Aza-Diels-Alder reactions of 2-(phenylthio)-1,3-butadiene with simple iminium salts

Article abstract of DOI:10.1081/SCC-100103543

The titled compound 2 was readily prepared by thermal desulfonylation of 3-(phenylthio)-3-sulfolene (1). The aza-Diels-Alder reactions of 2 with some simple iminium salts gave the cyclized products 3-7 in good yield with complete control of regiochemistry

Full text of DOI:10.1081/SCC-100103543

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AZA-DIELS-ALDER REACTIONS
OF 2-(PHENYLTHIO)-1,3-
BUTADIENE WITH SIMPLE
IMINIUM SALTS
Shang-Shing P. Chou a & Chia-Cheng Hung a
a Department of Chemistry , Fu Jen Catholic
University , Taipei, 242, Taiwan, R.O.C.
Published online: 09 Nov 2006.
To cite this article: Shang-Shing P. Chou & Chia-Cheng Hung (2001) AZA-DIELS-
ALDER REACTIONS OF 2-(PHENYLTHIO)-1,3-BUTADIENE WITH SIMPLE IMINIUM SALTS,
Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 31:7, 1097-1104, DOI: 10.1081/SCC-100103543
To link to this article: http://dx.doi.org/10.1081/SCC-100103543
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SYNTHETIC COMMUNICATIONS, 31(7), 1097–1104 (2001)
AZA-DIELS-ALDER REACTIONS OF
2-(PHENYLTHIO)-1,3-BUTADIENE WITH
SIMPLE IMINIUM SALTS
Shang-Shing P. Chou* and Chia-Cheng Hung
Department of Chemistry, Fu Jen Catholic University,
Taipei, Taiwan 242, Republic of China
ABSTRACT
The titled compound 2 was readily prepared by thermal
desulfonylation of 3-(phenylthio)-3-sulfolene (1). The aza-
Diels-Alder reactions of 2 with some simple iminium salts
gave the cyclized products 3–7 in good yield with complete
control of regiochemistry.
The piperidine ring is one of the most abundant molecular fragments
in both natural and synthetic compounds with various biological
activities.1–4 The aza-Diels-Alder reaction is potentially one of the most
versatile and rapid routes to substituted piperidines.5,6 Disappointingly,
most imines fail to participate in these [4þ2] cycloadditions. In general,
the use of strongly electron-deficient imines seems to be a prerequisite.
This can sometimes be accomplished by simple protonation,7–10 but
more general success has been achieved by the attachment of an acyl11
or a sulfonyl group12–14 to the nitrogen. When only an alkyl group is
attached to the imine nitrogen, the scope of the aza-Diels-Alder reaction
* Corresponding author.
1097
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

1098
CHOU AND HUNG
is considerably reduced; even in the presence of a Lewis acid, intermolecular
cycloadditions are possible only with highly reactive dienes.15–18 Another
major difficulty in using the aza-Diels-Alder reaction is the availability of
dienes with proper functional groups, which are often quite sensitive to heat,
light, and acids.19
Sulfur-substituted dienes have widely been used in the Diels-Alder
reaction.20 The sulfur atom not only enhances the reactivity of the diene,
but also adds control to the regioselectivity of this reaction and increases
the synthetic versatility of the cycloadducts. It is now well-established that
3-sulfolenes are useful precursors to 1,3-dienes.21,22 We have used this
method to synthesize many thio-23–25 and sulfone-substituted dienes,26
and have explored some of their synthetic applications.27–31 However, the
sulfur-substituted dienes in the aza-Diels-Alder reaction have little been
studied. Only strongly electron-deficient bis(phenylsulfonyl)butadienes
were reported to react with aryl imines.32,33 In this paper, we describe the
first reactions of a weakly electron-rich diene, 2-(phenylthio)-1,3-butadiene
(2), with some simple iminium salts prepared in situ from alkyl or aryl
amine hydrochlorides and aldehydes to give the cyclized products 3–7 with
complete regiocontrol.
The literature34 preparation of diene 2 by desulfonylation of
3-(phenylthio)-3-sulfolene (1)35 proceeded only in 64% yield. We modified
this reaction by using sodium bicarbonate to quench the acid generated, and
also by adding some hydroquinone (HQ) to prevent the free radical-
initiated polymerization of diene 2.21–25 The diene 2 can then be prepared
in 96% yield (Eq. 1).
(1)
After trying various activation methods reported in the litera-
ture,7–16,15–18 we found that the best results were obtained by the utilization
of iminium salts using the method developed by Grieco and coworkers.7 The
reactions of 2-(phenylthio)-1,3-butadiene (2) with the methyliminium salt
generated in situ from methylamine hydrochloride and phenylglyoxal gave
the cyclized product 3 (Eq. 2). The yields varied significantly with the solvent
used (Table 1), with DMF giving the best result, which is similar to that
reported for a related cyclization.10

2-(PHENYLTHIO)-1,3-BUTADIENE
1099
(2)
Based on the above results, further reactions of 2-(phenylthio)-
1,3-butadiene (2) with various iminium salts generated in situ from alkyl
or aryl amine hydrochlorides and phenylglyoxal or formaldehyde (35% in
H2O) were carried out in DMF and gave the cyclized products 3–7 in good
yield (Eq. 3). The results are summarized in Table 2.
(3)
The reactions of diene 2 with iminium salts derived from methylamine
hydrochloride or benzylamine hydrochloride and phenylglyoxal gave the
cyclized products 3 and 4 in good yields, whether the diene or the iminium
salt was used in excess (compare entries 1–4), but the iminium salts derived
from aniline hydrochloride and phenylglyoxal (entry 5) or amine hydro-
chlorides and formaldehyde (entries 6–7) gave good results only when the
diene was used in excess. When the less reactive formaldehyde was used as
the substrate (entries 6–7), higher reaction temperature was also needed.
Table 1. The Aza-Diels-Alder Reactions of Diene
Hydrochloride and Phenylglyoxal in Various Solventsa
2
with Methylamine
Yield (%)
Entry
Solventb
1
DMF
CH3CN
72
57
2
3EtOH (95% aq) 9
3
4
5
6
CH2Cl2
THF
H2O
31
29
trace
aThe diene was used in 1 equiv. and the other two reagents were used in 10 equiv.
bThe reaction was carried out at room temperature, for 24 h.

1100
CHOU AND HUNG
Table 2. The Aza-Diels-Alder Reactions of Diene 2 with Imines Derived from
Amine Hydrochlorides and Aldehydesa
Entry
R1
R2
Condition
Product
Yield (%)
1b
2c
Me (1 eq)
Me (10 eq)
Bz (2 eq)
Bn (10 eq)
Ph (1 eq)
Bz (2 eq)
Bz (10 eq)
DMF, rt, 24 h
DMF, rt, 24 h
3
3
4
4
5
6
7
63
72
74
82
95
88
81
3Bn (1 eq)
DMF, rt, 24 h
4c
5
6
7
Bz (10 eq)
Bz (2 eq)
H (2 eq)
H (2 eq)
DMF, rt, 24 h
DMF, rt, 24 h
DMF, 60ꢀC, 24 h
DMF, 60ꢀC, 24 h
Me (1 eq)
Bn (1 eq)
aThe diene was used in 10 equiv. unless noted otherwise.
bThe diene was used in 6.9 equiv.
cThe diene was used in 1 equiv.
Although the imino dienophiles are unsymmetrical, the reactions with
diene 2 gave only one regioisomer, which was shown by spectroscopic
methods to be the ‘‘para’’ adduct (with respect to the nitrogen). The regio-
chemistry is consistent with that predicted either by a concerted or stepwise
mechanism.36
We have also carried out the reaction of diene 2 with N-benzylidene-
benzenesulfonamide (R1 ¼ PhSO2, R2 ¼ Ph) under thermal or acidic
conditions to give the cyclized product in very low yield. Attempted reac-
tions of diene 2 with imines prepared in situ from amides (R1 ¼ Ts, Bz)
and aldehydes (R2 ¼ Ph, H) under aqueous acidic conditions resulted only
in the decomposition of the diene.
In summary, we have carried out the aza-Diels-Alder reactions of
diene 2 with some simple iminium salts to give the cyclized products 3–7
in good yield. The method is simple and high-yielding, and the product is
easy to isolate. Particularly notable is the complete regioselectivity of these
reactions. The thio-substituted piperidine derivatives obtained should be
quite useful for further synthetic applications.
EXPERIMENTAL
Infrared spectra were recorded with an FT-IR spectrometer Analect
1
RFX-65. H and 13C NMR spectra were measured for samples in CDCl3
with an FT-NMR spectrometer Bruker AC-300 at 300 and 75 MHz, respec-
tively, with tetramethylsilane as the internal standard. Mass spectra were
recorded with a spectrometer JEOL JMS-D-100. High-resolution mass
spectra were measured with a mass spectrometer JEOL TMS-HX 110.

2-(PHENYLTHIO)-1,3-BUTADIENE
1101
Melting points were measured with an apparatus Mel-Temp, and were
uncorrected. 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-butadiene (2)
A mixture of compound 1 (2.26 g, 10 mmol), hydroquinone (20 mg,
0.2 mmol), and NaHCO3 (840 mg, 10 mmol) was heated in toluene
(40 mL) at 110ꢀC for 5 h. The solvent was then removed by rotary evapora-
tion. The residue was purified by flash chromatography using hexane/ethyl
acetate (8:1) as eluent to give compound 2 (1.555 g, 96% yield) as a color-
less liquid.34
General Procedure for the Aza-Diels-Alder Reactions of
2-(Phenylthio)-1,3-butadiene with Imines Derived from
Amine Hydrochlorides and Aldehydes
A mixture of 2-(Phenylthio)-1,3-butadiene (2) with an amine hydro-
chloride and an aldehyde was stirred in DMF at ambient temperature or
60ꢀC for 24 h (see Table 2 for the equivalents of reagents used). The solvent
was removed under vacuum. The residue was then purified by flash chro-
matography using sequentially hexane and hexane/ethyl acetate (8:1) as the
eluent, both containing 5–10% (v/v) of triethylamine.
2-Benzoyl-1-methyl-4-(phenylthio)-1,2,3,6-tetrahydropyridine 3
Light yellow liquid; IR (film) 3056, 2924, 2853, 1670, 1630, 1594, 1556,
1
1475, 1448, 1373, 1268, 720, 691 cmꢁ1; H NMR ꢀ 2.39 (3 H, s), 2.35–2.63
(2 H, m), 3.23–3.31 (1 H, m), 3.62–3.69 (1 H, m), 4.15–4.20 (1 H, m), 6.06
(1 H, br s), 7.13–7.31 (5 H, m), 7.40–7.57 (3 H, m), 8.01–8.03 (2 H, m); 13C
NMR ꢀ 31.3, 41.6, 54.1, 64.5, 126.8, 127.1, 127.8, 128.5, 128.9, 129.0, 130.7,
133.2, 133.7, 135.8, 199.7; FABMS (relative intensity) m/z 310 (MþþH, 35),
308 (34), 306 (37), 204 (100), 202 (90), 148 (78), 105 (52), 91 (38), 69 (48), 57
(48), 55 (67); exact mass calc. for C19H19NOS m/z 309.1187, FABHRMS
(NBA) m/z 310.1276 (Mþþ H).
2-Benzoyl-1-benzyl-4-(phenylthio)-1,2,3,6-tetrahydropyridine 4
Light yellow liquid; IR (film) 3058, 2923, 2836, 1683, 1629, 1595,
1
1580, 1475, 1447, 1439, 1217, 1175, 1024, 739, 695 cmꢁ1; H NMR ꢀ 2.56

1102
CHOU AND HUNG
(2 H, br s), 3.27–3.33 (1 H, m), 3.57–3.63 (1 H, m), 3.63 (1 H, d, J ¼ 13Hz),
3.84 (1 H, d, J ¼ 13Hz), 4.38 (1 H, t, J ¼ 5.7 Hz), 6.02 (1 H, br s), 7.12–7.53
(13H, m), 7.94 (2 H, d, J ¼ 7.2 Hz); 13C NMR ꢀ 29.3, 50.2, 57.4, 61.8, 126.6,
127.2, 127.6, 128.2, 128.3, 128.5, 128.8, 129.1, 129.2, 130.5, 132.9, 133.8,
135.8, 138.2, 200.3; FABMS (relative intensity) m/z 386 (MþþH, 25), 384
(25), 280 (97), 278 (59), 224 (31), 105 (37), 91 (100), 77 (16); exact mass calc.
for C25H23NOS m/z 385.1500, FABHRMS (NBA) m/z 386.1580 (MþþH).
2-Benzoyl-1-phenyl-4-(phenylthio)-1,2,3,6-tetrahydropyridine 5
White solid; m.p. 121ꢀ–122ꢀC; IR (film) 3057, 2904, 2837, 1688, 1597,
1579, 1502, 1475, 1446, 1315, 1301, 1210, 1023, 937, 747, 690 cmꢁ1; 1H NMR
ꢀ 2.63(1 H, d, J ¼ 15.9 Hz), 2.88–3.02 (1 H, m), 4.13–4.30 (2 H, m),
5.56–5.59 (1 H, m), 6.19–6.22 (1 H, m), 6.78–6.84 (3H, m), 7.0–37.51
(10 H, m), 7.86 (2 H, d, J ¼ 7.2 Hz); 13C NMR ꢀ 31.1, 47.5, 57.3, 114.0,
118.7, 126.1, 126.6, 128.0, 128.6, 128.8, 128.8, 128.9, 129.3, 130.4, 133.1,
135.3, 148.8, 199.5; FABMS (relative intensity) m/z 372 (MþþH, 18), 371
(11), 370 (32), 368 (23), 267 (25), 266 (94), 264 (50), 262 (28), 210 (63), 172
(59), 156 (38), 154 (41), 105 (100), 104 (70), 91 (37), 77 (82), 69 (37), 57 (42),
55 (50); exact mass calc. for C24H21NOS m/z 371.1344, FABHRMS (NBA)
m/z 372.1412 (MþþH).
1-Methyl-4-(phenylthio)-1,2,3,6-tetrahydropyridine 6
Light yellow liquid; IR (film) 3055, 2937, 2840, 2779, 1599, 1475, 1438,
1200, 742, 691 cmꢁ1; 1H NMR ꢀ 2.27–2.31 (2 H, m), 2.34 (3 H, s), 2.56 (2 H,
t, J ¼ 5.7 Hz), 3.01–3.04 (2 H, m), 5.89–5.91 (1 H, m), 7.20–7.36 (5 H, m);
13C NMR ꢀ 30.5, 45.3, 52.5, 55.3, 126.7, 128.1, 128.8, 130.2, 131.0, 133.9;
FABMS (relative intensity) m/z 206 (MþþH, 64), 205 (19), 204 (94), 203
(77), 202 (100), 163 (32), 124 (51), 110 (56), 109 (25), 96 (93), 94 (43), 92 (46),
60 (58), 58 (57); exact mass calc. for C12H15NS m/z 205.0925, FABHRMS
(NBA) m/z 206.0997 (MþþH).
1-Benzyl-4-(phenylthio)-1,2,3,6-tetrahydropyridine 7
Light yellow liquid; IR (film) 3057, 2920, 2799, 1578, 1475, 1438,
1
1364, 1023, 738, 690 cmꢁ1; H NMR ꢀ 2.23–2.27 (2 H, m), 2.60 (2 H, t,
J ¼ 5.7 Hz), 3.05–3.07 (2 H, m), 3.57 (2 H, s), 5.84–5.87 (1 H, m), 7.19–7.35
(8 H, m), 7.46–7.49 (2 H, m); 13C NMR ꢀ 30.4, 50.1, 53.5, 62.2, 126.8,

2-(PHENYLTHIO)-1,3-BUTADIENE
1103
127.0, 127.5, 128.1, 128.9, 130.5, 130.7, 131.1, 133.9, 138.0; FABMS (relative
intensity) m/z 206 (MþþH, 64), 205 (19), 204 (94), 203(77), 202 (100), 163
(32), 124 (51), 110 (56), 109 (25), 96 (93), 94 (43), 92 (46), 60 (58), 58 (57);
exact mass calc. for C12H15NS m/z 205.0925, FABHRMS (NBA) m/z
206.0997 (MþþH).
ACKNOWLEDGMENTS
Financial support of this work by the National Science Council of the
Republic of China is gratefully acknowledged (NSC 88-2113-M-030-005).
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Received in Japan April 10, 2000