L.I. Pilkington et al. / European Journal of Medicinal Chemistry 191 (2020) 112162
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3.37 (4H, t, J ¼ 5.0 Hz, H-30), 3.86 (4H, t, J ¼ 5.0 Hz, H-20), 6.82 (2H, d,
J ¼ 9.4 Hz, H-3), 8.13 (2H, d, J ¼ 9.4 Hz, H-2). The 1H NMR data were
in agreement with literature values [20].
4-Morpholinoaniline 8; To a solution of 4-(4-nitrophenyl)mor-
pholine (8.45 g, 0.041 mol) in EtOH (250 mL) was added 10% Pd/C
(0.843 g, 10% w/w). The resulting mixture was stirred at room
temperature under an atmosphere of hydrogen for 23 h. After
completion, the mixture was filtered through Celite and washed
with EtOH. The solvent was removed in vacuo to give the title
compound 8 (5.25 g, 74%) as a pink solid which was used without
further purification. m.p. 129e130 ꢁC (Lit [21]. 129.5e130.5 ꢁC). dH
(400 MHz; CDCl3) 3.02 (4H, t, J ¼ 4.7 Hz, H-30), 3.44 (2H, s, NH2),
3.85, (4H, t, J ¼ 4.7 Hz, H-20), 6.66, (2H, d, J ¼ 8.8 Hz, H-3), 6.80 (2H,
d, J ¼ 8.8 Hz, H-2). dC (100 MHz; CDCl3) 51.1 (C-30), 67.0 (C-20), 116.2
(C-2), 118.1 (C-3), 140.3 (C-1), 144.4 (C-4); IR nmax(ATR)/cmꢂ1: 3393,
2855, 1641, 1411, 1259, 1107, 825; m/z (ESIþ): 227 (17%), 179 (MHþ,
100%); HRMS (ESIþ) found (MHþ): 179.1178, C10H15N2O requires
179.1179. The 1H NMR data were in agreement with literature
N-Benzyl-4-morpholinoaniline 10a; The reaction was carried out
according to General Procedure A-2 with benzaldehyde 6a
(0.20 mL, 1.96 mmol) and 4-morpholinoaniline
8 (0.200 g,
0.96 mmol) for 2 h to afford the crude imine (0.185 g, 0.695 mmol)
as a yellow solid that was reduced according to General Procedure
B-2 with NaBH4 (0.085 g, 2.25 mol) for 4 h to give the title compound
10a (0.130 g, 50%) as a white solid. m.p. 72e74 ꢁC. dH (400 MHz;
CDCl3) 3.01 (4H, t, J ¼ 4.7 Hz, H-30), 3.80 (1H, s, NH), 3.85 (4H, t,
J ¼ 4.7 Hz, H-20), 4.30 (2H, s, CH2), 6.63 (2H, d, J ¼ 8.9 Hz, H-2), 6.83,
(2H, d, J ¼ 8.9 Hz. H-3) 7.27e7.39 (5H, m, H-200, H-300, H-400, H-500, H-
600); dC (100 MHz; CDCl3) 49.2 (CH2), 51.4 (C-30), 67.3 (C-20), 114.1 (C-
2), 118.5 (C-3), 127.3 (C-400), 127.7 (C-200), 128.7 (C-300), 139.8 (C-100),
142.9 (C-1), 143.8 (C-4); IR nmax(ATR)/cmꢂ1: 3309, 2923, 2853, 1613,
1518, 1295, 1107; m/z (ESIþ): 269 (MHþ, 47%), 178 (M-CH2(C6H4),
100%); HRMS (ESIþ) found (MHþ): 269.1643, C17H21N2O2 requires
269.1648. The 1H and 13C NMR data were in agreement with liter-
1-(4-Nitrophenyl)piperidine 15; A mixture of piperidine (7.42 mL,
0.075 mol), 4-chloronitrobenzene 9 (11.82 g, 0.075 mol) and K2CO3
(10.37 g, 0.075 mol) in DMSO (50 mL) was heated at 120 ꢁC for 23 h
with stirring. The reaction was cooled to r.t., then 1:1 EtOH:H2O
(200 mL) added. The resulting precipitate was collected by filtration
and dried to give the title compound 15 (14.45 g, 93%) as an orange
solid which was used without further purification. m.p. 99e101 ꢁC
(Lit [24]. 101e102.5 ꢁC) The 1H NMR data were in agreement with
literature values [25]. dH (400 MHz; CDCl3) 1.67e1.70 (6H, m, H-30,
H-40), 3.43 (4H, s, H-20), 6.79 (2H, d, J ¼ 9.5 Hz, H-2), 8.10 (2H, d,
J ¼ 9.5 Hz, H-3).
Scheme 3. Synthesis of Series
2 analogues, varying at the saturated cyclic ring,
substituting morpholine with piperidine 11 and (methyl 12, N-Boc 13 and non-
functionalised 14) piperazine variants and altering the altering substitution (substit-
uent and position) on the N-benzyl ring.
aromatic), 2803 (CH alkane), 1717 (C]O ester), 1612, 1568 (C]C
aromatic), 1496, 1450 (CH alkane), 1309, 1202, 1069 (CeO ether),
926, 817, 743 (CH aromatic). m/z (ESIþ): 327 (MHþ, 100%), 295 (75).
HRMS (ESIþ) Found (MNaþ): 349.1531C19H19N2NaO3 requires
349.1523. Found (MHþ): 327.1711C19H23N2O3 requires 327.1703.
5-(Benzylamino)-2-morpholinobenzoic acid 1a; The reaction was
carried out following General Procedure C using methyl 5-(benzy-
lamino)-2-morpholinobenzoate 7a (0.10 g, 0.3 mmol) and 1M
NaOH (4.4 mL) in MeOH/THF (2:3, 10 mL) for 24 h, to give the title
product 1a (0.07 g, 70%) as a white solid. m.p.: >230 ꢁC. RF: 0.09 (1:1
petroleum ether-ethyl acetate). dH (400 MHz; (CD3)2SO) 2.96 (4H,
br s, N(CH2CH2)2O), 3.76 (4H, br s, N(CH2CH2)2O), 4.29 (2H, br s,
CH2), 6.71 (1H, br s, NH), 6.81 (1H, dd, J ¼ 3.0, 9.0 Hz, H-4), 7.23 (1H,
m, H-40), 7.25 (1H, d, J ¼ 3.0 Hz, H-6), 7.31e7.34 (4H, m, H-20, H-30),
7.43 (1H, d, J ¼ 9.0 Hz, H-3). dC (100 MHz; (CD3)2SO) 46.0 (CH2), 52.9
(N(CH2CH2)2O), 66.3 (N(CH2CH2)2O), 112.9 (C-6), 116.8 (C-4), 123.9
(C-3), 125.2 (C-1), 126.7 (C-40), 127.0 (C-20), 128.3 (C-30), 138.3 (C-2),
139.6 (C-10), 147.6 (C-5), 166.8 (C]O). IR: nmax(ATR)/cmꢂ1; 3322
(OH, NH), 2975 (CH aromatic), 2861 (CH alkane), 1689 (C]O car-
boxylic acid), 1607, 1514 (C]C aromatic), 1493, 1454 (CH alkane),
1331, 1260, 1067 (CeO ether), 976, 895, 654 (CH aromatic). m/z
(ESIþ): 355 (MNaþ, 100%), 313 (MHþ, 10). HRMS (ESIþ) Found
(MNaþ): 335.1372C18H20N2NaO3 requires 355.1366. Found (MHþ):
313.1542C18H21N2O3 requires 313.1542.
4-(Piperidin-10-yl)aniline 18; To a solution of 1-(4-nitrophenyl)
piperidine 15 (5.67 g, 0.028 mol) in EtOH (150 mL) was added 10%
Pd/C (0.586 g, 10% w/w). The resulting mixture was stirred at room
temperature under an atmosphere of hydrogen for 23 h. After
completion, the mixture was filtered through Celite and washed
with EtOH. The solvent was removed in vacuo to afford a red oil
which was extracted with DCM (3 ꢀ 10 mL) and washed with brine.
The combined organic extracts were dried (MgSO4) and the solvent
was removed in vacuo to give the title compound 18 (4.12 g, 85%) as a
red oil which was used without further purification. dH (400 MHz;
CDCl3) 1.51e1.57 (2H, m, H-40), 1.70e1.75 (4H, m, H-30), 3.00 (4H, t,
J ¼ 5.5 Hz, H-20), 3.41 (2H, s, NH2), 6.63 (2H, d, J ¼ 8.8 Hz, H-2), 6.83
(2H, d, J ¼ 8.8 Hz, H-3). dC (100 MHz; CDCl3) 24.2 (C-40), 26.2 (C-30),
52.6 (C-20), 116.2 (C-2), 119.1 (C-3), 139.8 (C-1), 145.8 (C-4); IR
nmax(ATR)/cmꢂ1: 3336, 2930, 2851, 1620, 1509, 1229, 819; m/z
(ESIþ): 259 (71%), 177 (100%); HRMS (ESIþ) found (MHþ): 177.1380,
4’-(4-Nitrophenyl)morpholine; A mixture of morpholine (6.6 mL,
0.075 mol), 4-chloronitrobenzene 9 (11.82 g, 0.075 mol) and K2CO3
(10.35 g, 0.075 mol) in DMSO (50 mL) was heated at 120 ꢁC for 19 h
with stirring. The reaction was cooled to r.t., then 1:1 EtOH:H2O
(200 mL) added. The resulting precipitate was collected by filtration
and dried to give the title compound (15.62 g, quant.) as an orange
solid. m.p. 147e149 ꢁC (Lit [19]. 147e149 ꢁC). dH (400 MHz; CDCl3)
C
11H17N2 requires 177.1386. The 1H NMR data were in agreement
with literature values [26].