, 131.16 and 131.88 (4 CH, Ar), 135.60 and 139.98 (2 C), 154.93 (C=CH), 165.18 and 165.33 (2 C=N), 168.89 and 172.62 (2 C=O).
4. Conclusion
In summary, the reaction between alkyl isocyanides and dialkyl acetylene dicarboxylates in the presence of 1,3-diimino isoindoline provides a simple one-pot entry into the synthesis of polyfunctional 2,6-dihydro[2,1-a]isoindole derivatives of potential synthetic and pharmaceutical interest. The present method carries the advantage that, not only is the reaction performed under neutral condition, but also the substances can be mixed without any activation or modification. The simplicity of the present procedure makes this protocol an interesting alternative to other approaches.
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Povzetek
V prispevku je opisana priprava visoko-funkcionaliziranih 2,6-dihidropirimido [2,1-a]izoindolnih derivatov s trokom-ponentno reakcijo med dialkilacetilendikarboksilati, izocianidiin 1,3-diiminoizoindolini. Reakcija poteka z dobrimi izkoristki, brez katalizatorja in pri milihpogojih.