Palladium-Catalysed Coupling of 4-Halopyrrolo[2,3-d]pyrimidines with Arylacetylenes: Synthesis of a New Heterocyclic System - 4H-Pyrrolo[2,3,4-de]pyrimido[5′,4′:5,6][1,3]diazepino[1,7-a]indole

Abstract

Palladium-catalysed reaction of methyl 5-amino-4-chloro(or iodo)-7-methyl-2-methylthiopyrrolo[2,3-d]pyrimidine-6-carboxylate with arylacetylenes affords the corresponding 4-(arylethynyl)pyrrolopyrimidines. Reaction of 5-amino-4-iodopyrrolopyrimidine with 2-ethynyl-N-mesylaniline in the presence of PdCl₂(PPh₃)₂ and CuI led to the formation of 5-amino-4-(1-mesylindol-2-yl)pyrrolopyrimidine which after the removing of mesyl group cyclised with ethyl orthoformate to give the first representative of a novel heterocycle - 4H-pyrrolo[2,3,4-de]pyrimido[5′,4′:5,6][1,3]diazepino[1,7-a]indole.

Key words

palladium - catalysis - arylacetylenes - pyrrolopyrimidines - cyclisation - pyrrolo[2,3,4-de]pyrimido[5′,4′:5,6][1,3]diazepino[1,7-a]indole

References

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8

Typical Procedure for the Synthesis of Methyl 5-Amino-4-(arylethynyl)-2-methylthiopyrrolo[2,3- d ]pyrimidine-6-carboxylates (3a-c). [17]
Through a mixture of compound 1a [6b] (0.20 g, 0.70 mmol), CuI (26 mg, 0.14 mmol), PPh₃ (0.10 g, 0.38 mmol), PdCl₂(PPh₃)₂ (49 mg, 0.07 mmol), Et₃N (0.2 mL, 0.14 g,
1.4 mmol) and DMF (3.0 mL) was bubbled Ar for 10 min. Then 4-methylphenylacetylene (2b) (0.80 g, 6.95 mmol) was added dropwise at 60-70 °C (bath temperature). The reaction mixture was stirred at 60-70 °C for 1 h and then cooled to -5 °C. The precipitate was filtered off, washed with cold 2-PrOH and purified by chromatography on silica gel eluting with CHCl₃ to give 0.12 g (15%, calculated in respect of 2b) of di(4-methylphenyl)-1,3-butandiyne (4b), mp 180-181 °C (from 1-BuOH), R _f = 0.5 (CHCl₃), lit. [18] mp 183 °C, and 0.15 g (60%) of compound 3b, mp 157.0-158.5 °C (from MeCN), R _f = 0.4 (CHCl₃).

9

Methyl 5-Amino-4-iodo-2-methylthiopyrrolo[2,3- d ]pyrimidine-6-carboxylate ( 1b). [17]
To a mixture, prepared by slow addition of 67% HI (15 mL) to acetone (15 mL), compound 1a (1.5 g, 5.23 mmol) was added. The mixture was stirred for 8 h at r.t., then poured onto ice (24 g) and 20% NaOH solution (33 mL) was added. The reaction mixture was stirred for 2-5 h till the colour of precipitate turned into bright yellow. The solid was filtered, dried and recrystallised to give 1.8 g (91%) of compound 1b, mp 160.5-161.0 °C (from 2-PrOH).

10

Methyl 5-Amino-4-(2-aminophenylethynyl)-2-methyl-thiopyrrolo[2,3- d ]pyrimidine-6-carboxylate ( 3d). [17]
Through a mixture of compound 1b (0.40 g, 1.060 mmol), CuI (40 mg, 0.210 mmol), PdCl₂(PPh₃)₂ (16 mg, 0.023 mmol) and Et₃N (15 mL) was bubbled Ar for 10 min. The mixture was heated to 50 °C (bath temperature) and then a solution of acetylene 2d (0.17 g, 1.450 mmol) in Et₃N (5 mL) was added dropwise. The reaction mixture was stirred under Ar at 55-60 °C for 1 h. The precipitate was filtered off and recrystallised to give 0.24 g (62%) of compound 3d, mp 227-230 °C (from CHCl₃).

14

Methyl 5-Amino-4-(1-mesylindol-2-yl)-2-methylthio-pyrrolo[2,3- d ]pyrimidine-6-carboxylate ( 7).
A mixture of compound 1b (0.24 g, 0.63 mmol), CuI (0.06 g, 0.32 mmol), Et₃N (25 mL), DMF (2.5 mL), PdCl₂(PPh₃)₂ (0.045 g, 0.064 mmol) and 2-ethynyl-N-mesylaniline [13a] (0.15 g, 0.77 mmol) was stirred under Ar at r.t. for 3 h. Then CuI (0.18 g, 0.95 mmol) was added and the reaction mixture was stirred for additional 3 h at 50-60 °C (bath temperature). The reaction mixture was diluted with H₂O and extracted with Et₂O (3 × 70 mL). The combined organic extracts were dried over Na₂SO₄, evaporated and purified using dry column vacuum chromatography [19] (eluent: CHCl₃). The solid was recrystallised to give 0.22 g (78%) of compound 7, mp 197.5-199.0 °C (from 2-PrOH). ¹H NMR (300 MHz, CDCl₃): δ = 2.60 (s, 3 H, SCH₃), 3.71 (s, 3 H, SO₂CH₃), 3.96 (s, 3 H, NCH₃), 4.00 (s, 3 H, OCH₃), 5.25 (s, 2 H, NH₂), 7.06 (d, J = 0.5 Hz, 1 H, C3′-H), 7.41-7.35 (m, 1 H, C5′-H), 7.49 (ddd, J = 1.3 Hz, J _{6 ′ -5 ′} = 7.3 Hz, J _{6 ′ -7 ′} = 8.5 Hz, 1 H, C6′-H), 7.70 (d, J _{4 ′ -5 ′} = 7.7 Hz, 1 H, C4′-H), 8.13 (dd, J = 0.6 Hz, J _{7 ′ -6 ′} = 8.4 Hz, 1 H, C7′-H). ¹³C NMR (75.4 MHz, CDCl₃): δ = 14.4, 31.0, 43.7, 51.5, 104.5, 107.9, 113.9, 114.9, 122.3, 124.2, 126.5, 128.7, 135.1, 136.0, 137.9, 151.4, 153.3, 163.5, 168.1. IR (nujol): 3460, 3361 (NH₂), 1677 (CO) cm^-1. Anal. Calcd for C₁₉H₁₉N₅O₄S₂: C, 51.22; H, 4.30; N, 15.72. Found: C, 51.55; H, 4.36; N, 15,76.

15

Methyl 5-Amino-4-(indol-2-yl)-2-methylthiopyrrolo[2,3- d ]pyrimidine-6-carboxylate ( 5). [17]
A solution of compound 3 (50 mg, 0.11 mmol) in 5% KOH solution in MeOH (25 mL) was refluxed for 45 min, then cooled to r.t., poured into H₂O and extracted with Et₂O. Extract was dried over Na₂SO₄ and evaporated. The solid was recrystallised to give 30 mg (73%) of compound 5, mp 172-174°C (from 2-PrOH).

16

Methyl 4-Methyl-2-methylthio-4 H -pyrrolo[2,3,4- de ]pyrimido[5′,4′:5,6][1,3]diazepino[1,7- a ]indole-5-carboxylate ( 8).
A mixture of compound 5 (30 mg, 0.08 mmol) and ethyl orthoformate (10 mL) was heated at 100-110 °C (bath temperature) for 2 h and NH₄Cl (5 mg, 0.09 mmol) was added. The reaction mixture was heated for additional 6 h and then cooled to r.t. The precipitate was filtered off, washed with cold EtOH and recrystallised to give 26 mg (84%) of compound 8, mp 267.0-268.5 °C (from DMF). ¹H NMR (300 MHz, CDCl₃): δ = 2.75 (s, 3 H, SCH₃), 4.10 (s, 3 H, NCH₃), 4.11 (s, 3 H, OCH₃), 7.39 (ddd, J = 0.9 Hz,
J _10-9 = 7.3 Hz, J _10-11 = 8.0 Hz, 1 H, C10-H), 7.51 (ddd, J = 1.3 Hz, J _9-10 = 7.2 Hz, J _9-8 = 8.5 Hz, 1 H, C9-H), 7.73 (d, J _8-9 = 8.3 Hz, 1 H, C8-H), 7.78 (d, J _11-10 = 8.0 Hz, 1 H, C11-H), 8.01 (s, 1 H, C12-H), 8.48 (s, 1 H, C7-H). ¹³C NMR (75.4 MHz, CDCl₃): δ = 14.7, 31.4, 52.7, 106.3, 110.8, 113.6, 120.9, 123.2, 124.5, 127.1, 127.9, 128.6, 135.8, 137.1, 140.1, 150.1, 151.0, 162.2, 169.7. IR (nujol): 1694 (CO) cm^-1. Anal. Calcd for C₁₉H₁₅N₅O₂S: C, 60.47; H, 4.01; N, 18.56. Found: C, 60.85; H, 3.95; N, 18.24.

17

Compounds 3a-d, 1b and 5 were fully characterised by IR, ¹H NMR, ¹³C NMR spectroscopy and microanalytical data.