An efficient one-pot multi-component synthesis of highly functionalized piperidines

Article abstract of DOI:10.1515/hc-2012-0105

A simple, inexpensive and efficient one-pot synthesis of piperidine derivatives was achieved in excellent yield via the three-component reaction of substituted aniline, 1,3-dicarbonyl compound and aromatic aldehyde using phenylboronic acid as catalyst.

Full text of DOI:10.1515/hc-2012-0105

ꢁꢁꢁꢂ
DOI 10.1515/hc-2012-0105SUPꢀ
ꢀHeterocycl. Commun. 2012; 18(5-6): Ad1–Ad9
Supplemental data
OCH3
Characterization of products
HN
N
Ethyl 4-(4-chlorophenylamino)-1,2,6-tris(4-
chlorophenyl)-1,2,5,6-tetrahydropyridine-
3-carboxylate (4a):
C2H5OOC
Cl
Cl
HN
Cl
C2H5OOC
OCH3
N
Scheme 3
Cl
Cl
Methyl 2,6-bis(4-methylphenyl)-1-(4-
methoxyphenyl)-4-(4-methoxyphe-
nylamino)-1,2,5,6-tetrahydropyridine-3-car-
boxylate (4c):
Cl
Scheme 2
OCH3
White solid, yield 89%, mp 168–169°C, Reaction time 14 h;
1H NMR: δ 1.25–1.35 (t, 3H), 2.70–2.85 (d, 2H) 4.15–4.30 (q,
2H) 5.25 (s, 1H), 6.05 (t, 1H), 7.05–7.25 (m, 5H), 7.30–7.50 (m,
8H), 7.75–7.90 (m, 4H), 9.72 (s, 1H); 13C NMR: δ 21.1, 39.6, 57.4,
62.8, 66.3, 106.3, 112.3, 121.5, 124.6, 125.8, 128.2, 131.7, 132.0,
132.2, 132.3, 133.0, 133.9, 134.2, 134.4, 134.8, 135.2, 136.3,
138.7, 139.3, 140.2, 147.5, 149.4, 149.6, 171.3; Mass LC-MS
(m/z): 614.6692 [M+]; Elemental analysis for C32H26Cl4N2O2:
C, 62.76; H, 4.28; N, 4.57; Found: C, 62.79; H, 4.25; N, 4.59.
HN
H3COOC
N
H3C
CH3
Ethyl 2,6-bis(3-chlorophenyl)-1-
(4-methoxyphenyl)-4-(4-
OCH3
methoxyphenylamino)-1,2,5,6-tetrahydro-
pyridine-3-carboxylate (4b):
Scheme 4
White solid, yield 89%, mp 224–226°C, lit mp 226–228°C,
1
Yellow solid, yield 86%, mp 170–171°C, lit mp 167–170°C, Reaction time 16 h, H NMR: δ 2.39 (s, 6H), 2.66 (d, 1H),
Reaction time 15 h, 1H NMR: δ 1.50 (t, 3H), 2.69 (d, 1H), 2.80 2.75 (d, 1H), 3.68 (s, 3H), 3.82 (s, 6H), 5.05 (d, 1H), 6.24 (d,
(d, 1H), 3.75 (s, 6H), 4.30–4.59 (q, 2H), 5.10 (s, 1H), 6.30–6.44 2H), 6.29 (s, 1H), 6.49 (d, 2H), 6.64 (d, 2H), 6.86 (d, 2H),
(m, 5H), 6.70–6.81 (m, 5H), 7.12–7.39 (m, 7H), 10.24 (s, 1H); 13C 7.02–7.10 (m, 6H), 7.16 (d, 2H), 10.15 (s, 1H); 13C NMR: δ 21.6,
NMR: δ 15.5, 34.1, 55.5, 55.9, 56.3, 57.8, 60.2, 97.1, 113.9, 114.6, 21.8, 33.6, 51.6, 55.9, 56.1, 56.3, 58.5, 97.9, 114.6, 126.2, 126.8,
115.3, 125.1, 125.4, 127.0, 127.5, 127.9, 128.6, 129.7, 130.7, 134.8, 128.5, 129.2, 129.8, 131.6, 135.8, 136.7, 139.8, 141.6, 142.2,
140.0, 141.4, 145.9, 147.2, 152.1, 156.7, 158.6, 167.9; Mass LC-MS 151.6, 157.8, 158.6, 168.2; Mass LC-MS (m/z): 549.2753 [M+];
(m/z):602.5125[M+]. Elemental analysis for C34H32Cl2N2O4: C, Elemental analysis for C34H32Cl2N2O4: C, 67.66; H, 5.34; N,
67.66; H, 5.34; N, 4.64. Found: C, 67.64; H, 5.38; N, 4.67.
4.64. Found: C, 67.68; H, 5.30; N, 4.68.

ꢁꢁꢁꢂ
Ad2ꢀ ꢀS.V. Goswami et al.: Highly functionalized piperidines
Methyl 1,2,6-tris(4-methoxyphenyl)-
4-(4-methoxyphenylamino)-1,2,5,6-
tetrahydropyridine-3-carboxylate (4d):
Yellow solid, yield 90%, mp 194–196°C, lit mp 195°C, Reac-
tion time 14 h, 1H NMR: δ 2.68 (d, 1H), 2.82 (d, 1H), 3.82 (s,
6H), 3.92 (s, 3H), 5.10 (s, 1H), 6.22–6.30 (m, 3H), 6.41–6.44
(d, 2H), 6.78–6.84 (m, 5H), 7.10–7.28 (m, 7H), 10.18 (s, 1H);
13C NMR: δ 33.9, 51.5, 55.3, 55.4, 55.8, 57.8, 97.6, 113.5, 117.3,
120.9, 121.6, 125.9, 126.4, 128.6, 128.5, 129.6, 131.3, 132.3,
138.2, 141.6, 143.4, 146.7, 156.2, 168.7; Mass LC-MS (m/z):
588.3562 [M+]; Elemental analysis for C33H30N2O4Cl2: C,
67.23; H, 5.13; N, 4.75. Found: C, 67.26; H, 5.10; N, 4.78.
OCH3
HN
H3COOC
Methyl 2,6-bis(4-bromophenyl)-1-(4-
chlorophenyl)-4-(4-chlorophenylamino)
-1,2,5,6-tetra hydropyridine-3-carboxylate
(4f):
N
H3CO
OCH3
Cl
OCH3
HN
Scheme 5
H3COOC
White solid, yield 88%, mp 160–161°C, lit mp 158–160°C,
1
Reaction time 14 h, H NMR: δ 2.59 (d, 1H), 2.72 (d, 1H),
3.66 (s, 6H), 3.89 (s, 6H), 3.92 (s, 3H), 4.98 (s, 1H), 6.25 (s,
1H), 6.32 (d, 2H), 6.43 (d, 2H), 6.68 (d, 4H), 6.75–6.82 (m,
4H), 7.10 (d, 2H), 7.18 (d, 2H), 10.18 (s, 1H); 13C NMR: δ 34.4,
51.5, 55.2, 55.3, 55.7, 56.1, 57.9, 97.2, 113.6, 114.1, 114.4, 114.6,
114.9, 128.1, 128.4, 128.6, 131.4, 135.7, 136.8, 141.7, 151.6, 157.2,
158.3, 158.5, 159.1, 168.7; Mass LC-MS (m/z): 580.2132 [M+].
Elemental analysis for C35H36N2O6: C, 72.39; H, 6.25; N, 4.82;
Found: C, 72.37; H, 6.27; N, 4.85.
N
Br
Br
Cl
Scheme 7
Methyl (4-chlorophenyl)-4-
Yellow solid, yield 80%, mp 163–164°C, lit mp 160–163°C,
(4-chlorophenylamino)-2,6-
1
Reaction time 15 h, H NMR: δ 2.71 (d, 1H), 2.83 (d, 1H),
bis(methoxyphenyl)-1,2,5,6-tetra hydropyri-
dine-3-carboxylate (4e):
3.96 (s, 3H), 5.12 (s, 1H), 6.28–6.39 (m, 5H), 6.92–6.98 (m,
4H), 7.10–7.24 (m, 4H), 7.35–7.43 (m, 4H), 10.21 (s, 1H); 13C
NMR: δ 33.7, 51.9, 55.1, 57.5, 98.4, 114.6, 121.1, 121.8, 122.5,
127.1, 128.5, 128.9, 129.2, 129.7, 132.0, 132.3, 132.7, 136.3, 141.4,
142.1, 145.5, 155.9, 167.8; Mass LC-MS (m/z): 683.1685 [M+].
Elemental analysis for C31H24Br2Cl2N2O2: C, 67.23; H, 5.13; N,
4.75. Found: C, 67.25; H, 5.11; N, 4.78.
Cl
HN
H3COOC
Methyl 4-(4-chlorophenylamino)-1-(4-
chlorophenyl)-1,2,5,6-tetrahydro-2,6-bis(4-
nitro phenyl)pyridine-3-carboxylate (4g):
N
H3CO
OCH3
White solid, yield 78%, mp 195–196°C, Reaction time 16 h,
1H NMR: δ 2.95 (d, 2H), 4.05 (s, 3H), 4.95 (s, 1H), 5.90 (t, 1H),
6.70–6.85 (m, 4H), 7.08–7.20 (m, 4H), 7.75–8.10 (m, 8H),
10.05 (s, 1H); 13C NMR: δ 32.2, 33.6, 52.5, 55.4, 58.2, 113.5,
117.5, 120.1, 121.6, 122.1, 123.6, 125.1, 126.2, 128.4, 129.3, 129.4,
Cl
Scheme 6

ꢂꢁꢁꢁ
S.V. Goswami et al.: Highly functionalized piperidinesꢀ
ꢀAd3
Cl
C31H24Cl2F2N2O2: C, 65.85; H, 4.28; N, 4.95; Found: C, 65.87;
H, 4.24; N, 4.97.
HN
N
H3COOC
Methyl 2,6-bis(3-nitrophenyl)-1-phenyl-
4-(phenylamino)-1,2,5,6-tetrahydropyridine-
3-carboxylate (4i):
O2N
NO2
HN
H3COOC
Cl
NO2
Scheme 8
N
130.2, 132.8, 141.5, 144.3, 150.1, 153.6, 178.2; Mass LC-MS
(m/z): 620.7535 [M+]; Elemental analysis for C34H32Cl2N2O4:
C, 67.66; H, 5.34; N, 4.64. Found: C, 67.63; H, 5.37; N, 4.67.
NO2
Scheme 10
White solid, yield 80%, mp 178–180°C, lit mp 180°C, Reac-
1
Methyl (4-chlorophenyl)-4-(4-
chlorophenylamino)-2,6-bis(4-fluorophe-
nyl)-1,2,5,6-tetra hydropyridine-3-carboxy-
late (4h):
tion time 15 h, H NMR: δ 2.75 (d, 2H), 4.21 (s, 3H), 5.21
(s, 1H), 6.05 (t, 1H), 6.60–6.71 (m, 5H), 7.05–7.15 (m, 5H),
7.72–7.95 (m, 8H), 10.48 (s, 1H); 13C NMR: δ 32.0, 33.1, 51.2,
55.9, 57.2, 113.1, 118.2, 121.1, 121.6, 122.4, 122.6, 126.3, 127.1,
129.2, 129.6, 129.8, 130.1, 132.5, 137.5, 144.3, 146.5, 149.3,
155.5, 168.2; Mass LC-MS (m/z): 551.7634 [M+]; Elemental
analysis for C31H26N4O6: C, 67.63; H, 4.76; N, 10.18; Found:
C, 67.66; H, 4.73; N, 10.14.
Cl
HN
H3COOC
Methyl 1,2,5,6-tetrahydro-2,6-bis(2-
nitrophenyl)-1-phenyl-4-(phenylamino)
pyridine-3-carboxylate (4j):
N
F
F
HN
Cl
H3COOC
NO2
Scheme 9
White solid, yield 77%, mp 178°C, lit mp 176°C, Reaction
time 14 h, 1H NMR: δ 2.74 (d, 1H), 2.85 (d, 1H), 4.02 (s, 3H),
5.01 (s, 1H), 5.90–6.31 (m, 6H), 6.85–7.28 (m, 11H), 10.22 (s,
1H); 13C NMR: δ 34.2, 51.4, 55.7, 57.2, 97.3, 114.6, 114.9, 115.2,
115.6, 115.8, 116.3, 128.0, 128.3, 128.5, 128.7, 129.1, 131.2,
139.2, 139.8, 141.6, 151.7, 156.5, 158.6, 159.2, 164.6, 168.1;
N
NO2
Mass LC-MS (m/z): 565.4452 [M+]; Elemental analysis for Scheme 11

ꢁꢁꢁꢂ
Ad4ꢀ ꢀS.V. Goswami et al.: Highly functionalized piperidines
CH3
White solid, yield 80%, mp 216°C, lit mp 218–219°C, Reac-
1
tion time 15 h.; H NMR: δ 2.80 (d, 2H), 4.39 (s, 3H), 5.10
(s, 1H), 6.29 (t, 1H), 6.80–6.85 (m, 5H), 7.12–7.23 (m, 5H),
7.82–8.05 (m, 8H), 10.23 (s, 1H); 13C NMR: δ 34.1, 35.3, 52.3,
55.4, 59.2, 114.3, 119.1, 122.3, 122.6, 122.8, 123.3, 127.2, 127.4,
129.6, 129.8, 130.2, 132.3, 133.7, 138.2, 146.1, 148.3, 151.1,
157.4, 165.5; Mass LC-MS (m/z): 551.4231 [M+]; Elemental
analysis for C31H26N4O6: C, 67.63; H, 4.76; N, 10.18; Found:
C, 67.65; H, 4.78; N, 10.16.
HN
N
H3COOC
NC
CN
Methyl 4-(4-bromophenylamino)-1-(4-
bromophenyl)-1,2,5,6-tetrahydro-2,6-bis(4-
methoxyphenyl)pyridine-3-carboxylate (4k):
CH3
Scheme 13
Br
HN
129.9, 133.2, 135.7, 137.2, 139.2, 146.4, 154.3, 160.8, 165.5,
166.8; Mass LC-MS (m/z): 562.3433 Elemental analysis for
C33H30N2O4Br2: Calcd C, 58.42; H, 4.46; N, 4.13. Found: C,
58.46; H, 4.49; N, 4.10.
H3COOC
N
Methyl 4-(p-tolylamino)-2,6-bis(4-
cyanophenyl)-1,2,5,6-tetrahydro-
1-p-tolylpyridine-3-carboxylate (4l):
H3CO
OCH3
Br
White solid, yield 82%, mp 210–212°C, lit mp 214°C, Reac-
tion time 16 h. 1H NMR: δ 2.81 (d, 2H), 3.12 (s, 6H), 4.16 (s,
3H), 5.02 (s, 1H), 5.85 (t, 1H), 6.73–6.84 (m, 4H), 7.08–7.21
Scheme 12
Yellow solid, yield 84%, mp 179°C, lit mp 178°C, Reac- (m, 4H), 7.89–8.20 (m, 8H), 10.18 (s, 1H); 13C NMR: δ 33.1,
tion time 14 h. 1H NMR: δ 2.84 (d, 1H), 2.90 (d, 1H), 3.72 (s, 34.4, 50.2, 54.8, 59.3, 110.1, 116.3, 120.6, 122.3, 124.1, 124.5,
3H), 3.91 (s, 6H), 5.12 (s, 1H), 6.20–6.27 (m, 3H), 6.38 (d, 125.7, 126.9, 129.2, 130.1, 130.4, 130.6, 134.1, 140.2, 145.5,
2H), 6.78–6.86 (m, 4H), 7.02–7.18 (m, 8H), 10.20 (s, 1H); 13
C
150.7, 155.2, 176.3; Mass LC-MS (m/z): 538.5176 [M+]; Ele-
NMR: δ 34.3, 50.3, 54.4, 58.1, 63.2, 111.7, 114.4, 115.1, 116.7, mental analysis for C35H30N4O2: C, 78.04; H, 5.61; N, 10.40;
116.9, 123.2, 126.3, 128.4, 128.6, 128.8, 129.1, 129.5, 129.7, Found: C, 78.02; H, 5.63; N, 10.44.

ꢂꢁꢁꢁ
S.V. Goswami et al.: Highly functionalized piperidinesꢀ
ꢀAd5
1H NMR, 13C NMR, and LC-MS of compound 4a
PIP1
1H IN CDCL3
AVANCE-300 MHz
C1
HN
C2H5OOC
N
C1
C1
C1
1.04
4.04 8.00 4.79
0.89
2.40
2.07
3.09
10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5
0
Scheme 14
PIP1
13C IN CDCL3
AVANCE-300 MHz
C1
HN
C2H5OOC
N
C1
C1
C1
190 180 170 160 150 140 130 120 110 100
ppm
90
80
70
60
50
40
30
20
10
Scheme 15

ꢁꢁꢁꢂ
Ad6ꢀ ꢀS.V. Goswami et al.: Highly functionalized piperidines
*LCMSMS – G Star pulsar
+TOF MS: 0.031 to 2.110 min from PIP1.wiff
a=3.31032170814603319e-003, t0=-2.87092848626704656e+001 R;
4.2
4.0
3.8
3.6
3.4
3.2
3.0
2.8
2.6
2.4
2.2
2.0
1.8
1.6
1.4
1.2
C1
HN
N
C2H5OOC
C1
C1
614.6692
C1
585.7732
1.0
360.4043
471.6239
0.8
0.6
0.4
0.2
0
370.9462
449.9723
620.3614
547.6194
540 560
320
340
360
380
400
420
440
460
480
500
520
580
600
620
640
m/z, amu
Scheme 16
1H NMR, 13C NMR, and LC-MS of compound 4g
PIP7
1H IN CDCL3
AVANCE-300 MHz
C1
HN
N
H3COOC
O2N
NO2
C1
1.17
3.91
4.01 4.27
4.11
0.90
1.02
3.20
1.97
10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5
0
Scheme 17

ꢂꢁꢁꢁ
S.V. Goswami et al.: Highly functionalized piperidinesꢀ
ꢀAd7
Scheme 18
*LCMSMS – Q-Star pulsar
+TOF MS: 0.033 to 2.150 min from PIP7.wiff
a=3.39162196819788330e-004, t0=-2.85292848626704650e+001 R;
4.2
4.0
3.8
3.6
3.4
3.2
3.0
2.8
2.6
2.4
2.2
2.0
1.8
1.6
1.4
1.2
1.0
C1
620.7535
HN
H3COOC
N
O2N
NO2
C1
600.8539
629.8056
0.8
0.6
0.4
0.2
0
439.4760
370.4238
380
330.3608
520.6232
520
320
340
360
400
420
440
460
480
500
540
560
580
600
620
640
m/z, amu
Scheme 19

ꢁꢁꢁꢂ
Ad8ꢀ ꢀS.V. Goswami et al.: Highly functionalized piperidines
1H NMR, 13C NMR, and LC-MS of compound 4i
PIP9
1H IN CDCL3
AVANCE-300 MHz
HN
N
H3COOC
NO2
NO2
0.94
8.01
5.11 4.87
1.05
1.17
2.97
2.04
10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5
0
Scheme 20
PIP9
13C IN CDCL3
AVANCE-300 MHz
HN
H3COOC
NO2
N
NO2
190 180 170 160 150 140 130 120 110 100
90
80
70
60
50
40
30
20
10
ppm
Scheme 21

ꢂꢁꢁꢁ
S.V. Goswami et al.: Highly functionalized piperidinesꢀ
ꢀAd9
*LCMSMS – Q-Star pulsar
+TOF MS: 0.038 to 2.167 min from PIP9.wiff
a=3.28762056828786765e-004, t0=-2.85812808602704081e+001 R;
4.2
4.0
3.8
3.6
3.4
3.2
3.0
2.8
2.6
2.4
2.2
2.0
1.8
1.6
1.4
HN
H3COOC
NO2
551.7634
N
NO2
397.6046
1.2
1.0
0.8
0.6
0.4
0.2
0
490.4756
562.3754
348.4604
449.7541
320
340
360
380
400
420
440
460
480
500
520
540
560
580
600
620
640
m/z, amu
Scheme 22