8
N.J. O’Brien et al. / Tetrahedron xxx (2014) 1e10
21.2; m/z (ESI): 814.3 (MHþ); HRMS (ESI): MHþ, found 814.3490.
44H48N9O5Sþ requires 814.3494.
mixture was refluxed for 3 h. To the cooled solution was added H2O
and the whole mixture was extracted with EtOAc (ꢂ2). The com-
bined organic extracts were washed with brine (ꢂ2), dried, filtered
and concentrated in vacuo to give a yellow residue. The residue was
purified by flash chromatography (EtOAc) and recrystallised from
EtOAc/hexanes to give the title compound 4a (62 mg, 58%) as
a yellow solid; mp 141e143 ꢀC; dH (CDCl3): 9.90 (1H, s), 8.71 (1H, d, J
1.5 Hz), 8.58 (1H, dd, J 5.0, 1.5 Hz), 8.17 (1H, s), 7.80 (1H, dt, J 8.0,
2.0 Hz), 7.73 (1H, dd app t, J 2.0 Hz), 7.71 (1H, d, J 8.0 Hz), 7.44 (1H, t,
J 8.0 Hz), 7.34 (1H, s), 7.32 (1H, dd, J 8.0, 5.0 Hz), 7.21e7.17 (2H, m),
7.10 (1H, dd, J 8.0, 2.0 Hz), 6.98 (1H, dt, J 7.0, 2.0 Hz), 6.81 (1H, dd, J
3.5, 2.0 Hz), 6.55 (1H, dd, J 3.5, 2.0 Hz), 6.28 (1H, s), 5.16 (2H, s),
3.36e3.33 (4H, m),1.87e1.84 (4H, m); dC (CDCl3): 158.7,158.1, 156.0,
154.3, 153.9, 149.5, 149.0, 140.9, 140.0, 139.9, 135.3, 132.5, 129.8,
129.2, 123.5, 123.0, 121.9, 116.9, 114.5, 113.2, 112.7, 109.9, 109.7, 101.2,
67.7, 45.8, 25.5; m/z (EþSI): 506.3 (MHþ); HRMS (ESI): MHþ, found
506.2296. C29H28N7O2 requires 506.2299.
C
4.2.20. N-(2-(Piperidin-1-yl)ethyl)-2-(3-((4-(3-(pyridin-3-
ylmethoxy)phenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)
phenyl)acetamide (35d). Precursor 33 (230 mg, 0.47 mmol) was
coupled with aniline 28a according to General procedure B. Puri-
fication by flash chromatography (1% MeOH/CH2Cl2 satd with NH3)
and recrystallisation from CCl4 afforded the 2-anilino-N-tosylpyr-
rolopyrimidine 35d (230 mg, 72%) as a yellow solid; mp 94e97 ꢀC;
dH (DMSO-d6): 9.80 (1H, s), 8.72 (1H, d, J 2.0 Hz), 8.57 (1H, dd, J 5.0,
2.0 Hz), 8.07 (2H, d, J 8.0 Hz), 7.92e7.90 (2H, m), 7.82 (2H, dd app t, J
8.0 Hz), 7.67 (1H, d, J 4.0 Hz), 7.65e7.64 (2H, m), 7.52 (1H, t, J 8.0 Hz),
7.46 (1H, ddd, J 8.0, 5.0, 1.0 Hz), 7.39 (2H, d, J 8.0 Hz), 7.30 (1H, t, J
8.0 Hz), 7.26e7.23 (1H, m), 6.94 (1H, s), 6.93 (1H, d, J 4.0 Hz), 5.27
(2H, s), 3.46 (2H, s), 3.16 (2H, br s), 2.34 (3H, s), 2.21 (4H, br s), 1.44
(4H, br s), 1.32 (2H, br s); dC (DMSO-d6): 169.9, 158.5, 158.4, 156.5,
153.3, 149.2, 149.0, 145.9, 140.4, 138.2, 136.7, 135.6, 134.3, 132.4,
130.1, 130.0, 128.3, 127.7, 123.8, 123.6, 122.2, 121.4, 119.7, 117.3, 116.8,
114.5, 109.8, 105.3, 67.1, 57.4, 53.9, 42.7, 36.2, 25.3, 23.8, 21.0; m/z
(ESI): 716.2 (MHþ); HRMS (ESI): MHþ, found 716.3009.
4.2.24. N-(3-(2-Oxo-2-((2-(piperidin-1-yl)ethyl)amino)ethyl)-5-((4-
(3-(pyridin-3-ylmethoxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)
amino)phenyl)pyrrolidine-1-carboxamide (4b). 2-Anilino-N-tosyl-
pyrrolopyrimidine 35b (146 mg, 0.18 mmol) was treated according
to General procedure C. Purification by flash chromatography (2.5%
MeOH/CH2Cl2 satd with NH3) and recrystallisation from EtOAc/
hexanes afforded the title compound 4b (101 mg, 85%) as a yellow
solid; mp 118e121 ꢀC; dH (DMSO-d6): 11.60 (1H, s), 9.11 (1H, s), 8.71
(1H, d, J 2.0 Hz), 8.56 (1H, dd, J 5.0, 2.0 Hz), 8.01 (1H, s), 7.91 (1H, ddd,
J 8.0, 2.0 Hz), 7.87 (1H, dd app t, J 2.0 Hz), 7.82e7.78 (2H, m), 7.78 (1H,
t, J 5.0 Hz), 7.49 (1H, t, J 8.0 Hz), 7.45 (1H, ddd, J 8.0, 5.0, 1.0 Hz), 7.31
(1H, s), 7.26 (1H, dd, J 3.5, 2.0 Hz), 7.21e7.19 (1H, m), 6.93 (1H, s), 6.64
(1H, dd, J 3.5, 2.0 Hz), 5.27 (2H, s), 3.15e3.12 (2H, m), 2.29 (6H, br t, J
6.5 Hz), 1.81e1.78 (4H, m), 1.45e1.40 (4H, m), 1.33e1.29 (2H, m); dC
(DMSO-d6): 170.0, 158.3, 155.96, 155.95 154.5, 154.0, 149.1, 149.0,
141.3, 140.4, 139.7, 135.9, 135.6, 132.6, 129.8, 124.4, 123.6, 121.5, 116.8,
114.2, 113.9,113.8,109.4, 108.8, 100.2, 67.0, 57.5, 53.9, 45.6, 43.0, 36.3,
25.4, 25.0, 24.0; m/z (ESI): 674.3 (MHþ); HRMS (ESI): MHþ, found
C
40H42N7O4Sþ requires 716.3014.
4.2.21. N-(2-(Piperidin-1-yl)ethyl)-3-((4-(3-(pyridin-3-ylmethoxy)
phenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)benzamide
(35e). Precursor 33 (250 mg, 0.51 mmol) was coupled with aniline
28b according to General procedure B. Purification by flash chro-
matography (1% MeOH/CH2Cl2 satd with NH3) and recrystallisation
from toluene afforded the 2-anilino-N-tosylpyrrolopyrimidine 35e
(260 mg, 73%) as a white solid; mp 200e202 ꢀC; dH (DMSO-d6): 9.95
(1H, s), 8.71 (1H, d, J 2.0 Hz), 8.56 (1H, dd, J 5.0, 1.5 Hz), 8.40 (1H, s),
8.21 (1H, t, J 5.5 Hz), 8.09 (2H, d, J 8.5 Hz), 8.04 (1H, dt, J 7.0, 2.0 Hz),
7.91 (1H, dt, J 8.0, 2.0 Hz), 7.69 (1H, d, J 4.0 Hz), 7.67e7.64 (2H, m),
7.51 (1H, t, J 8.0 Hz), 7.46e7.43 (3H, m), 7.38 (2H, d, J 8.0 Hz), 7.24
(1H, ddd, J 8.0, 2.5, 1.0 Hz), 6.94 (1H, d, J 4.0 Hz), 5.27 (2H, s),
3.38e3.35 (2H, m), 2.41 (2H, t, J 7.5 Hz), 2.33 (4H, br s), 2.32 (3H, s),
1.48e1.43 (4H, m), 1.37e1.32 (2H, m); dC (DMSO-d6): 166.6, 158.6,
158.4, 156.4, 153.3, 149.2, 149.1, 146.0, 140.6, 138.1, 135.7, 135.5,
134.2, 132.5, 130.12, 130.06, 128.4, 127.8, 124.1, 123.6, 121.5, 121.3,
120.0, 117.8, 117.5, 114.3, 110.2, 105.3, 67.1, 57.7, 54.1, 37.0, 25.6, 24.0,
21.1; m/z (ESI): 702.3 (MHþ); HRMS (ESI): MHþ, found 702.2852.
þ
674.3561. C38H44N9O3 requires 674.3562.
4.2.25. N-(3-((2-(Piperidin-1-yl)ethyl)carbamoyl)-5-((4-(3-(pyridin-
3-ylmethoxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phe-
nyl)pyrrolidine-1-carboxamide (4c). 2-Anilino-N-tosylpyrrolopyr-
imidine 35c (150 mg, 0.18 mmol) was treated according to General
procedure C. Purification by flash chromatography (10% MeOH/
CH2Cl2) and recrystallisation from EtOAc/hexanes afforded the title
compound 4c (100 mg, 89%) as a yellow solid; mp 138e141 ꢀC; dH
(DMSO-d6): 11.65 (1H, s), 9.29 (1H, s), 8.72 (1H, d, J 1.5 Hz), 8.56 (1H,
dd, J 5.0, 1.5 Hz), 8.19 (1H, s), 8.08 (1H, t, J 5.5 Hz), 8.03 (1H, dd app t,
J 1.5 Hz), 7.92e7.91 (2H, m), 7.83e7.80 (2H, m), 7.49 (1H, t, J 8.0 Hz),
7.44 (1H, dd, J 8.0, 5.0 Hz), 7.42 (1H, s), 7.28 (1H, dd, J 3.5, 2.5 Hz),
7.20 (1H, dd, J 8.0, 2.0 Hz), 6.66 (1H, dd, J 3.5, 2.0 Hz), 5.27 (2H, s),
3.35e3.30 (2H, m), 2.40 (2H, t, J 7.0 Hz), 2.27 (4H, br s), 1.83e1.80
(4H, m), 1.49e1.45 (4H, m), 1.38e1.34 (2H, m); dC (DMSO-d6): 167.1,
158.4, 156.0, 155.8, 154.5, 154.0, 149.1, 149.0, 141.4, 140.5, 139.7,
135.6, 135.3,132.6, 129.8,124.6, 123.6,121.5, 116.9, 114.1, 113.5, 112.2,
111.9, 109.1, 100.2, 67.0, 57.6, 54.0, 45.6, 36.8, 25.5, 25.0, 24.0; m/z
C
39H40N7O4Sþ requires 702.2857.
4.2.22. N-Phenyl-4-(3-(pyridin-3-ylmethoxy)phenyl)-7-tosyl-7H-
pyrrolo[2,3-d]pyrimidin-2-amine (35f). Precursor 33 (250 mg,
0.51 mmol) was coupled with aniline (56 mL, 0.61 mmol) according
to General procedure B. Purification by flash chromatography (70%
EtOAc/hexanes) and recrystallisation from CCl4 afforded the 2-
anilino-N-tosylpyrrolopyrimidine 35f (240 mg, 85%) as a light yel-
low solid; mp 129e131 ꢀC; dH (DMSO-d6): 9.81 (1H, s), 8.72 (1H, s),
8.58 (1H, d, J 3.5 Hz), 8.05 (2H, d, J 8.5 Hz), 7.94e7.91 (3H, m), 7.68
(1H, d, J 4.0 Hz), 7.66e7.63 (2H, m), 7.52 (1H, t, J 8.0 Hz), 7.46 (1H,
dd, J 8.0, 4.5 Hz), 7.41e7.37 (4H, m), 7.25 (1H, ddd, J 8.0, 2.5, 1.0 Hz),
7.02 (1H, tt, J 7.5, 1.0 Hz), 6.93 (1H, d, J 4.0 Hz), 5.27 (2H, s), 2.33 (3H,
s); dC (DMSO-d6): 158.6, 158.4, 156.5, 153.3, 149.2, 149.0, 145.9,
140.4, 138.1, 135.6, 134.3, 132.4, 130.1, 130.0, 128.5, 127.6, 123.8,
123.6, 121.5, 121.4, 118.7, 117.3, 114.5, 109.9, 105.2, 67.1, 21.0; m/z
(ESI): 548.2 (MHþ); HRMS (ESI): MHþ, found 548.1746.
(ESI): 660.3 (MHþ); HRMS (ESI): MHþ, found 660.3403.
þ
C
37H42N9O3 requires 660.3406.
C
31H26N5O3Sþ requires 548.1751.
4.2.26. N-(2-(Piperidin-1-yl)ethyl)-2-(3-((4-(3-(pyridin-3-
ylmethoxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)
acetamide (4d). 2-Anilino-N-tosylpyrrolopyrimidine 35d (125 mg,
0.17 mmol) was treated according to General procedure C. Purifi-
cation by flash chromatography (1% MeOH/CH2Cl2 satd with NH3)
and recrystallisation from EtOAc/hexanes afforded the title com-
pound 4d (92 mg, 93%) as a yellow solid; mp 78e82 ꢀC; dH (CDCl3):
10.38 (1H, s), 8.67 (1H, d, J 1.0 Hz), 8.57 (1H, dd, J 5.0, 1.0 Hz),
4.2.23. General procedure C: Preparation of 2-anilino-7H-pyrrolo-
pyrimidines via base promoted detosylation. N-(3-((4-(3-(Pyridin-3-
ylmethoxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)phenyl)
pyrrolidine-1-carboxamide (4a). To
a solution of 2-anilino-N-
tosylpyrrolopyrimidine 35a (140 mg, 0.21 mmol) in MeOH (5 mL)
and H2O (3 mL) was added K2CO3 (88 mg, 0.63 mmol) and the