Copper-Catalyzed Tandem Synthesis of Tetrasubstituted Pyrimidines from Alkynes, Sulfonyl Azides, Trichloroacetonitrile, and Tetramethylguanidine

Abstract

The synthesis of a novel class of pyrimidine derivatives via a copper-catalyzed tandem reaction of trichloroacetonitrile, 1,1,3,3-tetramethylguanidine, sulfonyl azides, and terminal alkynes is described.

In recent years, intensive studies in medicinal chemistry with regard to the structure–activity relationships of compounds being used in clinical praxis have revealed the exceptional position of heterocycles. Moreover, a large number of bioactive natural products contain a heteroatom. Therefore, the development of reliable and efficient methods for constructing heterocyclic frameworks is of major importance. Pyrimidine derivatives exhibit important biological activities and are widely used as key building blocks for pharmaceutical agents.[1] [2] [3] The pyrimidine skeleton has also been found in several marine natural products with interesting bioactivities.[ ⁴ ] Consequently, several methods have been developed for construction of this heterocyclic system.[ ^5–7 ] This biological and synthetic significance places this scaffold in a prestigious position in medicinal chemistry research.

Ketenimines[ ⁸ ] have attracted much attention due to their diverse chemical reactivity.[9] [10] [11] [12] One of the attractive methods for the generation of ketenimines is the copper-catalyzed azide–alkyne cycloaddition (Table [1]).[ ^13,14 ] The formation of ketenimine intermediates from terminal ­alkynes and sulfonyl azides, in the presence of Et₃N and copper catalysts,[ ¹⁵ ] has encouraged us to trap these ­intermediates using various nucleophilic addition reactions.[16] [17] [18]

Herein, we report a simple and efficient procedure for the synthesis of N-[6-(dimethylamino)-5-aryl(alkyl)-2-(trichloromethyl)pyrimidin-4-yl]-4-aryl(alkyl)sulfonamide via the copper-catalyzed four-component coupling reaction of terminal alkynes 1, sulfonyl azides 2, trichloro­acetonitrile (3), and 1,1,3,3-tetramethylguanidine (4, Table [1]).[ ¹⁹ ]

Initially, phenylacetylene (1a), p-toluenesulfonyl azide (2a), 3, and 4 were selected as the model substrates. Several catalysts such as CuI, CuBr, CuCl, and copper powder were tested with CuI giving the best results. Among several solvents screened, MeCN was the best. When the reaction was performed in MeCN in the presence of one equivalent of Et₃N at room temperature for eight hours, it was found that the desired product 5a was indeed obtained in 83% yield (Table [1]). Thus, the optimized reaction conditions used were 10 mol% of CuI, 1 mmol of alkyne, 1.2 mmol of sulfonyl azide, 1 mmol of 3, and 1 mmol of 4 in MeCN at room temperature.

Table 1 Copper-Catalyzed Azide–Alkyne Cycloaddition for the Synthesis of 5

Entry	1, 2, 5	R1	R2	Yield of 5 (%)
1	a	Ph	4-Tol	83
2	b	Ph	Ph	87
3	c	Ph	Me	79
4	d	n-Pr	4-Tol	65
5	e	n-Pr	Ph	63
6	f	n-Pr	Me	60
7	g	n-Bu	4-Tol	60
8	h	n-Bu	Ph	57
9	i	n-Bu	Me	52

Phenylacetylene readily participates in the coupling reaction to furnish the corresponding N-[6-(dimethylamino)-5-phenyl-2-(trichloromethyl)pyrimidin-4-yl]-4-aryl(alkyl)sulfonamides 5a–c in good yields (Table [1]). Aliphatic acetylenes served as low-yielding substrates compared to phenylacetylene. Aromatic and aliphatic sulfonyl azides reacted efficiently, and the corresponding products were obtained in good yields.

Structures of compounds 5a–i were assigned by IR, ¹H NMR, ¹³C NMR, and mass spectral data. The ¹H NMR spectrum of 5a exhibited three singlets for methyl (δ = 2.87 ppm), dimethyl amino (δ = 2.95 ppm), and NH (δ = 8.03 ppm) protons, along with characteristic multiplets for the phenyl protons. The ¹³C NMR spectrum of 5a exhibits 15 signals in agreement with the proposed structure. The mass spectrum of 5a displayed the molecular ion peak at m/z = 484. The NMR spectra of compounds 5b–i are similar to those of 5a, except for the substituents, which showed characteristic signals in the appropriate regions of the spectra.

A plausible mechanism for the formation of compounds 5 is given in Scheme [1]. The yellow copper acetylide 7, formed from 1 and CuI, undergoes a 1,3-dipolar cycloaddition reaction with sulfonyl azide 2, to generate the triazole derivative 8.[ ²⁰ ] This intermediate can then react by ring opening leading to the formation of α-diazoimino species 9 and thereafter ketenimine 10 by loss of nitrogen gas.[21] [22] Intermediate 6, formed from 3 and 4, undergoes a nucleophilic addition reaction with ketenimine 10 to afford 11. This intermediate is converted into 5 by ring-­formation reaction, loss of dimethylamine, and tautomerization.

In conclusion, we have developed a multicomponent reaction involving ketenimine intermediates, 1,1,3,3-tetramethylguanidine, and trichloroacetonitrile, which provides a new route to the synthesis of functionalized ­pyrimidine derivatives in moderate to good yields.

• References and Notes

• 1 Sasada T, Kobayashi F, Sakai N, Konakahara T. Org. Lett. 2009; 11: 2161
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• 2 Ahmad OK, Hill MD, Movassaghi M. J. Org. Chem. 2009; 74: 8460
  CrossrefPubMedSearch in Google Scholar
• 3 Barthakur MG, Borthakur M, Devi P, Saikia CJ, Saikia A, Bora U, Chetia A, Boruah RC. Synlett 2007; 223
• 4 Heys L, Moore CG, Murphy PJ. Chem. Soc. Rev. 2000; 29: 57
  CrossrefSearch in Google Scholar
• 5 Rewcastle GW. Comprehensive Heterocyclic Chemistry III: Pyrimidines and their Benzo Derivatives. Vol. 8. Elsevier; Oxford: 2008: 117-272
  CrossrefSearch in Google Scholar
• 6 von Angerer S. Six-Membered Hetarenes with Two Identical Heteroatoms: Pyrimidines. In Science of Synthesis. Vol. 16. Thieme; Stuttgart: 2003: 379-572
  Search in Google Scholar
• 7 Brown DJ, Evans RF, Cowden WB, Fenn MD. The Pyrimidines . In Chemistry of Heterocyclic Compounds . Vol. 52. Taylor EC. Wiley; New York: 1994: 1
  CrossrefSearch in Google Scholar
• 8 Bae I, Han H, Chang S. J. Am. Chem. Soc. 2005; 127: 2038
  CrossrefPubMedSearch in Google Scholar
• 9 Staudinger H, Hauser E. Helv. Chim. Acta 1921; 4: 887
  CrossrefSearch in Google Scholar
• 10 Lu P, Wang YG. Synlett 2010; 166
• 11 Hein JE, Fokin VV. Chem. Soc. Rev. 2010; 39: 1302
  Search in Google Scholar
• 12 Yoo EJ, Chang S. Curr. Org. Chem. 2009; 13: 1766
  CrossrefSearch in Google Scholar
• 13 Rostovtsev VV, Green LG, Fokin VV, Sharpless KB. Angew. Chem. Int. Ed. 2002; 41: 2596
  Search in Google Scholar
• 14 Tornøe CW, Christensen C, Meldal M. J. Org. Chem. 2002; 67: 3057
  CrossrefSearch in Google Scholar
• 15 Jin H, Zhou B, Wu Z, Shen Y, Wang Y. Tetrahedron 2011; 67: 1178
  CrossrefSearch in Google Scholar
• 16 Yavari I, Nematpour M. Synlett 2012; 23: 2215
  Thieme ConnectSearch in Google Scholar
• 17 Yavari I, Nematpour M, Yavari S, Sadeghizadeh F. Tetrahedron Lett. 2012; 53: 1889
  CrossrefSearch in Google Scholar
• 18 Yavari I, Nematpour M. Mol. Diversity 2012; 16: 651
  CrossrefSearch in Google Scholar
• 19 Typical Procedure for the Preparation of Compounds 5 Compounds 3 (1 mmol) and 4 (1 mmol) were dissolved in MeCN (2 mL) and stirred for 30 min. Then, a mixture of sulfonyl azide 2 (1.2 mmol), alkyne 1 (1 mmol), CuI (0.1 mmol), and Et₃N (1 mmol) in MeCN (3 mL) was slowly added to the mixture and stirred at r.t. under N₂ atmosphere. After completion of the reaction [about 8 h; TLC (EtOAc–hexane = 1:5) monitoring], the mixture was diluted with CH₂Cl₂ (2 mL) and aq NH₄Cl solution (3 mL), stirred for 30 min, and the layers were separated. The aqueous layer was extracted with CH₂Cl₂ (3 × 3 mL). The combined organic fractions were dried (Na₂SO₄) and concentrated under reduced pressure. The residue was purified by flash column chromatography [silica gel (230–400 mesh; Merck), hexane–EtOAc = 5:1] to give the product. N-[6-(Dimethylamino)-5-phenyl-2-(trichloromethyl)-pyrimidin-4-yl]-4-methylbenzenesulfonamide (5a) Cream powder; mp 159–161 °C; yield 0.40 g (83%). IR (KBr): ν_max = 3061, 1682, 1590, 1445, 1375, 1172, 1071, 754 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 2.87 (3 H, s, Me), 2.95 (6 H, s, NMe₂), 7.07 (2 H, d, ³ J = 7.4 Hz, Ar), 7.18 (1 H, t, ³ J = 7.4 Hz, Ar), 7.28 (2 H, t, ³ J = 7.4 Hz, Ar), 7.39 (2 H, d, ³ J = 7.9 Hz, Ar), 7.91 (2 H, d, ³ J = 7.9 Hz, Ar), 8.03 (1 H, s, NH). ¹³C NMR (125.7 MHz, CDCl₃): δ = 32.4 (Me), 37.5 (NMe₂), 90.4 (CCl₃), 110.0 (C), 122.5 (C), 127.4 (2 CH), 128.7 (2 CH), 129.2 (CH), 130.7 (2 CH), 132.5 (2 CH), 142.1 (C), 147.3 (C), 163.6 (C), 168.9 (C), 171.0 (C). MS: m/z (%) = 484 (1) [M⁺], 439 (6), 406 (12), 392 (16), 367 (21), 170 (23), 155 (100), 116 (43), 91 (70), 77 (51), 44 (31). Anal. Calcd (%) for C₂₀H₁₉Cl₃N₄O₂S (484.03): C, 49.45; H, 3.94; N, 11.53. Found: C, 49.68; H, 4.02; N, 11.62. N-[6-(Dimethylamino)-5-phenyl-2-(trichloromethyl)-pyrimidin-4-yl]benzenesulfonamide (5b) Cream powder; mp 167–170 °C; yield 0.40 g (87%). IR (KBr): ν_max = 3060, 1681, 1595, 1441, 1373, 1270, 1182, 1072, 750 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 2.96 (6 H, s, NMe₂), 7.25–7.31 (3 H, m, Ph), 7.45 (2 H, d, ³ J = 7.4 Hz, Ar), 7.58 (2 H, t, ³ J = 7.4 Hz, Ar), 7.69 (1 H, t, ³ J = 7.9 Hz, Ar), 8.00 (2 H, d, ³ J = 7.9 Hz, Ar), 8.07 (1 H, s, NH). ¹³C NMR (125.7 MHz, CDCl₃): δ = 37.5 (NMe₂), 90.4 (CCl₃), 110.3 (C), 122.5 (C), 127.4 (2 CH), 128.7 (2 CH), 129.2 (CH), 130.2 (2 CH), 132.5 (2 CH), 135.7 (CH), 144.8 (C), 163.6 (C), 167.8 (C), 171.1 (C). MS: m/z (%) = 470 (1) [M⁺], 425 (3), 392 (21), 314 (17), 156 (31), 141 (100), 91 (71), 77 (50), 44 (31). Anal. Calcd (%) for C₁₉H₁₇Cl₃N₄O₂S (470.01): C, 48.37; H, 3.63; N, 11.88. Found: C, 48.63; H, 3.69; N, 12.01. N-[6-(Dimethylamino)-5-phenyl-2-(trichloromethyl)-pyrimidin-4-yl]methanesulfonamide (5c) Cream powder; mp 123–125 °C; yield 0.32 g (79%). IR (KBr): ν_max = 3031, 1684, 1592, 1446, 1361, 1278, 1170, 1073, 757 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 2.93 (6 H, s, NMe₂), 3.65 (3 H, s, Me), 7.25–7.35 (3 H, m, Ph), 7.48 (2 H, d, ³ J = 7.4 Hz, Ar), 8.11 (1 H, s, NH). ¹³C NMR (125.7 MHz, CDCl₃): δ = 33.0 (Me), 37.8 (NMe₂), 90.4 (CCl₃), 110.1 (C), 122.6 (C), 128.7 (2 CH), 129.2 (CH), 132.5 (2 CH), 163.0 (C), 167.0 (C), 170.0 (C). MS: m/z (%) = 409 (1) [M⁺], 363 (11), 330 (14), 329 (18), 314 (17), 116 (31), 94 (100), 78 (54), 77 (32), 44 (22). Anal. Calcd (%) for C₁₄H₁₅Cl₃N₄O₂S (409.72): C, 41.04; H, 3.69; N, 13.67. Found: C, 41.42; H, 3.76; N, 13.52. N-[6-(Dimethylamino)-5-propyl-2-(trichloromethyl)-pyrimidin-4-yl]-4-methylbenzenesulfonamide (5d) Cream powder; mp 113–115 °C; yield 0.29 g (65%). IR (KBr): ν_max = 3039, 1633, 1590, 1368, 1218, 1018, 751 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 0.96 (3 H, t, ³ J = 6.8 Hz, Me), 1.48–1.55 (2 H, m, CH₂), 2.13 (2 H, t, ³ J = 6.8 Hz, CH₂), 2.45 (3 H, s, Me), 3.07 (6 H, s, NMe₂), 7.38 (2 H, d, ³ J = 7.9 Hz, Ar), 7.89 (2 H, d, ³ J = 7.9 Hz, Ar), 8.21 (1 H, s, NH). ¹³C NMR (125.7 MHz, CDCl₃): δ = 13.7 (Me), 20.8 (CH₂), 22.3 (CH₂), 33.3 (Me), 38.6 (NMe₂), 90.4 (CCl₃), 111.0 (C), 127.4 (2 CH), 129.6 (2 CH), 142.1 (C), 147.3 (C), 164.7 (C), 168.6 (C), 170.0 (C). MS: m/z (%) = 450 (1) [M⁺], 406 (11), 391 (8), 343 (14), 280 (17), 170 (21), 155 (100), 116 (31), 91 (45), 44 (20), 43 (30). Anal. Calcd (%) for C₁₇H₂₁Cl₃N₄O₂S (450.05): C, 45.19; H, 4.68; N, 12.40. Found: C, 45.54; H, 4.55; N, 12.51. N-[6-(Dimethylamino)-5-propyl-2-(trichloromethyl)-pyrimidin-4-yl]benzenesulfonamide (5e) Cream powder; mp 100–103 °C; yield 0.27 g (63%). IR (KBr): ν_max = 3061, 1680, 1571, 1435, 1377, 1235, 1163, 1075, 748 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 0.97 (3 H, t, ³ J = 6.8 Hz, Me), 1.48–1.56 (2 H, m, CH₂), 2.12 (2 H, t, ³ J = 6.8 Hz, CH₂), 3.10 (6 H, s, NMe₂), 7.60 (2 H, t, ³ J = 7.8 Hz, Ar), 7.74 (1 H, t, ³ J = 7.8 Hz, Ar), 8.00 (2 H, d, ³ J = 7.8 Hz, Ar), 8.24 (1 H, s, NH). ¹³C NMR (125.7 MHz, CDCl₃): δ = 13.7 (Me), 20.8 (CH₂), 22.4 (CH₂), 38.7 (NMe₂), 91.0 (CCl₃), 110.6 (C), 127.3 (2 CH), 130.1 (2 CH), 135.7 (CH), 144.8 (C), 164.8 (C), 168.9 (C), 171.0 (C). MS: m/z (%) = 436 (1) [M⁺], 392 (15), 319 (13), 296 (21), 280 (17), 156 (45), 144 (100), 116 (35), 77 (49), 44 (25), 43 (22). Anal. Calcd (%) for C₁₆H₁₉Cl₃N₄O₂S (436.03): C, 43.90; H, 4.37; N, 12.80. Found: C, 44.21; H, 4.48; N, 12.91. N-[6-(Dimethylamino)-5-propyl-2-(trichloromethyl)-pyrimidin-4-yl]methanesulfonamide (5f) Cream powder; mp 90–93 °C; yield 0.22 g (60%). IR (KBr): ν_max = 3064, 1679, 1565, 1459, 1370, 1271, 1180, 1049, 749 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 0.99 (3 H, t, ³ J = 6.8 Hz, Me), 1.49–1.57 (2 H, m, CH₂), 2.14 (2 H, t, ³ J = 6.8 Hz, CH₂), 2.96 (6 H, s, NMe₂), 3.56 (3 H, s, Me), 8.28 (1 H, s, NH). ¹³C NMR (125.7 MHz, CDCl₃): δ = 13.7 (Me), 20.8 (CH₂), 22.3 (CH₂), 33.0 (Me), 39.7 (NMe₂), 90.4 (CCl₃), 111.0 (C), 165.6 (C), 167.7 (C), 170.0 (C). MS: m/z (%) = 374 (1) [M⁺], 330 (11), 329 (9), 295 (25), 280 (13), 116 (30), 94 (100), 78 (39), 44 (29), 43 (26). Anal. Calcd (%) for C₁₁H₁₇Cl₃N₄O₂S (374.01): C, 35.17; H, 4.56; N, 14.91. Found: C, 35.40; H, 4.63; N, 15.03. N-[5-Butyl-6-(dimethylamino)-2-(trichloromethyl)-pyrimidin-4-yl]-4-methylbenzenesulfonamide (5g) Cream powder; mp 119–122 °C; yield 0.28 g (60%). IR (KBr): ν_max = 3032, 1627, 1551, 1450, 1365, 1222, 1177, 1079, 739 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 0.92 (3 H, t, ³ J = 6.8 Hz, Me), 1.36–1.43 (2 H, m, CH₂), 1.46–1.51 (2 H, m, CH₂), 2.14 (2 H, t, ³ J = 6.8 Hz, CH₂), 2.50 (3 H, s, Me), 3.00 (6 H, s, NMe₂), 7.39 (2 H, d, ³ J = 8.0 Hz, Ar), 7.92 (2 H, d, ³ J = 8.0 Hz, Ar), 8.30 (1 H, s, NH). ¹³C NMR (125.7 MHz, CDCl₃): δ = 13.9 (Me), 18.5 (CH₂), 21.8 (CH₂), 22.2 (CH₂), 33.8 (Me), 39.3 (NMe₂), 90.4 (CCl₃), 110.1 (C), 127.5 (2 CH), 129.6 (2 CH), 142.0 (C), 147.3 (C), 163.7 (C), 169.0 (C), 172.0 (C). MS: m/z (%) = 464 (1) [M⁺], 420 (8), 406 (11), 347 (13), 170 (21), 155 (100), 116 (50), 91 (42), 57 (44), 44 (45). Anal. Calcd (%) for C₁₈H₂₃Cl₃N₄O₂S (464.06): C, 46.41; H, 4.98; N, 12.03. Found: C, 46.67; H, 5.07; N, 12.16. N-[5-Butyl-6-(dimethylamino)-2-(trichloromethyl)-pyrimidin-4-yl]benzenesulfonamide (5h) Cream powder; mp 111–114 °C; yield 0.26 g (57%). IR (KBr): ν_max = 3031, 1613, 1592, 1451, 1376, 1220, 1177, 1079, 743 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 0.88 (3 H, t, ³ J = 6.8 Hz, Me), 1.35–1.41 (2 H, m, CH₂), 1.43–1.50 (2 H, m, CH₂), 2.13 (2 H, t, ³ J = 6.8 Hz, CH₂), 2.96 (6 H, s, NMe₂), 7.61 (2 H, t, ³ J = 7.8 Hz, Ar), 7.71 (1 H, t, ³ J = 7.8 Hz, Ar), 7.99 (2 H, d, ³ J = 7.8 Hz, Ar), 8.18 (1 H, s, NH). ¹³C NMR (125.7 MHz, CDCl₃): δ = 13.9 (Me), 18.4 (CH₂), 20.8 (CH₂), 22.2 (CH₂), 38.3 (NMe₂), 90.1 (CCl₃), 111.4 (C), 127.3 (2 CH), 130.2 (2 CH), 135.7 (CH), 144.8 (C), 164.3 (C), 169.0 (C), 171.0 (C). MS: m/z (%) = 450 (1) [M⁺], 406 (6), 392 (10), 373 (22), 294 (25), 156 (100), 141 (23), 116 (50), 57 (41), 44 (22). Anal. Calcd (%) for C₁₇H₂₁Cl₃N₄O₂S (450.05): C, 45.19; H, 4.68; N, 12.40. Found: C, 45.52; H, 4.71; N, 12.52. N-[5-Butyl-6-(dimethylamino)-2-(trichloromethyl)-pyrimidin-4-yl]methanesulfonamide (5i) Cream powder; mp 95–98 °C; yield 0.20 g (52%). IR (KBr): ν_max = 3030, 1669, 1582, 1451, 1376, 1179, 1078, 741 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 0.89 (3 H, t, ³ J = 6.8 Hz, Me), 1.34–1.40 (2 H, m, CH₂), 1.44–1.52 (2 H, m, CH₂), 2.14 (2 H, t, ³ J = 6.8 Hz, CH₂), 2.96 (6 H, s, NMe₂), 3.46 (3 H, s, Me), 8.24 (1 H, s, NH). ¹³C NMR (125.7 MHz, CDCl₃): δ = 13.9 (Me), 18.4 (CH₂), 20.8 (CH₂), 22.7 (CH₂), 33.6 (Me), 38.3 (NMe₂), 90.1 (CCl₃), 111.0 (C), 165.8 (C), 167.9 (C), 171.3 (C). MS: m/z (%) = 388 (1) [M⁺], 343 (8), 315 (10), 294 (22), 279 (25), 116 (23), 94 (100), 78 (23), 44 (43). Anal. Calcd (%) for C₁₂H₁₉Cl₃N₄O₂S (388.03): C, 36.98; H, 4.91; N, 14.38. Found: C, 37.29; H, 4.85; N, 14.47.
• 20 Yoo EJ, Ahlquist M, Kim SH, Bae I, Fokin VV, Sharpless KB, Chang S. Angew. Chem. Int. Ed. 2007; 46: 1730
  CrossrefPubMedSearch in Google Scholar
• 21 Cassidy MP, Raushel J, Fokin VV. Angew. Chem. Int. Ed. 2006; 45: 3154
  CrossrefPubMedSearch in Google Scholar
• 22 Yoo EJ, Ahlquist M, Bae I, Sharpless KB, Fokin VV, Chang S. J. Org. Chem. 2008; 73: 5520
  CrossrefPubMedSearch in Google Scholar

• References and Notes

• 1 Sasada T, Kobayashi F, Sakai N, Konakahara T. Org. Lett. 2009; 11: 2161
  CrossrefPubMedSearch in Google Scholar
• 2 Ahmad OK, Hill MD, Movassaghi M. J. Org. Chem. 2009; 74: 8460
  CrossrefPubMedSearch in Google Scholar
• 3 Barthakur MG, Borthakur M, Devi P, Saikia CJ, Saikia A, Bora U, Chetia A, Boruah RC. Synlett 2007; 223
• 4 Heys L, Moore CG, Murphy PJ. Chem. Soc. Rev. 2000; 29: 57
  CrossrefSearch in Google Scholar
• 5 Rewcastle GW. Comprehensive Heterocyclic Chemistry III: Pyrimidines and their Benzo Derivatives. Vol. 8. Elsevier; Oxford: 2008: 117-272
  CrossrefSearch in Google Scholar
• 6 von Angerer S. Six-Membered Hetarenes with Two Identical Heteroatoms: Pyrimidines. In Science of Synthesis. Vol. 16. Thieme; Stuttgart: 2003: 379-572
  Search in Google Scholar
• 7 Brown DJ, Evans RF, Cowden WB, Fenn MD. The Pyrimidines . In Chemistry of Heterocyclic Compounds . Vol. 52. Taylor EC. Wiley; New York: 1994: 1
  CrossrefSearch in Google Scholar
• 8 Bae I, Han H, Chang S. J. Am. Chem. Soc. 2005; 127: 2038
  CrossrefPubMedSearch in Google Scholar
• 9 Staudinger H, Hauser E. Helv. Chim. Acta 1921; 4: 887
  CrossrefSearch in Google Scholar
• 10 Lu P, Wang YG. Synlett 2010; 166
• 11 Hein JE, Fokin VV. Chem. Soc. Rev. 2010; 39: 1302
  Search in Google Scholar
• 12 Yoo EJ, Chang S. Curr. Org. Chem. 2009; 13: 1766
  CrossrefSearch in Google Scholar
• 13 Rostovtsev VV, Green LG, Fokin VV, Sharpless KB. Angew. Chem. Int. Ed. 2002; 41: 2596
  Search in Google Scholar
• 14 Tornøe CW, Christensen C, Meldal M. J. Org. Chem. 2002; 67: 3057
  CrossrefSearch in Google Scholar
• 15 Jin H, Zhou B, Wu Z, Shen Y, Wang Y. Tetrahedron 2011; 67: 1178
  CrossrefSearch in Google Scholar
• 16 Yavari I, Nematpour M. Synlett 2012; 23: 2215
  Thieme ConnectSearch in Google Scholar
• 17 Yavari I, Nematpour M, Yavari S, Sadeghizadeh F. Tetrahedron Lett. 2012; 53: 1889
  CrossrefSearch in Google Scholar
• 18 Yavari I, Nematpour M. Mol. Diversity 2012; 16: 651
  CrossrefSearch in Google Scholar
• 19 Typical Procedure for the Preparation of Compounds 5 Compounds 3 (1 mmol) and 4 (1 mmol) were dissolved in MeCN (2 mL) and stirred for 30 min. Then, a mixture of sulfonyl azide 2 (1.2 mmol), alkyne 1 (1 mmol), CuI (0.1 mmol), and Et₃N (1 mmol) in MeCN (3 mL) was slowly added to the mixture and stirred at r.t. under N₂ atmosphere. After completion of the reaction [about 8 h; TLC (EtOAc–hexane = 1:5) monitoring], the mixture was diluted with CH₂Cl₂ (2 mL) and aq NH₄Cl solution (3 mL), stirred for 30 min, and the layers were separated. The aqueous layer was extracted with CH₂Cl₂ (3 × 3 mL). The combined organic fractions were dried (Na₂SO₄) and concentrated under reduced pressure. The residue was purified by flash column chromatography [silica gel (230–400 mesh; Merck), hexane–EtOAc = 5:1] to give the product. N-[6-(Dimethylamino)-5-phenyl-2-(trichloromethyl)-pyrimidin-4-yl]-4-methylbenzenesulfonamide (5a) Cream powder; mp 159–161 °C; yield 0.40 g (83%). IR (KBr): ν_max = 3061, 1682, 1590, 1445, 1375, 1172, 1071, 754 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 2.87 (3 H, s, Me), 2.95 (6 H, s, NMe₂), 7.07 (2 H, d, ³ J = 7.4 Hz, Ar), 7.18 (1 H, t, ³ J = 7.4 Hz, Ar), 7.28 (2 H, t, ³ J = 7.4 Hz, Ar), 7.39 (2 H, d, ³ J = 7.9 Hz, Ar), 7.91 (2 H, d, ³ J = 7.9 Hz, Ar), 8.03 (1 H, s, NH). ¹³C NMR (125.7 MHz, CDCl₃): δ = 32.4 (Me), 37.5 (NMe₂), 90.4 (CCl₃), 110.0 (C), 122.5 (C), 127.4 (2 CH), 128.7 (2 CH), 129.2 (CH), 130.7 (2 CH), 132.5 (2 CH), 142.1 (C), 147.3 (C), 163.6 (C), 168.9 (C), 171.0 (C). MS: m/z (%) = 484 (1) [M⁺], 439 (6), 406 (12), 392 (16), 367 (21), 170 (23), 155 (100), 116 (43), 91 (70), 77 (51), 44 (31). Anal. Calcd (%) for C₂₀H₁₉Cl₃N₄O₂S (484.03): C, 49.45; H, 3.94; N, 11.53. Found: C, 49.68; H, 4.02; N, 11.62. N-[6-(Dimethylamino)-5-phenyl-2-(trichloromethyl)-pyrimidin-4-yl]benzenesulfonamide (5b) Cream powder; mp 167–170 °C; yield 0.40 g (87%). IR (KBr): ν_max = 3060, 1681, 1595, 1441, 1373, 1270, 1182, 1072, 750 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 2.96 (6 H, s, NMe₂), 7.25–7.31 (3 H, m, Ph), 7.45 (2 H, d, ³ J = 7.4 Hz, Ar), 7.58 (2 H, t, ³ J = 7.4 Hz, Ar), 7.69 (1 H, t, ³ J = 7.9 Hz, Ar), 8.00 (2 H, d, ³ J = 7.9 Hz, Ar), 8.07 (1 H, s, NH). ¹³C NMR (125.7 MHz, CDCl₃): δ = 37.5 (NMe₂), 90.4 (CCl₃), 110.3 (C), 122.5 (C), 127.4 (2 CH), 128.7 (2 CH), 129.2 (CH), 130.2 (2 CH), 132.5 (2 CH), 135.7 (CH), 144.8 (C), 163.6 (C), 167.8 (C), 171.1 (C). MS: m/z (%) = 470 (1) [M⁺], 425 (3), 392 (21), 314 (17), 156 (31), 141 (100), 91 (71), 77 (50), 44 (31). Anal. Calcd (%) for C₁₉H₁₇Cl₃N₄O₂S (470.01): C, 48.37; H, 3.63; N, 11.88. Found: C, 48.63; H, 3.69; N, 12.01. N-[6-(Dimethylamino)-5-phenyl-2-(trichloromethyl)-pyrimidin-4-yl]methanesulfonamide (5c) Cream powder; mp 123–125 °C; yield 0.32 g (79%). IR (KBr): ν_max = 3031, 1684, 1592, 1446, 1361, 1278, 1170, 1073, 757 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 2.93 (6 H, s, NMe₂), 3.65 (3 H, s, Me), 7.25–7.35 (3 H, m, Ph), 7.48 (2 H, d, ³ J = 7.4 Hz, Ar), 8.11 (1 H, s, NH). ¹³C NMR (125.7 MHz, CDCl₃): δ = 33.0 (Me), 37.8 (NMe₂), 90.4 (CCl₃), 110.1 (C), 122.6 (C), 128.7 (2 CH), 129.2 (CH), 132.5 (2 CH), 163.0 (C), 167.0 (C), 170.0 (C). MS: m/z (%) = 409 (1) [M⁺], 363 (11), 330 (14), 329 (18), 314 (17), 116 (31), 94 (100), 78 (54), 77 (32), 44 (22). Anal. Calcd (%) for C₁₄H₁₅Cl₃N₄O₂S (409.72): C, 41.04; H, 3.69; N, 13.67. Found: C, 41.42; H, 3.76; N, 13.52. N-[6-(Dimethylamino)-5-propyl-2-(trichloromethyl)-pyrimidin-4-yl]-4-methylbenzenesulfonamide (5d) Cream powder; mp 113–115 °C; yield 0.29 g (65%). IR (KBr): ν_max = 3039, 1633, 1590, 1368, 1218, 1018, 751 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 0.96 (3 H, t, ³ J = 6.8 Hz, Me), 1.48–1.55 (2 H, m, CH₂), 2.13 (2 H, t, ³ J = 6.8 Hz, CH₂), 2.45 (3 H, s, Me), 3.07 (6 H, s, NMe₂), 7.38 (2 H, d, ³ J = 7.9 Hz, Ar), 7.89 (2 H, d, ³ J = 7.9 Hz, Ar), 8.21 (1 H, s, NH). ¹³C NMR (125.7 MHz, CDCl₃): δ = 13.7 (Me), 20.8 (CH₂), 22.3 (CH₂), 33.3 (Me), 38.6 (NMe₂), 90.4 (CCl₃), 111.0 (C), 127.4 (2 CH), 129.6 (2 CH), 142.1 (C), 147.3 (C), 164.7 (C), 168.6 (C), 170.0 (C). MS: m/z (%) = 450 (1) [M⁺], 406 (11), 391 (8), 343 (14), 280 (17), 170 (21), 155 (100), 116 (31), 91 (45), 44 (20), 43 (30). Anal. Calcd (%) for C₁₇H₂₁Cl₃N₄O₂S (450.05): C, 45.19; H, 4.68; N, 12.40. Found: C, 45.54; H, 4.55; N, 12.51. N-[6-(Dimethylamino)-5-propyl-2-(trichloromethyl)-pyrimidin-4-yl]benzenesulfonamide (5e) Cream powder; mp 100–103 °C; yield 0.27 g (63%). IR (KBr): ν_max = 3061, 1680, 1571, 1435, 1377, 1235, 1163, 1075, 748 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 0.97 (3 H, t, ³ J = 6.8 Hz, Me), 1.48–1.56 (2 H, m, CH₂), 2.12 (2 H, t, ³ J = 6.8 Hz, CH₂), 3.10 (6 H, s, NMe₂), 7.60 (2 H, t, ³ J = 7.8 Hz, Ar), 7.74 (1 H, t, ³ J = 7.8 Hz, Ar), 8.00 (2 H, d, ³ J = 7.8 Hz, Ar), 8.24 (1 H, s, NH). ¹³C NMR (125.7 MHz, CDCl₃): δ = 13.7 (Me), 20.8 (CH₂), 22.4 (CH₂), 38.7 (NMe₂), 91.0 (CCl₃), 110.6 (C), 127.3 (2 CH), 130.1 (2 CH), 135.7 (CH), 144.8 (C), 164.8 (C), 168.9 (C), 171.0 (C). MS: m/z (%) = 436 (1) [M⁺], 392 (15), 319 (13), 296 (21), 280 (17), 156 (45), 144 (100), 116 (35), 77 (49), 44 (25), 43 (22). Anal. Calcd (%) for C₁₆H₁₉Cl₃N₄O₂S (436.03): C, 43.90; H, 4.37; N, 12.80. Found: C, 44.21; H, 4.48; N, 12.91. N-[6-(Dimethylamino)-5-propyl-2-(trichloromethyl)-pyrimidin-4-yl]methanesulfonamide (5f) Cream powder; mp 90–93 °C; yield 0.22 g (60%). IR (KBr): ν_max = 3064, 1679, 1565, 1459, 1370, 1271, 1180, 1049, 749 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 0.99 (3 H, t, ³ J = 6.8 Hz, Me), 1.49–1.57 (2 H, m, CH₂), 2.14 (2 H, t, ³ J = 6.8 Hz, CH₂), 2.96 (6 H, s, NMe₂), 3.56 (3 H, s, Me), 8.28 (1 H, s, NH). ¹³C NMR (125.7 MHz, CDCl₃): δ = 13.7 (Me), 20.8 (CH₂), 22.3 (CH₂), 33.0 (Me), 39.7 (NMe₂), 90.4 (CCl₃), 111.0 (C), 165.6 (C), 167.7 (C), 170.0 (C). MS: m/z (%) = 374 (1) [M⁺], 330 (11), 329 (9), 295 (25), 280 (13), 116 (30), 94 (100), 78 (39), 44 (29), 43 (26). Anal. Calcd (%) for C₁₁H₁₇Cl₃N₄O₂S (374.01): C, 35.17; H, 4.56; N, 14.91. Found: C, 35.40; H, 4.63; N, 15.03. N-[5-Butyl-6-(dimethylamino)-2-(trichloromethyl)-pyrimidin-4-yl]-4-methylbenzenesulfonamide (5g) Cream powder; mp 119–122 °C; yield 0.28 g (60%). IR (KBr): ν_max = 3032, 1627, 1551, 1450, 1365, 1222, 1177, 1079, 739 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 0.92 (3 H, t, ³ J = 6.8 Hz, Me), 1.36–1.43 (2 H, m, CH₂), 1.46–1.51 (2 H, m, CH₂), 2.14 (2 H, t, ³ J = 6.8 Hz, CH₂), 2.50 (3 H, s, Me), 3.00 (6 H, s, NMe₂), 7.39 (2 H, d, ³ J = 8.0 Hz, Ar), 7.92 (2 H, d, ³ J = 8.0 Hz, Ar), 8.30 (1 H, s, NH). ¹³C NMR (125.7 MHz, CDCl₃): δ = 13.9 (Me), 18.5 (CH₂), 21.8 (CH₂), 22.2 (CH₂), 33.8 (Me), 39.3 (NMe₂), 90.4 (CCl₃), 110.1 (C), 127.5 (2 CH), 129.6 (2 CH), 142.0 (C), 147.3 (C), 163.7 (C), 169.0 (C), 172.0 (C). MS: m/z (%) = 464 (1) [M⁺], 420 (8), 406 (11), 347 (13), 170 (21), 155 (100), 116 (50), 91 (42), 57 (44), 44 (45). Anal. Calcd (%) for C₁₈H₂₃Cl₃N₄O₂S (464.06): C, 46.41; H, 4.98; N, 12.03. Found: C, 46.67; H, 5.07; N, 12.16. N-[5-Butyl-6-(dimethylamino)-2-(trichloromethyl)-pyrimidin-4-yl]benzenesulfonamide (5h) Cream powder; mp 111–114 °C; yield 0.26 g (57%). IR (KBr): ν_max = 3031, 1613, 1592, 1451, 1376, 1220, 1177, 1079, 743 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 0.88 (3 H, t, ³ J = 6.8 Hz, Me), 1.35–1.41 (2 H, m, CH₂), 1.43–1.50 (2 H, m, CH₂), 2.13 (2 H, t, ³ J = 6.8 Hz, CH₂), 2.96 (6 H, s, NMe₂), 7.61 (2 H, t, ³ J = 7.8 Hz, Ar), 7.71 (1 H, t, ³ J = 7.8 Hz, Ar), 7.99 (2 H, d, ³ J = 7.8 Hz, Ar), 8.18 (1 H, s, NH). ¹³C NMR (125.7 MHz, CDCl₃): δ = 13.9 (Me), 18.4 (CH₂), 20.8 (CH₂), 22.2 (CH₂), 38.3 (NMe₂), 90.1 (CCl₃), 111.4 (C), 127.3 (2 CH), 130.2 (2 CH), 135.7 (CH), 144.8 (C), 164.3 (C), 169.0 (C), 171.0 (C). MS: m/z (%) = 450 (1) [M⁺], 406 (6), 392 (10), 373 (22), 294 (25), 156 (100), 141 (23), 116 (50), 57 (41), 44 (22). Anal. Calcd (%) for C₁₇H₂₁Cl₃N₄O₂S (450.05): C, 45.19; H, 4.68; N, 12.40. Found: C, 45.52; H, 4.71; N, 12.52. N-[5-Butyl-6-(dimethylamino)-2-(trichloromethyl)-pyrimidin-4-yl]methanesulfonamide (5i) Cream powder; mp 95–98 °C; yield 0.20 g (52%). IR (KBr): ν_max = 3030, 1669, 1582, 1451, 1376, 1179, 1078, 741 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 0.89 (3 H, t, ³ J = 6.8 Hz, Me), 1.34–1.40 (2 H, m, CH₂), 1.44–1.52 (2 H, m, CH₂), 2.14 (2 H, t, ³ J = 6.8 Hz, CH₂), 2.96 (6 H, s, NMe₂), 3.46 (3 H, s, Me), 8.24 (1 H, s, NH). ¹³C NMR (125.7 MHz, CDCl₃): δ = 13.9 (Me), 18.4 (CH₂), 20.8 (CH₂), 22.7 (CH₂), 33.6 (Me), 38.3 (NMe₂), 90.1 (CCl₃), 111.0 (C), 165.8 (C), 167.9 (C), 171.3 (C). MS: m/z (%) = 388 (1) [M⁺], 343 (8), 315 (10), 294 (22), 279 (25), 116 (23), 94 (100), 78 (23), 44 (43). Anal. Calcd (%) for C₁₂H₁₉Cl₃N₄O₂S (388.03): C, 36.98; H, 4.91; N, 14.38. Found: C, 37.29; H, 4.85; N, 14.47.
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