Pyrrole-Aminopyrimidine Ensembles: Cycloaddition of Guanidine to Acylethynylpyrroles.

An efficient method for the synthesis of pharmaceutically prospective pyrrole-aminopyrimidine ensembles (in up to 91% yield) by the cyclocondensation of easily available acylethynylpyrroles with guanidine nitrate has been developed. The reaction proceeds under heating (110-115 °C, 4 h) in the KOH/DMSO system. In the case of 2-benzoylethynylpyrrole, the unexpected addition of the formed pyrrole-aminopyrimidine as N- (NH moiety of the pyrrole ring) and C- (CH of aminopyrimidine) nucleophiles to the triple bond is observed.

1. Introduction

One of the main trends in modern organic chemistry is the synthesis of heterocyclic ensembles, each of the fragments of which has promising biological activity. These ensembles include, in particular, n class="Chemical">pyrrole–pyrimidines, which combine two of the most fundamental life-supporting molecular systems in their molecule and represent privileged objects for drug design.

The pyrrole core is a key structural motif in a plethora of natural products such as n class="Chemical">chlorophyll, hemoglobin, bile pigments, vitamin B12, and others [1]. Pyrrole and its derivatives are also important components of a number of pharmaceuticals and new compounds with a variety of pharmacological activity [2,3]. Basing on pyrroles, anti-tumor agent sunitinib, the anti-hyperlipidemic atorvastatin [2,3], neotropic aloracetam [2], antipsychotic elopiprazole [2], and nonsteroidal anti-inflammatory agent tolmetin [2] were created.

The pyrimidine ring is a main structural moiety of nucleic acids, vitamins, coenzymes, and n class="Chemical">uric acid [4], as well as the frequent scaffold in medicines [4,5]. According to the literature data, the presence of the amino group in pyrimidine enhances its pharmacological properties [5]. The aminopyrimidine ring is a fragment of nucleotide bases in DNA and RNA, which are important components of living cells [4]. Substituted 2-aminopyrimidines exhibit cardiotonic [6], antitrypanosomal and antiplasmodial [7], antimicrobial [8,9,10,11] and antiplatelet aggregation activity [12]. They are also ligands of histamine H4 and H3 receptors [13,14], inhibitors of IRAK4 (interleukin-1 receptor-associated kinase 4) [15], the vascular endothelial growth factor inhibitor [16], serine/threonine protein kinase inhibitors, candidates for treating drug-resistant tuberculosis [17]. There are numerous 2-aminopyrimidine-tailored pharmaceuticals [18,19] including antiviral (Lamivudine [18], Etravirine and Rilpivirine [19]), anti-cancer (Imatinib [18,19], Erlotinib, Lapatinib [18], Nilotinib, Dabrafenib, Ceritinib, Osimertinib, and Pazopanib [19]), anxiolytic (Buspirone) [19], hypolipidemic (Rosuvastatin) [18], etc.

2-Aminopyrimidines with n class="Chemical">pyrrole substituents represent molecular systems, which could be particularly promising for medicinal chemistry, due to the presence of two pharmacologically active units in their structure. This assumption is supported by the fact that among pyrrole–aminopyrimidines there are inhibitors of JAK2 (Janus kinase 2) [20,21], Cdc7 kinase (Cell division cycle 7-related protein kinase) [22,23], and Polo-like kinase 1 [24], as well as representatives with prominent antifungal activity against Aspergillus niger [25].

The fact that pyrrole–aminopyrimidines have a great potential for cancer treatment [20,21,22,23,24] generates interest in the targeted synthesis of these derivatives.

Few known syntheses of pyrrole–aminopyrimidine ensembles are based on three approaches. The first is to build up the pyrrole moiety on aminopyrimidines starting from 1-(2-aminopyrimidin-4-yl)-2-bromoethanones [20,23,26].

The second approach involves construction of the aminopyrimidine ring via the addition of n class="Chemical">guanidine to pyrroles with ethylenic substituents. Among the latter are 3-dimethylamino-2-(pyrrole-2-carbonyl)acrylonitrile [27], benzylidene acetyl pyrrole [28], pyrrolylenaminone [20], pyrrolyl vinamidinium salts [29].

The third approach to the synthesis of pyrrole–n class="Chemical">aminopyrimidine ensembles is the coupling of halopyrimidines with pyrroles under Buchwald–Hartwig conditions [21] or their boronate derivative under Suzuki reaction conditions and PdCl2(dppf) catalysis [21]. (Pyrrol-2-yl)-2-aminopyrimidine was also obtained from N-Boc-pyrrole, which was deprotonated upon treatment with LiTMP (Lithium tetramethylpiperidide) and, after subsequent transmetalation (using ZnCl2·TMEDA) and coupling with 2,4-dichloropyrimidine, was transformed into N-Boc-2-(2-chloro-4-pyrimidyl)pyrrole [30]. The chloro group of the latter was substituted with allylamine, and after subsequent cleavage of the allyl group under classical conditions afforded the target product.

The most common approach to the synthesis of aminopyrimidines, i.e., cyclocondensation of alkynones with guanidine [31,32,33,34,35,36,37,38], was not always applied to the preparation of pyrrole–aminopyrimidines.

To our knowledge, there is only one work concerning the synthesis of pyrrole–n class="Chemical">aminopyrimidines from guanidine and pyrrol-2-ylhexynones [39], obtained by glyoxylation of N-methyl- and N-benzylpyrroles with oxalyl chloride and subsequent Pd/Cu-catalyzed decarbonylative alkynylation of the pyrrolylglyoxylyl chlorides with hexyne (Scheme 1).

Scheme 1

Synthesis of pyrrole–aminopyrimidines from pyrrol-2-ylhexynones and guanidine. Previous work [39].

This is likely due to the fact that, until recently, alkynones with n class="Chemical">pyrrole substituents were difficult to obtain. Such compounds have become readily available owing to the discovery of the cross-coupling reaction of pyrroles with acylhaloacetylenes in the medium of solid oxides and metal salts [40,41,42], and was widely used by us in the synthesis of diverse pyrrole heterocyclic ensembles and fused heterocyclic systems [42].

2. Results and Discussion

In the present paper, we have developed an effective method for the assembly of pyrrole–n class="Chemical">aminopyrimidines via the reaction of 2-acylethynylpyrroles 1a–v, obtained according to Scheme 2, with guanidine nitrate.

Scheme 2

Synthesis of 2-acylethynylpyrroles.

To commence the investigation, 2-benzoylethynyl-5-phenylpyrrole (1l, 1.0 equiv) was refluxed with n class="Chemical">guanidine nitrate (2, 1.0 equiv) in the presence of Na2CO3 (2.0 equiv) in MeCN for 4 h (Scheme 3). These conditions are known [36] to be effective for the synthesis of 2-aminopyrimidines from alkynones and guanidine. However, in our case, the yield of the target pyrrole–aminopyrimidine 3l did not exceed 11%.

Scheme 3

The reaction of 2-benzoylethynyl-5-phenylpyrrole (1l) with guanidine nitrate.

Therefore, in order to find optimal reaction conditions for the construction of pyrrole–n class="Chemical">aminopyrimidine ensembles, we screened combinations of bases, solvents, reagent ratio, temperature, and reaction time using the same pyrrole 1l and guanidine nitrate as reference reagents (Scheme 3, Table 1). The reaction was carried out open to air and controlled by the 1H-NMR spectroscopy.

Table 1

Effect of reaction conditions on the synthesis of pyrrole–aminopyrimidine ensemble 3l from 2-benzoylethynyl-5-phenylpyrrole (1l) and guanidine nitrate 2.

Entry	Base	Solvent	Ratio 1l/2/Base, mol	T, °C	Time, h	Content of 3l in the Reaction Mixture, % a
1	Na2CO3	MeCN	1/1/1.5	82	4	11 b
2	KOH	MeCN	1/1/1.5	82	4	68 c
3	Et3N	t-BuOH	1/1/1.5	82	4	0
4	DBU	t-BuOH	1/1/1.5	82	4	0 d
5	Cs2CO3	THF	1/2/1.5	66	4	0
6	Cs2CO3	THF	1/2/2	66	14	0
7	Cs2CO3	THF	1/2/4	66	18	15
8	Cs2CO3	THF	1/6/12	66	4	62
9	Cs2CO3	THF	1/10/20	66	4	68
10	Cs2CO3	THF	1/10/20	66	7	74
11	Cs2CO3	THF	1/10/20	66	12	89
12	Cs2CO3	THF	1/10/20	66	18	91
13	K3PO4	DMSO	1/5/6	20	16	0
14	K3PO4	DMSO	1/5/6	65–70	4	traces
15	K3PO4	DMSO	1/5/6	85–90	4	59 e
16	K3PO4	DMSO	1/5/6	85–90	6	80 e
17	KOH	DMSO	1/1/2	20	1	0
18	KOH	DMSO	1/2/4	70–75	13	93
19	KOH	DMSO	1/1/2	110–115	4	100 (77)
20	KOH	DMSO	1/1/1	110–115	4	95 (82)
21	KOH	DMSO	1/1.5/2	110–115	4	100 (88)
22	KOH	DMSO	1/1/1.5	110–115	4	100 (89)

a The isolated yield of the product is indicated in parentheses; b conversion of pyrrole 1l is 89%; c content of unidentified products is ~20%; d mixture of unidentified compounds; e strong tarring of the reaction mixture. THF: tetrahydrofuran; DMSO: dimethyl sulfoxide.

The results showed that the yield of the pyrrole–n class="Chemical">aminopyrimidine 3l depended on the nature of the base, solvent and other reaction conditions. As seen from Table 1, among the bases tested, only KOH, Cs2CO3 and K3PO4 demonstrated a good activity (entries 11, 12, 16 and 18–22). However, in the case of the latter two bases, a significant excess of both the base and guanidine should be used to achieve a preparatively acceptable yield of aminopyrimidine 3l. As the solvents, MeCN, t-BuOH, THF (tetrahydrofuran) and DMSO (dimethyl sulfoxide) were checked and it was established that yields of aminopyrimidine 3l reached a maximum, when the reaction was carried out in DMSO in the presence of KOH (entry 22). Using this catalytic system, the effect of the ratio of reagents and reaction conditions on the yield of the target product was examined. Finally, the desired aminopyrimidine 3l was obtained in 89% isolated yield, when 2-benzoylethynyl-5-phenylpyrrole (1l), guanidine and KOH in a ratio of 1:1:1.5 were reacted in DMSO at 110–115 °C for 4 h (entry 22).

Having established near to optimal reaction conditions, we have further investigated the substrate scope of this reaction (Figure 1). The experiments revealed that the reaction of 2-acylethynylpyrroles 1a–v with n class="Chemical">guanidine nitrate in these conditions proceeded efficiently and selectively thus offering a short-cut to pyrrole–aminopyrimidine ensembles 3a–v in good to high yields.

Figure 1

Synthesis of pyrrole–aminopyrimidine ensembles 3a–v from 2-acylethynylpyrroles 1a–v and guanidine nitrate. Reagents and conditions: (i) guanidine nitrate (0.40 mmol), KOH·0.5H2O (0.60 mmol), DMSO (8 mL), 110–115 °C, 0.5 h; (ii) 2-acylethynylpyrrole (0.40 mmol), 110–115 °C, 4 h.

As follows from Figure 1, the reaction tolerates different (aliphatic, cycloaliphatic, aromatic and vinyl) substituents in the pyrrole ring, i.e., the synthesis has quite general character.

The moderate yield of aminopyrimidine 3a is due to the formation of side products: 3-[2-(2-amino-6-phenylpyrimidin-4-yl)-1H-pyrrol-1-yl]-1-phenyl-3-(1H-pyrrol-2-yl)prop-2-en-1-one (4a, 13%) and 3-[2-amino-4-phenyl-6-(1H-pyrrol-2-yl)pyrimidin-5-yl]-1-phenyl-3-(1H-pyrrol-2-yl)prop-2-en-1-one (5a, 8%) (Scheme 4). Using the reagents ratio of 1a:2:KOH = 1:2:2.5 allowed to increase the yield of the aminopyrimidine 3a to 40%, the content of adduct 4a in this case in the reaction mixture did not exceed 6% and adduct 5 was not detected at all.

Scheme 4

The reaction of 2-benzoylethynylpyrrole 1a with guanidine nitrate.

The formation of pyrrole–aminopyrimidine 3, probably, proceeds as nucleophilic addition of guanidine to the triple bond of 2-acylethynylpyrrole 1, intramolecular cyclization of adduct A with participation of the carbonyl group and elimination of water from the intermediate 3,4-dihydropyrimidin-4-ol B (Scheme 5).

Scheme 5

Proposed route of pyrrole–aminopyrimidine ensembles 3 formation.

The formation of compound 4 likely involves the nucleophilic addition of N-anion C of adduct A, existing in the reaction mixture due to the deprotonating ability of the super-base n class="Chemical">KOH/DMSO system, to the starting 2-acylethynylpyrrole 1a (Scheme 6).

Scheme 6

Proposed route of adduct 4a formation.

Adduct 5, is, probably, a result of the attack of carbocentered anion D of the aminopyrimidine ring to the triple bond of pyrrole 1a (Scheme 7).

Scheme 7

Proposed route of adduct 5a formation.

A control experiment showed that adducts 4 and 5 did not result from the direct addition of aminopyrimidine 3a to the triple bond of the starting n class="Chemical">2-acylethynylpyrrole 1a.

3. Materials and Methods

3.1. General Procedures

1H, n class="Chemical">13C, 15N and 19F NMR spectra (Nuclear magnetic resonance spectra) were recorded in CDCl3 and DMSO-d6 using a Bruker Avance 400 NMR spectrometer (Germany, 400.13, 100.6, 40.5 and 376.5 MHz, respectively). The assignment of signals in the 1H NMR spectra was made using COSY and NOESY experiments. Resonance signals of carbon atoms were assigned based on 1H-13C HSQC and 1H-13C HMBC experiments. The values of the δ 15N were measured through the 2D 1H-15N HMBC experiment. The chemical shifts (δ) are given in ppm and referenced to residual solvent: 7.27 ppm (CDCl3) and 2.50 ppm (DMSO-d6) for 1H, 77.1 ppm (CDCl3) and 39.5 ppm (DMSO-d6) for 13C and 15N-MeNO2 (0.0 ppm), respectively. The 19F chemical shifts were referenced to CFCl3. Coupling constants in hertz (Hz) were measured from one-dimensional spectra and multiplicities were abbreviated as following: br (broad), s (singlet), d (doublet), dd (doublet of doublets), m (multiplet). The chemical shifts were recorded in ppm, coupling constants (J) in Hz. 1H-,13C- and 19F- NMR spectra of all new synthetized molecules available in Supplementary Materials.

Infrared (IR) spectra were obtained on a Varian 3100 IF-IR spectrometer (Germany; 400–4000 cm−1, KBr pellets or films). The (C, H, N) microanalyses were performed on a Flash EA 1112 CHn class="Chemical">NS-O/MAS (CHN Analyzer, Thermo Fisher Scientific, Monza, Italy) instrument. The chlorine and sulfur content was determined by using the titrimetric method. Fluorine content was determined on a SPECOL 11 (Carl Zeiss, Jena, Germany) spectrophotometer. Melting points (uncorrected) were determined with melting point SMP50 (Stone, Staffordshire, UK).

3.2. Synthetic Procedures

2-Acylethynylpyrroles 1a,f–l,n–r were obtained from pyrroles and 2-acylbromoacetylenes accordingly to methodology [40,41,42]. Physico-chemical characteristics 2-acylethynylpyrroles 1a,f–l,n–r were given in [40,43,44,45,46,47]. 2-Acylethynylpyrroles 1b,c–e,m,s–v were obtained accordingly to the following procedure:

The corresponding pyrrole (1 mmol) and acyl(bromo)acetylene (1 mmol) were carefully ground in a porcelain mortar with alumina [10-fold amount by weight of combined mass of pyrrole and acyl(bromo)acetylene] at 20–25 °C for 5 min. The reaction mixture was left for 2 h. Then the mixture was subjected to column chromatography (alumina, eluent–n-hexane/diethyl ether, gradient 1:0–1:1); this afforded pure 2-acylethynylpyrroles 1b,c–e,m,s–v.

3-(1-Methyl-1H-pyrrol-2-yl)-1-phenylprop-2-yn-1-one (1b): 182 mg (87%), yellow crystals, m.p. 59 °C; 1H-NMR (400.13 MHz, CDCl3) δ: 8.20–8.18 (m, 2H, H-2,6, COPh), 7.64–7.61 (m, 1H, H-4, COPh), 7.54–7.50 (m, 2H, H-3,5, COPh), 6.86–6.85 (m, 2H, H-3,5, pyrrole), 6.21–6.20 (m, 1H, H-4, pyrrole), 3.85 (s, 3H, NMe); 13C-NMR (100.6 MHz, CDCl3) δ: 176.9, 136.7, 133.4, 128.8 (2C), 128.3 (2C), 127.6, 120.9, 112.5, 109.4, 94.7, 87.4, 34.6; IR (KBr) ν: 3114, 2936, 2362, 2168, 1630, 1448, 1326, 1255, 1173, 1035, 998, 729, 695, 649. Anal. Calcd. for C14H11NO: C, 80.36%; H, 5.30%; N, 6.69%. Found: C, 80.12%; H, 5.03%; N, 6.37%.

3-(1-Benzyl-1H-pyrrol-2-yl)-1-phenylprop-2-yn-1-one (1c): 271 mg (95%), light yellow crystals, m.p. 111 °C; 1H-NMR (400.13 MHz, CDCl3) δ: 8.07–8.04 (m, 2H, H-2,6, COPh), 7.61–7.57 (m, 1H, H-4, COPh), 7.47–7.43 (m, 2H, H-3,5, COPh), 7.39–7.35 (m, 2H, H-3,5 Ph), 7.33–7.27 (m, 1H, H-4, Ph), 7.23–7.21 (m, 2H, H-2,6, Ph), 6.92–6.91 (m, 2H, H-3,5, pyrrole), 6.28–6.27 (m, 1H, H-4, pyrrole), 5.34 (s, 2H, CH2); 13C-NMR (100.6 MHz, CDCl3) δ: 177.4, 137.1, 133.7, 129.2 (2C), 129.0 (2C), 128.9, 128.6 (2C), 128.0, 127.2 (2C), 126.9, 121.4, 112.9, 110.3, 95.1, 87.3, 51.9; IR (KBr) ν: 3115, 3061, 3027, 2170, 1612, 1572, 1470, 1445, 1412, 1329, 1308, 1260, 1218, 1165, 1072, 1000, 748, 730, 697, 651. Anal. Calcd. for C20H15NO: C, 84.19%; H, 5.30%; N, 4.91%. Found: C, 84.12%; H, 5.37%; N, 4.87%.

3-(4-Ethyl-5-propyl-1H-pyrrol-2-yl)-1-phenylprop-2-yn-1-one (1d): 125 mg (47%), yellow crystals, m.p. 162 °C; 1H-NMR (400.13 MHz, CDCl3) δ: 8.57 (br s, 1H, NH), 8.19–8.16 (m, 2H, H-2,6, Ph), 7.61–7.58 (m, 1H, H-4, Ph), 7.51–7.47 (m, 2H, H-3,5, Ph), 6.74 (d, J = 2.3 Hz, 1H, H-3, pyrrole), 2.61–2.57 (m, 2H, CH2), 2.47–2.41 (m, 2H, CH2), 1.69–1.60 (m, 2H, CH2), 1.21–1.17 (m, 3H, CH3), 0.99–0.96 (m, 3H, CH3); 13C-NMR (100.6 MHz, CDCl3) δ: 177.7, 137.2, 136.2, 133.6, 129.3 (2C), 128.5 (2C), 124.8, 121.2, 107.1, 93.7, 91.5, 28.1, 22.8, 18.8, 15.3, 13.9; IR (KBr) ν: 3438, 2955, 2867, 2430, 2362, 2160, 1601, 1564, 1473, 1345, 1256, 1164, 1033, 829, 692, 645. Anal. Calcd. for C18H19NO: C, 81.47%; H, 7.22%; N, 5.28%. Found: C, 81.23%; H, 7.08%; N, 5.19%.

3-(5-Butyl-4-propyl-1H-pyrrol-2-yl)-1-phenylprop-2-yn-1-one (1e): 150 mg (51%), yellow crystals, m.p. 62–63 °C; 1H-NMR (400.13 MHz, CDCl3) δ: 8.57 (br s, 1H, NH), 8.19–8.17 (m, 2H, H-2,6, Ph), 7.61–7.58 (m, 1H, H-4, Ph), 7.51–7.48 (m, 2H, H-3,5, Ph), 6.71 (d, J = 2.3 Hz, 1H, H-3, pyrrole), 2.62–2.59 (m, 2H, CH2), 2.40–2.36 (m, 2H, CH2), 1.61–1.55 (m, 4H, 2CH2), 1.41–1.33 (m, 2H, CH2), 0.98–0.93 (m, 6H, 2CH3); 13C-NMR (100.6 MHz, CDCl3) δ: 177.7, 137.1, 137.0, 133.4, 129.2 (2C), 128.4 (2C), 122.9, 121.9, 106.9, 93.9, 92.4, 31.6, 27.6, 25.8, 24.0, 22.4, 13.9, 13.7; IR (film) ν: 3298, 2956, 2928, 2865, 2377, 2157, 1614, 1567, 1469, 1318, 1241, 1164, 1040, 976, 823, 698, 646. Anal. Calcd. for C20H23NO: C, 81.87%; H, 7.90%; N, 4.77%. Found: C, 81.64%; H, 7.55%; N, 4.70%.

1-(Furan-2-yl)-3-(5-phenyl-1H-pyrrol-2-yl)prop-2-yn-1-one (1m): 154 mg (59%), red crystals, m.p. 164 °C; 1H-NMR (400.13 MHz, CDCl3) δ: 9.15 (br s, 1H, NH), 7.69–7.68 (m, 1H, H-5, furyl), 7.57–7.55 (m, 2H, H-2,6, Ph), 7.45–7.39 (m, 3H, H-3,4,5, Ph), 7.34–7.30 (m, 1H, H-3, furyl), 6.91 (dd, J = 2.5, 3.8 Hz, 1H, H-3, pyrrole), 6.60–6.57 (m, 2H, H-4, furyl, H-4, pyrrole); 13C-NMR (100.6 MHz, CDCl3) δ: 164.7, 153.2, 147.7, 137.7, 131.0, 129.2 (2C), 128.1, 124.8 (2C), 122.6, 120.1, 112.7, 110.7, 108.4, 92.5, 88.1; IR (KBr) ν: 3311, 2172, 1661, 1608, 1550, 1457, 1388, 1258, 1160, 1043, 972, 910, 760, 695, 593. Anal. Calcd. for C17H11NO2: C, 78.15%; H, 4.24%; N, 5.36%. Found: C, 78.04%; H, 4.13%; N, 5.22%.

3-(4,5-Diphenyl-1-vinyl-1H-pyrrol-2-yl)-1-phenylprop-2-yn-1-one (1s): 291 mg (78%), yellow crystals, m.p. 106 °C; 1H-NMR (400.13 MHz, CDCl3) δ: 8.21–8.20 (m, 2H, Ph), 7.65–7.62 (m, 1H, Ph), 7.55–7.51 (m, 2H, Ph), 7.42–7.40 (m, 3H, Ph), 7.33–7.31 (m, 2H, Ph), 7.23–7.15 (m, 6H, Ph, H-3, pyrrole), 6.79 (dd, J = 9.0, 15.8 Hz, 1H, HX), 5.19 (d, J = 15.8 Hz, 1H, HB), 5.67 (d, J = 9.0 Hz, 1H, HA); 13C-NMR (100.6 MHz, CDCl3) δ: 177.4, 137.1, 135.3, 134.2, 133.8, 131.0 (2C), 130.9, 130.6, 129.4 (2C), 128.8, 128.7 (2C), 128.6 (2C), 128.4 (2C), 128.1 (2C), 126.5, 125.2, 123.1, 111.9, 108.8, 95.4, 87.8; IR (KBr) ν: 3060, 2162, 1617, 1575, 1455, 1385, 1310, 1269, 1165, 1008, 821, 767, 697. Anal. Calcd. for C27H19NO: C, 86.84%; H, 5.13%; N, 3.75%. Found: C, 86.61%; H, 5.03%; N, 3.88%.

3-(5-(4-Chlorophenyl)-1-vinyl-1H-pyrrol-2-yl)-1-phenylprop-2-yn-1-one (1t): 289 mg (87%), yellow crystals, m.p. 100–102 °C; 1H-NMR (400.13 MHz, CDCl3) δ: 8.19–8.17 (m, 2H, H-2,6, COPh), 7.64–7.61 (m, 1H, H-4, COPh), 7.54–7.50 (m, 2H, H-3,5, COPh), 7.41–7.40 (m, 4H, H-2,3,5,6, 4-Cl-C6H4), 7.02 (d, J = 3.9 Hz, 1H, H-3, pyrrole), 6.88 (dd, J = 8.8, 15.8 Hz, 1H, HX), 6.36 (d, J = 3.9 Hz, 1H, H-4, pyrrole), 5.69 (d, J = 15.8 Hz, 1H, HB), 5.32 (d, J = 8.8 Hz, 1H, HA); 13C-NMR (100.6 MHz, CDCl3) δ: 177.4, 137.8, 137.0, 134.4, 133.9, 130.7, 130.2 (2C), 129.9, 129.4 (2C), 128.9 (2C), 128.6 (2C), 123.4, 113.6, 111.7, 110.3, 95.4, 87.7; IR (film) ν: 3063, 2236, 2172, 1630, 1458, 1313, 1259, 1093, 993, 780, 698. Anal. Calcd. for C21H14NOCl: C, 76.02%; H, 4.25%; Cl, 10.68%; N, 4.22%. Found: C, 75.91%; H, 4.11%; Cl, 10.57%; N, 4.37%.

3-(5-(2-Fluorophenyl)-1-vinyl-1H-pyrrol-2-yl)-1-(furan-2-yl)prop-2-yn-1-one (1u): 226 mg (74%), yellow crystals, m.p. 55–57 °C; 1H-NMR (400.13 MHz, CDCl3) δ: 7.68–7.67 (m, 1H, H-5, furyl), 7.44–7.35 (m, 3H, H-4,5,6, 2-F-C6H4), 7.25–7.15 (m, 2H, H-3, 2-F-C6H4, H-3, furyl), 7.01 (d, J = 3.8 Hz, 1H, H-3, pyrrole), 6.89 (dd, J = 8.9, 15.8 Hz, 1H, HX), 6.60 (dd, J = 1.8, 3.7 Hz, 1H, H-4, furyl), 6.37 (d, J = 3.8 Hz, 1H, H-4, pyrrole), 5.57 (d, J = 15.8 Hz, 1H, HB), 5.14 (d, J = 8.9 Hz, 1H, HA); 13C-NMR (100.6 MHz, CDCl3) δ: 164.1, 159.3 (d, 1JCF = 249.2 Hz, C-2, 2-F-C6H4), 152.8, 147.5, 132.5, 131.5, 130.5 (d, 3JCF = 8.3 Hz, C-4, 2-F-C6H4), 130.2 (d, 4JCF = 2.4 Hz, C-5, 2-F-C6H4), 124.1 (d, 3JCF = 3.7 Hz, C-6, 2-F-C6H4), 123.0, 119.8, 119.1 (d, 2JCF = 14.9 Hz, C-1, 2-F-C6H4), 115.9 (d, 2JCF = 21.6 Hz, C-3, 2-F-C6H4), 112.8, 112.5 (2C), 108.0, 94.1, 86.3; 19F-NMR (376.5 MHz, CDCl3) δ: −112.8. IR (KBr) ν: 2925, 2361, 2175, 1626, 1458, 1394, 1280, 1037, 759. Anal. Calcd. for C19H12FNO2: C, 74.75%; H, 3.96%; F, 6.22%; N, 4.59%. Found: C, 74.68%; H, 3.77%; F, 6.18%; N, 4.63%.

3-(5-(2-Fluorophenyl)-1-vinyl-1H-pyrrol-2-yl)-1-(thiophen-2-yl)prop-2-yn-1-one (1v): 260 mg (81%), yellow crystals, m.p. 67–69 °C; 1H-NMR (400.13 MHz, CDCl3) δ: 7.94 (dd, J = 1.0, 3.8 Hz, 1H, H-3, thienyl), 7.72 (dd, J = 1.0, 4.9 Hz, 1H, H-5, thienyl), 7.44–7.38 (m, 2H, H-4,6, 2-F-C6H4), 7.25–7.15 (m, 3H, H-3,5, 2-F-C6H4, H-4, thienyl), 7.02 (d, J = 3.8 Hz, 1H, H-3, pyrrole), 6.90 (dd, J = 8.8, 15.8 Hz, 1H, HX), 6.39 (d, J = 3.8 Hz, 1H, H-4, pyrrole), 5.53 (d, J = 15.8 Hz, 1H, HB), 5.16 (d, J = 8.8 Hz, 1H, HA); 13C-NMR (100.6 MHz, CDCl3) δ: 168.9, 159.4 (d, 1JCF = 249.2 Hz, C-2, 2-F-C6H4), 144.7, 134.6, 134.2, 132.4, 131.5 (d, 4JCF = 2.9 Hz, C-5, 2-F-C6H4), 130.5 (d, 3JCF= 7.9 Hz, C-4, 2-F-C6H4), 130.3, 128.2, 124.2 (d, 3JCF = 3.7 Hz, C-6, 2-F-C6H4), 123.0, 119.2 (d, 2JCF = 14.5 Hz, C-1, 2-F-C6H4), 115.9 (d, 2JCF = 22.0 Hz, C-3, 2-F-C6H4), 112.9, 112.7, 108.5, 94.2, 85.9; 19F-NMR (376.5 MHz, CDCl3) δ: −112.6. IR (KBr) ν: 2925, 2859, 2361, 2170, 1603, 1462, 1409, 1267, 1226, 1045, 966, 760, 716. Anal. Calcd. for C19H12FNOS: C, 71.01%; H, 3.76%; F, 5.91%; N, 4.36%; S, 9.98%. Found: C, 70.88%; H, 3.66%; F, 5.70%; N, 4.45%; S, 9.61%.

General Procedure for the pyrrole–n class="Chemical">aminopyrimidine ensembles3a–vsynthesis: A mixture of guanidine nitrate (49 mg, 0.40 mmol) and KOH·0.5H2O (39 mg, 0.60 mmol) was stirred in DMSO (8 mL) at 110–115 °C for 30 min. Then the 2-acylethynylpyrrole 1 (0.40 mmol) was added, and the mixture was stirred for 4 h. After cooling to 20–25 °C, the reaction mixture was diluted with saturated solution of NaCl (40 mL). The precipitate was filtered off, washed with water (3 × 20 mL) and dried. The obtained pyrrole–aminopyrimidines were purified by column chromatography (SiO2, eluent–n-hexane/diethyl ether, gradient 1:0–0:1).

4-Phenyl-6-(1H-pyrrol-2-yl)pyrimidin-2-amine (3a): 24 mg (25%), beige crystals, m.p. 96 °C; 1H-NMR (400.13 MHz, CDCl3) δ: 9.75 (br s, 1H, NH), 8.04–8.02 (m, 2H, H-2,6, Ph), 7.50–7.49 (m, 3H, H-3,4,5, Ph), 7.28 (s, 1H, H-5, pyrimidine), 6.95–6.92 (m, 2H, H-3,5, pyrrole), 6.35–6.34 (m, 1H, H-4, pyrrole), 5.13 (br s, 2H, NH2); 13C-NMR (100.6 MHz, CDCl3) δ: 165.5 (C-6, pyrimidine), 163.3 (C-2, pyrimidine), 158.3 (C-4, pyrimidine), 137.8 (C-1, Ph), 130.4 (C-4, Ph), 129.9 (C-2, pyrrole), 128.8 (C-3,5, Ph), 127.1 (C-2,6, Ph), 121.5 (C-5, pyrrole), 110.8 (C-4, pyrrole), 110.5 (C-3, pyrrole), 101.9 (C-5, pyrimidine); 15N-NMR (40.5 MHz, CDCl3) δ: −304.9 (NH2), −233.8 (NH), −157.3 (N-1), −148.9 (N-3); IR (KBr) ν: 3464, 3418, 3350, 3175, 1634, 1582, 1555, 1534, 1468, 1454, 1423, 1359, 1257, 1227, 1112, 1035, 997, 911, 880, 773, 732, 701. Anal. Calcd. for C14H12N4: C, 71.17%; H, 5.12%; N, 23.71%. Found: C, 70.83%; H, 4.74%; N, 23.45%.

4-(1-Methyl-1H-pyrrol-2-yl)-6-phenylpyrimidin-2-amine (3b): 81 mg (81%), beige crystals, m.p. 129 °C; 1H-NMR (400.13 MHz, CDCl3) δ: 8.03–8.01 (m, 2H, H-2,6, Ph), 7.49–7.48 (m, 3H, H-3,4,5, Ph), 7.29 (s, 1H, H-5, pyrimidine), 6.85–6.84 (m, 1H, H-5, pyrrole), 6.79–6.78 (m, 1H, H-3, pyrrole), 6.21–6.20 (m, 1H, H-4, pyrrole), 5.07 (br s, 2H, NH2), 4.08 (s, 3H, NMe); 13C-NMR (100.6 MHz, CDCl3) δ: 165.1, 163.0, 160.6, 138.8, 130.4, 130.2, 128.7 (2C), 128.3, 127.0 (2C), 113.4, 108.2, 104.4, 37.7; IR (KBr) ν: 3478, 3319, 3199, 3059, 2956, 1628, 1570, 1528, 1487, 1455, 1433, 1381, 1345, 1216, 1117, 1090, 1057, 838, 802, 766, 736, 694, 644. Anal. Calcd. for C15H14N4: C, 71.98%; H, 5.64%; N, 22.38%. Found: C, 71.80%; H, 5.48%; N, 22.31%.

4-(1-Benzyl-1H-pyrrol-2-yl)-6-phenylpyrimidin-2-amine (3c): 107 mg (82%), light yellow crystals, m.p. 112–114 °C; 1H-NMR (400.13 MHz, CDCl3) δ: 7.99–7.97 (m, 2H, H-2,6, Ph), 7.47–7.46 (m, 3H, H-3,4,5, Ph), 7.31–7.26 (m, 3H, H-3,5, CH2Ph, H-5, pyrimidine), 7.24–7.20 (m, 1H, H-4, CH2Ph), 7.11–7.09 (m, 2H, H-2,6, CH2Ph), 6.92–6.91 (m, 1H, H-5, pyrrole), 6.89–6.88 (m, 1H, H-3, pyrrole), 6.29–6.28 (m, 1H, H-4, pyrrole), 5.82 (s, 2H, CH2), 4.97 (br s, 2H, NH2); 13C-NMR (100.6 MHz, CDCl3) δ: 165.1, 162.9, 160.4, 139.5, 138.0, 130.2, 130.1, 128.7 (2C), 128.6 (2C), 128.0, 127.2, 127.0 (2C), 126.7 (2C), 113.9, 108.9, 104.5, 52.6; IR (KBr) ν: 3493, 3319, 3197, 3113, 3023, 2926, 1625, 1569, 1537, 1479, 1453, 1430, 1407, 1359, 1229, 1114, 1087, 1025, 834, 802, 769, 739, 720, 694, 643. Anal. Calcd. for C21H18N4: C, 77.28%; H, 5.56%; N, 17.17%. Found: C, 77.20%; H, 5.49%; N, 17.23%.

4-(4-Ethyl-5-propyl-1H-pyrrol-2-yl)-6-phenylpyrimidin-2-amine (3d): 103 mg (84%), yellow crystals, m.p. 162 °C; 1H-NMR (400.13 MHz, CDCl3) δ: 9.19 (br s, 1H, NH), 8.02–8.01 (m, 2H, H-2,6, Ph), 7.48–7.47 (m, 3H, H-3,4,5, Ph), 7.20 (s, 1H, H-5, pyrimidine), 6.75 (d, J = 2.2 Hz, 1H, H-3, pyrrole), 4.95 (br s, 2H, NH2), 2.61–2.57 (m, 2H, CH2), 2.49–2.44 (m, 2H, CH2), 1.69–1.64 (m, 2H, CH2), 1.24–1.20 (m, 3H, CH3), 1.00–0.96 (m, 3H, CH3); 13C-NMR (100.6 MHz, CDCl3) δ: 165.0, 163.2, 158.1, 138.1, 133.2, 130.1, 128.7 (2C), 127.1, 127.0 (2C), 124.6, 110.7, 101.3, 28.0, 23.1, 19.0, 15.6, 13.9; IR (KBr) ν: 3483, 3307, 3184, 2959, 2927, 2867, 1631, 1589, 1566, 1536, 1501, 1458, 1420, 1370, 1324, 1237, 1188, 1072, 1006, 920, 824, 768, 696, 642. Anal. Calcd. for C19H22N4: C, 74.48%; H, 7.24%; N, 18.29%. Found: C, 74.31%; H, 7.11%; N, 17.98%.

4-(5-Butyl-4-propyl-1H-pyrrol-2-yl)-6-phenylpyrimidin-2-amine (3e): 122 mg (91%), yellow crystals, m.p. 98–99 °C; 1H-NMR (400.13 MHz, CDCl3) δ: 9.19 (br s, 1H, NH), 8.03–8.00 (m, 2H, H-2,6, Ph), 7.48–7.46 (m, 3H, H-3,4,5, Ph), 7.19 (s, 1H, H-5, pyrimidine), 6.72 (d, J = 2.2 Hz, 1H, H-3, pyrrole), 4.98 (br s, 2H, NH2), 2.62–2.58 (m, 2H, CH2), 2.43–2.39 (m, 2H, CH2), 1.67–1.57 (m, 4H, 2CH2), 1.44–1.35 (m, 2H, CH2), 1.00–0.93 (m, 6H, 2CH3); 13C-NMR (100.6 MHz, CDCl3) δ: 164.9, 163.2, 158.1, 138.1, 133.9, 130.1, 128.7 (2C), 127.0, 126.9 (2C), 122.8, 111.4, 101.3, 32.0, 28.0, 25.7, 24.3, 22.6, 14.1, 13.9; IR (KBr) ν: 3484, 3450, 3311, 3191, 2954, 2926, 2863, 1635, 1588, 1565, 1535, 1500, 1459, 1421, 1370, 1333, 1231, 1188, 1073, 1008, 919, 812, 766, 696, 644. Anal. Calcd. for C21H26N4: C, 75.41%; H, 7.84%; N, 16.75%. Found: C, 75.34%; H, 7.63%; N, 16.51%.

4-Phenyl-6-(4,5,6,7-tetrahydro-1H-indol-2-yl)pyrimidin-2-amine (3f): 95 mg (82%), dark orange crystals, m.p. 100–102 °C; 1H-NMR (400.13 MHz, CDCl3) δ: 9.32 (br s, 1H, NH), 8.03–8.01 (m, 2H, H-2,6, Ph), 7.48–7.47 (m, 3H, H-3,4,5, Ph), 7.20 (s, 1H, H-5, pyrimidine), 6.68 (d, J = 2.0 Hz, 1H, H-3, pyrrole), 5.03 (br s, 2H, NH2), 2.62–2.55 (m, 4H, CH2-4,7), 1.84–1.79 (m, 4H, CH2-5,6); 13C-NMR (100.6 MHz, CDCl3) δ: 165.0, 163.1, 158.3, 138.0, 132.2, 130.2, 128.7 (2C), 127.8, 127.0 (2C), 120.2, 110.0, 101.4, 23.7, 23.1, 22.9, 22.8; IR (KBr) ν: 3404, 3311, 3195, 3060, 2925, 2848, 1593, 1568, 1535, 1503, 1423, 1346, 1224, 1143, 1005, 830, 808, 770, 695. Anal. Calcd. for C18H18N4: C, 74.46%; H, 6.25%; N, 19.30%. Found: C, 74.14%; H, 6.05%; N, 19.18%.

4-(1-Methyl-4,5,6,7-tetrahydro-1H-indol-2-yl)-6-phenylpyrimidin-2-amine (3g): 99 mg (81%), dark yellow crystals, m.p. 182 °C; 1H-NMR (400.13 MHz, CDCl3) δ: 8.01–7.99 (m, 2H, H-2,6, Ph), 7.48–7.47 (m, 3H, H-3,4,5, Ph), 7.23 (s, 1H, H-5, pyrimidine), 6.64 (s, 1H, H-3, pyrrole), 5.04 (br s, 2H, NH2), 3.91 (s, 3H, NMe), 2.63–2.60 (m, 2H, CH2-7), 2.57–2.54 (m, 2H, CH2-4), 1.91–1.86 (m, 2H, CH2-6), 1.79–1.75 (m, 2H, CH2-5); 13C-NMR (100.6 MHz, DMSO-d6) δ: 163.1, 162.9, 160.3, 137.7, 134.3, 129.9, 128.4 (2C), 128.1, 126.6 (2C), 117.2, 112.0, 101.5, 32.6, 23.1, 22.7, 22.6, 21.7; IR (KBr) ν: 3489, 3376, 2941, 2915, 2363, 1604, 1585, 1561, 1530, 1495, 1449, 1401, 1369, 1223, 1183, 1147, 826, 803, 772, 695. Anal. Calcd. for C19H20N4: C, 74.97%; H, 6.62%; N, 18.41%. Found: C, 74.58%; H, 6.41%; N, 18.32%.

4-(2-Furyl)-6-(1-methyl-4,5,6,7-tetrahydro-1H-indol-2-yl)pyrimidin-2-amine (3h): 64 mg (54%), light brown crystals, m.p. 218 °C; 1H-NMR (400.13 MHz, CDCl3) δ: 7.56–7.55 (m, 1H, H-5, furyl), 7.17 (s, 1H, H-5, pyrimidine), 7.10–7.09 (m, 1H, H-3, furyl), 6.65 (s, 1H, H-3, pyrrole), 6.54 (dd, J = 1.3, 2.0 Hz, 1H, H-4, furyl), 4.99 (br s, 2H, NH2), 3.90 (s, 3H, NMe), 2.61–2.58 (m, 2H, CH2-7), 2.56–2.53 (m, 2H, CH2-4), 1.90–1.84 (m, 2H, CH2-6), 1.78–1.74 (m, 2H, CH2-5); 13C-NMR (100.6 MHz, CDCl3) δ: 162.7, 160.7, 155.4, 152.6, 144.1, 135.4, 128.7, 118.6, 112.3, 112.1, 110.7, 102.0, 33.0, 23.5, 23.2, 23.0, 22.5; IR (KBr) ν: 3474, 3298, 3182, 2931, 2839, 1606, 1544, 1533, 1489, 1449, 1398, 1369, 1223, 1183, 1146, 1010, 953, 800, 753, 743. Anal. Calcd. for C17H18N4O: C, 69.37%; H, 6.16%; N, 19.03%. Found: C, 69.14%; H, 6.05%; N, 19.04%.

4-(1-Benzyl-4,5,6,7-tetrahydro-1H-indol-2-yl)-6-phenylpyrimidin-2-amine (3i): 73 mg (48%), yellow crystals, m.p. 128–129 °C; 1H-NMR (400.13 MHz, CDCl3) δ: 8.00–7.98 (m, 2H, H-2,6, Ph), 7.49–7.48 (m, 3H, H-3,4,5, Ph), 7.33–7.22 (m, 4H, H-5, pyrimidine, H-3,4,5, CH2Ph), 7.06–7.04 (m, 2H, H-2,6, CH2Ph), 6.79 (s, 1H, H-3, pyrrole), 5.82 (s, 2H, CHPh), 4.90 (br s, 2H, NH2), 2.63–2.61 (m, 2H, CH2-7), 2.53–2.51 (m, 2H, CH2-4), 1.85–1.78 (m, 4H, CH2-5,6); 13C-NMR (100.6 MHz, CDCl3) δ: 164.6, 162.8, 160.5, 139.7, 138.2, 135.5, 130.0, 128.8, 128.7 (2C), 128.5 (2C), 127.0 (2C), 126.7, 126.2 (2C), 119.1, 112.7, 104.1, 48.6, 23.5, 23.2, 23.1, 22.4; IR (KBr) ν: 3426, 3299, 3188, 3031, 2926, 2847, 2361, 1965, 1622, 1560, 1497, 1442, 1409, 1340, 1232, 1177, 1104, 830, 768, 699. Anal. Calcd. for C25H24N4: C, 78.92%; H, 6.36%; N, 14.73%. Found: C, 78.83%; H, 6.30%; N, 14.80%.

4-(1-Benzyl-4,5,6,7-tetrahydro-1H-indol-2-yl)-6-(2-furyl)pyrimidin-2-amine (3j): 87 mg (59%), dark yellow crystals, m.p. 182 °C; 1H-NMR (400.13 MHz, CDCl3) δ: 7.54–7.53 (m, 1H, H-5, furyl), 7.28–7.25 (m, 2H, H-2,6, Ph), 7.21–7.18 (m, 2H, H-5, pyrimidine, H-4, Ph), 7.06–7.05 (m, 1H, H-3, furyl), 7.01–6.99 (m, 2H, H-3,5, Ph), 6.75 (s, 1H, H-3, pyrrole), 6.52 (dd, J = 1.8, 3.2 Hz, 1H, H-4, furyl), 5.78 (s, 2H, CHPh), 4.80 (br s, 2H, NH2), 2.59–2.56 (m, 2H, CH2-7), 2.50–2.47 (m, 2H, CH2-4), 1.82–1.72 (m, 4H, CH2-5,6); 13C-NMR (100.6 MHz, CDCl3) δ: 162.6, 160.5, 155.4, 152.6, 144.1, 139.6, 135.7, 128.5 (2C), 128.4, 126.7, 126.2 (2C), 119.1, 113.0, 112.1, 110.6, 101.8, 48.5, 23.5, 23.1, 23.0, 22.4; IR (KBr) ν: 3315, 3178, 2997, 2935, 2843, 1643, 1603, 1549, 1495, 1458, 1406, 1377, 1242, 1180, 1146, 1103, 1019, 951, 810, 764, 734, 694. Anal. Calcd. for C23H22N4O: C, 74.57%; H, 5.99%; N, 15.12%. Found: C, 74.28%; H, 5.78%; N, 15.04%.

4-Phenyl-6-(1-vinyl-4,5,6,7-tetrahydro-1H-indol-2-yl)pyrimidin-2-amine (3k): 82 mg (65%), yellow crystals, m.p. 118 °C; 1H-NMR (400.13 MHz, CDCl3) δ: 8.01–7.99 (m, 2H, H-2,6 Ph), 7.51–7.44 (m, 4H, H-3,4,5, Ph, HX), 7.23 (s, 1H, H-5, pyrimidine), 6.68 (s, 1H, H-3, pyrrole), 5.10 (br s, 2H, NH2), 5.04 (d, J = 16.0 Hz, 1H, HB), 5.01 (d, J = 8.9Hz, 1H, HA), 2.75–2.72 (m, 2H, CH2-7), 2.59–2.56 (m, 2H, CH2-4), 1.86–1.76 (m, 4H, CH2-6, CH2-5); 13C-NMR (100.6 MHz, CDCl3) δ: 165.0, 163.0, 160.2, 138.1, 134.1, 133.1, 130.2, 129.8, 128.8 (2C), 127.0 (2C), 120.4, 113.7, 105.4, 105.0, 24.8, 23.6, 23.2, 23.1; IR (KBr) ν: 3485, 3312, 3199, 2927, 2847, 1636, 1564, 1537, 1501, 1459, 1397, 1368, 1227, 1184, 1145, 980, 861, 827, 766, 698, 642. Anal. Calcd. for C20H20N4: C, 75.92%; H, 6.37%; N, 17.71%. Found: C, 75.87%; H, 6.33%; N, 17.81%.

4-Phenyl-6-(5-phenyl-1H-pyrrol-2-yl)pyrimidin-2-amine (3l): 111 mg (89%), brown crystals, m.p. 194–196 °C; 1H-NMR (400.13 MHz, DMSO-d6) δ: 11.55 (br s, 1H, NH), 8.17–8.15 (m, 2H, Ph), 7.88–7.85 (m, 2H, Ph), 7.68 (s, 1H, H-5, pyrimidine), 7.53–7.52 (m, 4H, Ph), 7.28–7.24 (m, 2H, Ph), 7.06–7.05 (m, 1H, H-3, pyrrole), 6.66–6.65 (m, 1H, H-4, pyrrole), 6.47 (br s, 2H, NH2); 13C-NMR (100.6 MHz, DMSO-d6) δ: 163.9, 163.7, 158.1, 137.5, 134.4, 131.8, 130.2, 128.6 (2C), 128.5 (2C), 126.7 (2C), 126.6 (2C), 115.6, 115.4, 112.5, 108.2, 99.9; IR (KBr) ν: 3442, 3369, 3274, 3161, 3058, 1602, 1570, 1537, 1457, 1432, 1366, 1301, 1235, 1071, 1046, 1002, 912, 836, 755, 691, 614. Anal. Calcd. for C20H16N4: C, 76.90%; H, 5.16%; N, 17.94%. Found: C, 76.75%; H, 5.04%; N, 17.88%.

4-(2-Furyl)-6-(5-phenyl-1H-pyrrol-2-yl)pyrimidin-2-amine (3m): 93 mg (77%), brown crystals, m.p. 208–210 °C; 1H-NMR (400.13 MHz, DMSO-d6) δ: 11.59 (br s, 1H, NH), 7.92–7.91 (m, 1H, H-5, furyl), 7.85–7.83 (m, 2H, H-2,6, Ph), 7.50 (s, 1H, H-5, pyrimidine), 7.43–7.39 (m, 2H, H-3,5, Ph), 7.27–7.23 (m, 1H, H-4, Ph), 7.16–7.15 (m, 1H, H-3, furyl), 7.01–7.00 (m, 1H, H-4, furyl), 6.71–6.69 (m, 2H, H-3,4, pyrrole), 6.50 (br s, 2H, NH2); 13C-NMR (100.6 MHz, DMSO-d6) δ: 163.5, 158.1, 155.7, 152.5, 145.0, 135.5, 131.9, 131.7 128.7 (2C), 126.7, 124.7 (2C), 112.6, 112.5, 110.9, 108.3, 98.1; IR (KBr) ν: 3482, 3454, 3298, 3181, 2924, 1631, 1588, 1566, 1541, 1445, 1386, 1351, 1299, 1237, 1214, 1160, 1044, 1011, 879, 812, 750, 681, 595, 554, 424. Anal. Calcd. for C18H14N4O: C, 71.51%; H, 4.67%; N, 18.53%. Found: C, 71.39%; H, 4.59%; N, 18.65%.

4-[5-(4-Fluorophenyl)-1H-pyrrol-2-yl]-6-phenylpyrimidin-2-amine (3n): 116 mg (88%), light yellow crystals, m.p. 221–222 °C; 1H-NMR (400.13 MHz, CDCl3) δ: 9.75 (br s, 1H, NH), 8.05–8.03 (m, 2H, H-2,6, Ph), 7.59–7.56 (m, 2H, H-2,6, 4-F-C6H4), 7.51–7.49 (m, 3H, H-3,4,5, Ph), 7.29 (s, 1H, H-5, pyrimidine), 7.14–7.09 (m, 2H, H-3,5, 4-F-C6H4), 6.96 (dd, J = 0.8, 2.6 Hz, 1H, H-3, pyrrole), 6.57 (dd, J = 0.8, 2.9 Hz, 1H, H-4, pyrrole), 5.07 (br s, 2H, NH2); 13C NMR (100.6 MHz, DMSO-d6) δ: 163.5 (C-2, pyrimidine), 163.3 (C-6, pyrimidine), 160.7 (d, 1JCF = 243.9 Hz, C-4, 4-F-C6H4), 157.7 (C-4, pyrimidine), 137.1 (C-1, Ph), 134.0 (C-5, pyrrole), 131.5 (C-2, pyrrole), 129.8 (C-4, Ph), 128.2 (d, 4JCF = 2.9 Hz, C-1, 4-F-C6H4), 128.1 (C-3,5, Ph), 126.3 (C-2,6, Ph), 126.2 (d, 3JCF = 8.7 Hz, C-2,6, 4-F-C6H4), 115.1 (d, 2JCF = 21.5 Hz, C-3,5, 4-F-C6H4), 112.0 (C-3, pyrrole), 107.8 (C-4, pyrrole), 99.5 (C-5, pyrimidine); 15N-NMR (40.5 MHz, DMSO-d6) δ: −298.9 (NH2), −233.8 (NH, pyrrole), −151.2 (N-3), −147.4 (N-1); IR (KBr) ν: 3445, 3388, 3270, 3159, 1602, 1575, 1524, 1478, 1451, 1433, 1366, 1301, 1233, 1157, 1047, 832, 765, 697. Anal. Calcd. for C20H15FN4: C, 72.71%; H, 4.58%; F, 5.75%; N, 16.96%. Found: C, 72.62%; H, 4.48%; F, 5.60%; N, 17.07%.

4-[5-(4-Chlorophenyl)-1H-pyrrol-2-yl]-6-phenylpyrimidin-2-amine (3o): 117 mg (84%), brown crystals, m.p. 226 °C; 1H-NMR (400.13 MHz, CDCl3) δ: 9.80 (br s, 1H, NH), 8.05–8.03 (m, 2H, H-2,6, Ph), 7.54–7.49 (m, 5H, H-3,4,5, Ph, H-2,6, 4-Cl-C6H4), 7.39–7.37 (m, 2H, H-3,5, 4-Cl-C6H4), 7.29 (s, 1H, H-5, pyrimidine), 6.96–6.95 (m, 1H, H-3, pyrrole), 6.62–6.61 (m, 1H, H-4, pyrrole), 5.11 (br s, 2H, NH2); 13C-NMR (100.6 MHz, DMSO-d6) δ: 164.0, 163.7, 158.1, 137.5, 134.1, 132.3, 131.0, 130.9, 130.3, 128.7 (2C), 128.6 (2C), 126.8 (2C), 126.3 (2C), 112.6, 108.9, 100.1; IR (KBr) ν: 3434, 2925, 2858, 1622, 1583, 1531, 1470, 1432, 1360, 1290, 1231, 1113, 1095, 1048, 829, 770, 692; Anal. Calcd. for C20H15ClN4: C, 69.26%; H, 4.36%; Cl, 10.22%; N, 16.15%. Found: C, 69.13%; H, 4.28%; Cl, 10.14%; N, 16.09%.

4-[5-(4-Methoxyphenyl)-1H-pyrrol-2-yl]-6-phenylpyrimidin-2-amine (3p): 108 mg (79%), yellow crystals, m.p. 217 °C; 1H-NMR (400.13 MHz, CDCl3) δ: 9.72 (br s, 1H, NH), 8.05–8.02 (m, 2H, H-2,6, Ph), 7.56–7.54 (m, 2H, H-2,6, 4-MeO-C6H4), 7.50–7.49 (m, 3H, H-3,4,5, Ph), 7.28 (s, 1H, H-5, pyrimidine), 6.97–6.95 (m, 3H, H-3,5, 4-MeO-C6H4, H-3, pyrrole), 6.54 (dd, J = 0.6, 2.9 Hz, 1H, H-4, pyrrole), 5.06 (br s, 2H, NH2), 3.85 (s, 3H, MeO); 13C-NMR (100.6 MHz, DMSO-d6) δ: 163.9, 163.8, 158.4, 158.3, 137.7, 135.7, 131.1, 130.4, 128.7 (2C), 126.8 (2C), 126.2 (2C), 124.9, 114.3 (2C), 112.8, 107.4, 99.9, 55.3; IR (KBr) ν: 3484, 3430, 3298, 3144, 2953, 2928, 1634, 1569, 1530, 1479, 1455, 1433, 1359, 1251, 1178, 1048, 1030, 1005, 833, 774, 706, 645. Anal. Calcd. for C21H18N4O: C, 73.67%; H, 5.30%; N, 16.36%. Found: C, 73.59%; H, 5.24%; N, 16.27%.

4-Phenyl-6-(1-methyl-5-phenyl-1H-pyrrol-2-yl)pyrimidin-2-amine (3q): 91 mg (70%), yellow crystals, m.p. 60–62 oC; 1H-NMR (400.13 MHz, CDCl3) δ: 8.05–8.03 (m, 2H, H-2,6, Ph), 7.49–7.44 (m, 7H, Ph), 7.40–7.36 (m, 1H, H-4, Ph), 7.33 (s, 1H, H-5, pyrimidine), 6.90 (d, J = 3.8 Hz, 1H, H-3, pyrrole), 6.32 (d, J = 3.8 Hz, 1H, H-4, pyrrole), 5.11 (br s, 2H, NH2), 3.98 (s, 3H, NMe); 13C-NMR (100.6 MHz, CDCl3) δ: 165.2, 163.0, 160.7, 140.8, 138.1, 132.9, 132.6, 130.3, 129.3 (2C), 128.8 (2C), 128.6 (2C), 127.6, 127.1 (2C), 113.5, 109.6, 105.1, 35.7; IR (KBr) ν: 3476, 3397, 3303, 3182, 3059, 1565, 1528, 1455, 1293, 1347, 1312, 1221, 1113, 1087, 1027, 989, 919, 836, 757, 695, 642. Anal. Calcd. for C21H18N4: C, 77.28%; H, 5.56%; N, 17.17%. Found: C, 77.03%; H, 5.32%; N, 17.09%.

4-Phenyl-6-(5-phenyl-1-vinyl-1H-pyrrol-2-yl)pyrimidin-2-amine (3r): 123 mg (91%), light yellow crystals, m.p. 124–125 °C; 1H-NMR (400.13 MHz, CDCl3) δ: 8.03–8.01 (m, 2H, Ph), 7.62 (dd, J = 8.5, 15.8 Hz, 1H, HX), 7.50–7.46 (m, 5H, Ph), 7.42–7.38 (m, 2H, Ph), 7.34–7.31 (m, 1H, Ph), 7.30 (s, 1H, H-5, pyrimidine), 6.89 (d, J = 3.7 Hz, 1H, H-3, pyrrole), 6.38 (d, J = 3.7 Hz, 1H, H-4, pyrrole), 5.10 (br s, 2H, NH2), 4.96 (d, J = 8.5 Hz, 1H, HA), 4.68 (d, J = 15.8 Hz, 1H, HB); 13C-NMR (100.6 MHz, CDCl3) δ: 165.3, 163.1, 160.2, 138.9, 137.8, 133.0, 132.8, 132.7, 130.3, 129.3 (2C), 128.8 (2C), 128.2 (2C), 127.3, 127.0 (2C), 114.6, 111.8, 111.2, 105.8; IR (KBr) ν: 3463, 3407, 3312, 3187, 3060, 2953, 2922, 2854, 1622, 1566, 1531, 1451, 1429, 1389, 1376, 1343, 1291, 1220, 1076, 1026, 963, 900, 837, 761, 695, 640. Anal. Calcd. for C22H18N4: C, 78.08%; H, 5.36%; N, 16.56%. Found: C, 78.14%; H, 5.31%; N, 16.32%.

4-(4,5-diphenyl-1-vinyl-1H-pyrrol-2-yl)-6-phenylpyrimidin-2-amine (3s): 146 mg (88%), yellow crystals, m.p. 202 °C; 1H-NMR (400.13 MHz, CDCl3) δ: 8.06–8.03 (m, 2H, H, Ph), 7.51–7.49 (m, 3H, Ph, HX), 7.40–7.32 (m, 7H, Ph), 7.21–7.13 (m, 5H, Ph, H-5, pyrimidine), 7.06 (s, 1H, H-3, pyrrole), 5.10 (br s, 2H, NH2), 4.89 (d, J = 8.2 Hz, 1H, HA), 4.60 (d, J = 16.4 Hz, 1H, HB); 13C-NMR (100.6 MHz, CDCl3) δ: 165.4, 163.1, 160.2, 137.8, 135.3, 137.8, 132.4, 132.3, 131.8, 131.4 (2C), 130.4, 128.8 (2C), 128.5 (2C), 128.2 (2C), 128.1 (2C), 128.0, 127.1 (2C), 125.9, 125.0, 114.9, 110.8, 106.1. IR (KBr) ν: 3418, 3059, 2363, 1637, 1588, 1567, 1535, 1498, 1449, 1408, 1291, 1206, 1075, 955, 910, 832, 770, 696, 638. Anal. Calcd. for C28H22N4: C, 81.13%; H, 5.35%; N, 13.52%. Found: C, 78.99%; H, 5.16%; N, 13.37%.

4-[5-(4-Chlorophenyl)-1-vinyl-1H-pyrrol-2-yl]-6-phenylpyrimidin-2-amine (3t): 78 mg (52%), light brown crystals, m.p. 156 °C; 1H-NMR (400.13 MHz, CDCl3) δ: 8.04–8.01 (m, 2H, H-2,6, Ph), 7.63 (dd, J = 8.5, 15.8 Hz, 1H, HX), 7.51–7.49 (m, 3H, H-3,4,5, Ph), 7.41–7.35 (m, 4H, 4-Cl-C6H4), 7.29 (s, 1H, H-5, pyrimidine), 6.88 (d, J = 3.8 Hz, 1H, H-3, pyrrole), 6.36 (d, J = 3.8 Hz, 1H, H-4, pyrrole), 5.16 (br s, 2H, NH2), 5.99 (d, J = 8.5 Hz, 1H, HA), 4.67 (d, J = 15.8 Hz, 1H, HB); 13C-NMR (100.6 MHz, CDCl3) δ: 165.5, 163.0, 160.1, 137.8, 137.5, 133.3, 133.2, 132.7, 131.5, 130.6 (2C), 130.5, 128.8 (2C), 128.5 (2C), 127.1 (2C), 114.5, 112.2, 111.7, 105.8; IR (KBr) ν: 3499, 3441, 3313, 3189, 2362, 1617, 1565, 1532, 1458, 1434, 1384, 1224, 1083, 1010, 957, 896, 831, 766, 700, 642, 580, 521. Anal. Calcd. for C22H17ClN4: C, 70.87%; H, 4.60%; Cl, 9.51%; N, 15.03%. Found: C, 70.77%; H, 4.38%; Cl, 9.51%; N, 15.02%.

4-[5-(2-Fluorophenyl)-1-vinyl-1H-pyrrol-2-yl]-6-(2-furyl)pyrimidin-2-amine (3u): 104 mg (75%), orange crystals, m.p. 169 °C; 1H-NMR (400.13 MHz, CDCl3) δ: 7.63–7.56 (m, 2H, HX, H-5, furyl), 7.44–7.40 (m, 1H, H-6, 2-F-C6H4), 7.37–7.32 (m, 1H, H-4, 2-F-C6H4), 7.25 (s, 1H, H-5, pyrimidine), 7.21–7.09 (m, 3H, H-3,5, 2-F-C6H4, H-3, furyl), 6.94 (d, J = 3.8 Hz, 1H, H-3, pyrrole), 6.56 (dd, J = 1.8, 3.4 Hz, 1H, H-4, furyl), 6.39 (d, J = 3.8 Hz, 1H, H-4, pyrrole), 5.19 (br s, 2H, NH2), 4.87 (d, J = 8.5 Hz, 1H, HA), 4.62 (d, J = 15.8 Hz, 1H, HB); 13C-NMR (100.6 MHz, CDCl3) δ: 162.9, 160.0, 159.4 (d, 1JCF = 248.3 Hz, C-2, 2-F-C6H4), 156.2, 152.3, 144,4, 133.2, 132.5 (d, 3JCF = 5.9 Hz, C-4, 2-F-C6H4), 131.9, 131.8, 129.7 (d, 3JCF = 8.1 Hz, C-6, 2-F-C6H4), 124.1 (d, 4JCF = 3.4 Hz, C-5, 2-F-C6H4), 121.4 (d, 2JCF = 14.9 Hz, C-1, 2-F-C6H4), 115.9 (d, 2JCF = 22.0 Hz, C-3, 2-F-C6H4), 114.3, 112.7, 112.2, 111.3, 109.7, 103.3; IR (KBr) ν: 3433, 3363, 3195, 1631, 1600, 1550, 1459, 1408, 1222, 1160, 1108, 1079, 1017, 945, 817, 771, 750. Anal. Calcd. for C20H15FN4O: C, 69.35%; H, 4.37%; F, 5.49%; N, 16.18%. Found: C, 69.27%; H, 4.15%; F, 5.36%; N, 16.11%.

4-[5-(2-Fluorophenyl)-1-vinyl-1H-pyrrol-2-yl]-6-(2-thienyl)pyrimidin-2-amine (3v): 99 mg (68%), brown crystals, m.p. 144 °C; 1H-NMR (400.13 MHz, CDCl3) δ: 7.73–7.72 (m, 1H, H-6, 2-F-C6H4), 7.57 (dd, J = 8.5, 15.7 Hz, 1H, Hx), 7.48–7.47 (m, 1H, H-3, thienyl), 7.43–7.40 (m, 1H, H-5, thienyl), 7.38–7.33 (m, 1H, H-4, 2-F-C6H4),7.22 (s, 1H, H-5, pyrimidine), 7.19–7.09 (m, 3H, H-3,5, 2-F-C6H4, H-4, thienyl), 6.91 (d, J = 3.7 Hz, 1H, H-3, pyrrole), 6.39 (d, J = 3.7 Hz, 1H, H-4, pyrrole), 5.08 (br s, 2H, NH2), 4.89 (d, J = 8.5 Hz, 1H, HA), 4.65 (d, J = 15.7 Hz, 1H, HB); 13C-NMR (100.6 MHz, CDCl3) δ: 162.9, 159.9, 159.8, 159.5 (d, 1JCF = 248.4 Hz, C-2, 2-F-C6H4), 143.2, 133.2, 132.5 (d, 2JCF = 21.5 Hz, C-1, 2-F-C6H4), 132.0, 131.9, 129.8 (d, 3JCF = 8.0 Hz, C-4, 2-F-C6H4), 129.0, 128.1, 126.7, 124.1 (d, 4JCF = 2.8 Hz, C-5, 2-F-C6H4), 121.4 (d, 3JCF = 15.0 Hz, C-6, 2-F-C6H4), 115.9 (d, 2JCF = 22.0 Hz, C-3, 2-F-C6H4), 114.1, 112.7, 109.7, 103.8; IR (KBr) ν: 3404, 3340, 3223, 1638, 1567, 1531, 1448, 1431, 1376, 1347, 1223, 1105, 1073, 1045, 947, 898, 816, 766, 710. Anal. Calcd. for C20H15FN4S: C, 66.28%; H, 4.17%; F, 5.24%; N, 15.46%; S, 8.85%. Found: C, 65.93%; H, 4.02%; F, 5.48%; N, 15.11%; S, 8.79%.

3-[2-(2-Amino-6-phenylpyrimidin-4-yl)-1H-pyrrol-1-yl]-1-phenyl-3-(1H-pyrrol-2-yl)prop-2-en-1-one (4a): 11 mg (13%), yellow crystals, m.p. 137–139 °C; 1H-NMR (400.13 MHz, CDCl3) δ: 13.64 (br s, 1H, NH), 7.90–7.85 (m, 4H, H-2,6, COPh, H-2,6, Ph), 7.55–7.51 (m, 1H, H-4, COPh), 7.45–7.42 (m, 5H, H-3,5, COPh, H-3,4,5, Ph), 7.19 (s, 1H, H-5, pyrimidine), 7.16–7.15 (m, 2H, H-5, H-5′, pyrrole), 7.06 (dd, J = 1.7, 3.6 Hz, 1H, H-3, pyrrole), 6.76 (s, 1H, HC=), 6.42 (dd, J = 2.8, 3.6 Hz, 1H, H-4, pyrrole), 6.28 (dd, J = 2.2, 3.8 Hz, 1H, H-4′, pyrrole), 6.24–6.23 (m, 1H, H-3′, pyrrole), 4.88 (br s, 2H, NH2); 13C-NMR (100.6 MHz, CDCl3) δ: 189.9, 165.2, 162.9, 158.8, 146.3, 139.4, 137.7, 133.1, 132.8, 130.3, 129.9, 129.3, 128.7 (2C), 128.6 (2C), 128.3 (2C), 127.0 (2C), 124.5, 118.6, 114.3, 112.7, 111.9, 109.7, 104.3; 15N-NMR (40.5 MHz, CDCl3) δ: −304.9 (NH2), −220.9 (NH), −208.8 (N-pyrrole), −148.2 (N-1), −145.2 (N-3); IR (KBr) ν: 3480, 3401, 3356, 3120, 3106, 1623, 1577, 1526, 1438, 1353, 1320, 1297, 1220, 1184, 1128, 1088, 1036, 998, 931, 909, 881, 833, 768, 696, 641. Anal. Calcd. for C27H21N5O: C, 75.16%; H, 4.91%; N, 16.23%. Found: C, 75.04%; H, 4.77%; N, 16.14%.

3-[2-Amino-4-phenyl-6-(1H-pyrrol-2-yl)pyrimidin-5-yl]-1-phenyl-3-(1H-pyrrol-2-yl)prop-2-en-1-one (5a): 7 mg (8%), dark yellow crystals, m.p. 182 °C; 1H-NMR (400.13 MHz, CDCl3) δ: 9.96 (br s, 1H, NH’), 8.95 (br s, 1H, NH), 7.59–7.56 (m, 2H, H-2,6, COPh), 7.45–7.42 (m, 1H, H-4, COPh), 7.31–7.30 (m, 1H, H-4, Ph), 7.29 (s, 1H, HC=), 7.25–7.23 (m, 2H, H-3,5,COPh), 7.21–7.19 (m, 2H, H-2,6, Ph), 7.14–7.10 (m, 2H, H-3,5, Ph), 6.83–6.82 (m, 1H, H-5′, pyrrole), 6.78–6.77 (m, 1H, H-5, pyrrole), 6.72–6.71 (m, 1H, H-3, pyrrole), 6.66–6.65 (m, 1H, H-3′, pyrrole), 6.31–6.30 (m, 1H, H-4′, pyrrole), 6.09–6.06 (m, 1H, H-4, pyrrole), 5.12 (br s, 2H, NH2); 13C-NMR (100.6 MHz, DMSO-d6) δ: 187.7 (C=O), 164.9 (C-4, pyrimidine), 161.4 (C-2, pyrimidine), 154.6 (C-6, pyrimidine), 144.4 (C=), 139.6 (C-1, Ph), 139.1 (C-1, COPh), 132.3 (C-2′, pyrrole), 132.0 (C-4, COPh), 128.4 (C-2, pyrrole), 128.3 (C-3,5, COPh), 127.8 (C-2,4,6, Ph), 127.5 (C-2,6, COPh), 127.0 (C-3,5, Ph), 123.8 (C-5′, pyrrole), 120.7 (C-5, pyrrole), 114.9 (C-3′, pyrrole), 114.8 (C-5, pyrimidine, HC=), 112.5 (C-3, pyrrole), 110.3 (C-4′, pyrrole), 109.4 (C-4, pyrrole); 15N-NMR (40.5 MHz, CDCl3) δ: −225.5 (NH’), −223.7 (NH); IR (KBr) ν: 3471, 3426, 3173, 2967, 2863, 1635, 1597, 1536, 1444, 1418, 1227, 1120, 1034, 1020, 910, 738, 697. Anal. Calcd. for C27H21N5O: C, 75.16%; H, 4.91%; N, 16.23%. Found: C, 74.98%; H, 4.64%; N, 16.14%.

4. Conclusions

In summary, we developed an effective access to novel families of pyrrole–n class="Chemical">pyrimidine ensembles, decorated with alkyl, cycloalkyl, aryl and vinyl groups, attractive objects for drug design, by using acylethynylpyrroles as the synthetic platform. This method has several synthetic advantages, such as the one-pot procedure, the use of readily available starting materials and good to high yields of the target ensembles and therefore can activate the interest of both synthetic and pharmaceutical communities.