Cabello-Sanchez et al.
hydrochloride (0.6 mmol), NaOtBu (67 mg, 0.70 mmol, 1.4 equiv;
or 212 mg, 2.2 mmol, 4.5 equiv when the dihydrochloride was
employed), ligand (0.015 mmol, 3% mol), Pd2dba3 (0.005 mmol,
4.6 mg, 2% mol in Pd), and degassed toluene or xylene (3 mL).
Then, the aryl halide (0.5 mmol) was added, and the mixture was
heated under nitrogen at 110 or 130 °C for 24 h. After cooling to
room temperature, the mixture was diluted with CH2Cl2, filtered
over a celite pad, and analyzed by GC to determine the conversion
and the ratio of monoarylated compounds by comparing with
authentic samples. After evaporation of the volatile compounds,
2.18 (br d, J ≈ 11 Hz, 2H), 1.65 (qd, J ) 3.4, 11 Hz, 2H), 1.26 (t,
J ) 7.5 Hz, 3H), 1.25 (t, overlapped, J ) 7.5, 3H). 13C NMR
(CDCl3, 62.9 MHz): δ 151.7 (C), 144.4 (C), 139.2 (C), 128.8 (CH),
128.1 (CH), 127.5 (C), 126.9 (CH), 126.3 (CH), 123.8 (CH), 119.8
(CH), 116.8 (CH), 110.7 (CH), 52.1 (CH2), 49.7 (CH), 33.5 (CH2),
23.9 (CH2), 23.4 (CH2), 14.8 (CH3), 12.9 (CH3). MS (EI) m/z (%):
309 (M+1, 22), 308 (M, 53), 188 (19), 187 (100), 186 (26), 173
(6), 172 (35), 160 (9), 159 (9), 158 (13), 146 (20), 145 (8), 144
(15), 134 (6), 133 (8), 132 (28), 131 (7), 130 (12), 119 (8), 118
(19), 117 (14), 91 (10), 77 (11). HRMS (ESI) calcd for C21H29N2
(M + H) 309.2331, found 309.2333. IR (neat, cm-1) 2967, 2790,
1603, 1585, 1509, 1451, 1381, 1297, 1143, 923. Rf (CH2Cl2) 0.92.
Competitive Experiments. General Procedure. A Schlenk flask
was backfilled with nitrogen and charged with 0.4 mmol of each
amine, PhBr (0.4 mmol, 65 mg), ligand L10 (0.012 mmol, 6.5 mg),
NaOtBu, Pd2dba3 (3.6 mg, 0.004 mmol), and 3 mL of degassed
toluene. This mixture was heated at 100 °C, and its composition
was analyzed by GC after 1 and 17 h. The results are summarized
in the text (Table 3).
Competitive Experiment between 3-Aminopyrrolidine Dihy-
drochloride (1a‚2HCl) and 3-Aminopiperidine Dihydrochloride
(1b‚2HCl). The reaction was carried out according to the general
procedure by using 1a‚2HCl (65 mg, 0.4 mmol), 1b‚2HCl (69 mg,
0.4 mmol), PhBr (65 mg, 0.4 mmol), NaOtBu (245 mg, 2.6 mmol),
Pd2dba3 (3.6 mg, 0.004 mmol), L10 (6.5 mg, 0.012 mmol), and 3
mL of degassed toluene. The reaction was monitored by GC
(aliquots after 1 and 17 h). GC tR: 2a, 11.3 min; 3a, 10.9 min; 2b,
11.5 min; 3b, 13.0 min. Ratio (2a + 3a)/(2b + 3b) ) 80/20.
Competitive Experiment between 3-Aminopyrrolidine Dihy-
drochloride (1a‚2HCl) and Pyrrolidine (40). The reaction was
carried out according to the general procedure by using 1a‚2HCl
(65 mg, 0.4 mmol), pyrrolidine 40 (28 mg, 0.4 mmol), PhBr (65
mg, 0.4 mmol), NaOtBu (173 mg, 1.8 mmol), Pd2dba3 (3.6 mg,
0.004 mmol), L10 (0.012 mmol, 6.5 mg), and 3 mL of degassed
toluene. The reaction was monitored by GC (aliquots after 1 and
17 h). GC tR: 2a, 11.3 min; 3a, 10.9 min; 1-phenylpyrrolidine, 6.9
min. The results are summarized in the text (Table 3).
Competitive Experiment between 3-Aminopiperidine Dihy-
drochloride (1b‚2HCl) and Piperidine (41). The reaction was
carried out according to the general procedure by using 1b‚2HCl
(69 mg, 0.4 mmol), piperidine 41 (34 mg, 0.4 mmol), PhBr (65
mg, 0.4 mmol), NaOtBu (173 mg, 1.8 mmol), Pd2dba3 (3.6 mg,
0.004 mmol), L10 (0.012 mmol, 6.5 mg), and 3 mL of degassed
toluene. The reaction was monitored by GC (aliquots after 1 and
17 h). GC tR: 2b, 11.5 min; 3b, 13.0 min; 1-phenylpiperidine, 7.1
min. The results are summarized in the text (Table 3).
Competitive Experiment between 4-Aminopiperidine (1d) and
Piperidine (41). The reaction was carried out according to the
general procedure by using 1d (40 mg, 0.4 mmol), piperidine 41
(34 mg, 0.4 mmol), PhBr (65 mg, 0.4 mmol), NaOtBu (96 mg, 1.0
mmol), Pd2dba3 (3.6 mg, 0.004 mmol), L10 (6.5 mg, 0.012 mmol),
and 3 mL of degassed toluene. The reaction was monitored by GC
(aliquots after 1 and 17 h of reaction). GC tR: 2d, 12.0 min; 3d,
13.2 min; 1-phenylpiperidine, 7.1 min. The results are summarized
in the text (Table 3).
1
the crude mixture was analyzed by H NMR by using 1,4-bis-
(trichloromethyl)benzene as internal standard. Flash chromatography
on SiO2 afforded the pure arylation products when necessary.
Arylation of 3-Aminopiperidine (1b). Arylation of 3-aminopi-
peridine 1b‚2HCl (0.6 mmol) was carried out according to the
general procedure by using L2 and PhBr (80 mg, 0.5 mmol) in
xylene at 130 °C. After purification of the crude mixture by flash
chromatography using CH2Cl2/MeOH/NH3 (v/v/v 95:5:1) as eluent,
1-phenyl-3-(phenylamino)piperidine 4b was obtained as a yellow
oil (30 mg, 0.12 mmol, 23% yield). Further elution afforded
3-amino-1-phenylpiperidine 2b and 3-phenylaminopiperidine 3b as
a mixture (28 mg, 0.16 mmol, 32% yield). Comparison of the
retention times [tR (2b) 11.5 min, tR (3b) 13.0 min] and NMR
spectra with authentic samples and the literature data2 allowed an
unambiguous characterization of both monoarylated products.
General Procedure for the Pd-Catalyzed Arylation of Un-
protected Diamines with Substituted Aryl Halides (unless
otherwise stated, see Table 2). A Schlenk flask backfilled with
nitrogen was charged with the diamine or the diamine dihydro-
chloride (0.6 mmol), NaOtBu (212 mg, 2.2 mmol, 4.5 equiv; or 67
mg, 0.75 mmol, 1.2 equiv when the free amine was employed),
(()-BINAP L1 (0.007 mmol, 4.6 mg, 1.5% mol), Pd2dba3 (0.0025
mmol, 2.3 mg, 1% mol in Pd), and 3 mL of degassed toluene. The
aryl halide (0.5 mmol) was then added, and the mixture was heated
under nitrogen at 110 °C for 24 h. After cooling to room
temperature, the mixture was diluted with CH2Cl2 and filtered over
a celite pad, and the volatile compounds were evaporated under
1
reduced pressure. The crude product was analyzed by H NMR,
using 1,4-bis(trichloromethyl)benzene as an internal standard to
determine the composition of the reaction mixture. Flash chroma-
tography on SiO2 afforded the arylation products when necessary.
4-[(2-Ethylphenyl)amino]piperidine (29) and 1-(2-Ethylphe-
nyl)-4-[(2-ethylphenyl)amino]piperidine (30). Arylation of 4-ami-
nopiperidine 1c with 2-bromo-ethylbenzene was carried out in
toluene at 110 °C according to the general procedure. Purification
of the crude mixture by flash chromatography by using CH2Cl2/
MeOH/NH3 (v/v/v 95:5:1) as eluent afforded 30 as a yellow oil
(16 mg, 0.05 mmol, 10% yield). Further elution of the chromato-
graphic column afforded 29 as a yellow oil (40 mg, 0.2 mmol,
40% yield).
4-[(2-Ethylphenyl)amino]piperidine (29). 1H NMR (CDCl3,
250 MHz) δ 7.14-7.05 (m, 2H), 6.71-6.64 (m, 2H), 3.44 (m, 2H),
3.12 (dt, J ) 3.5, 12.7, 2H), 2.73 (td, J ) 2.3, 11-13 Hz, 2H),
2.47 (q, J ) 7.5 Hz, 2H), 2.10 (d, J ) 11.8 Hz, 2H), 2.03 (s, 1H),
1.36 (qd, J ) 3.5, 10-12 Hz, 2H), 1.25 (t, J ) 7.5 Hz, 3H). 13C
NMR (CDCl3, 62.9 MHz): δ 144.1 (C), 128.1 (CH), 127.5 (C),
126.9 (CH), 116.9 (CH), 110.6 (CH), 49.9 (CH), 45.3 (CH), 33.7
(CH), 23.8 (CH), 12.8 (CH3). MS (EI) m/z (%): 206 (M+2, 15),
205 (M+1, 100), 204 (M, 70), 188 (17), 187 (88), 186 (38), 172
(36), 160 (9), 159 (8), 158 (16), 146 (17), 145 (8), 144 (19), 134
(11), 133 (8), 132 (30), 131 (7), 130 (16), 119 (8), 118 (24), 117
(13), 103 (5), 91 (9), 77 (9), 56 (8), 43 (5), 42 (9). HRMS (ESI)
calcd for C13H21N2 (M + H) 205.1705, found 205.1711. IR (neat,
cm-1) 3038, 2932, 2851, 1603, 1584, 1507, 1451, 1413, 1306, 1262,
1238, 1149. Rf (CH2Cl2/MeOH/NH3, 95:5:1) 0.24.
Synthesis of (BINAP)Pd(Ph)I (A) and Study of Its Complex-
ation with 3-Aminopyrrolidine (1a). A Schlenk flask was back-
filled with nitrogen and charged with Pd2dba3 (58.6 mg, 0.065
mmol), (()-BINAP L1 (73.5 mg, 0.12 mmol), and 0.5 mL of
degassed acetone. This mixture was stirred for 4 h at room
temperature, and then an excess of PhI was added (1.2 mmol, 0.13
mL). The resulting solution was stirred for a further 48 h. A
precipitate appeared that was filtered and washed with pentane to
afford 40 mg (0.04 mmol, 31% yield) of a brown solid, corre-
sponding to the complex A (BINAP)Pd(Ph)I.18 A part of this solid
(28.6 mg, 0.03 mmol) was dissolved under nitrogen in degassed
C6D6, (R)-3-aminopyrrolidine 1a was added (0.03 mmol, 2.6 µL),
and a precipitate appeared. The 31P NMR spectrum recorded after
1 h showed the appearance of new peaks at -13.7 (free BINAP),
1-(2-Ethylphenyl)-4-[(2-ethylphenyl)amino]piperidine (30). 1H
NMR (CDCl3, 250 MHz) δ 7.24-7.01 (m, 6H), 6.71-6.66 (m,
2H), 3.55-3.45 (m, 2H), 3.08 (br d, J ≈ 12 Hz, 2H), 2.83 (d, J ≈
11 Hz, 2H), 2.71 (q, J ) 7.5 Hz, 2H), 2.49 (q, J ) 7.5 Hz, 2H),
2038 J. Org. Chem., Vol. 72, No. 6, 2007