Convenient one-pot multicomponent strategy for the synthesis of 6-pyrrolylpyrimidines

Abstract

We have developed an easy method to construct diheteroaryls from α-aroylidineketene dithioacetals in a multicomponent manner. The reaction proceeded with high chemo/regioselectivity to yield 4-alkoxy-6-(4-aryl-1H-pyrrol-3-yl)pyrimidin-2-amines under milder conditions. It is found that α-aroylidineketene dithioacetals (2) undergo cycloaddition with (p-tolylsulfonyl)methyl isocyanide (3) [TosMIC], guanidine nitrate (5) and alcohol in the presence of NaH/THF to furnish the target 6-pyrrolylpyrimidines (8) in excellent yields.

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Pyrimidines are bases present in nucleic acids and play significant roles in medicinal chemistry¹ by exhibiting antibacterial,² anti-inflammatory,³ cytotoxicity,⁴ and anticancer⁵ properties. They have a long and distinguished history extending from the day of their discovery to their current use in chemotherapy, HIV treatment and in other clinical applications. Interestingly, pyrrole derivatives also find significant applications in the field of medicinal chemistry because of their pharmacological properties⁶ and as synthons for porphyrins⁷/boron-dipyrromethanes (BODIPY)⁸ synthesis etc. Pyrimidine and pyrrole heterocycles combined together as a single molecule could be expected to exhibit excellent biological activity.

Over the past decade, α-oxoketene dithioacetals have emerged as versatile intermediates in organic synthesis and have found applications in the synthesis of substituted and fused aromatic heterocyclic frameworks.^9,10

The α-aroylidineketene dithioacetals¹¹ 2 are five-carbon 1,5-bielectrophilic species, have dense and flexible substitution patterns, and good leaving alkylthio groups open to S_NV-type reactions. The α-aroylidineketene dithioacetals 2 have two different double bonds between C1–C2 (A) and C4–C5 (B). Double bond A is a push–pull type flanked by two electron donating methyl sulfanyl and one electron withdrawing carbonyl group, and B is flanked by an electron withdrawing carbonyl and aryl group (Fig. 1). Double bond A is more polarized than B because of the electron donating characteristics of the two methyl sulfanyl groups and has the structural features of a α,β-unsaturated carbonyl group with different reactivity toward addition/substitution reactions for the synthesis of various heterocyclic compounds.

Fig. 1 General structure of α-aroylidineketene dithioacetals 2.

α-Aroylidineketene dithioacetals 2 of aromatic substrates are very useful synthons for a variety of heterocycles. To examine the reactivity of β-unsaturated ketones and push–pull alkenes together, we synthesized several α-aroylidineketene dithioacetals 2a–o by aldol condensation between aryl aldehydes and 4,4-bis(methylthio)but-3-en-2-one 1 by following a previously reported procedure¹² (Scheme 1 and Table 1).

Table 1 Synthesis of α-aroylidineketene dithioacetals 2a–o from 1

Entry	Ar		Time (min)	Yield^b %
a Optimal reaction conditions: 1 (1 eq.), Ar-CHO (1.1 eq.), 10% NaOH (1.5 eq.), ethanol (5 ml), water (1 ml), 10 °C – RT, 30–90 min.b Isolated yields after recrystallization.c Compounds 2a, 2d, 2g, and 2k,^13 2h and 2j^14 are known.
1	4-OMe–C6H4–	2a	30	90^c
2	2,4-Cl2–C6H3–	2b	30	99
3	3-Cl–C6H4–	2c	45	85
4	C6H5–	2d	45	81^c
5	2,4-F2–C6H3–	2e	30	88
6	2-OMe,5-Br–C6H3–	2f	40	87
7	4-Cl–C6H4–	2g	30	99^c
8	3,4,5-OMe–C6H2–	2h	30	88^c
9	3-OH–C6H4–	2i	40	87
10	3,4-OMe–C6H3–	2j	30	89^c
11	4-CH3–C6H4–	2k	30	90^c
12	2 F–C6H4–	2l	45	92
13	2-Furyl–	2m	90	87
14	2-Thienyl–	2n	60	86
15	5-Br–C5H3N–	2o	60	82

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Scheme 1 Synthesis of α-aroylidineketene dithioacetals 2a–o from 1.

Following our earlier report,¹⁵ 3,3-bis(methylthio)-1-(4-aryl-1H-pyrrol-3-yl)prop-2-en-1-one 4 was synthesized selectively via 1,3-dipolar cycloaddition by involving (p-tolylsulfonyl)methyl isocyanide¹⁶ 3 and 2 in the presence of NaH/THF at room temperature (Scheme 2). Similarly, styrylpyrimidines 6 was synthesized by following a previously reported procedure by mixing guanidine nitrate 5 and 2 under reflux condition (Scheme 2).^17,18

Scheme 2 Synthesis of 4 and 6 by the cycloaddition of 2d with 3 and 5.

Utilizing the structural features of α-aroylidineketene dithioacetal 2, we generated novel heterocyclic molecule 4-alkoxy-6-(4-aryl-1H-pyrrol-3-yl)pyrimidin-2-amines 8 in a multicomponent fashion with excellent yields. To the best of our knowledge, no such study on the synthesis of a diheteroaryl core has been reported using this methodology.

In continuation of our earlier work,¹⁵ compound 8a was synthesized by considering the reaction as a test case to evaluate the cycloaddition of 3, 5 with 2a and methanol in a multicomponent manner. Several reactions were tried to optimize the reaction conditions (Scheme 3 and Table 2).

Scheme 3 Optimization of reaction conditions for the synthesis of 8a in a multicomponent manner.

Table 2 Optimization of reaction conditions for the synthesis of 8a in a multicomponent mannera

Entry	Bases	Solvents	Temp. (°C)	Time (h)	Yield (%)
a Isolated yields after column chromatography.b Starting material 2a recovered.
1	NaH	THF	70	10	75^a
2	NaH	THF	70	15	75^a
3	NaH	1,4-Dioxane	110	12	40^b
4	NaH	Benzene	100	12	20^b
5	NaH	Toluene	110	12	15^b
6	NaH	DMF	120	12	<5^b
7	NaH	Xylene	140	12	<5^b
8	K2CO3	Toluene	110	12	—^b
9	K2CO3	THF	70	12	—^b
10	K2CO3	1,4-Dioxane	110	12	—^b
11	DBU	THF	70	12	<5^b
12	DBN	THF	70	12	—^b

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A model cycloaddition reaction between 3, 5 with 2a and methanol in the presence of NaH/THF at RT-70 °C for 10 h was explored in our initial effort (entry 1, Table 2). Indeed, the reaction proceeds to give the desired product 8a in good yield. The yield of the product does not change, even when the reaction continued up to 15 h (entry 2, Table 2). In contrast, reactions occurring in other solvents, such as 1,4-dioxane, toluene, benzene dimethylformamide (DMF) and xylene, proceed with very poor yields, even with a prolonged reaction time (entries 3–7, Table 2). The cycloaddition did not occur when the reactions were performed using other bases such as K₂CO₃, DBU and DBN (entries 8–12, Table 2).

The cyclization was optimized with 8, which was obtained by the cyclocondensation of 2a, 3, 5 and alcohol in a multicomponent manner with excellent yields (Scheme 4). Ensuing studies showed that the efficiency of the formation of this product was highly dependent on solvent as well as the base. Importantly, the reaction in NaH/THF yields 75% of 8a in a highly chemo/regioselective manner. To explore the scope of this novel strategy, we consecutively investigated the cycloaddition of 2a–o with 3, 5 and alcohol by following the optimized condition 8a–ad obtained in excellent yields 70–97% (Table 3).

Scheme 4 Synthesis of 8a–ad in a multicomponent fashion by reacting 2 with 3, 4 and alcohol.

Table 3 Synthesis of 8a–ad in a multicomponent fashion by reacting 2 with 3, 4 and alcohol^a

Entry	Ar		R	Yield^b (%)
a 2a–o (1 eq.), NaH (2 eq.), TosMIC 3 (1.5 eq.), guanidine nitrate 5 (2 eq.), alcohol (3 ml) (v/v), RT-70 °C, 10 h.b Isolated yields.
1	4-OMe–C6H4–	8a	Me	75
2	4-OMe–C6H4–	8b	Et	87
3	2,4-Cl2–C6H3–	8c	Me	85
4	2,4-Cl2–C6H3–	8d	Et	89
5	3-Cl–C6H4–	8e	Me	97
6	3-Cl–C6H4–	8f	Et	95
7	C6H5–	8g	Me	85
8	C6H5–	8h	Et	83
9	2,4-F2–C6H3–	8i	Me	80
10	2,4-F2–C6H3–	8j	Et	82
11	2-OMe,5-Br–C6H3–	8k	Me	70
12	2-OMe,5-Br–C6H3–	8l	Et	72
13	4-Cl–C6H4–	8m	Me	87
14	4-Cl–C6H4–	8n	Et	89
15	3,4,5-OMe–C6H2–	8o	Me	84
16	3,4,5-OMe–C6H2–	8p	Et	87
17	3-OH–C6H4–	8q	Me	77
18	3-OH–C6H4–	8r	Et	78
19	3,4-OMe–C6H3–	8s	Me	85
20	3,4-OMe–C6H3–	8t	Et	82
21	4-CH3–C6H4–	8u	Me	88
22	4-CH3–C6H4–	8v	Et	86
23	2-F–C6H4–	8w	Me	88
24	2-F–C6H4–	8x	Et	90
25	2-Furyl–	8y	Me	83
26	2-Furyl–	8z	Et	85
27	2-Thienyl–	8aa	Me	87
28	2-Thienyl–	8ab	Et	87
29	5-Br–C5H3N–	8ac	Me	78
30	5-Br–C5H3N–	8ad	Et	75

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The ¹H NMR spectrum of 8a was taken as an example and the chemical shifts were analysed. The ¹H NMR spectrum assigned two singlets at δ 3.66 and 3.74 ppm to two methoxy groups at C-4 and C-4′′, respectively. The free amino proton at C-2 position appeared as a singlet at δ 6.24 ppm and at the same time the NH proton of the pyrrole ring displayed a broad singlet at δ 11.11 ppm. We also noticed that the chemical shift appearing at δ 5.58 ppm for the C-5 proton was shifted slightly upfield compared with the chemical shift of a simple pyrimidine molecule (δ ∼ 6.46 ppm). This upfield shift may be because of the shielding effect of a pyrrole ring at C-6 position. The ¹³C NMR of 8a displayed fourteen signals with diagnostic signals at δ 52.9 and 55.2 ppm assignable to two methoxy groups at C-4 and C-4′′, respectively. In addition, to support analytical data, the structure of 8e was confirmed on the basis of single-crystal X-ray structural analysis (Fig. 2).¹⁹

Fig. 2 ORTEP representation of 8e.

The compounds 8e, 8f, 8v and 8d were isolated in highest yields at the level of 97, 95, 90 and 89%, respectively. In addition, we synthesized few triheteroaryl derivatives 8y–ad by introducing five and six membered heterocycles, such as 2-furyl, 2-thienyl and pyridine, instead of a phenyl group at the C-4′′ position (Table 3, entries 25–30). Interestingly, without any decomposition, all the triheteroaryl compounds 8y–ad were obtained as a single product in very good yields. The R group was appropriately fixed as a methyl/ethyl at the C-4 position of 8. The yield of the product 8a–ad varied on changing the substitution by electron donating/withdrawing groups in the phenyl ring. All other structures of 6-pyrrolylpyrimidines 8a–ad were analysed by ¹H and ¹³C NMR, and mass spectroscopy.

On the other hand, the 1,3-dipolar cycloaddition between 3 and 6 was employed in the presence of NaH/THF at RT for 2 h to afford 8a in a very poor yield of 30% (Scheme 5). Subsequently, 4a was cyclized with guanidine nitrate 5 to afford 8a in 86% yield (Scheme 5). Although compound 8a was obtained in good yield from 2a via 4a, the cycloaddition proceeds in multi-steps. To avoid multi-steps as well as processing time, we focused our interest on the synthesis of 8a–ad in a multicomponent manner.

Scheme 5 Stepwise synthesis of 8a from 4a and 6.

A postulated reaction pathway for the formation of 4-alkoxy-6-(4-aryl-1H-pyrrol-3-yl)pyrimidin-2-amines 8a–ad is illustrated (Scheme 6). To evaluate cycloaddition in a multicomponent manner, 3, 5 with 2a was combined together in the presence of NaH/THF at RT. Interestingly, 3 undergoes 1,3-dipolar cycloaddition selectively with double bond B of 2, followed by the removal of the tosyl group to yield the corresponding 4. The 1,3-dipolar cycloaddition did not proceed with the push–pull alkene because the double bond A of 2 is more polarized than B due to two electron donating methyl sulfanyls and one electron withdrawing carbonyl group, which makes C-1 electron rich. Thus, the chemo/regioselecive formation of 4 was obtained on the less polarized double bond B of 2. On the other hand, 5 did not react with 2 at RT, and requires more vigorous conditions to undergo Michael addition. Hence, the temperature was increased gradually up to 70 °C. During this period, alcohol was added and replaced one MeSH group from 4, and then 5 undergoes Michael addition with push–pull alkene, which was followed by intramolecular cyclization by the removal of one MeSH group to afford 8 in excellent yields.

Scheme 6 Plausible mechanism for the formation of 8.

Conclusions

In summary, we described the development of efficient formation of 4-alkoxy-6-(4-aryl-1H-pyrrol-3-yl)pyrimidin-2-amines 8a–ad via a multicomponent approach with high chemo/regioselectivity. The salient features of our method are the facile introduction of various substitutions in a one-step process from readily preparable starting materials 2a–o. The 6-pyrrolylpyrimidines 8a–ad were characterized by ¹H and ¹³C NMR, mass spectroscopy and single crystal X-ray analysis.

Experimental section

General experimental

Melting points were determined on a melting point apparatus equipped with a thermometer, and were uncorrected. Unless stated otherwise, solvents and chemicals were obtained from commercial sources and used without further purification. The ¹H and ¹³C NMR spectra of the new compounds were measured at 400 MHz, 300 MHz and 100 MHz, 75 MHz using Bruker NMR instrument in DMSO-d₆, CDCl₃ and chemical shifts are reported as δ values (ppm) relative to tetramethylsilane. IR was measured by a Thermo Nicolet 6700 FT IR Spectrometer using ATR (attenuated total reflection) KBr cell. Mass analysis was performed by Agilent LC-MS instruments, and spectra were recorded in positive and negative mode. Elemental analysis was recorded on Thermofinnigan flash 2000 organic elemental CHNS analyser. Petroleum ether employed in column chromatographic purification refers to the fraction boiling at 40–60 °C.

General procedure for the synthesis of 4,4-bis(methylthio)but-3-en-2-one 1. A solution of acetone (100 g, 1.721 mol) in carbon disulphide (131 g, 1.721 mol) was added to a suspension of sodium-tert-butoxide (331 g, 3.442 mol) in benzene (500 ml) while maintaining the reaction temperature below 10 °C. The reaction mixture was stirred at RT for 3 h and methyl iodide (489 g, 3.442 mol) was added at 10 °C. The resulting reaction mixture was stirred at RT overnight. Then, the reaction mixture was diluted with ethyl acetate and washed twice with water. The organic layer was dried over sodium sulphate, filtered and concentrated in vacuum. The crude product was washed well with hexane to give 172 g of 4,4-bis(methylthio)but-3-en-2-one in 65% yield as a pale yellow crystalline solid. ¹H NMR (400 MHz, CDCl₃) δ 2.20 (s, 3H), 2.45 (s, 3H), 2.47 (s, 3H), 6.04 (s, 1H); LC-MS calcd m/z 162, found 163 [(M + 1)]⁺.

General procedure for the preparation of 1,1-bis(methylthio)-5-arylpenta-1,4-dien-3-one (2a–o). To a solution of 4,4-bis(methylthio)but-3-en-2-one 1 (1 eq.) in ethanol (5 ml), NaOH (1.5 eq.) and aryl aldehyde (1.1 eq.) were added under constant stirring. After the starting material was consumed by TLC, the reaction mixture was poured onto ice water, and the resulting solid was filtered and washed well with water (20 ml). The solid material obtained was crystallized from ethanol to furnish 1,1-bis(methylthio)-5-arylpenta-1,4-dien-3-one 2a–o in 81–99% yield as a yellow solid.
(E)-1,1-Bis(methylthio)-5-(4-methoxyphenyl)penta-1,4-dien-3-one (2a)¹³. Yellow solid; yield: 90% (3.1 g); mp 104–106 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 2.48 (s, 3H), 2.56 (s, 3H), 3.79 (s, 3H), 6.45 (s, 1H), 6.93 (d, J = 16 Hz, 1H), 6.98 (d, J = 8 Hz, 2H), 7.45 (d, J = 15.9 Hz, 1H), 7.64 (d, J = 8.8 Hz, 2H); ¹³C NMR (75 MHz, DMSO-d₆) δ 14.8, 17.2, 55.8, 114.2, 114.9, 126.2, 128.0, 130.3, 140.4, 161.3, 163.5, 183.7; IR (ATR KBr cell, cm⁻¹) 1581, 1644; LC-MS calcd m/z 280, found 281 [(M + 1)]⁺.
(E)-5-(2,4-Dichlorophenyl)-1,1-bis(methylthio)penta-1,4-dien-3-one (2b). Pale yellow solid; yield: 99% (3.9 g); mp 126 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 2.40 (s, 3H), 2.45 (s, 3H), 5.29–5.31 (m, 1H), 5.55 (s, 1H), 6.17 (s, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.50 (s, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 8.4 Hz, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ 14.8, 17.3, 114.3, 128.4, 129.4, 129.9, 131.8, 132.3, 133.9, 135.0, 135.3, 166.3, 182.6; IR (ATR KBr cell, cm⁻¹) 1500, 1650; HRMS (ESI-TOF) calcd for C₁₃H₁₂Cl₂OS₂Na [M + Na]⁺ 340.9604, found 340.9601.
(E)-5-(3-Chlorophenyl)-1,1-bis(methylthio)penta-1,4-dien-3-one (2c). Pale yellow solid; yield: 85% (3 g); mp 136 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 2.46 (s, 3H), 2.57 (s, 3H), 6.49 (s, 1H), 7.17 (d, J = 16 Hz, 1H), 7.43–7.47 (m, 3H), 7.62–7.65 (m, 1H), 7.79 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ 14.8, 17.3, 113.9, 127.3, 127.9, 129.9, 130.1, 131.2, 134.2, 137.8, 138.6, 165.2, 183.3; IR (ATR KBr cell, cm⁻¹) 1567, 1632; HRMS (ESI-TOF) calcd for C₁₃H₁₃Cl₂OS₂Na [M + Na]⁺ 306.9994, found 306.9993.
(E)-1,1-Bis(methylthio)-5-phenylpenta-1,4-dien-3-one (2d)¹³. Pale yellow solid; yield: 81% (2.5 g); mp 150 °C; ¹H NMR (400 MHz, CDCl₃) δ 2.52 (s, 6H), 6.23 (s, 1H), 6.82 (d, J = 16Hz, 1H), 7.35–7.40 (m, 3H), 7.55–7.57 (m, 2H), 7.61 (d, J = 16 Hz, 1H); LC-MS calcd m/z: 252, found 253 [(M + 1)] ⁺.
(E)-5-(2,4-Difluorophenyl)-1,1-bis(methylthio)penta-1,4-dien-3-one (2e). Pale yellow solid; yield: 88% (3.1 g); mp 152–154 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 2.44 (s, 3H), 2.56 (s, 3H), 6.45 (s, 1H), 7.11 (d, J = 16 Hz, 1H), 7.15–7.18 (m, 1H), 7.31–7.35 (m, 1H), 7.47 (d, J = 15.6 Hz, 1H) 7.89 (q, J = 15.6 Hz, 1H); ¹³C NMR (75 MHz, DMSO-d₆) δ 14.3, 16.7, 104.3, 104.8, 112.2, 112.3, 112.5, 113.6, 119.4, 119.5, 130.5, 130.3, 130.4, 159.5, 161.6, 162.1, 164.1, 164.3, 165.1, 182.5; IR (ATR KBr cell, cm⁻¹) 1460, 1630; HRMS (ESI-TOF) calcd for C₁₃H₁₂F₂OS₂Na [M + Na]⁺ 309.0195, found 309.0194.
(E)-5-(5-Bromo-2-methoxyphenyl)-1,1-bis(methylthio)penta-1,4-dien-3-one (2f). Pale yellow solid; yield: 87% (3.9 g); mp 156–158 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 2.45 (s, 3H), 2.56 (s, 3H), 3.86 (s, 3H), 6.44 (s, 1H), 7.04 (d, J = 8.8 Hz, 1H), 7.15 (d, J = 16.4 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H) 7.61 (d, J = 15.6 Hz, 1H), 7.88 (s, 1H); ¹³C NMR (75 MHz, DMSO-d₆) δ 14.8, 17.2, 56.5, 112.8, 114.6, 126.1, 129.9, 130.1, 133.2, 134, 157.4, 165, 183.3; IR (ATR KBr cell, cm⁻¹) 1469, 1642; HRMS (ESI-TOF) calcd for C₁₄H₁₅BrO₂S₂Na [M + Na]⁺ 380.9595, found 380.9594.
(E)-5-(4-Chlorophenyl)-1,1-bis(methylthio)penta-1,4-dien-3-one (2g)¹³. Yellow solid; yield: 99% (3.4 g); mp 144 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 2.46 (s, 3H), 2.48 (s, 3H), 6.47 (s, 1H), 7.07 (d, J = 16 Hz, 1H), 7.44–7.48 (m, 3H), 7.69 (d, J = 8.4 Hz, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ 14.3, 16.7, 113.4, 128.8, 128.9, 129.7, 133.9, 134.3, 138.4, 164.4, 182.8; IR (ATR KBr cell, cm⁻¹), 1598, 1646; LC-MS calcd m/z: 284, found 285 [(M +1)] ⁺.
(E)-1,1-Bis(methylthio)-5-(3,4,5-trimethoxyphenyl)penta-1,4-dien-3-one (2h)¹⁴. Pale yellow solid; yield: 88% (3.7 g); mp 140–142 °C; ¹H NMR (300 MHz, DMSO-d₆) δ 2.52 (s, 3H), 2.53 (s, 3H), 3.87 (s, 3H), 3.93 (s, 6H), 6.45 (s, 1H), 7.02 (s, 2H), 7.03 (d, J = 15.6 Hz, 1H), 7.26 (s, 1H), 7.42 (d, J = 15.8 Hz, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ 14.3, 16.8, 55.9, 60.1, 105.6, 113.5, 127.3, 130.5, 139.1, 140.3, 153.1, 163.7, 183.1; IR (ATR KBr cell, cm⁻¹) 1578, 1640; LC-MS calcd m/z 340, found 341 [(M + 1)]⁺.
(E)-5-(3-Hydroxyphenyl)-1,1-bis(methylthio)penta-1,4-dien-3-one (2i). Pale yellow solid; yield: 87% (2.9 g); mp 156–158 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 2.43 (s, 3H), 2.56 (s, 3H), 6.47 (s, 1H), 6.79 (d, J = 10.0 Hz, 1H), 6.95 (d, J = 15.6 Hz, 1H), 7.01 (s, 1H), 7.08 (d, J = 7.6 Hz, 1H), 7.19 (t, J = 8 Hz, 1H), 7.37 (d, J = 16 Hz, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ 14.7, 17.2, 114.1, 114.9, 117.6, 119.6, 128.4, 130.4, 136.8, 140.6, 158.2, 164.5, 183.6; IR (ATR KBr cell, cm⁻¹) 1470, 1600; HRMS (ESI-TOF) calcd for C₁₃H₁₄O₂S₂Na [M + Na]⁺ 289.0333, found 289.0331.
(E)-5-(3,4-Dimethoxyphenyl)-1,1-bis(methylthio)penta-1,4-dien-3-one (2j)¹⁴. Pale yellow solid; yield: 89% (3.4 g); mp 125–127 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 2.42 (s, 3H), 2.56 (s, 3H), 3.78 (s, 3H), 3.80 (s, 3H) 6.44 (s, 3H), 6.95 (d, J = 15.8 Hz, 1H), 6.97 (d, J = 8.31 Hz, 2H), 7.21 (d, J = 10.5 Hz, 1H), 7.29 (s, 1H) 7.42 (d, J = 15.9 Hz, 1H); ¹³C NMR (75 MHz, DMSO-d₆) δ 14.8, 17.2, 56.1, 110.5, 112.1, 114.1, 123.2, 126.3, 128.2, 140.8, 149.4, 151.1, 163.5, 183.7; IR (ATR KBr cell, cm⁻¹) 1565, 1637; UPLC-MS calcd m/z 310, found 311 [(M + 1)]⁺.
(E)-1,1-Bis(methylthio)-5-p-tolylpenta-1,4-dien-3-one (2k)¹³. Pale yellow solid; yield: 90% (2.9 g); mp 130 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 2.31 (s, 3H), 2.43 (s, 3H), 2.56 (s, 3H), 6.46 (s, 1H), 7.00 (d, J = 16.40 Hz, 1H), 7.21 (d, J = 7.6 Hz, 2H), 7.43 (d, J = 16 Hz, 2H), 7.55 (d, J = 8 Hz, 2H); ¹³C NMR (75 MHz, DMSO-d₆) δ 14.8, 17.2, 21.5, 114.1, 127.6, 128.5, 129.9, 132.7, 140.3, 140.4, 164.1, 183.7; IR (ATR KBr cell, cm⁻¹) 1477, 1604; LC-MS calcd m/z 264, found 265 [(M + 1)]⁺.
(E)-5-(2-Fluorophenyl)-1,1-bis(methylthio)penta-1,4-dien-3-one (2l). Pale yellow solid; yield: 92% (3 g); mp 109 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 2.45 (s, 3H), 2.57 (s, 3H), 6.47 (s, 3H), 7.15 (d, J = 15.60 Hz, 1H), 7.23–7.29 (m, 2H), 7.42–7.46 (m, 1H), 7.53 (d, J = 16.4 Hz, 1H), 7.79 (t, J = 8 Hz, 1H); ¹³C NMR (75 MHz, DMSO-d₆) δ 15.1, 17.2, 113.1, 115.9, 116.2, 123.2, 123.3, 124.3, 129.4, 129.8, 130.9, 131.1, 133.8, 159.7, 163.1, 166.1, 183.7; IR (ATR KBr cell, cm⁻¹) 1502, 1544, 1618; HRMS (ESI-TOF) calcd for C₁₃H₁₃FOS₂Na [M + Na]⁺ 291.0290, found 291.0289.
(E)-5-(Furan-2-yl)-1,1-bis(methylthio)penta-1,4-dien-3-one (2m). Low melting solid; yield: 87% (2.6 g); mp 109 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 2.42 (s, 3H), 2.54 (s, 3H), 6.43 (s, 1H), 6.60 (bs, 1H), 6.75 (d, J = 15.60 Hz, 1H), 6.87 (bs, 1H), 7.29 (d, J = 15.60 Hz, 1H), 7.81 (bs, 1H); ¹³C NMR (75 MHz, DMSO-d₆) δ 14.8, 17.2, 113.3, 114.1, 115.7, 125.7, 127.4, 145.8, 151.7, 164.4, 183.1; IR (ATR KBr cell, cm⁻¹) 1465, 1642; HRMS (ESI-TOF) calcd for C₁₁H₁₂O₂S₂Na [M + Na]⁺ 263.0176, found 263.0173.
(E)-1,1-Bis(methylthio)-5-(thiphen-2-yl)-penta-1,4-dien-3-one (2n). Brown solid; yield: 86% (2.7 g); mp 90 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 2.43 (s, 3H), 2.55 (s, 3H), 6.42 (s, 1H), 6.86 (d, J = 15.6 Hz, 1H), 7.48 (s, 1H), 7.49 (d, J = 16 Hz, 1H), 7.59–7,61 (m, 1H) 7.89 (s, 1H); ¹³C NMR (75 MHz, DMSO-d₆) δ 14.8, 17.2, 56.0, 113.8, 125.9, 128.1, 128.2, 129.3, 134.5, 138.8, 164.0, 183.9; IR (ATR KBr cell, cm⁻¹) 1567, 1634; HRMS (ESI-TOF) calcd for C₁₁H₁₂OS₃Na [M + Na]⁺ 278.9948, found 278.9945.
(E)-5-(5-Bromopyridin-3-yl)-1,1-bis(methylthio)penta-1,4-dien-3-one (2o). Pale yellow solid; yield: 82% (3.3 g); mp 146 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 2.43 (s, 3H), 2.56 (s, 3H), 6.46 (s, 1H), 7.29 (d, J = 16.00 Hz, 1H), 7.45 (d, J = 16.00 Hz, 1H), 8.41 (s, 3H), 8.66 (s, 1H), 8.82 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ 14.8, 17.2, 56.1, 112.2, 114.5, 121.1, 123.7, 128.3, 128.5, 131.9, 135.2, 158.4, 164.2, 183.9; IR (ATR KBr cell, cm⁻¹) 1165, 1488, 1590, 1646; HRMS (ESI-TOF) calcd for C₁₂H₁₂BrNOS₂Na [M + Na]⁺ 351.9441, found 351.9449.

General procedure for the synthesis of 8a via 1,3-dipolar cycloaddition followed by cyclisation.
Step i: synthesis of 4 by reacting 2a with 3. To a stirred and cleaned suspension of NaH (60% suspension in oil (0.10 g, 0.00427 mol)) in dry THF (2 ml) at 0 °C, a mixture of TosMIC 3 (1.04 g, 0.0053 mol) and (E)-1-(4-methoxyphenyl)-5,5-bis(methylthio)pent-1-en-3-one 2a (1 g, 0.00357 mol) was added in dry THF (5 ml) over 15 min. The reaction mixture was then stirred at room temperature for 10 min. After completion of the reaction (TLC), the mixture was carefully acidified with dilute acetic acid (pH 6.5) and extracted with ethyl acetate (3 × 20 ml). The combined organic phase was washed with water (15 ml) and brine (10 ml), and then dried over anhydrous Na₂SO₄ filtered and concentrated in vacuo. The crude product was purified by column chromatography using silica gel (60–120 mesh) with increasing amounts of ethyl acetate–petroleum ether (3 : 7) as the eluent. Pale yellow solid; yield: 1 g (89%); mp 156 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 2.18 (s, 3H), 2.37 (s, 3H), 3.76 (s, 3H), 6.30 (s, 1H), 6.81 (s, 1H), 6.90 (d, J = 8.60 Hz, 2H), 7.28 (d, J = 8.60 Hz, 2H), 7.54 (s, 1H), 11.44 (s, 1H);¹³C NMR (100 MHz, DMSO-d₆) δ 14.6, 16.4, 55.6, 113.7, 114.1, 119.1, 124.1, 124.4, 124.9, 128.8, 130.7, 158.3, 158.6, 182.3; LC-MS calcd m/z 319, found 320 [(M + 1)]⁺; IR (ATR KBr cell, cm⁻¹), 1474, 1599, 3355.
Step ii: synthesis of 8a by reacting 4 and 5. To a stirred and cleaned suspension of sodium hydride (60% suspension in oil 0.03 g, 0.00113 mol) in dry methanol (5 ml) at 0 °C, guanidine nitrate 5 (0.23 g, 0.00188 mol) was added, and the reaction mixture was allowed to stir at room temperature for 15 min. Then, 1-(4-(4-methoxyphenyl)-1H-pyrrol-3-yl)-3,3-bis(methylthio)prop-2-en-1-one (0.3 g, 0.000939 mol) 4a was added and allowed to reflux for 8–10 h. The solvent was removed from the reaction mixture under reduced pressure. Then, water was added (5 ml) and the aqueous phase was extracted by ethyl acetate. The organic layer was washed with water (2 × 5 ml) and brine (2 × 5 ml) and dried over anhydrous Na₂SO₄, and then filtered and concentrated. The crude product was subjected to column chromatography on silica gel (100–120 mesh) using ethyl acetate–petroleum ether (8 : 2) to afford the pure compound 8a in 86% (0.21 g) yield.

General procedure for the preparation of 4-alkoxy-6-(4-(4-aryl)-1H-pyrrol-3-yl)pyrimidin-2-amine (8a–ad). To a stirred suspension of sodium hydride (60% suspension in oil (2 eq.)) in dry THF (5 ml) at 0 °C, 1,1-bis(methylthio)-5-arylpenta-1,4-dien-3-one 2 (1 eq.), TosMIC 3 (1.5 eq.) and guanidine nitrate 5 (2 eq.) was added, and the reaction mixture was stirred at RT for 5 min. Later, alcohol (3 ml (v/v)) was added and allowed to reflux for 10 h. The solvent was then removed from the reaction mixture under reduced pressure, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water (2 × 5 ml) and brine (2 × 5 ml) and dried over anhydrous Na₂SO₄, followed by filtration and concentration. The crude product was subjected to column chromatography on silica gel (100–120 mesh) using ethyl acetate–petroleum ether (1 : 1) to afford the pure compounds 8a–ad in excellent yields of 70–97%.
4-Methoxy-6-(4-(4-methoxyphenyl)-1H-pyrrol-3-yl)pyrimidin-2-amine (8a). Colourless solid; yield: 75% (0.24 g); mp 180 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 3.66 (s, 3H), 3.74 (s, 3H), 5.59 (s, 1H), 6.23 (s, 2H), 6.74 (s, 1H), 6.88 (d, J = 8.8 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H), 7.25 (s, 1H), 11.11 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ 52.9, 55.5, 92.7, 114.1, 118.8, 120.7, 121.0, 123.2, 129.1, 130.4, 158.1, 163.5, 163.6, 170.3; IR (ATR KBr cell, cm⁻¹), 1770, 2350, 3500; LC-MS calcd m/z 296, found 297 [(M + 1)]⁺. Anal. calcd for C₁₆H₁₆N₄O₂: C, 64.85; H, 5.44; N, 18.91; found C, 64.82; H, 5.39; N, 18.89.
4-Ethoxy-6-(4-(4-methoxyphenyl)-1H-pyrrol-3-yl)pyrimidin-2-amine (8b). Colourless solid; yield: 87% (0.29 g); mp 142 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 1.17 (t, J = 7.2 Hz, 3H), 3.75 (s, 3H), 4.15 (q, J = 7.2 Hz, 2H), 5.58 (s, 1H), 6.17 (s, 1H), 6.74 (s, 1H), 6.88 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H), 7.25 (s, 1H), 11.11 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ 14.9, 55.5, 61.1, 92.7, 114.0, 118.8, 120.7, 121.0, 123.2, 129.1, 130.4, 158.1, 163.5, 163.6, 169.9; IR (ATR KBr cell, cm⁻¹), 1890, 2360, 3379; LC-MS calcd m/z 310, found 311 [(M + 1)]⁺. Anal. calcd for C₁₇H₁₈N₄O₂: C, 65.79; H, 5.85; N, 18.05; found C, 65.72; H, 5.79; N, 18.01.
4-Methoxy-6-(4-(2,4-dichlorophenyl-1H-pyrrol-3-yl)pyrimidin-2-amine) (8c). Colourless solid; yield: 85% (0.27 g); mp 152 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 3.65 (s, 3H), 5.33 (s, 1H), 6.17 (s, 2H), 6.81 (s, 1H), 7.31–7.41 (m, 3H), 7.62 (s, 1H), 11.31 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ 52.9, 91.0, 119.0, 119.9, 120.7, 121.6, 127.5, 129.1, 132.4, 133.9, 134.9, 135.2, 163.1, 163.5, 170.5; IR (ATR KBr cell, cm⁻¹), 1800, 2320, 3470; LC-MS calcd m/z 335, found 336 [(M + 1)]⁺. Anal. calcd for C₁₅H₁₂Cl₂N₄O: C, 53.75; H, 3.61; N, 16.72; found C, 53.71; H, 3.59; N, 16.69.
4-Ethoxy-6-(4-(2,4-dichlorophenyl-1H-pyrrol-3-yl)pyrimidin-2-amine) (8d). Colourless solid; yield: 89% (0.28 g); mp 156 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 1.15–1.22 (t, J = 7.2 Hz, 3H), 4.12 (q, J = 7.2 Hz, 2H), 5.34 (s, 1H), 6.10 (s, 2H), 6.80 (s, 1H), 7.31–7.41 (m, 3H), 7.61 (s, 1H), 11.30 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ 14.8, 61.1, 91.2, 118.9, 119.9, 120.7, 121.7, 127.5, 129.1, 132.4, 133.9, 134.8, 135.3, 163.2, 163.4, 170.2; IR (ATR KBr cell, cm⁻¹), 1683, 2300, 2900, 3320; UPLC-MS calcd. m/z 349, found 350 [(M + 1)]⁺. Anal. calcd for C₁₆H₁₄Cl₂N₄O: C, 55.03; H, 4.04; N, 16.04; found C, 55.00; H, 4.01; N, 15.99.
4-Methoxy-6-(4-(3-chlorophenyl-1H-pyrrol-3-yl)pyrimidin-2-amine) (8e). Colourless solid; yield: 97% (0.31 g); mp 122 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 3.69 (s, 3H), 5.65 (s, 1H), 6.24 (s, 2H), 6.95 (s, 1H), 7.22–7.32 (m, 5H), 11.34 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ 52.6, 92.5, 119.2, 120.3, 121.0, 121.4, 125.4, 127.2, 127.8, 129.7, 132.6, 138.4, 162.9, 163.1, 169.9; IR (ATR KBr cell, cm⁻¹), 1860, 2372, 3174; LC-MS calcd m/z 300, found 301 [(M + 1)]⁺. Anal. calcd for C₁₅H₁₃ClN₄O: C, 59.91; H, 4.36; N, 18.63; found C, 59.87; H, 4.28; N, 18.57.
4-Ethoxy-4-(4-(3-chlorophenyl-1H-pyrrol-3-yl)pyrimidin-2-amine) (8f). Colourless solid; yield: 95% (0.31 g); mp 186 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 1.19 (t, J = 7.2 Hz, 3H), 4.18 (q, J = 7.2 Hz, 2H), 5.64 (s, 1H), 6.20 (s, 2H), 6.95 (s, 1H), 7.23–7.32 (m, 5H), 11.36 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ 19.2, 65.4, 97.5, 123.9, 125.8, 126.1, 130.1, 131.9, 132.6, 134.5, 137.4, 143.2, 167.8, 174.3; IR (ATR KBr cell, cm⁻¹), 1840, 2370, 3320; LC-MS calcd m/z 311, found 312 [(M + 1)]⁺. Anal. calcd for C₁₆H₁₅ClN₄O: C, 61.05; H, 4.80; N, 17.80; found C, 61.01; H, 4.75; N, 17.77.
4-Methoxy-6-(4-phenyl-1H-pyrrol-3-yl)pyrimidin-2-amine (8g). Colourless solid; yield: 85% (0.27 g); mp 174 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 3.66 (s, 3H), 5.58 (s, 1H), 6.23 (s, 2H), 6.83 (s, 1H), 7.19 (s, 1H), 7.19–7.32 (m, 6H), 11.19 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ 52.5, 92.3, 118.6, 120.2, 120.7, 123.0, 125.7, 128.0, 128.7, 136.2, 163.0, 163.1, 169.8; IR (ATR KBr cell, cm⁻¹), 1760, 2380, 3420; LC-MS calcd. m/z 266, found 267 [(M + 1)]⁺. Anal. calcd for C₁₅H₁₄N₄O: C, 67.65; H, 5.30; N, 21.04; found C, 67.59; H, 5.23; N, 21.00.
4-Ethoxy-6-(4-phenyl-1H-pyrrol-3-yl)pyrimidin-2-amine (8h). Colourless solid; yield: 83% (0.28 g); mp 126 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 1.18 (t, J = 7.2 Hz, 3H), 4.14 (q, J = 7.2 Hz, 2H), 5.57 (s, 1H), 6.18 (s, 2H), 6.82 (s, 1H), 7.18–7.32 (m, 6H), 11.29 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ 14.4, 60.6, 92.5, 118.6, 120.3, 120.7, 122.9, 125.8, 128.0, 128.7, 136.3, 163.1, 169.5; IR (ATR KBr cell, cm⁻¹), 1670, 2680, 3392; LC-MS calcd m/z 280, found 281 [(M + 1)]⁺. Anal. calcd for C₁₆H₁₆N₄O: C, 68.55; H, 5.75; N, 19.99; found C, 68.50; H, 5.69; N, 19.91 (two carbon signals merged with one another).
4-Methoxy-6-(2,4-difluorophenyl-1H-pyrrol-3-yl)pyrimidin-2-amine (8i). Colourless solid; yield: 80% (0.27 g); mp 150 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 3.67 (s, 3H), 5.52 (s, 1H), 6.16 (s, 2H), 6.85 (s, 1H), 7.05–7.07 (m, 1H), 7.15–7.21 (m, 1H), 7.29–7.53 (m, 2H), 11.31 (s, 1H); ¹³C NMR (75 MHz, DMSO-d₆) δ 53.0, 91.3, 104.2, 104.6, 111.4, 111.6, 115.2, 120.1, 121.0, 121.6, 133.1, 158.3, 160.0, 161.4, 161.6, 163.5, 170.5; IR (ATR KBr cell, cm⁻¹), 1868, 2360, 3418; LC-MS calcd. m/z 302, found 303 [(M + 1)]⁺. Anal. calcd for C₁₅H₁₂F₂N₄O: C, 59.60; H, 4.00; N, 18.53; found C, 59.55; H, 3.93; N, 18.50.
4-Ethoxy-6-(2,4-difluorophenyl-1H-pyrrol-3-yl)pyrimidin-2-amine (8j). Colourless solid; yield: 82% (0.29 g); mp 160 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 1.86 (t, J = 7.2 Hz, 3H), 4.15 (q, J = 7.2 Hz, 2H), 5.52 (s, 1H), 6.10 (s, 2H), 6.84 (s, 1H), 7.02–7.07 (m, 1H), 7.15–7.21 (m, 1H), 7.29–7.35 (m, 2H), 11.30 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ 14.9, 61.1, 91.5, 104.6, 111.4, 111.7, 115.2, 120.1, 121.1, 121.6, 133.2, 158.3, 159.8, 161.4, 163.1, 163.2, 163.5, 170.2; IR (ATR KBr cell, cm⁻¹), 2360, 2989, 3436; LC-MS calcd m/z 316, found 317 [(M + 1)]⁺. Anal. calcd for C₁₆H₁₄F₂N₄O: C, 60.75; H, 4.46; N, 17.71; found C, 60.71; H, 4.43; N, 17.65.
4-Methoxy-6-(4-(5-bromo-2-methoxyphenyl)-1H-pyrrol-3-yl)pyrimidin-2-amine (8k). Colourless solid; yield: 70% (0.22 g); mp 182 °C; 1H NMR (400 MHz, DMSO-d₆): δ 3.52 (s, 3H), 3.74 (s, 3H) 5.44 (s, 1H), 6.14 (s, 2H), 6.78 (s, 1H), 6.94 (d, J = 8.8 Hz, 1H), 7.28 (d, J = 14.8 Hz, 2H), 7.42 (d, J = 8.8 Hz, 1H), 11.17 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ 52.9, 55.8, 91.1, 111.9, 113.8, 117.9, 120.4, 121.7, 128.5, 130.7, 133.5, 156.8, 163.3, 170.5; IR (ATR KBr cell, cm⁻¹), 2360, 3362; LC-MS calcd. m/z 375, found 376 [(M + 1)]⁺. Anal. calcd for C₁₆H₁₅BrN₄O₂: C, 51.22; H, 4.03; N, 14.93; found C, 51.12; H, 3.99; N, 14.86.
4-Ethoxy-6-(4-(5-bromo-2-methoxyphenyl)-1H-pyrrol-3-yl)pyrimidin-2-amine (8l). Colourless solid; yield: 72% (0.23 g); mp 170 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 1.18 (t, J = 7.2 Hz, 3H) 3.52 (s, 3H), 4.14 (q, J = 7.2 Hz, 2H), 5.44 (s, 1H), 6.07 (s, 2H), 6.77 (s, 1H), 6.94 (d, J = 8.8 Hz, 1H), 7.26 (d, J = 12 Hz, 2H), 7.41 (d, J = 8.8 Hz, 1H), 11.16 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ 14.9, 55.8, 60.9, 91.4, 111.9, 113.8, 117.8, 120.4, 121.9, 128.6, 130.6, 133.4, 156.8, 163.4, 163.7, 170.1; IR (ATR KBr cell, cm⁻¹), 1868, 2360, 3365; LC-MS calcd m/z 389, found 390 [(M + 1)]⁺. Anal. calcd for C₁₇H₁₇BrN₄O₂: C, 52.46; H, 4.40; N, 14.39; found C, 52.41; H, 4.33; N, 14.30.
4-Methoxy-6-(4-(4-chlorophenyl-1H-pyrrol-3-yl)pyrimidin-2-amine) (8m). Colourless solid; yield: 87% (0.28 g); mp 194 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 3.69 (s, 3H), 5.63 (s, 1H), 6.26 (s, 2H), 6.89 (s, 1H), 7.25 (s, 1H), 7.34 (q, J = 8.4 Hz, 4H), 11.34 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ 53.0, 92.9, 119.4, 120.8, 121.5, 122.1, 128.4, 130.8, 135.6, 163.5, 163.6, 170.4; IR (ATR KBr cell, cm⁻¹), 1867, 2369, 3420; LC-MS calcd m/z 300, found 301 [(M + 1)]⁺. Anal. calcd for C₁₅H₁₃ClN₄O: C, 59.91; H, 4.36; N, 18.63; found: C, 59.80; H, 4.27; N, 18.51 (two carbons merged with one another).
4-Ethoxy-6-(4-(4-chlorophenyl-1H-pyrrol-3-yl)pyrimidin-2-amine) (8n). Colourless solid; yield: 89% (0.3 g); mp 174 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 1.20 (t, J = 7.2 Hz, 3H), 4.17 (q, J = 7.2 Hz, 2H), 5.62 (s, 1H), 6.20 (s, 2H), 6.89 (s, 1H), 7.24 (s, 1H), 7.34 (q, J = 8.8 Hz, 4H), 11.25 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ 14.9, 61.2, 93.1, 119.4, 120.8, 121.5, 122.1, 128.4, 130.7, 135.6, 163.6, 163.6, 170.1; IR (ATR KBr cell, cm⁻¹), 1844, 2360, 3387; LC-MS calcd m/z 314, found 315 [(M + 1)]⁺. Anal. calcd for C₁₆H₁₅ClN₄O: C, 61.05; H, 4.80; N, 17.80; found C, 60.88; H, 4.72; N, 17.71 (two carbons merged with one another).
4-Methoxy-6-(4-(3,4,5-trimethoxyphenyl)-1H-pyrrol-3-yl)pyrimidin-2-amine (8o). Colourless solid; yield: 84% (0.26 g); mp 168 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 3.65 (s, 3H), 3.69 (s, 9H), 5.74 (s, 1H), 6.24 (s, 2H), 6.59 (s, 2H), 6.89 (s, 1H), 7.23 (s, 1H), 11.18 (s, 1H); ¹³C NMR (75 MHz, DMSO-d₆) δ 53.2, 56.1, 60.9, 94.9, 106.3, 118.2, 120.7, 120.9, 124.3, 131.1, 136.7, 152.8, 162.5, 170.8; IR (ATR KBr cell, cm⁻¹), 1800, 2370, 3495; LC-MS calcd m/z 356, found 357 [(M + 1)]⁺. Anal. calcd for C₁₈H₂₀N₄O₄: C, 60.66; H, 5.66; N, 15.72; found C, 60.59; H, 5.58; N, 15.62.
4-Ethoxy-6-(4-(3,4,5-trimethoxyphenyl)-1H-pyrrol-3-yl)pyrimidin-2-amine (8p). Colourless solid; yield: 87% (0.28 g); mp 170 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 1.18 (t, J = 7.2 Hz, 3H), 3.69 (s, 9H), 4.16 (q, J = 7.2 Hz, 2H), 5.72 (s, 1H), 6.21 (s, 2H), 6.60 (s, 2H), 6.89 (s, 1H), 7.23 (s, 1H), 11.18 (s, 1H); ¹³C NMR (75 MHz, DMSO-d₆) δ 14.4, 56.1, 60.8, 61.7, 95.0, 106.3, 118.1, 120.6, 120.9, 124.3, 131.1, 136.6, 152.8, 162.6, 162.8, 170.5; IR (ATR KBr cell, cm⁻¹), 1790, 2400, 3298; LC-MS calcd m/z 370, found 371 [(M + 1)]⁺. Anal. calcd for C₁₉H₂₂N₄O₄: C, 61.61; H, 5.99; N, 15.13; found C, 61.50; H, 5.92; N, 15.04.
4-Methoxy-6-(4-(3-hydroxyphenyl)-1H-pyrrol-3-yl)pyrimidin-2-amine (8q). Colourless solid; yield: 77% (0.24 g); mp 148–150 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 3.67 (s, 3H), 5.62 (s, 1H), 6.23 (s, 2H), 6.62 (d, J = 8 Hz, 1H), 6.69 (s, 2H), 6.77 (s, 1H), 7.09 (t, J = 8 Hz, 1H), 7.24 (s, 1H), 9.21 (s, 1H), 11.14 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ 20.9, 52.5, 92.4, 112.9, 115.7, 118.4, 119.6, 120.2, 120.6, 121.9, 123.2, 127.1, 128.9, 129.7, 138.1, 143.5, 156.9, 162.9, 163.1, 169.8; IR (ATR KBr cell, cm⁻¹), 1650, 2200, 3200; LC-MS calcd m/z 282, found 283 [(M + 1)]⁺. Anal. calcd for C₁₅H₁₄N₄O₂: C, 63.82; H, 5.00; N, 19.85; found C, 63.74; H, 4.89; N, 19.78.
4-Ethoxy-6-(4-(3-hydroxyphenyl)-1H-pyrrol-3-yl)pyrimidin-2-amine (8r). Colourless solid; yield: 78% (0.26 g); mp 126 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 1.19 (t, J = 7.2 Hz, 3H), 4.14 (q, J = 7.2 Hz, 2H), 5.60 (s, 1H), 6.18 (s, 2H), 6.61 (d, J = 7.6 Hz, 1H), 6.72 (s, 1H), 6.76 (s, 1H), 7.07 (t, J = 8 Hz, 1H), 7.23 (s, 1H), 9.21 (s, 1H), 11.13 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ 14.4, 60.6, 92.5, 112.9, 115.7, 118.4, 119.6, 120.3, 120.6, 123.2, 127.1, 128.9, 129.6, 137.6, 156.9, 163.0, 163.1, 169.5; IR (ATR KBr cell, cm⁻¹), 1750, 2300, 3470; LC-MS calcd m/z 296, found 297 [(M + 1)]⁺. Anal. calcd for C₁₆H₁₆N₄O₂: C, 64.85; H, 5.44; N, 18.91; found C, 64.79; H, 5.35; N, 18.83.
4-Methoxy-6-(4-(3,4-dimethoxyphenyl)-1H-pyrrol-3-yl)pyrimidin-2-amine (8s). Colourless solid; yield: 85% (0.27 g); mp 182 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 3.66 (s, 6H), 3.74 (s, 3H), 5.66 (s, 1H), 6.23 (s, 2H), 6.79–6.81 (m, 2H), 6.86–6.93 (m, 2H), 7.25 (s, 1H), 11.13 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ 52.5, 55.4, 55.5, 92.3, 111.7, 113.1, 118.3, 120.2, 120.5, 120.8, 122.9, 128.8, 147.2, 148.2, 163.1, 169.9; IR (ATR KBr cell, cm⁻¹), 1790, 2490, 3220; LC-MS calcd. m/z 326, found 327 [(M + 1)]⁺. Anal. calcd for C₁₇H₁₈N₄O₃: C, 62.57; H, 5.56; N, 17.17; found C, 62.49; H, 5.45; N, 17.10.
4-Ethoxy-6-(4-(3,4-dimethoxyphenyl)-1H-pyrrol-3-yl)pyrimidin-2-amine (8t). Colourless solid; yield: 82% (0.27g); mp 180 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 1.19 (t, J = 7.2 Hz, 3H), 3.66 (s, 3H), 3.74 (s, 3H), 4.16 (q, J = 7.2 Hz, 2H), 5.65 (s, 1H), 6.17 (s, 2H), 6.78–6.82 (m, 2H), 6.86–6.90 (m, 2H), 7.23 (s, 1H), 11.12 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ 55.3, 55.5, 60.5, 92.5, 111.7, 113.3, 118.3, 120.2, 120.5, 120.7, 122.9, 128.9, 147.2, 148.2, 163.0, 163.2, 169.5; IR (ATR KBr cell, cm⁻¹), 1820, 2500, 3390; LC-MS calcd m/z 340, found 341 [(M + 1)]⁺. Anal. calcd for C₁₈H₂₀N₄O₃: C, 63.52; H, 5.92; N, 16.46; found C, 63.42; H, 5.83; N, 16.39.
4-Methoxy-6-(4-p-tolyl-1H-pyrrol-3-yl)pyrimidin-2-amine (8u). Colourless solid; yield: 88% (0.28 g); mp 150 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 2.36 (s, 3H), 3.66 (s, 3H), 5.60 (s, 1H), 6.23 (s, 2H), 6.77 (s, 1H), 7.09–7.16 (m, 4H), 7.25 (s, 1H), 11.15 (s, 1H); ¹³C NMR (75 MHz, DMSO-d₆) δ 21.5, 52.9, 92.8, 118.9, 120.7, 121.2, 123.4, 127.7, 130.3, 133.8, 135.3, 163.5, 163.6, 170.3; IR (ATR KBr cell, cm⁻¹), 1720, 2300, 3630; LC-MS calcd m/z 280, found 281 [(M + 1)]⁺. Anal. calcd for C₁₆H₁₆N₄O: C, 68.55; H, 5.75; N, 19.99; found C, 68.48; H, 5.69; N, 19.90.
4-Ethoxy-6-(4-p-tolyl-1H-pyrrol-3-yl)pyrimidin-2-amine (8v). Colourless solid; yield: 86% (0.29 g); mp 170–172 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 1.18 (t, J = 6.8 Hz, 3H), 2.33 (s, 3H), 4.12 (q, J = 7.2 Hz, 2H), 5.59 (s, 1H), 6.17 (s, 2H), 6.77 (s, 1H), 7.11 (d, J = 8 Hz, 2H), 7, 16 (d, J = 7.6 Hz, 2H), 7.24 (s, 1H), 11.14 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ 14.9, 21.2, 61.1, 92.9, 118.9, 120.7, 121.2, 123.4, 129.1, 133.8, 135.3, 163.6, 169.9; IR (ATR KBr cell, cm⁻¹), 1854, 2330, 3570; LC-MS calcd m/z 294, found 295 [(M + 1)]⁺. Anal. calcd for C₁₇H₁₈N₄O: C, 69.37; H, 6.16; N, 19.03; found C, 69.28; H, 6.10; N, 18.92.
4-Methoxy-6-(4-(2-fluorophenyl)-1H-pyrrol-3-yl)pyrimidin-2-amine (8w). Colourless solid; yield: 88% (0.28 g); mp 172 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 3.65 (s, 3H), 5.48 (s, 1H), 6.17 (s, 2H), 6.85 (s, 1H), 7.18 (d, J = 7.6 Hz, 2H), 7.27–7.34 (m, 3H), 11.29 (s, 1H); ¹³C NMR (75 MHz, DMSO-d₆) δ 50.7, 89.8, 113.3, 113.6, 114.1, 117.6, 118.7, 119.5, 120.1, 122.3, 122.5, 125.5, 126.2, 130.1, 156.2, 159.5, 161.2, 168.5; IR (ATR KBr cell, cm⁻¹), 1633, 2360, 3380; LC-MS calcd m/z 284, found 285 [(M + 1)]⁺. Anal. calcd for C₁₅H₁₃FN₄O: C, 63.37; H, 4.61; N, 19.71; found C, 63.25; H, 4.52; N, 19.57.
4-Ethoxy-6-(4-(2-fluorophenyl)-1H-pyrrol-3-yl)pyrimidin-2-amine (8x). Colourless solid; yield: 90% (0.3 g); mp 130 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 1.17 (t, J = 7.2 Hz, 3H), 4.12 (q, J = 6.4 Hz, 2H), 5.47 (s, 1H), 6.12 (s, 2H), 6.84 (s, 1H), 7.13–7.18 (m, 2H), 7.28–7.33 (m, 3H), 11.30 (s, 1H); ¹³C NMR (75 MHz, DMSO-d₆) δ 14.3, 61.8, 94.1, 115.3, 115.6, 116.9, 119.6, 120.5, 123.7, 127.9, 128.1, 131.9, 158.4, 161.7, 162.6, 162.9, 170.8; IR (ATR KBr cell, cm⁻¹), 1795, 2288, 3400; LC-MS calcd m/z 298, found 299 [(M + 1)]⁺. HRMS (ESI-TOF) calcd for C₁₆H₁₅FN₄O [M + H]⁺ 299.1308, found 299.1307.
4-Methoxy-6-(4-(furan-2-yl)-1H-pyrrol-3-yl)pyrimidin-2-amine (8y). Pale yellow solid; yield: 83% (0.24 g); mp 168 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 3.73 (s, 3H), 5.80 (s, 1H), 6.30 (s, 2H), 6.45 (s, 1H), 6.53 (s, 1H), 7.01 (s, 1H), 7.29 (s, 1H), 7.56 (s, 1H), 11.30 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ 53.1, 92.1, 107.2, 111.6, 113.2, 119.7, 120.9, 121.4, 141.5, 150.3, 163.1, 163.5, 170.6; IR (ATR KBr cell, cm⁻¹), 1420, 2300, 3100; LC-MS calcd m/z 256, found 257 [(M + 1)]⁺. Anal. calcd for C₁₃H₁₂N₄O₂: C, 60.93; H, 4.72; N, 21.86; found C, 60.79; H, 4.64; N, 21.79.
4-Ethoxy-6-(4-(furan-2-yl)-1H-pyrrol-3-yl)pyrimidin-2-amine (8z). Pale yellow solid; yield: 85% (0.26 g); mp 126 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 1.22 (t, J = 7.2 Hz, 3H), 4.22 (q, J = 6.4 Hz, 2H), 5.79 (s, 1H), 6.26 (s, 2H), 6.44 (s, 1H), 6.54 (s, 1H), 7.01 (s, 1H), 7.29 (s, 1H), 7.56 (s, 1H), 11.29 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ 14.4, 61.8, 94.8, 106.5, 110.9, 113.8, 118.8, 120.6, 120.8, 140.7, 149.5, 162.6, 162.7, 170.8, IR (ATR KBr cell, cm⁻¹), 1485, 2239, 3465; LC-MS calcd m/z 270, found 271 [(M + 1)]⁺. Anal. calcd for C₁₄H₁₄N₄O₂: C, 62.21; H, 5.22; N, 20.73; found C, 62.09; H, 5.17; N, 20.63.
4-Methoxy-6-(4-(thiophen-2-yl)-1H-pyrrol-3-yl)pyrimidin-2-amine (8aa). Colourless solid; yield: 87% (0.28 g); mp 170–172 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 3.70 (s, 3H), 5.74 (s, 1H), 6.27 (s, 2H), 6.89 (s, 1H), 7.08 (d, J = 5.2 Hz, 1H), 7.24 (s, 1H), 7.42–7.47 (m, 2H), 11.16 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ 92.5, 118.2, 119.2, 121.1, 121.4, 125.5, 129.4, 129.6, 136.8, 163.5, 163.7, 170.5; IR (ATR KBr cell, cm⁻¹), 1597, 1800, 2365, 3400; LC-MS calcd m/z 272, found 273 [(M + 1)]⁺. HRMS (ESI-TOF) calcd for C₁₃H₁₂N₄OS [M + H]⁺ 273.0810, found 273.0812.
4-Ethoxy-6-(4-(thiophen-2-yl)-1H-pyrrol-3-yl)pyrimidin-2-amine (8ab). Colourless solid; yield: 87% (0.29 g); mp 140–142 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 1.21 (t, J = 7.2 Hz, 3H), 4.16 (q, J = 7.6 Hz, 2H), 5.73 (s, 1H), 6.23 (s, 2H), 6.88 (s, 1H), 7.10 (d, J = 4.6 Hz, 1H), 7.24 (s, 1H), 7.45–7.47 (m, 2H), 11.15 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ 14.9, 61.1, 92.7, 118.1, 119.2, 121.0, 121.1, 121.2, 125.5, 129.6, 136.9, 163.5, 163.7, 170.1; IR (ATR KBr cell, cm⁻¹), 1559, 1645, 2209, 3406; LC-MS calcd m/z 286, found 287 [(M + 1)]⁺. Anal. calcd for C₁₄H₁₄N₄OS: C, 58.72; H, 4.93; N, 19.57; found C, 58.65; H, 4.84; N, 19.47.
4-Methoxy-6-(4-(5-bromopyridin-3yl)-1H-pyrrol-3-yl)pyrimidin-2-amine (8ac). Colourless solid; yield: 78% (0.25 g); mp 158–160 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 3.74 (s, 3H), 5.82 (s, 1H), 6.22 (s, 2H), 7.13 (s, 1H), 7.30 (s, 1H), 7.94 (s, 1H), 8.51 (s, 2H), 11.43 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ 53.2, 92.9, 118.0, 120.1, 120.6, 121.1, 122.0, 134.4, 137.9, 147.2, 147.8, 163.3, 163.6, 170.6; IR (ATR KBr cell, cm⁻¹), 1468, 1820, 2220, 3280, LC-MS calcd m/z 347, found 348 [(M + 1)]⁺. Anal. calcd for C₁₄H₁₂BrN₅O. C, 48.57; H, 3.49; N, 20.23; found C, 48.44; H, 3.41; N, 20.14.
4-Ethoxy-6-(4-(5-bromopyridin-3yl)-1H-pyrrol-3-yl)pyrimidin-2-amine (8ad). Colourless solid; yield: 75% (0.25 g); mp 126 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 1.23 (t, J = 7.2 Hz, 3H), 4.21 (q, J = 7.2 Hz, 2H), 5.81 (s, 1H), 6.17 (s, 2H), 7.17 (s, 1H), 7.31 (s, 1H), 7.95 (s, 1H), 8.46 (s, 2H), 11.43 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆) δ 14.9, 61.2, 93.0, 118.0, 120.1, 120.5, 121.0, 121.9, 134.5, 137.8, 147.1, 147.8, 158.2, 163.6, 170.2; IR (ATR KBr cell, cm⁻¹), 1440, 1860, 2300, 3320; LC-MS calcd. m/z 294, found 295 [(M + 1)]⁺. Anal. calcd for C₁₅H₁₄BrN₅O: C, 50.02; H, 3.92; N, 19.44; found C, 49.92; H, 3.88; N, 19.32.

Acknowledgements

SS thanks UGC and DST–MRP, New Delhi for financial assistance. PD thanks UGC for meritorious fellowship. We thank Prof. H. Surya Prakash Rao, Department of Chemistry, Pondicherry University, Pondicherry for generous help in recording spectra and helpful discussions. We thank Dr P. Thilagar, Department of IPC, IISc Bangalore for helpful discussions and analyzing the single crystal X-ray data.

Notes and references

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19. ESI.†.

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Footnote

† Electronic supplementary information (ESI) available. CCDC 955689. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ra02891k

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