Facile Synthesis of Fluorinated Pyrrolo[2,3-b]pyridines

Abstract

With the purpose to synthesize novel ADAs (adenosine deaminase) and IMPDH (inosine 5′-monophosphate dehydroge­nase) inhibitors the reaction of 5-amino-1-tert-butyl-1H-pyrrolo-3-carbonitrile with fluorinated 1,3 -biselectrophiles was studied. An efficient and convenient synthetical approach to obtain fluorinated pyrrolo[2,3-b]pyridines was developed. tert-Butyl protecting group was successfully cleaved by treating of synthesized pyrrolo­pyridines with concentrated sulfuric acid.

Key words

pyrrol - amine - fluorine - pyridine - annulation - electrophilic aromatic substitution

References and Notes

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20

1- tert -Butyl-4-[chloro(difluoro)methyl]-6-phenyl-1 H -pyrrolo[2,3- b ]pyridine-3-carbonitrile (11e)
Colorless solid (0.65g, 90%); mp 234 ˚C (from EtOH). ^¹H NMR (400 MHz, DMSO-d ₆): δ = 1.87 (9 H, s, CH₃), 7.53
(3 H, br m), 8.07 (1 H, s), 8.18 (2 H, d, ^³ J _CH = 7.8 Hz), 8.70 (1 H, s). ^¹³C NMR (100.5 MHz, DMSO-d ₆): δ = 28.9, 59.5, 81.9, 109.4 (t, ^³ J _CF = 6.4 Hz), 112.8 (t, ^³ J _CF = 2.4 Hz), 114.9, 124.6, (t, ^¹ J _CF = 290 Hz), 126.9, 129.0, 129.6, 135.2 (t, ^² J _CF = 30 Hz), 137.8, 139.7, 148.0, 151.3. MS: m/z (%) = 361(13) [M⁺ + 2], 359(36) [M⁺], 304(23), 303(100), 269(16), 268(75), 57(13). Anal. Calcd for C₁₉H₁₆ClF₂N₃: C, 63.42; H, 4.48; Cl, 9.85; F, 10.56; N, 11.68. Found: C, 63.50; H, 4.53; N, 11.75.

21

The General Procedure for Synthesis of Pyrrolo[2,3- b ]pyridines 11 and 13 5-Amino-1-tert-butyl-1H-pyrrole-3-carbonitrile (0.33 g, 2 mmol) and diketone 10 (or 12, 2.2 mmol) were dissolved in AcOH (20 mL) and heated under reflux in the inert atmosphere during 1 h. Then this solution was evaporated under reduced pressure, treated with H₂O, filtrated, and dried on the air and recrystallized from an appropriate solvent, or was subjected to column chromatography over SiO₂.

23

The Procedure for the Synthesis of ( E )-1- tert -Butyl-5-(4,4,4-trifluoro-3-oxobut-1-enylamino)-1 H -pyrrole-3-carbonitrile (15) 5-Amino-1-tert-butyl-1H-pyrrole-3-carbonitrile (0.66 g,
4 mmol) and 14 (0.68 g, 4.4 mmol) were dissolved in abs. DMF (10 mL) and heated under inert atmosphere at 85 ˚C for 12 h. The solution was evaporated under reduced pressure, treated with H₂O, and dried under reduced pressure. Afterwards, the residue was subjected to column chromatography over SiO₂. Colorless solid (0.78 g, 68%); mp 116-118 ˚C; R _f = 0.75 (hexane-EtOAc, 5:1). ^¹H NMR (400 MHz, CDCl₃): d = 1.59 (9 H, s, CH₃), 5.68 (1 H, d, ^³ J _HH = 8 Hz), 6.20 (1 H, s.), 7.13 (1 H, s), 7.29 (1 H, dd, ^³ J _HH = 8 Hz, ^³ J _HH = 4 Hz), 11.80
(1 H, d, ^³ J _HH = 4 Hz, NH). ^¹³C NMR (100.5 MHz, CDCl₃): d = 29.9, 58.1, 90.7, 91.0, 103.7, 119.8 (d, ^¹ J _CF = 285 Hz), 117.7, 131.0, 140.7, 153.3, 180.2 (q, ^² J _CF = 33 Hz). MS: m/z (%) = 286(11) [M⁺ + 1], 285(56) [M⁺], 239(22), 229(77), 170(11), 160(90), 57(100), 41(37). Anal. Calcd for C₁₃H₁₄F₃N₃O: C, 54.73; H, 4.95; F, 19.98; N, 14.73; O, 5.61. Found: C, 54.80; H, 4.98; N, 14.78.

24

Procedure for the Synthesis of 1- tert -Butyl-4-(trifluoro-methyl)-1 H -pyrrolo[2,3- b ]pyridine-3-carbonitrile (16)
1-tert-Butyl-5-(4,4,4-trifluoro-3-oxobut-1-enylamino)-1H-pyrrole-3-carbonitrile (15, 0.57 g, 2 mmol) in a 10 mL flask was melted for 5 h under inert atmosphere at 180 ˚C (temperature of the oil bath), then the dark-green residue formed was subjected to column chromatography over SiO₂.
Colorless solid (0.38 g, 71%); mp 161-163 ˚C. R _f = 0.75 (hexane-EtOAc, 5:1). ^¹H NMR (400 MHz, CDCl₃): δ = 1.78 (9 H, s, CH₃), 7.41 (1 H, d, ^³ J _HH = 4.7 Hz, H), 7.99 (1 H, s), 8.49 (1 H, d, ^³ J _HH = 4.7 Hz). ^¹³C NMR (100.5 MHz, CDCl₃): δ = 29.0, 59.3, 82.8, 113.8 (q, ^³ J _CF = 4.7 Hz), 114.5, 115.7, 122.8 (q, ^² J _CF = 270 Hz), 129.8 (q, ^² J _CF = 35 Hz), 136.3, 143.7, 148.3. MS: m/z (%) = 267(48) [M⁺], 212(58), 211(100), 192(24), 57(39), 56(10), 41(25). Anal. Calcd for C₁₃H₁₂F₃N₃: C, 58.42; H, 4.53; F, 21.33; N, 15.72. Found: C, 58.50; H, 4.59; N, 15.71.

25

Crystallographic data (excluding structure factors) for the structure11c reported in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC 683574 and can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax: [phone]; email: [e-mail], or via www.ccdc.cam.ac.uk/data_request/cif.