Stepwise Aromatic Nucleophilic Substitution in Continuous Flow

STEpwise Aromatic nucleophilic substitution in continuous flow. synthesis of AN UnsymmetricaLLy Substituted 3,5-Diamino-benzonitrile LIBRARY

László Lengyel1, Viktor Gyóllai1, Tamás Nagy1[‡], György Dormán1, Péter Terleczky2, Viktor Háda2, Katalin Nógrádi2, Ferenc Sebők2, László Ürge1 and Ferenc Darvas1

1ThalesNano Inc., Záhony u. 7. H-1031 Budapest, Hungary

2Gedeon Richter plc. Gyömrői út 19-21. H-1103 Budapest, Hungary

Supplementary Material

High-resolution MS measurements were carried out on a Thermo LTQ FT Ultra mass spectrometer using ESI (4.2 2kV source voltage, 280 ◦219 C capillary temperature, solvent:MeOH:H2O 1:1 + 1 V/V% cc. AcOH) ionization technique.The protonated molecular ion peaks were fragmented byCID at a normalized collision energy of 65%. The relativeabundance values of the fragment ions in the MS–MS spectra are given in brackets. The high-resolution MS measurement of compound 6 was performed on a Finnigan MAT95XP mass spectrometer using EI (electron impact) ionizationechnique (70 eV, 220 ◦ C source temperature, perfluorokerosene reference compound). The elative abundancevalues of the fragment ions in the MS spectra are given inbrackets.

1H and 13C NMR spectra were recorded on a Varian VNMRS 500 spectrometer operating at a field strength of500 MHz (1H) and 125 MHz (13C), and a Varian VNMRS

800 spectrometer operating at a field strength of 800 MHz(1H) and 200 MHz (13C).

Chemical shifts are reported in parts per million (δ) and coupling constants (J) in Hz.

Peak multiplicities are labeled as follows: s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets (etc.); br, broad signal; m, multiplet. Chloroform-D1 with a minimum deuteration degree of 99.96% was purchased from Uvasol and used as received as solvent. Tetramethyl-silane was used as a reference for both 1H and 13C measurements

(δ = 0.00 ppm).

3-(piperidin-1-yl)-5-(pyrrolidin-1-yl)benzonitrile (7)

MS: M+H (ESI): m/z 256.18089, calculated value for C16H22N3: 256.18082 (delta: 0.3 ppm). MS-MS of m/z 256: m/z 226(5), 214(11), 200(100), 188(14).

NMR: (89.3 n/n%),

NMR:1H NMR (500 MHz, CDCl3): δ (ppm): 1.59 (m, 2H, H-C10), 1.69 (br, 4H, H-C9, H-C11), 2.00 (m, 4H, H-C14, H-C15), 3.16 (m, 4H, H-C8, H-C12), 3.26 (m, 4H, H-C13, H-C16), 6.22 (br, 1H, H-C4), 6.27 (br, 1H, H-C2), 6.49 (br, 1H, H-C6). 13C NMR (500 MHz, CDCl3): δ (ppm): 24.2 (C10), 25.4 (C14, C15), 25.6 (C9, C11), 47.6 (C13, C16), 50.4 (C8, C12), 103.6 (C4), 106.2 (C2), 107.5 (C6), 113.0 (C1), 120.5 (C7), 148.6 (C5), 153.2 (C3).

3-(azepan-1-yl)-5-(4-methylpiperidin-1-yl)- benzonitrile (8)

MS: M+H (ESI): m/z 298.22784, calculated value for C19H28N3: 298.22777 (delta: 0.2 ppm). MS-MS of m/z 298: m/z 254(5), 242(29), 228(100), 216(7).

NMR:: (91.6 n/n%)

NMR:1H NMR (500 MHz, CDCl3): δ (ppm): 0.97 (d, 3JH-H = 6.5 Hz, 3H, H-C19), 1.32 (m, 2H, H-C15, H-C17), 1.51 (m, 1H, H-C16), 1.54 (m, 4H, H-C10, H-C11), 1.73 (br d, 3JH-H = 13.3 Hz, 2H, H-C15, H-C17), 1.77 (br m, 4H, H-C9, H-C12), 2.71 (m, 2H, H-C14, H-C18), 3.42 (dd, 3JH-H =6.9 Hz, 3JH-H = 5.5 Hz, 4H, H-C8, H-C13), 3.61 (br d, 3JH-H = 12.5 Hz, 2H, H-C14, H-C18), 6.35 (br dd, 4JH-H = 2.3 Hz, 4JH-H = 2.3 Hz, 1H, H-C4), 6.39 (br dd, 4JH-H = 2.3 Hz, 4JH-H = 1.2 Hz, 1H, H-C2), 6.47 (br dd, 4JH-H = 2.3 Hz, 4JH-H = 1.2 Hz, 1H, H-C6). 13C NMR (500 MHz, CDCl3): δ (ppm): 21.8 (C19), 27.0 (C10, C11), 27.5 (C9, C12), 30.7 (C16), 33.9 (C15, C17), 49.3 (C8, C13), 49.8 (C14, C18), 103.1 (C4), 106.0 (C6), 107.3 (C2), 113.1 (C1), 120.6 (C7), 149.8 (C3), 153.2 (C5).

3-(4-methylpiperidin-1-yl)-5-(piperidin-1-yl)-benzonitrile (9)

MS: M+H (ESI): m/z 284.21220, calculated value for C18H26N3: 284.21212 (delta: 0.3 ppm). MS-MS of m/z 284: m/z 240(7), 228(100), 214(77), 202(3).

NMR:: (91.5 n/n%),

NMR:1H NMR (800 MHz, CDCl3): δ (ppm): 0.97 (d, 3JH-H = 6.6 Hz, 3H, H-C13), 1.30 (m, 2H, H-C9, H-C11), 1.52 (br m, 1H, H-C10), 1.58 (m, 2H, H-C16), 1.68 (m, 4H, H-C15, H-C17), 1.73 (br d, 3JH-H = 13.5 Hz, 2H, H-C9, H-C11), 2.71 (m, 2H, H-C8, H-C12), 3.14 (dd, 3JH-H = 7.0 Hz, 3JH-H = 4.7 Hz, 4H, H-C14, H-C18), 3.61 (br d, 3JH-H = 12.6 Hz, 2H, H-C8, H-C12), 6.62 (m, 3H, H-C2, H-C4, H-C6). 13C NMR (800 MHz, CDCl3): δ (ppm): 21.8 (C13), 24.2 (C16), 25.6 (C15, C17), 30.7 (C10), 33.9 (C9, C11), 49.6 (C8, C12), 50.3 (C14, C18), 108.5 (C4), 110.4 (C2), 110.4 (C6), 113.0 (C1), 120.2 (C7), 152.9 (C3) 153.2 (C5).

3-(morpholin-4-yl)-5-(piperidin-1-yl)-benzonitrile (10)

MS: M+H (ESI): m/z 272.17583, calculated value for C16H22ON3: 272.17574 (delta: 0.3 ppm). MS-MS of m/z 272: m/z 254(3), 228(14), 216(100), 204(9).

NMR: (87.0 n/n%), major impurities are unkown: (8.7 n/n%), (4.3 n/n%).

NMR:1H NMR (800 MHz, CDCl3): δ (ppm): 1.60 (m, 2H, H-C14), 1.69 (m, 4H, H-C13, H-C15), 3.15 (m, 4H, H-C8, H-C11), 3.17 (m, 4H, H-C12, H-C16), 3.85 (m, 4H, H-C9, H-C10), 6.59 (m, 2H, H-C2, H-C4), 6.68 (m, 1H, H-C6). 13C NMR (800 MHz, CDCl3): δ (ppm): 24.1 (C14), 25.6 (C13, C15), 49.0 (C8, C11), 50.1 (C12, C16), 66.7 (C9, C10), 107.6 (C4), 109.7 (C2), 111.3 (C6), 113.3 (C1), 119.9 (C7), 152.5 (C3), 153.5 (C5).

3-(4-methylpiperidin-1-yl)-5-(pyrrolidin-1-yl)-benzonitrile(11)

MS: M+H (ESI): m/z 270.19653, calculated value for C17H24N3: 270.19647 (delta: 0.2 ppm). MS-MS of m/z 270: m/z 226(12), 214(31), 200(100), 188(5).

NMR:(93.0 n/n%), contains toluene as a minor impurity (7.0 n/n%)

NMR:1H NMR (500 MHz, CDCl3): δ (ppm): 0.97 (d, 3JH-H = 6.6 Hz, 3H, H-C13), 1.31 (m, 2H, H-C9, H-C11), 1.52 (br m, 1H, H-C10), 1.72 (br d, 3JH-H = 13.0 Hz, 2H, H-C9, H-C11), 2.00 (m, 4H, H-C15, H-C16), 2.71 (m, 2H, H-C8, H-C12), 3.26 (m, 4H, H-C14, H-C17), 3.63 (br d, 3JH-H = 12.5 Hz, 2H, H-C8, H-C12), 6.21 (br, 1H, H-C4), 6.26 (br, 1H, H-C6), 6.49 (br, 1H, H-C2). 13C NMR (500 MHz, CDCl3): δ (ppm): 21.8 (C13), 25.4 (C15, C16), 30.7 (C10), 33.9 (C9, C11), 47.6 (C14, C17), 49.7 (C8, C12), 103.3 (C4), 106.1 (C6), 107.4 (C2), 112.9 (C1), 120.5 (C7), 148.7 (C5), 152.9 (C3).

3-(3-methlypiperazin-1-yl)-5-(piperidin-1-yl)-benzonitrile (12)

MS: M+H (ESI): m/z 285.20745, calculated value for C17H25N4: 285.20737 (delta: 0.3 ppm). MS-MS of m/z 285: m/z 268(100), 242(97), 228(24).

NMR: (98.4 n/n%),

NMR:1H NMR (800 MHz, CDCl3): δ (ppm): 1.14 (d, 3JH-H = 6.4 Hz, 3H, H-C12), 1.59 (m, 2H, H-C15), 1.69 (m, 4H, H-C14, H-C16), 2.37 (dd, 2JH-H = 11.8 Hz, 3JH-H = 10.3 Hz, 1H, H-C8), 2.73 (ddd, 2JH-H = 11.7 Hz , 3JH-H = 11.7 Hz, 3JH-H = 3.4 Hz, 1H, H-C11), 2.95 (m, 1H, H-C9), 3.00 (ddd, 2JH-H = 11.7 Hz , 3JH-H = 11.7 Hz, 3JH-H = 3.4 Hz, 1H, H-C10), 3.12 (ddd, 2JH-H = 11.7 Hz , 3JH-H = 3.1 Hz, 3JH-H = 2.1 Hz, 1H, H-C10), 3.16 (m, 4H, H-C13, H-C17), 3.47 (m, 1H, H-C11), 6.61 (m, 2H, H-C2, H-C4), 6.65 (dd, 4JH-H = 2.2 Hz, 4JH-H = 1.4 Hz, 1H, H-C6). 13C NMR (800 MHz, CDCl3): δ (ppm): 19.8 (C12), 24.2 (C15), 25.6 (C14, C16), 45.8 (C10), 49.2 (C11), 50.2 (C13, C17), 50.5 (C9), 56.6 (C8), 108.1 (C4), 110.2 (C2), 110.9 (C6), 113.1 (C1), 120.0 (C7), 152.7 (C3), 153.2 (C5).

3-(azepan-1-yl)-5-(pyrrolidin-1-yl)- benzonitrile (13)

MS: M+H (ESI): m/z 270.19652, calculated value for C17H24N3: 270.19647 (delta: 0.2 ppm). MS-MS of m/z 270: m/z 228(11), 214(8), 200(100), 188(31).

NMR: (95.5 n/n%),

NMR:1H NMR (500 MHz, CDCl3): δ (ppm): 1.54 (m, 4H, H-C11, H-C10), 1.77 (br, 4H, H-C9, H-C12), 2.00 (m, 4H, H-C15, H-C16), 3.26 (m, 4H, H-C14, H-C17), 3.43 (m, 4H, H-C8, H-C13), 5.94 (br, 1H, H-C4), 6.13 (br, 1H, H-C2), 6.27 (br, 1H, H-C6). 13C NMR (500 MHz, CDCl3): δ (ppm): 25.4 (C15, C16), 27.0 (C10, C11), 27.6 (C9, C12), 47.6 (C14, C17), 49.3 (C8, C13), 97.8 (C4), 103.0 (C2), 103.1 (C6), 113.1 (C1), 120.9 (C7), 148.9 (C5), 149.8 (C3).

3-(3-methylpiperazin-1-yl)-5-(pyrrolidin-1-yl)-benzonitrile (14)

MS: M+H (ESI): m/z 271.19187, calculated value for C16H23N4: 271.19172 (delta: 0.5 ppm). MS-MS of m/z 271: m/z 254(100), 228(87), 214(20).

NMR: (85.7 n/n%), major impurity: 3-(pyrrolidin-1-yl)-5-amino-benzonitrile (9.4 n/n%)

NMR:1H NMR (800 MHz, CDCl3): δ (ppm): 1.13 (d, 3JH-H = 6.3 Hz, 3H, H-C12), 2.02 m (m, 4H, H-C14, H-C15), 2.36 (dd, 2JH-H = 11.8 Hz, 3JH-H = 10.3 Hz, 1H, H-C8), 2.72 (ddd, 2JH-H = 11.7 Hz , 3JH-H = 11.7 Hz, 3JH-H = 3.4 Hz, 1H, H-C11), 2.96 (m, 1H, H-C9), 3.01 (ddd, 2JH-H = 11.7 Hz , 3JH-H = 11.7 Hz, 3JH-H = 3.4 Hz, 1H, H-C10), 3.12 (ddd, 2JH-H = 11.7 Hz , 3JH-H = 3.1 Hz, 3JH-H = 2.1 Hz, 1H, H-C10), 3.27 (m, 4H, H-C13, H-C16), 3.50 (m, 1H, H-C11), 6.19 (dd, 4JH-H = 2.3 Hz, 4JH-H = 2.2 Hz, 1H, H-C4), 6.30 (dd, 4JH-H = 2.2 Hz, 4JH-H = 1.2 Hz, 1H, H-C2), 6.48 (dd, 4JH-H = 2.3 Hz, 4JH-H = 1.2 Hz, 1H, H-C6). 13C NMR (800 MHz, CDCl3): δ (ppm): 19.8 (C12), 25.4 (C14, C15), 45.8 (C10), 47.6 (C13, C16), 49.2 (C11), 50.5 (C9), 56.6 (C8), 102.9 (C4), 106.6 (C2), 107.1 (C6), 113.3 (C1), 120.3 (C7), 148.6 (C5), 152.8 (C3).

3-(morpholin-4-yl)-5-(pyrrolidin-1-yl)-benzonitrile (15)

MS: M+H (ESI): m/z 258.16012, calculated value for C15H20ON3: 258.16009 (delta: 0.1 ppm). MS-MS of m/z 258: m/z 240(40), 230(9), 214(100), 213(78), 212(28), 211(10), 200(3).

NMR: (>99 n/n%).

NMR:1H NMR (500 MHz, CDCl3): δ (ppm): 2.02 (m, 4H, H-C13, H-C14), 3.15 (m, 4H, H-C8, H-C11), 3.27 (m, 4H, H-C12, H-C15), 3.85 (m, 4H, H-C9, H-C10), 6.18 (br dd, 4JH-H = 2.2 Hz, 4JH-H = 2.2 Hz, 1H, H-C4), 6.33 (br dd, 4JH-H = 2.2 Hz, 4JH-H = 1.3 Hz, 1H, H-C6), 6.46 (br dd, 4JH-H = 2.2 Hz, 4JH-H = 1.3 Hz, 1H, H-C2). 13C NMR (500 MHz, CDCl3): δ (ppm): 25.4 (C13, C14), 47.6 (C12, C15), 49.1 (C8, C11), 66.9 (C9, C10), 102.5 (C4), 106.6 (C2), 107.1 (C6), 113.2 (C1), 120.2 (C7), 148.7 (C5), 152.6 (C3).

3,5-bis(4-methylpiperidin-1-yl)benzonitrile(16)

MS: M+H (ESI): m/z 298.22780, calculated value for C19H28N3: 298.22777 (delta: 0.1 ppm). MS-MS of m/z 298: m/z 254(7), 242(29), 228(100), 216(5).

NMR: (>99 n/n%)

NMR: 1H NMR (500 MHz, CDCl3): δ (ppm): 0.97 (d, 3JH-H = 6.5 Hz, 6H, H-C13, H-C19), 1.31 (m, 4H, H-C9, H-C11, H-C15, H-C17), 1.52 (br m, 2H, H-C10, H-C16), 1.73 (br d, 3JH-H = 12.9 Hz, 4H, H-C9, H-C11, H-C15, H-C17), 2.71 (ddd, 2JH-H = 12.4 Hz, 3JH-H = 12.9 Hz, 3JH-H = 2.6 Hz, 4H, H-C8, H-C12, H-C14, H-C18), 3.61 (br d, 2JH-H = 12.4 Hz, 4H, H-C8, H-C12, H-C14, H-C18), 6.61 (br, 2H, H-C2, H-C6), 6.63 (br, 1H, H-C4). 13C NMR (500 MHz, CDCl3): δ (ppm): 21.8 (C13, C19), 30.7 (C10, C16), 33.9 (C9, C11, C15, C17), 49.6 (C8, C12, C14, C18), 108.4 (C4), 110.4 (C2, C6), 113.0 (C1), 120.1 (C7), 152.9 (C3, C5).

3-(diethylamino)-5-(pyrrolidin-1-yl)benzonitrile (17)

MS: M+H (ESI): m/z 244.18084, calculated value for C15H22N3: 244.18082 (delta: 0.1 ppm). MS-MS of m/z 244: m/z 216.

NMR:(>99 n/n%)

NMR:1H NMR (500 MHz, CDCl3): δ (ppm): 1.16 (t, 3JH-H = 7.1 Hz, 6H, H-C9, H-C10), 2.00 (m, 4H, H-C13, H-C14), 3.26 (m, 4H, H-C12, H-C15), 3.33 (q, 3JH-H = 7.1 Hz, 4H, H-C8, H-C11), 5.94 (dd, 4JH-H = 2.8 Hz, 4JH-H = 2.2 Hz, 1H, H-C4), 6.14 (dd, 4JH-H = 2.2 Hz, 4JH-H = 1.5 Hz, 1H, H-C2), 6.25 (dd, 4JH-H = 2.8 Hz, 4JH-H = 1.5 Hz, 1H, H-C6). 13C NMR (500 MHz, CDCl3): δ (ppm): 12.5 (C9, C10), 25.5 (C13, C14), 44.5 (C8, C11), 47.6 (C12, C15), 98.3 (C4), 103.1 (C2), 103.4 (C6), 113.2 (C1), 120.9 (C1), 148.7 (C3), 148.9 (C5).

3-(propan-2-ylamino)-5-(pyrrolidin-1-yl)benzonitrile (18)

MS: M+H (ESI): m/z 230.16518, calculated value for C14H20N3: 230.16517 (delta: 0.03 ppm). MS-MS of m/z 230: m/z 188.

NMR:94.0 n/n%), contains toluene as a minor impurity (6.0 n/n%)

NMR:1H NMR (500 MHz, CDCl3): δ (ppm): 1.99 (m, 4H, H-C12, H-C13), 3.23 (m, 4H, H-C11, H-C14), 3.60 (m, 1H, H-C8), 5.88 (dd, 4JH-H = 2.3 Hz, 4JH-H = 2.3 Hz, 1H H-C4), 6.16 (d, 4JH-H = 2.3 Hz, 2H, H-C2, H-C6). 13C NMR (500 MHz, CDCl3): δ (ppm): 22.9 (C9, C10), 25.4 (C12, C13), 44.1 (C8), 47.5 (C11, C14), 99.8 (C4), 103.9 (C6), 104.8 (C2), 113.1 (C1), 120.5 (C7), 148.6 (C3), 148.7 (C5).

3-amino-5-fluoro-benzonitrile (6)

MS: M (EI): m/z 136.04304, calculated value for C7H5N2F: 136.04313 (delta: -0.6 ppm). m/z (%): 136(M+, 100), 109(34), 89(5), 82(11).

NMR: (>99 n/n%).

NMR:1H NMR (800 MHz, CDCl3): δ (ppm): 6.57 (dt 3JF-H = 10.4 Hz, 4JH-H = 2.4 Hz, 1H, H-C4), 6.70 (dd 4JH-H = 2.3 Hz, 4JH-H = 1.3 Hz, 1H, H-C2), 6.71 (ddd 3JF-H = 8.1 Hz, 4JH-H = 2.3 Hz, 4JH-H = 1.3 Hz, 1H, H-C6). 13C NMR (800 MHz, CDCl3): δ (ppm): 106.2 (d 2JC-F = 24.6 Hz, C4), 108.6 (d 2JC-F = 25.5 Hz, C6), 113.8 (d 4JC-F = 2.5 Hz, C2), 114.0 (d 3JC-F = 11.9 Hz, C1), 118.0 (d 4JC-F = 3.7 Hz, C7), 148.9 (d 3JC-F = 11.6 Hz, C3), 163.3 (d 1JC-F = 245.4 Hz, C5).

[‡]Present address: EGIS plc., Keresztúri út 30-38.H-1106 Budapest, Hungary