Stereoselective synthesis of 2,6-disubstituted tetrahydropyridines via aza-diels-alder reactions

Article abstract of DOI:10.1081/SCC-200043268

The aza-Diels-Alder reactions of (E)-2-(phenylthio)-1,3-pentadiene (2) with iminium salts gave the 2,6-disubstituted tetrahydropyridines 3-8. Factors influencing the stereochemistry and reactivity of these reactions were also studied.

Full text of DOI:10.1081/SCC-200043268

SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 24, pp. 4573–4582, 2004
Stereoselective Synthesis of
2,6-Disubstituted Tetrahydropyridines
Via Aza-Diels-Alder Reactions
*
Shang-Shing P. Chou and Kai-Wei Chen
Department of Chemistry, Fu Jen Catholic University, Taipei, Taiwan,
Republic of China
ABSTRACT
The aza-Diels-Alder reactions of (E)-2-(phenylthio)-1,3-pentadiene (2)
with iminium salts gave the 2,6-disubstituted tetrahydropyridines 3–8.
Factors influencing the stereochemistry and reactivity of these reactions
were also studied.
Key Words: Aza-Diels-Alder reactions; Tetrahydropyridines; Thio-
substituted dienes.
The piperidine ring is one of the most abundant molecular fragments in
both natural and synthetic compounds with various biological activities.[1–4]
*
Correspondence: Shang-Shing P. Chou, Department of Chemistry, Fu Jen Catholic
University, Taipei, Taiwan 24205, Republic of China; Fax: 886-2-29023209; E-mail:
chem1004@mails.fju.edu.tw.
4573
DOI: 10.1081/SCC-200043268
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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Chou and Chen
The aza-Diels-Alder reaction is potentially one of the most versatile and rapid
routes to substituted piperidines.[5,6] However, most imines fail to participate
in these [4 þ 2] cycloadditions. In general, a strongly electron-withdrawing
group such as an acyl[7] or a sulfonyl group[8–10] attached to the nitrogen or
carbon of the imine is needed. When only an alkyl group is attached to the
imine nitrogen, the scope of the aza-Diels-Alder reaction is considerably
reduced; even in the presence of a Lewis acid, intermolecular cycloadditions
are possible only with highly reactive dienes.[11–14]
We have recently reported effective aza-Diels-Alder reactions of thio-
substituted dienes with unactivated imines,[15,16] simply by in situ preparation
of the iminium salts from amine hydrochlorides and aldehydes.[17–19] In
this paper we describe the aza-Diels-Alder reactions of 2-(phenylthio)-
1,3-pentadiene (2) with iminium salts to achieve the synthesis of 2,6-disubsti-
tuted tetrahydropyridines 3–8, and disclose some factors affecting the
stereochemistry and reactivity of these reactions.
(E)-2-(Phenylthio)-1,3-pentadiene (2) was conveniently prepared by
desulfonylation of 2-methyl-4-(phenylthio)-3-sulfolene (1).[20] We modified
the literature procedure[21] by adding some sodium bicarbonate to remove
the acid generated, and also by using hydroquinone (HQ) to prevent the free
radical-initiated polymerization of diene 2. The diene 2 was prepared from
1 in 92% yield, and its structure had previously[20] been shown to have the
trans configuration (Eq. 1).
Following our previous method,[15] the diene 2 (1 equiv.) was treated with
a mixture of an amine hydrochloride (10 equiv.) and an aldehyde (10 equiv.) in
DMF to give the cyclized products 3–8 (Eq. 2 and Table 1). It can be seen that
the reactivity of the aldehydes (compare entries 1, 5, 8, 9) varies with the sub-
stituent R2 (Bz . CO2Et . Ph . H), indicating that electron-withdrawing
groups enhance the reactivity of the iminium ions. The reactivity of methyl-
amine is greater than that of benzylamine (compare entry 1 with 12, and 5
with 17), probably due to the steric effect. It is also interesting to note that
the ratio of the trans/cis products increases with the reaction temperature.
The stereochemistry of the products is determined by NOE experiments.
For example, the methyl group of 3b has an NOE enhancement with the
H-6, whereas the methyl group of 3a does not have such an NOE effect.
We have also used the PM3 method of the HyperChem package to calculate
the relative energies of the most stable conformers of 3a and 3b. Indeed,

Synthesis of 2,6-Disubstituted Tetrahydropyridines
4575
Table 1. The Aza-Diels-Alder reactions of diene 2 with imines derived from amine
hydrochlorides and aldehydes.a
Entry
R1
R2
Temp
Product
Yield (%)
Cis : Trans
1
2
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Me
Me
Me
Me
Me
Me
Me
Me
Me
Bz
Bz
rt
08C
2208C
908C
rt
3
3
3
4
4
5
5
5
6
7
7
7
7
7
8
8
8
8
60
60
52
34
33
27
22
26
14
78
88
76
52
75
67
72
58
38
trans only
2 : 7
2 : 5
3b
4
Bz
CO2Et
CO2Et
Ph
1 : 9
5
12 : 5
5 : 9
4 : 3
6
908C
608C
rt
7
Ph
Ph
8
cis only
9
H
Bz
608C
908C
608C
rt
10
11
12
13
14b
15
16
17
18
2 : 7
1 : 2
1 : 3
3 : 4
1 : 1
5 : 9
1 : 1
5 : 2
7 : 2
Bz
Bz
Bz
Bz
2108C
2208C
908C
608C
rt
CO2Et
CO2Et
CO2Et
CO2Et
2108C
aThe diene 2 (1 equiv.) was reacted with amine hydrochloride (10 equiv.) and aldehyde
(10 equiv.) in DMF at the specified temperature for 24 h.
bThe reaction time was 5 d.
the trans-3b is more stable than the cis-3a, probably because the latter has an
axial benzoyl group.

4576
Chou and Chen
To show that trans-3b is thermodynamically more stable than the cis-3a,
a mixture of 3a and 3b (2 : 7) was stirred at 608C for 24 h to give only 3b
(Eq. 3). Thus, the trans products are thermodynamic products, and the cis pro-
ducts are kinetic products. The cis product arises from an endo transition state,
which is probably favored by a secondary orbital interaction of the unsaturated
R2 substituent with the diene moiety.
It was reported that the rate of the aza-Diels-Alder reactions of vinyl
ethers with arylimines increases significantly when trifluoroethanol was
used as solvent.[22] Thus, we also studied the cycloaddition reactions of
diene 2 with imines in trifluoroethanol. An equimolar mixture of an amine
and an aldehyde was stirred in trifluoroethanol at room temperature for 1 h.
Then another equivalent of the diene 2 was added (Eq. 4, Table 2). It can
be seen that the yields of some of these reactions increased significantly
(entries 2, 3, and 4), but the other reactions (entries 1, 5, and 6) gave very
low yield or no products at all. It can be reasoned that aqueous methylamine
(entries 5 and 6) or phenylglyoxal monohydrate (entry 1) is not easily con-
verted to the imine in trifluoroethanol under neutral conditions. It should
also be noted that the stereoselectivity of the reaction in CF3CH2OH is con-
siderably lower than that in DMF (compare entries 1–3 of Table 2 with
entries 1, 5, 8 of Table 1, respectively).
In summary, we have shown that diene 2, generated conveniently
from 3-sulfolene 1, can undergo the aza-Diels-Alder reactions with imines
derived from aldehydes and amine hydrochlorides in DMF to give the
2,6-disubstituted tetrahydropyridine products 3–8. The reaction temperature
has an important effect on the ratio of the cis/trans products: lower
reaction temperatures favor the kinetic cis products, whereas higher reaction

Synthesis of 2,6-Disubstituted Tetrahydropyridines
4577
Table 2. The Aza-Diels-Alder reactions of diene 2 in trifluoroethanol.
Entry
R1
R2
Temp
Product
Yield (%)
Cis : Trans
1
Bn
Bn
Bz
CO2Et
Ph
rt
rt
rt
rt
rt
rt
3
4
5
6
25
96
76
67
1 : 1.1
1 : 1.4
1 : 1.7
2
3b
4
Bn
Bn
H
Bz
a
5
CH3
CH3
—
a
6
CO2Et
—
aOnly unreacted diene 2 was recovered.
temperatures favor the thermodynamic trans products. The cis products
can be converted to the trans products simply by heating at higher
temperatures in DMF. Trifluoroethanol can increase significantly the
yields of some of these cyclization reactions, but the stereoselectivity
decreases.
EXPERIMENTAL
Infrared spectra were recorded with an FT-IR spectrometer Perkin
Elmer-1600. 1H and 13C NMR spectra were measured for samples in
CDCl3 with an FT-NMR spectrometer Bruker AVANCE-300, Bruker
DMX-600, Bruker AV-500 or Bruker AV-400, with tetramethylsilane as
the internal standard. Mass spectra (MS) and high-resolution mass spectra
(HRMS) were recorded with a spectrometer JEOL JMS-SX102A. The
silica gel used for flash column chromatography was made by Merck
(60 H). All reagents were of reagent grade, and DMF was distilled from
CaH2 before use.
2-(Phenylthio)-1,3-Pentadiene (2)
A mixture of compound 1 (1.34 g, 5.57 mmol), hydroquinone (10 mg,
0.1 mmol), and NaHCO3 (467 mg, 5.56 mmol) was heated in toluene (20 mL)
at 1108C for 5 h. The solvent was then removed by rotary evaporation. The
residue was purified by flash chromatography using hexane/ethyl acetate
(8 : 1) as eluent to give compound 2 (0.90 g, 92% yield) as a colorless
liquid.[20]

4578
Chou and Chen
General Procedure for the Aza-Diels-Alder Reactions of
2-(Phenylthio)-1,3-Pentadiene with Imines Derived from
Amine Hydrochlorides and Aldehydes
A mixture of 2-(phenylthio)-1,3-pentadiene (2, 176 mg, 1.0 mmol), an
amine hydrochloride (10.0 mmol), and an aldehyde (10.0 mmol) was stirred
in DMF (10 mL) for 24 h (see Table 1 for the reaction temperatures used).
The solvent was removed under vacuum. The residue was then purified by
flash chromatography using hexane/ethyl acetate (10 : 1) as the eluent, con-
taining 5–10% (v/v) of triethylamine.
cis-6-Benzoyl-1-benzyl-2-methyl-4-(phenylthio)-1,2,5,6-tetrahydro-
pyridine 3a. Light yellow liquid; IR (film) 3064, 2922, 1709, 1680, 1642,
1
1548, 1535, 1477, 1449, 1265, 1175, 735, 693 cm21; H NMR d 1.00 (3 H,
d, J ¼ 6.8 Hz), 3.49–3.58 (1 H, m), 3.84 (1 H, d, J ¼ 14.4 Hz), 3.96 (1 H,
d, J ¼ 14.4 Hz), 4.38 (1 H, t, J ¼ 5.4 Hz), 5.88–5.89 (1 H, m); 13C NMR d
20.8, 27.1, 55.6, 57.1, 63.0, 128.3, 128.4, 128.5, 128.98, 129.01, 129.8,
130.0, 131.2, 132.5, 132.8, 132.9, 136.1, 136.4, 138.8, 199.7.
trans-6-Benzoyl-1-benzyl-2-methyl-4-(phenylthio)-1,2,5,6-tetrahydro-
pyridine 3b. Light yellow liquid; IR (film) 3064, 2922, 2854, 1709, 1622,
1
1556, 1540, 1473, 1455, 1266, 726, 693 cm21; H NMR d 1.34 (3 H, d,
J ¼ 6.9 Hz), 2.26 (1 H, dd, J ¼ 5.0, 18.0 Hz), 2.72 (1 H, dd, J ¼ 9.0,
18.0 Hz), 3.47 (1 H, d, J ¼ 13.8 Hz), 3.49–3.58 (1 H, m), 3.60 (1 H, d,
J ¼ 13.8 Hz), 4.57 (1 H, dd, J ¼ 5.0, 9.0 Hz), 5.98–6.00 (1 H, m), 7.04–
7.57 (13 H, m), 8.05 (2 H, d, J ¼ 7.2 Hz); 13C NMR d 20.5, 26.8, 53.3,
54.5, 58.5, 127.03, 127.05, 128.05, 128.25, 128.4, 128.5, 128.8, 129.11,
129.14, 131.10 (ꢀ2), 133.8, 136.1, 139.3, 200.6; MS (relative intensity)
m/z 399 (Mþ, 36), 398 (26), 294 (88), 105 (31), 91 (100), 77 (24); exact
mass calcd for C26H25NOS m/z 399.1657, HRMS m/z 399.1705.
cis-Ethyl 1-Benzyl-2-methyl-4-(phenylthio)-1,2,5,6-tetrahydropyridine-
6-carboxylate 4a. Light yellow liquid; IR (film) 3060, 3027, 2979, 2930,
1
2853, 1731, 1582, 1495, 1475, 1455, 1189, 1026, 743, 697 cm21; H NMR
d 1.15 (3 H, d, J ¼ 6.8 Hz), 1.22 (3 H, t, J ¼ 7.1 Hz), 2.34 (1 H, ddd,
J ¼ 1.6, 5.5, 16.8 Hz), 2.57 (1 H, ddd, J ¼ 1.6, 5.5, 16.8 Hz), 3.45–3.51
(1 H, m), 3.53 (1 H, t, J ¼ 5.5 Hz), 3.94 (1 H, d, J ¼ 14.7 Hz), 3.99 (1 H, d,
J ¼ 14.7 Hz), 4.03 (1 H, dq, J ¼ 10.8, 7.1 Hz), 4.08 (1 H, dq,
J ¼ 10.8, 7.1 Hz), 5.87 (1 H, t, J ¼ 1.6 Hz), 7.21–7.39 (10 H, m); 13C NMR
d 14.2, 18.3, 31.8, 54.9, 56.1, 59.2, 60.7, 126.9, 127.1, 127.8, 128.2, 128.4,
128.8, 129.0, 131.1, 133.9, 138.8, 173.4; MS (relative intensity) m/z 367
(Mþ, 29), 366 (51), 294 (62), 258 (23), 91 (100), 77 (26), 73 (19); exact
mass calcd for C22H25NO2S m/z 367.1606, HRMS m/z 367.1628.
trans-Ethyl 1-Benzyl-2-methyl-4-(phenylthio)-1,2,5,6-tetrahydropyri-
dine-6-carboxylate 4b. Light yellow liquid; IR (film) 3060, 3027, 2975,

Synthesis of 2,6-Disubstituted Tetrahydropyridines
4579
2925, 2850, 1923, 1731, 1583, 1475, 1454, 1439, 1369, 1186, 1160, 1025,
1
870, 828, 741, 697 cm21; H NMR d 1.17 (3 H, t, J ¼ 7.1 Hz), 1.23 (3 H, d,
J ¼ 6.5 Hz), 2.37 (1 H, ddd, J ¼ 2.5, 5.5, 17.0 Hz), 2.54 (1 H, ddd, J ¼ 2.9,
5.7, 17.0 Hz), 3.58 (1 H, dt, J ¼ 2.5, 5.6 Hz), 3.73 (1 H, d, J ¼ 14.4 Hz),
3.83–3.89 (1 H, m), 3.99 (1 H, d, J ¼ 14.4 Hz), 4.05 (1 H, dq, J ¼ 10.7,
7.1 Hz), 4.15 (1 H, dq, J ¼ 10.7, 7.1 Hz), 5.96 (1 H, br s), 7.20–7.33 (10
H, m); 13C NMR d 14.3, 20.9, 32.4, 53.6, 54.6, 57.2, 60.3, 126.9,
127.0, 128.38, 128.45, 128.98, 129.04, 130.8, 134.3, 136.3, 139.8, 172.6;
MS (relative intensity) m/z 367 (Mþ, 29), 366 (51), 294 (62), 258 (23), 91
(100), 77 (26), 73 (19); exact mass calcd for C22H25NO2S m/z 367.1606,
HRMS m/z 367.1628.
cis-1-Benzyl-2-methyl-6-phenyl-4-(phenylthio)-1,2,5,6-tetrahydro-
pyridine 5a. Light yellow liquid; IR (film) 3059, 3027, 2965, 2923, 2851,
1642, 1613, 1582, 1493, 1453, 1440, 1343, 1171, 1075, 1025, 757, 741,
1
700 cm21; H NMR d 1.11 (3 H, d, J ¼ 5.9 Hz), 2.21–2.25 (1 H, m), 2.51–
2.56 (1 H, m), 3.43–3.46 (1 H, m), 3.58 (1 H, d, J ¼ 15.2 Hz), 3.78–3.81
(1 H, m), 3.80 (1 H, d, J ¼ 15.2 Hz), 5.82 (1 H, br s), 7.14–7.36 (15 H, m);
13C NMR d 21.7, 39.5, 55.7, 57.8, 64.7, 125.9, 126.3, 126.9, 127.2, 127.8,
128.2, 128.3, 128.4, 129.0, 131.0, 131.7, 134.6, 140.1, 143.4; MS (relative
intensity) m/z 371 (Mþ, 16), 370 (32), 294 (48), 262 (16), 185 (20), 91
(31), 77 (100); exact mass calcd for C25H25NS m/z 371.1708, HRMS m/z
371.1688.
trans-1-Benzyl-2-methyl-6-phenyl-4-(phenylthio)-1,2,5,6-tetrahydro-
pyridine 5b. Light yellow liquid; IR (film) 3060, 3027, 2959, 2922, 2850,
1
1658, 1613, 1582, 1494, 1475, 1453, 1440, 1025, 745, 697 cm21; H NMR
d 1.27 (3 H, d, J ¼ 6.8 Hz), 2.43 (1 H, dd, J ¼ 4.2, 17.1 Hz), 2.60 (1 H, dd,
J ¼ 10.2, 17.1 Hz), 3.36–3.38 (1 H, m), 3.42 (2 H, s), 4.25 (1 H, dd,
J ¼ 4.2, 10.2 Hz), 6.03–6.09 (1 H, m), 7.19–7.45 (15 H, m); 13C NMR d
19.1, 30.7, 51.0, 53.4, 55.5, 126.8, 127.0, 127.7, 128.1, 128.2, 129.1, 129.2,
129.5, 130.7, 133.4, 134.2, 135.0, 140.1, 141.9; MS (relative intensity) m/z
371 (Mþ, 16), 370 (32), 294 (48), 262 (16), 185 (20), 91 (31), 77 (100);
exact mass calcd for C25H25NS m/z 371.1708, HRMS m/z 371.1688.
1-Benzyl-2-methyl-4-(phenylthio)-1,2,5,6-tetrahydropyridine 6. Color-
less liquid; IR (film) 3060, 3028, 2957, 2923, 2802, 1658, 1565, 1483, 1409,
1
1166, 1072, 1043, 1021, 886, 838, 750, 697 cm21; H NMR d 1.23 (3 H,
d, J ¼ 6.6 Hz), 2.04–2.27 (2 H, m), 2.38–2.46 (1 H, m), 2.84–2.92 (1 H,
m), 3.15–3.21 (1 H, m), 3.42 (1 H, d, J ¼ 13.6Hz), 3.94 (1 H, d,
J ¼ 13.6Hz), 5.80–5.85 (1 H, m), 7.09–7.38 (10 H, m); 13C NMR d 19.0,
29.6, 47.3, 55.8, 57.1, 126.81, 126.97, 127.03, 127.13, 128.2, 128.9, 129.0,
131.0, 134.8, 139.0.
cis-6-Benzoyl-1,2-dimethyl-4-(phenylthio)-1,2,5,6-tetrahydropyridine 7a.
Light yellow liquid; 1H NMR d 1.28 (3 H, d, J ¼ 6.5 Hz), 2.16–2.22 (1 H, m),

4580
Chou and Chen
2.24 (3 H, s), 2.66–2.72 (1 H, m), 3.16–3.18 (1 H, m), 4.03 (1 H, dd, J ¼ 3.9,
10.8 Hz), 5.86 (1 H, br s), 7.14–7.54 (8 H, m), 8.16 (2 H, d, J ¼ 7.5 Hz);
trans-6-Benzoyl-1,2-dimethyl-4-(phenylthio)-1,2,5,6-tetrahydro-
pyridine 7b. Light yellow liquid; 1H NMR d 1.35 (3 H, d, J ¼ 7.0 Hz), 2.33
(3 H, s), 2.38 (1 H, dd, J ¼ 5.2, 17.9 Hz), 2.63 (1 H, dd, J ¼ 7.1, 17.9 Hz),
3.63–3.65 (1 H, m), 4.53 (1 H, dd, J ¼ 5.2, 7.1 Hz), 6.01–6.02 (1 H, m),
7.14–7.54 (8 H, m), 8.01 (2 H, d, J ¼ 7.5 Hz). The following spectra were
obtained from a mixture (1 : 3) of 7a and 7b: 13C NMR d 19.78, 19.98,
27.53, 32.23, 38.36, 38.52, 57.41, 58.99, 60.15, 68.47, 126.87, 127.13,
127.45, 128.53, 128.71, 129.01, 129.06, 129.13. 129.26, 130.78, 131.04,
133.14, 133.40, 133.57, 133.88, 133.92, 134.13, 134.34, 135.61, 136.07,
199.55, 199.87 (some characteristic absorptions for 7a: 19.98, 32.23, 38.52,
58.99, 68.46, 199.55; 7b: 19.78, 27.53, 38.36, 57.41, 60.15, 199.87); MS (rela-
tiveintensity)m/z323(Mþ,20),322(23),218(100),214(14), 105(60),77(22);
exact mass calcd for C20H21NOS m/z 323.1344, HRMS m/z 323.1321.
cis-Ethyl 1,2-dimethyl-4-(phenylthio)-1,2,5,6-tetrahydropyridine-6-
carboxylate 8a. Colorless liquid; IR (film) 2975, 2923, 1738, 1475, 1440,
1258, 1201, 1160, 1033, 742, 691 cm21 1H NMR d 1.26 (3 H, t,
;
J ¼ 7.4 Hz), 1.29 (3 H, d, J ¼ 7.0 Hz), 2.29 (1 H, dd, J ¼ 17.0, 3.9 Hz), 2.37
(3 H, s), 2.59 (1 H, dd, J ¼ 17.0, 10.5 Hz), 3.00–3.15 (1 H, m), 3.31–3.33
(1 H, dd, J ¼ 3.9, 10.5 Hz), 4.16–4.24 (2 H, m), 5.75 (1 H, br s), 7.23–7.36
(5 H, m); 13C NMR d 14.4, 19.4, 32.6, 38.3, 58.9, 61.0, 65.1, 127.3, 128.5,
129.2, 131.2, 133.3, 135.1, 171.9; MS (relative intensity) m/z 291 (Mþ, 5),
290 (72), 218 (100), 182 (11), 109 (83), 73 (45); exact mass calcd. for
C16H21NO2S m/z 291.1293, HRMS m/z 291.1316.
trans-Ethyl 1,2-dimethyl-4-(phenylthio)-1,2,5,6-tetrahydropyridine-
6-carboxylate 8b. Colorless liquid; IR (film) 2977, 2928, 2810, 1731, 1582,
1
1475, 1440, 1184, 1156, 1031, 743, 692 cm21; H NMR d 1.20 (3 H, t,
J ¼ 6.8 Hz), 1.22 (3 H, t, J ¼ 7.4 Hz), 2.41 (1 H, ddd, J ¼ 17.2, 6.4, 3.2 Hz),
2.53 (3 H, s), 2.67 (1 H, ddd, J ¼ 17.2, 3.2, 2.4 Hz), 3.64 (1 H, dd, J ¼ 3.2,
6.4 Hz), 3.66 (1 H, dq, J ¼ 2.4, 6.8 Hz), 4.10 (1 H, dq, J ¼ 10.8, 7.2 Hz),
4.16 (1 H, dq, J ¼ 10.8, 7.2 Hz), 5.94 (1 H, t, J ¼ 2.4 Hz), 7.19–7.33 (5 H,
m); 13C NMR d 14.3, 19.7, 32.3, 39.8, 54.7, 60.4, 61.3, 126.4, 126.9, 129.0,
130.7, 134.2, 136.0, 172.0; MS (relative intensity) m/z 291 (Mþ, 5), 290
(72), 218 (100), 182 (11), 109 (83), 73 (45); exact mass calcd. for
C16H21NO2S m/z 291.1293, HRMS m/z 291.1316.
ACKNOWLEDGMENT
Financial support of this work by the National Science Council of the
Republic of China is gratefully acknowledged (NSC 91-2113-M-030-005).

Synthesis of 2,6-Disubstituted Tetrahydropyridines
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Received in the USA August 24, 2004