The Journal of Organic Chemistry
Article
Methyl 4-(2,5-dimethyl-1H-pyrrol-1-yl)benzoate (10). Yield
344 mg (81%): white crystals; mp 106−108 °C; Rf = 0.4 (EtOAc/
m/z = 271.14 [M + H]+. The data were in accordance with those
previously reported.19
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hexanes, 1:19−1:9); H NMR (500 MHz, CDCl3) δ 8.14 (d, J = 8.6
(9H-Fluoren-9-yl)methyl (4-(2-aminoethyl)phenyl)-
carbamate (13c). Yield 472 mg (79%): white solid; mp 207−209
°C; H NMR (500 MHz, DMSO-d6) δ 7.92−8.05 (m, 2H), 7.89 (d, J =
7.6 Hz, 2H), 7.73 (d, J = 7.4 Hz, 2H), 7.31−7.43 (m, 4H), 7.13 (d, J =
8.2 Hz, 2H), 4.45 (d, J = 6.7 Hz, 2H), 4.28 (t, J = 6.5 Hz, 1H), 2.93−
2.97 (m, 2H), 2.78−2.82 (m, 2H); 13C NMR (126 MHz, DMSO-d6)
δ 153.47, 143.66, 140.73, 137.54, 131.25, 128.97, 127.72, 127.13,
125.09, 120.14, 118.57, 66.28, 46.54, 32.19, 21.03; LRMS (ESI) m/z =
359.17 [M + H]+. The data were in accordance with those previously
reported.19
Hz, 2H), 7.30 (d, J = 8.5 Hz, 2H), 5.93 (s, 2H), 3.96 (s, 3H), 2.05 (s,
6H); 13C NMR (126 MHz, CDCl3) δ 166.6, 143.2, 130.6, 129.4,
128.8, 128.2, 106.6, 52.5, 13.2; HRMS (ESI-TOF) m/z [M + H]+
calcd for C14H16NO2 230.1176, found 230.1182.
2-(2,5-Dimethyl-1H-pyrrol-1-yl)thiazole (11). Yield 321 mg
1
(88%): colorless oil; Rf = 0.2 (EtOAc/hexanes, 1:19−1:9); H NMR
(500 MHz, CDCl3) δ 7.75 (d, J = 3.6 Hz, 1H), 7.36 (d, J = 3.6 Hz,
1H), 5.92 (s, 2H), 2.23 (s, 6H); 13C NMR (126 MHz, CDCl3) δ
159.2, 140.6, 129.9, 119.7, 107.8, 13.2; LRMS (ESI) m/z = 179.06 [M
+ H]+. The data were in accordance with those previously reported.25
tert-Butyl (4-(2-(2,5-dimethyl-1H-pyrrol-1-yl)ethyl)phenyl)-
carbamate (14a). Yield 362 mg (78%): yellow oil; Rf = 0.15
(EtOAc/hexanes, 1:7−1:4); 1H NMR (500 MHz, CDCl3) δ 7.30 (d, J
= 8.0 Hz, 2H), 7.02 (m, 2H), 6.55 (s, 1H), 5.78 (s, 2H), 3.93 (m, 2H),
2.84 (m, 2H), 2.15 (s, 6H), 1.54 (s, 9H); 13C NMR (126 MHz,
CDCl3) δ 152.8, 146.8, 137.0, 133.1, 129.4, 127.4, 118.7, 105.2, 85.3,
80.5, 45.4, 36.9, 28.4, 27.5, 12.5; HRMS (ESI-TOF) m/z [M + Na]+
calcd for C19H26N2NaO2 337.1886, found 337.1889.
2-(4-(2,5-Dimethyl-1H-pyrrol-1-yl)phenyl)ethanamine HCl
(16). Using method B, starting material 15 was converted to the
intermediate 2-(4-(2,5-dimethyl-1H-pyrrol-1-yl)phenyl)acetonitrile.
The data were in accordance with those previously reported.27 Yield
862 mg (86%): white crystal, mp 102−104 °C; Rf = 0.6 (EtOAc/
1
hexanes, 1:8); H NMR (500 MHz, CDCl3) δ 7.48 (d, J = 8.3 Hz,
2H), 7.28 (d, J = 8.3 Hz, 2H), 5.95 (s, 2H), 3.87 (s, 2H), 2.06 (s, 6H);
13C NMR (126 MHz, CDCl3) δ 138.91, 129.42, 128.95, 128.80,
128.75, 117.64, 106.06, 23.38, 13.07. After mixing this intermediate
(0.210 g, 1 mmol) with Raney Nickel (0.1 mL, 50% in water) in
ethanol (30 mL), the mixture was stirred under hydrogen balloon at
room temperature for 2 h. The reaction mixture was filtered by using
membrane filter (25 mm, 0.22 μm PVDF), and the filtrate was
concentrated in a vacuum to give colorless oil. This oil was dissolved in
hydrochloric acid in methanol and reconcentrated in a vacuum to give
16 as pale yellow HCl salt. (93%). This amine HCl salt was used
Benzyl (4-(2-(2,5-dimethyl-1H-pyrrol-1-yl)ethyl)phenyl)-
carbamate (14b). Yield 331 mg (78%): colorless oil; Rf = 0.2
1
(EtOAc/hexanes, 1:7−1:4); H NMR (500 MHz, CDCl3) δ 7.48−
7.31 (m, 7H), 7.09−7.02 (m, 2H), 6.75 (s, 1H), 5.82 (s, 2H), 5.25 (s,
2H), 3.99−3.91 (m, 2H), 2.94−2.84 (m, 2H), 2.18 (s, 6H); 13C NMR
(126 MHz, CDCl3) δ 153.4, 136.4, 136.1, 133.7, 129.5, 128.7, 128.4,
128.4, 127.4, 118.9, 105.2, 67.06, 45.3, 36.9, 12.5; HRMS (ESI-TOF)
m/z [M + H]+ calcd for C22H25N2O2 349.1911, found 349.1898.
(9H-Fluoren-9-yl)methyl (4-(2-(2,5-dimethyl-1H-pyrrol-1-yl)-
ethyl)phenyl)carbamate (14c). Yield 421 mg (79%): pale white
solid; mp 227−229 °C; Rf = 0.2 (EtOAc/hexanes, 1:7−1:4); 1H NMR
(500 MHz, CDCl3) δ 7.86−7.71 (m, 2H), 7.68−7.56 (m, 2H), 7.49−
7.36 (m, 2H), 7.40−7.29 (m, 4H), 7.01 (d, J = 7.9 Hz, 2H), 6.62 (s,
1H), 5.76 (s, 2H), 4.54 (d, J = 6.6 Hz, 2H), 4.44 (d, J = 6.6 Hz, 1H),
3.91 (t, J = 7.6 Hz, 2H), 2.84 (t, J = 7.6 Hz, 2H), 2.13 (s, 6H); 13C
NMR (126 MHz, CDCl3) δ 155.8, 143.7, 141.4, 129.5, 127.8, 127.6,
127.4, 127.1, 127.0, 124.9, 120.1, 119.9, 105.2, 66.9, 47.1, 45.3, 36.8,
12.4; HRMS (ESI-TOF) m/z [M + H]+ calcd for C29H29N2O2
437.2224, found 437.2224.
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directly in the next step without further purification: H NMR (500
MHz, CDCl3) δ 8.54 (bs, 3H), 7.36 (d, J = 7.9 Hz, 2H), 7.19 (d, J =
7.9 Hz, 2H), 5.91 (s, 2H), 3.45−3.29 (m, 2H), 3.27−3.15 (m, 2H),
2.05 (s, 6H) ; 13C NMR (126 MHz, CDCl3) δ 138.2, 135.4, 129.5,
128.8, 105.9, 41.1, 33.4, 13.1; HRMS (ESI-TOF) m/z [M + H ]+ calcd
for C14H19N2 215.1548, found 215.1540.
Compounds 17a−c were synthesized using following method from
compound 16.
To a dry 25 mL round-bottom flask equipped with a magnetic stir
bar was added compound 16 (0.200 g, 1 mmol) dissolved in
dichloromethane (15 mL). Boc2O (0.23 mL, 1.2 mmol), CbzCl (0.143
mL, 1.2 mmol), or Fmoc-OSu (0.337 g, 1.2 mmol) were added to the
mixture depending on if 17a, 17b, or 17c was desired, respectively.
Triethylamine (0.028 mL, 1.2 mmol) was also added dropwise to the
reaction mixture to deprotonate the HCl salt. The reaction mixture
was stirred at room temperature for 4 h and then concentrated by
rotary evaporation. The resulting yellow oil was purified by flash
column chromatography using a 25 g silica gel cartridge to give the
protected amine.
2-(2,5-Dimethyl-1H-pyrrol-1-yl)-5-nitropyridine (19). Yield
145 mg (82%): yellow crystals; mp 206−208 °C; Rf = 0.4 (EtOAc/
hexanes, 1:19−1:9); 1H NMR (500 MHz, CDCl3) δ 9.45 (s, 1H), 8.63
(d, J = 8.8 Hz, 1H), 7.40 (d, J = 8.7 Hz, 1H), 6.00 (s, 2H), 2.25 (s,
6H); 13C NMR (126 MHz, CDCl3) δ 156.1, 145.1, 142.1, 133.2,
129.1, 120.7, 109.3, 13.8; LRMS (ESI) m/z = 218.09 [M + H]+. The
data were in accordance with those previously reported.26
5-Chloro-2-(2,5-dimethyl-1H-pyrrol-1-yl)benzonitrile (21).
Yield 66.9 mg (78%): yellow crystals; mp 106−108 °C; Rf = 0.3
(EtOAc/hexanes, 1:19−1:9); 1H NMR (500 MHz, CDCl3) δ 7.77 (d,
J = 2.4 Hz, 1H), 7.68 (dd, J = 8.5, 2.4 Hz, 1H), 7.30 (d, J = 8.5 Hz,
1H), 5.97 (s, 2H), 2.02 (s, 6H); 13C NMR (126 MHz, CDCl3) δ
140.6, 134.6, 134.0, 133.1, 131.3, 128.8, 114.9, 114.7, 107.5, 12.8;
HRMS (ESI-TOF) m/z [M + Na]+ calcd for C13H11ClN2Na
253.0503, found 253.0506.
t e r t - B u t y l 4 - ( 2 , 5 - d i m e t h y l - 1 H - p y r r o l - 1 - y l ) -
phenethylcarbamate (17a). Yield 249 mg (79%): white crystals;
mp 170−172 °C; Rf = 0.3 (EtOAc/hexanes, 1:15−1:6); 1H NMR (500
MHz, CDCl3) δ 7.29 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 8.1 Hz, 2H),
5.90 (s, 2H), 4.71 (m, 1H), 3.49−3.35 (m, 2H), 2.92−2.80 (m, 2H),
2.04 (s, 6H), 1.52−1.42 (s, 9H); 13C NMR (126 MHz, CDCl3) δ
155.9, 138.6, 137.2, 129.4, 128.8, 128.3, 105.6, 79.3, 41.7, 36.0, 28.5,
13.1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C19H26N2NaO2
337.1886, found 337.1893.
Benzyl 4-(2,5-dimethyl-1H-pyrrol-1-yl)phenethylcarbamate
(17b). Yield 280 mg (86%): clear oil; Rf = 0.3 (EtOAc/hexanes,
1:15−1:6); 1H NMR (500 MHz, CDCl3) δ 7.47−7.35 (m, 5H), 7.32−
7.25 (m, 2H), 7.21−7.14 (m, 2H), 5.94 (s, 2H), 5.15 (s, 2H), 4.90 (m,
1H), 3.58−3.49 (q, J = 6.8 Hz, 2H), 2.96−2.87 (t, J = 7.0 Hz, 2H),
2.06 (s, 6H); 13C NMR (126 MHz, CDCl3) δ 156.3, 138.2, 137.4,
136.5, 129.4, 128.9, 128.6, 128.4, 128.3, 128.2, 105.6, 66.8, 42.1, 35.8,
13.1; HRMS (ESI-TOF) m/z [M + H]+ calcd for C22H25N2O2
349.1911, found 349.1905.
Compounds 13a−c were synthesized by a procedure described in
Perron et al.20 for selective protection of an aromatic amine.
tert-Butyl (4-(2-aminoethyl)phenyl)carbamate (13a). Yield
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405 mg (78%): white solid; mp 88−91 °C; H NMR (500 MHz,
MeOD) δ 7.38 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 8.4 Hz, 2H), 2.84 (t, J
= 7.2 Hz, 2H), 2.69 (t, J = 7.2 Hz, 2H), 1.52 (s, 9H); 13C NMR (126
MHz, MeOD) δ 155.4, 138.9, 134.9, 130.2, 120.1, 80.7, 44.1, 39.0,
28.9; LRMS (ESI) m/z = 259.15 [M + Na]+. The data were in
accordance with those previously reported.19
Benzyl (4-(2-aminoethyl)phenyl)carbamate (13b). Yield 438
1
mg (81%): pale yellow solid; mp 151−153 °C; H NMR (500 MHz,
(9H-Fluoren-9-yl)methyl 4-(2,5-dimethyl-1H-pyrrol-1-yl)-
phenethylcarbamate (17c). Yield 243 mg (84%): white crystals;
mp 215−218 °C; Rf = 0.3 (EtOAc/hexanes, 1:15−1:6); 1H NMR (500
MHz, CDCl3) δ 7.85−7.78 (d, J = 7.6 Hz, 2H), 7.67−7.60 (d, J = 7.4
Hz, 2H), 7.48−7.42 (t, J = 7.4 Hz, 2H), 7.40−7.32 (t, J = 7.4 Hz, 2H),
CD3OD) δ = 7.30−7.42 (m, 7H), 7.13 (d, J = 8.6 Hz, 2H), 5.16 (s,
2H), 2.87 (t, J = 6.8 Hz, 2H), 2.72 (t, J = 7.0 Hz, 2H); 13C NMR (126
MHz, CD3OD) δ 155.9, 142.7, 138.5, 138.2, 135.4, 130.2, 129.6, 129.4,
129.1, 129.0, 128.3, 128.0, 120.2, 67.5, 65.3, 44.1, 39.1; LRMS (ESI)
F
dx.doi.org/10.1021/jo401778e | J. Org. Chem. XXXX, XXX, XXX−XXX