N. Sakai et al. / Tetrahedron 71 (2015) 4722e4729
4727
4.1.6.4. Methyl 2-(4-(dimethylamino)phenyl)-2-(piperidin-1-yl)
d 21.5, 23.1, 45.8, 51.5, 61.5, 127.1, 128.1, 128.3,129.3,176.1; MS (FAB):
acetate16d (3da). 47% yield (52.0 mg); yellow oil; 1H NMR
m/z 250 [MþH]þ; HRMS (FAB-Magnetic Sector): Calcd for
(500 MHz, CDCl3)
d
1.42 (m, 2H), 1.59 (m, 4H), 2.37 (m, 4H), 2.95 (s,
C15H24NO2: 250.1807, Found: 250.1797.
6H), 3.67 (s, 3H), 3.83 (s, 1H), 6.68 (d, 2H, J¼9.0 Hz), 7.28 (d, 2H,
J¼9.0 Hz); 13C NMR (125 MHz, CDCl3)
d
24.4, 25.7, 40.4, 51.8, 52.5,
4.1.6.13. Methyl 2-(diallylamino)-2-phenylacetate28 (3ad). 48%
74.6, 112.1, 123.5, 129.6, 150.3, 173.0; MS (FAB): m/z 277 [MþH]þ.
yield (47.1 mg); yellow oil; 1H NMR (300 MHz, CDCl3)
d
3.21 (d,
4H, J¼6.6 Hz), 3.71 (s, 3H), 4.61 (s, 1H), 5.14 (m, 4H), 5.82 (m,
2H), 7.33 (m, 5H); 13C NMR (75 MHz, CDCl3)
51.6, 53.2, 67.6,
4.1.6.5. Methyl 2,2-bis(4-(dimethylamino)phenyl)acetate (3da0).
d
26% yield (16.2 mg); yellow oil; 1H NMR (500 MHz, CDCl3)
d
2.90 (s,
117.6, 127.9, 128.4, 128.6, 135.6, 136.5, 172.6; MS (FAB): m/z 246
12H), 3.71 (s, 3H), 4.86 (s, 1H), 6.68 (d, 4H, J¼8.5 Hz), 7.16 (d, 4H,
[MþH]þ.
J¼8.5 Hz); 13C NMR (125 MHz, CDCl3)
d 39.3, 50.7, 53.9, 111.3, 117.9,
127.8, 148.3, 172.8; MS (FAB): m/z 312 [M]þ; HRMS (FAB-Magnetic
4.1.6.14. Methyl 2-morpholino-2-phenylacetate29 (3ae). 99%
Sector): Calcd for C19H24N2O2: 312.1838, Found: 312.1824.
yield (93.2 mg); yellow oil; 1H NMR (300 MHz, CDCl3)
d
2.45 (m,
4H), 3.68 (m, 7H), 3.98 (s, 1H), 7.33 (m, 3H), 7.43 (m, 2H); 13C NMR
4.1.6.6. Methyl
2-(2-hydroxyphenyl)-2-(piperidin-1-yl)acetate
(75 MHz, CDCl3) d 51.5, 52.0, 66.7, 74.4, 128.5, 128.6, 128.8, 135.2,
(3ga). 46% yield (45.9 mg); yellow oil; 1H NMR (300 MHz, CDCl3)
d
171.6; MS (FAB): m/z 236 [MþH]þ.
1.50 (m, 2H), 1.66 (m, 4H), 2.57 (m, 4H), 3.71 (s, 3H), 4.15 (s, 1H),
6.75e6.85 (m, 2H), 7.00 (d, 1H, J¼7.8 Hz), 7.22 (t, 1H, J¼7.8 Hz); 13
C
4.1.6.15. 1-Benzhydrylpiperidine30 (3ag). 99% yield (99.5 mg);
NMR (75 MHz, CDCl3)
d
24.0, 25.8, 51.7, 52.1, 73.8, 116.8,119.2, 128.9,
colorless oil; 1H NMR (500 MHz, CDCl3)
d 1.42 (m, 2H), 1.55 (m, 4H),
129.7, 157.6, 170.4; MS (FAB): m/z 250 [MþH]þ; HRMS (FAB-Mag-
2.31 (m, 4H), 4.21 (s, 1H), 7.15 (t, 2H, J¼7.5 Hz), 7.25 (t, 4H, J¼7.5 Hz),
netic Sector): Calcd for C14H19NO3: 249.1365, Found: 249.1335.
7.39 (d, 4H, J¼7.5 Hz); 13C NMR (75 MHz, CDCl3)
d 24.7, 26.2, 53.1,
76.7, 126.6, 128.0, 128.3, 143.2; MS (FAB): m/z 251 [M]þ.
4.1.6.7. Methyl 2-(4-fluorophenyl)-2-(piperidin-1-yl)acetate16f
(3ha). 98% yield (98.5 mg); yellow oil; 1H NMR (300 MHz, CDCl3)
4.1.6.16. 2-(Benzhydryl(methyl)amino)ethanol31
(3ah). 70%
2.19 (s,
3H), 2.54 (t, 2H, J¼5.4 Hz), 2.76 (br s, 1H), 3.62 (t, 2H, J¼5.4 Hz),
4.48 (s, 1H), 7.18e7.39 (m, 10H); 13C NMR (75 MHz, CDCl3)
39.5,
d
1.43 (m, 2H), 1.59 (m, 4H), 2.36 (m, 4H), 3.69 (s, 3H), 3.95 (s, 1H),
yield (67.6 mg); colorless oil; 1H NMR (300 MHz, CDCl3)
d
7.02 (m, 2H), 7.41 (m, 2H); 13C NMR (75 MHz, CDCl3)
d
24.3, 25.7,
52.0, 52.3, 74.2, 115.3 (d, JCeF¼21 Hz), 130.4 (d, JCeF¼8 Hz), 132.0,
d
162.6 (d, JCeF¼247 Hz), 172.2; MS (EI): m/z 251 [M]þ.
56.0, 58.7, 75.6, 127.0, 128.0, 128.5, 142.2; MS (FAB): m/z 241
[M]þ.
4.1.6.8. Methyl 2-(4-chlorophenyl)-2-(piperidin-1-yl)acetate16f
(3ia). 99% yield (106.0 mg); yellow oil; 1H NMR (500 MHz,
4.1.6.17. 1-Benzylpiperidine32 (4ai). 95% yield (66.6 mg); color-
CDCl3)
d
1.43 (m, 2H),1.59 (m, 4H), 2.36 (m, 4H), 3.68 (s, 3H), 3.95 (s,
less oil; 1H NMR (300 MHz, CDCl3)
d
1.42 (m, 2H), 1.56 (m, 4H), 2.37
(m, 4H), 3.47 (s, 2H), 7.30 (m, 5H); 13C NMR (75 MHz, CDCl3)
24.4,
25.9, 54.5, 63.9, 126.8, 128.1, 129.2, 138.6; MS (EI): m/z 175 [M]þ.
1H), 7.31 (d, 2H, J¼8.5 Hz), 7.38 (d, 2H, J¼8.5 Hz); 13C NMR
d
(125 MHz, CDCl3)
d 24.2, 25.7, 52.0, 52.3, 74.2, 128.6, 130.1, 134.0,
134.8, 171.9; MS (FAB): m/z 267 [MþH]þ; HRMS (FAB-Magnetic
Sector): Calcd for C14H19NO2Cl: 268.1104, Found: 268.1133.
4.1.6.18. 1-(4-Methylbenzyl)piperidine32
(65.9 mg); colorless oil; 1H NMR (500 MHz, CDCl3)
(4ci). 87%
yield
d
1.61e2.90 (m,
4.1.6.9. Methyl 2-(piperidin-1-yl)-2-(2-(trifluoromethyl)phenyl)
acetate (3ja). 83% yield (100.0 mg); yellow oil; 1H NMR (300 MHz,
10H), 3.78 (s, 3H), 3.88 (s, 2H), 6.80e7.27 (m, 4H); 13C NMR
(125 MHz, CDCl3)
d 21.2, 24.5, 26.0, 54.5, 63.7, 128.9, 129.4, 135.3,
CDCl3)
d
1.44 (m, 2H),1.57 (m, 4H), 2.35 (m, 4H), 3.67 (s, 3H), 4.35 (s,
136.6; MS (FAB): m/z 190 [MþH]þ.
1H), 7.42 (t, 1H, J¼7.8 Hz), 7.57 (t, 1H, J¼7.8 Hz), 7.64 (d, 1H,
J¼7.8 Hz), 8.08 (d, 1H, J¼7.8 Hz); 13C NMR (75 MHz, CDCl3)
d
24.2,
4.1.6.19. 2-(Piperidin-1-ylmethyl)phenol33
(4gi). 80%
yield
25.8, 52.1, 52.5, 69.4, 124.1 (q, JCeF¼275 Hz), 125.5 (q, JCeF¼6 Hz),
128.0, 129.3 (q, JCeF¼30 Hz), 130.7, 132.1, 135.8, 171.9; MS (FAB): m/z
302 [MþH]þ; HRMS (FAB-Magnetic Sector): Calcd for C15H19NO2F3:
302.1368, Found: 302.1389.
(61.2 mg); colorless oil; 1H NMR (300 MHz, CDCl3)
d
1.40e1.65 (m,
6H), 2.49 (m, 4H), 3.66 (s, 2H), 6.77 (m, 2H), 6.95 (d, 1H, J¼6.6 Hz),
7.15 (m, 1H), 10.7 (br s, 1H); 13C NMR (75 MHz, CDCl3)
d
23.9, 25.8,
53.8, 62.1, 115.9, 118.8, 121.6, 128.4128.5, 158.0; MS (FAB): m/z 192
[MþH]þ.
4.1.6.10. Methyl
2-(4-acetylphenyl)-2-(piperidin-1-yl)acetate
(3ka). 84% yield (92.5 mg); yellow oil; 1H NMR (500 MHz, CDCl3)
4.1.6.20. N-(4-Chlorobenzyl)piperidine32
(70.5 mg); colorless oil; 1H NMR (300 MHz, CDCl3)
(4ii). 84%
yield
d
1.44 (m, 2H), 1.60 (m, 4H), 2.38 (m, 4H), 2.60 (s, 3H), 3.70 (s, 3H),
d
1.42 (m, 2H),
4.06 (s, 1H), 7.55 (d, 2H, J¼8.5 Hz), 7.94 (d, 2H, J¼8.5 Hz); 13C NMR
1.56 (m, 4H), 2.34 (m, 4H), 3.41 (s, 2H), 7.22e7.28 (m, 4H); 13C NMR
(125 MHz, CDCl3)
d
24.2, 25.7, 26.6, 52.1, 52.3, 74.6, 128.4, 128.9,
(75 MHz, CDCl3) d 24.3, 25.9, 54.4, 63.0, 128.2, 130.4, 132.4, 137.1;
136.8, 141.6, 171.6, 197.7; MS (FAB): m/z 276 [MþH]þ; HRMS (FAB-
MS (FAB): m/z 210 [MþH]þ.
Magnetic Sector): Calcd for C16H22NO3: 276.1600, Found: 276.1576.
4.1.7. General procedure for the coupling reaction of boronic acid 1
with N,N-aminal 5. In a glove box, CuBr (2.87 mg, 0.0200 mmol)
and 2,20-bipyridyl (3.12 mg, 0.0200 mmol) was weighed directly
into a screw glass vial. The vial was sealed with a PTFE sealed screw
cap under a N2 atmosphere and was removed from the glove box.
To the vial was added a distilled DCE (0.6 mL). The solution was
stirred at room temperature for 1 min. To the mixture was suc-
cessively added an N,N-aminal (0.400 mol) and a boronic acid
(0.800 mol). The solution was stirred at 70 ꢀC under air until TLC
analysis indicated the disappearance of the starting material. After
the reaction, the mixture was directly subjected to silica gel with-
out the usual work-up, and was purified via silica gel
4.1.6.11. Methyl 2-(diethylamino)-2-phenylacetate27 (3ab). 70%
yield (62.0 mg); yellow oil; 1H NMR (500 MHz, CDCl3)
d 0.99
(m, 6H), 2.62 (m, 4H), 3.70 (s, 3H), 4.49 (s, 1H), 7.31 (m, 3H),
7.43 (d, 2H, J¼7.0 Hz); 13C NMR (125 MHz, CDCl3)
d 11.7, 43.6,
51.7, 69.3, 127.9, 128.3, 128.7, 137.0, 172.9; MS (FAB): m/z 222
[MþH]þ.
4.1.6.12. Methyl 2-(diisopropylamino)-2-phenylacetate
(3ac). 30% yield (29.9 mg); colorless oil; 1H NMR (300 MHz,
CDCl3)
d
0.96 (d, 6H, J¼6.6 Hz), 1.11 (d, 6H, J¼6.6 Hz), 3.30 (m, 2H),
3.74 (s, 3H), 3.79 (s, 1H), 7.30 (m, 5H); 13C NMR (75 MHz, CDCl3)