Synthesis and applications of tetrahydro-2-pyridinones via aza-Diels - Alder reactions of thio-substituted 1,3-dienes with arylsulfonyl isocyanates

Article abstract of DOI:10.1055/s-2001-18710

The first aza-Diels - Alder reactions of arylsulfonyl isocyanates with thio-substituted 1,3-dienes via the 3-sulfolene precursors 1 gave the cyclized products 3 with complete control of chemo- and regioselectivity. The cyclized products 3a and 5 underwent further reactions with nucleophiles and bases to give useful heterocyclic compounds. The N-tosyl group of the cyclic products could be selectively replaced by hydrogen or another substituent.

Full text of DOI:10.1055/s-2001-18710

2450
PAPER
Synthesis and Applications of Tetrahydro-2-pyridinones via aza-Diels–Alder
Reactions of Thio-substituted 1,3-Dienes with Arylsulfonyl Isocyanates
T
etrahydro-2-
h
v
a
ia aza-Die
n
g
c
tions -Shing P. Chou,* Chia-Cheng Hung
Department of Chemistry, Fu Jen Catholic University, Taipei, Taiwan 242, Republic of China
Fax +886(2)29041942; E-mail: chem1004@mails.fju.edu.tw
Received 23 July 2001; revised 28 August 2001
Abstract: The first aza-Diels–Alder reactions of arylsulfonyl iso-
cyanates with thio-substituted 1,3-dienes via the 3-sulfolene precur-
sors 1 gave the cyclized products 3 with complete control of chemo-
and regioselectivity. The cyclized products 3a and 5 underwent fur-
ther reactions with nucleophiles and bases to give useful heterocy-
clic compounds. The N-tosyl group of the cyclic products could be
selectively replaced by hydrogen or another substituent.
Key words: tetrahydropyridines, 2-pyridinones, aza-Diels–Alder
reactions, thiosubstituted 1,3-dienes, arylsulfonyl isocyanates
Scheme 1
The cycloaddition of thio-substituted 3-sulfolene 1a with
Reactions of dienes with compounds containing C=N
double bonds to give six-membered aza-heterocycles
have opened up a wide variety of opportunities for organic
synthesis, in particular for the construction of alkaloids
and other natural products.1–3 In general, the use of strong-
ly electron-deficient imines is a prerequivuisite. This can
sometimes be accomplished by the attachment of an acyl4
or a sulfonyl group5–7 to the nitrogen. Although arylsulfo-
nyl isocyanates have an electron-deficient C=N moiety,
their aza-Diels–Alder reactions with dienes were rarely
reported8,9 because the [2+2] cycloaddition or electro-
philic substitution predominates.10–13
p-toulenesulfonyl isocyanate (PTSI) could be carried out
in refluxing toluene to give the cyclized product 2a and a
small amount of the double bond-isomerized product 3a
(entry 1). Under this condition the diene was generated in
situ from desulfonylation of the 3-sulfolene 1a. In this re-
action one equivalent of sodium bicarbonate was added to
remove the sulfur dioxide generated and a catalytic
amount of hydroquinone (HQ) was used to prevent poly-
1
merization of the diene. Since the H NMR spectrum of
the crude product did not show the presence of 3a, its for-
mation probably resulted from isomerization of 2a during
the silica gel chromatography. Indeed, when 10% of tri-
ethylamine was included in the eluent of chromatography,
complete isomerization to product 3a was achieved (entry
2). If the cycloaddition was carried out in the absence of
NaHCO3, only product 3a was obtained (entry 3), no trace
It is well established that 3-sulfolenes are useful precur-
sors to 1,3-dienes.14,15 We have used this method to syn-
thesize many sulfur-substituted dienes.16–18 As an
extension of our interest in the synthesis and reactions of
sulfur-substituted dienes via 3-sulfolenes, we herein re-
port the first aza-Diels–Alder reactions of thiosubstituted
1,3-butadienes with arylsulfonyl isocyanates to give the
cyclized products with complete control of chemo- and re-
gioselectivity.19 The cyclized products could further un-
dergo reactions with nucleophiles and bases to give useful
heterocyclic compounds. The N-tosyl group of the cyclic
products could also be selectively replaced by hydrogen
or another substituent.
The thio-substituted 3-sulfolenes 120,21 can undergo in situ
thermal desulfonylation and subsequent cycloaddition
with arylsulfonyl isocyanates to give the cyclized prod-
ucts 2 and 3 (Scheme 1). The results are summarized in
Table 1.
1
of 2a being detected from the H NMR spectrum of the
crude product. Apparently, the sulfur dioxide generated
from the reaction caused the isomerization of 2a to 3a.
Thus, both acid and base catalyzed the isomerization of 2
to 3. The cycloaddition of 1a also proceeded with other ar-
ylsulfonyl isocyanates (entries 5–8). In all these reactions
the C=N bond of the arylsulfonyl isocyanates acts as the
dienophile to react with the diene chemo- and regioselec-
tively.
Polar solvents cannot be used for the cycloaddition be-
cause they react with the isocyanates. It was found that
toluene was a better solvent than THF (compare entry 2
with 4, 6 with 7). Furthermore, the presence of sodium bi-
carbonate increased the yield (compare entry 2 with 3, 5
and 7, 9 with 10). Under similar conditions, 3-sulfolene
1b16 and 1c22 reacted with PTSI to give the cyclized prod-
ucts 3d and 3e in 81% and 70% yield, respectively (entries
10 and 11). The cycloaddition reactions of bis(phenylth-
io)-substituted 3-sulfolene 1d21,23 with arylsulfonyl isocy-
anates were similar to those of 1a, but required higher
Synthesis 2001, No. 16, 30 11 2001. Article Identifier:
1437-210X,E;2001,0,16,2450,2462,ftx,en;F06001SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

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Tetrahydro-2-pyridinones via aza-Diels–Alder Reactions
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Table 1 Aza-Diels-Alder Reactions of 3-Sulfolenes 1 with Arylsulfonyl Isocyanates
Entry
1b,c
2b
1
Ar
Conditiona
Product
2a
Yield (%)
51d
71
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1c
1d
1d
1d
1d
Ts (5 equiv)
110 °C, 4.5 h
110 °C, 4.5 h
110 °C, 4.5 h
110 °C, 4.5 h
110 °C, 4 h
110 °C, 4.5 h
110 °C, 4.5 h
110 °C, 4 h
110 °C, 4.5 h
110 °C, 4.5 h
110 °C, 4.5 h
130 °C, 8 h
130 °C, 8 h
130 °C, 8 h
130 °C, 8 h
Ts (3 equiv)
3a
3
Ts (3 equiv)
3a
46
4b,e
5
Ts (5 equiv)
3a
17
PhSO2 (5 equiv)
PhSO2 (5 equiv)
PhSO2 (5 equiv)
p-ClPhSO2 (5 equiv)
Ts (5 equiv)
3b
3b
3b
3c
30
6b,e
7b
23
50
8
38
9
3d
3d
3e
62
10b
11b
12
13b
14
15
Ts (5 equiv)
81
Ts (5 equiv)
70
Ts (5 equiv)
3f
72
Ts (5 equiv)
3f
67
PhSO2 (5 equiv)
p-ClPhSO2 (5 equiv)
3g
73
3h
47
a Unless noted otherwise, a mixture of the 3-sulfolene 1, the isocyanate and a catalytic amount of hydroquinone (HQ) was heated at 110 °C in
toluene under nitrogen. If a higher temperature was needed, then a sealed tube was used. After workup the crude product was purified by silica
gel column chromatography using hexane–EtOAc–Et3N as eluent.
b One equivalent of anhydrous NaHCO3 was also added.
c Triethylamine was not included in the eluent of the silica gel chromatography.
d Product 3a was also obtained in 6% yield.
e THF was used as the solvent.
temperatures (entries 12–15). Furthermore, the presence It is interesting to note that the sterically hindered diene
of sodium bicarbonate caused a slight decrease of yield derived from 3-(phenylthio)-1-thia-spiro[4,3]oct-3-ene-
(compare entry 12 with 13). It should be noted that iso- 1,1-dioxide (1e) reacted with PTSI to give the spiro bicy-
prene (5–10 equiv) reacted with PTSI under similar con- clic product 3i in reasonable yield (Scheme 2).
ditions to give the cyclized product 3 only in 5–7% yield.
Obviously, the thio-substituent enhances the reactivity of
the diene toward PTSI. We have also examined similar re-
actions with other monosubstituted dienes such as 2-trim-
ethylsilyloxy-1,3-butadiene, 2-phenylsulfinyl-1,3-buta-
diene, 2-phenylsulfonyl-1,3-butadiene, or disubstituted
dienes derived from 1 (R1 = NHAc, SOPh, SO2Ph,
R2 = H), but they all failed to undergo aza-Diels–Alder re-
Scheme 2
actions with PTSI. It appears that the thiosubstituent on
the diene strikes a balance of reactivity with PTSI: an
Refluxing a toluene solution of 2-methyl-3-(phenylthio)-
2-sulfolene (4)24 and PTSI in the presence of DBU did not
result in situ thermal desulfonylation and tandem cycload-
dition, but only gave intractable materials. However, com-
pound 4 could be desulfonylated by first heating with
DBU at 130 °C to generate the diene, which could then
undergo cycloaddition with PTSI to give the cyclized
product 3j (Scheme 3).
electron-donating group is needed to increase the reactiv-
ity of cycloaddition, but too strong an electron-donating
group (such as –OTMS and –NHAc) leads to other reac-
tion pathways. It should also be noted that aryl, alkyl or
acyl isocyanates did not undergo the aza-Diels–Alder re-
action with thiosubstituted dienes.
Synthesis 2001, No. 16, 2450–2462 ISSN 0039-7881 © Thieme Stuttgart · New York

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S.-S. P. Chou, C.-C. Hung
PAPER
Scheme 3
Scheme 4
Although the thio-substituted 1,3-dienes are unsymmetri-
cal, their aza-Diels–Alder reactions with arylsulfonyl iso-
cyanates gave only one regioisomer, which was shown by
spectroscopic methods to be the “para” adduct (with re-
spect to the nitrogen). The regiochemistry is consistent
with that predicted either by a concerted or stepwise
mechanism.1
ucts 6 (Scheme 5). The results are summarized in Table 2.
Decreasing the amount of nucleophiles and/or lowering
the reaction temperatures still led to the double addition
products, albeit in lower yields. The sulfone-substituted
lactam 5 also yielded the double addition product 6g–i
with Grignard reagents (entries 12–16), but no identifiable
products were obtained with organolithium reagents.
When sulfone-substituted lactam 5 was reacted with a
softer BnMgCl nucleophile, both the double addition
product 6g and substitution product 7a were obtained (en-
tries 12 and 13). Lowering the reaction temperature in-
creased the amount of the substitution product 7a.
The cyclized products 3 all contain an interesting structure
of an , -unsaturated lactam which also bears a phenylth-
io group at the -position. The sulfide group in 3a could
be easily oxidized to the sulfone 5 by mCPBA
(Scheme 4).
The lactams 3a and 5 could react with various nucleo-
philes and bases to give addition, substitution, or elimina-
tion products. The sulfide-substituted lactam 3a reacted
with Grignard reagents, organolithium compounds and
hydride reducing agents to give the double addition prod-
The sulfide- and sulfone-substituted lactams 3a and 5 also
underwent substitution reactions (Scheme 6). The results
are summarized in Table 3. Compound 3a reacted
Table 2 Reactions of Lactams 3a and 5 with Nucleophiles
Entry
1
3a or 5
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
5
R’M
Condition
Product
6a
Yield (%)
25a
66
MeLi (1.2 equiv)
MeLi (4 equiv)
THF, r.t., 1 h
2
THF, r.t., 1 h
6a
3
BuLi (4 equiv)
THF, r.t., 1 h
6b
6c
60
4
BnMgCl (1.2 equiv)
BnMgCl (1.2 equiv)
BnMgCl (4 equiv)
PhMgCl (1.2 equiv)
PhMgCl (4 equiv)
Allyl–MgBr (1.1 equiv)
Allyl–MgBr (4 equiv)
LiAlH4 (2.5 equiv)
BnMgCl (1.2 equiv)
BnMgCl (1.2 equiv)
PhMgCl (1.2 equiv)
PhMgCl (4 equiv)
Allyl–MgBr (4 equiv)
THF, r.t., 3 h
44a
40a
68
5
THF, 70 °C, 4.5 h
THF, r.t., 1 h
6c
6
6c
7
THF, 72 °C, 7 h
THF, r.t., 1 h
6d
6d
6e
23a
95
8
9
THF, r.t., 1 h
15a
91
10
11
12
13
14
15
16
THF, r.t., 70 min
THF, r.t., 5 h
6e
6f
23
THF, r.t., 3 h
6g
33b
14c
48d
94
5
THF, –70 °C, 4.5 h
THF, –72 °C, 7 h
THF, r.t., 1 h
6g
5
6h
6h
6i
5
5
THF, r.t., 1 h
88
a Some of the starting material 3a or 5 was also recovered.
b Substitution product 7a was also obtained in 22% yield.
c Substitution product 7a was also obtained in 34% yield.
d An inseparable mixture of 6h and 5 (7:3) was obtained.
Synthesis 2001, No. 16, 2450–2462 ISSN 0039-7881 © Thieme Stuttgart · New York

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Tetrahydro-2-pyridinones via aza-Diels–Alder Reactions
2453
Scheme 5
Scheme 6
smoothly with organocopper reagents derived from Grig- gave the elimination product 8 in good yield. Inorganic
nard reagents or organolithium compounds to give the salts (entries 5–8) varied in their efficiency for elimina-
substitution products 7a–d (entries 1–5). However, its re- tion. Enamine (entry 9) or the enolate derived from acety-
action with the organocopper reagent derived from Allyl– lacetone (entry 10) did not undergo the expected
MgBr and CuI gave only the double addition product 6e substitution reaction, but gave the elimination product 8
(entry 6). Attempted reactions of 3a with weaker nucleo- instead. It should be noted that treatment of the sulfide-
philes (NaN3, NaCN or Et2NH) led only to the recovered substituted lactam 3a with diethylamine under reflux or at
starting material. The sulfone-substituted lactam 5 also re- 90 °C led only to recovered starting material.
acted with methylcopper reagent to give the substitution
product 7b (entry 7), although the yield was much lower
than that obtained from 3a (entry 1). On the other hand,
compound 5 reacted efficiently with sodium azide, sodi-
um cyanide, and dimethyl malonate anion to give the sub-
stitution products 7e–g (entries 8–10), indicating its
higher reactivity than 3a toward nucleophiles. It should
also be noted that lactam 5 reacted with the anion of ethyl
acetoacetate to yield the deacetylated product 7h (entry
Scheme 7
11).
Following Parsons’ method of using Bu3SnH/AIBN to
Reactions of lactam 5 with a variety of bases led to the
elimination product 8 (Scheme 7), presumably via a series
cleave the N-tosyl group of amides,25 we prepared the lac-
tams 9 in high yields (Scheme 8 and Table 5). Under this
of double bond isomerization followed by elimination of
condition the ring substituents (PhS, PhSO2, RCO2Me,
the phenylsulfonyl group. The results are summarized in
alkenyl, etc) were not affected.
Table 4. Aliphatic and aromatic amines (entries 1–4) all
Table 3 Substitution Reactions of Lactams 3a and 5 with Nucleophiles
Entry
3a or 5
R’M
Condition
Product
7a
Yield (%)
91
1
3a
3a
3a
3a
3a
3a
5
BnMgCl (4 euiv), CuI (4 equiv)
MeLi (4 equiv), CuI (4 equiv)
MeLi (4 equiv), CuI (2 equiv)
BuLi (4 equiv), CuI (4 equiv)
PhMgBr (4 equiv), CuI (4 equiv)
Allyl-MgBr (4 equiv), CuI (4 equiv)
MeLi (4 equiv), CuI (4 equiv)
NaN3 (1.1 equiv)
THF, –78 °C, 8 h
THF, –78 °C, 3 h
THF, –78 °C, 3 h
THF, –78 °C, 3 h
THF, –78 °C, 8 h
THF, –78 °C 3 h
THF, –78 °C–0°C
DMF, 0 °C , 0.5 h
DMF, 0 °C, 30 min
THF,–78 °C–r.t., 2 h
THF, r.t., 2 h
2
7b
90
3
7b
82
4
7c
91
5
7d
59a
66
6
6e
7
7b
47
8
5
7e
76
9
5
NaCN (1.1 equiv)
7f
93
10
11
5
NaCH(CO2Me)2 (2 equiv)
NaCHCOCH3(CO2Et) (2 equiv)
7g
63
5
7h
35
a An inseparable mixture of 7d and 3a (7:3) was obtained.
Synthesis 2001, No. 16, 2450–2462 ISSN 0039-7881 © Thieme Stuttgart · New York

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S.-S. P. Chou, C.-C. Hung
PAPER
Table 4 Reactions of Lactam 5 with Bases to give 8
Entry
Base
Condition
Yield (%)
1
2
Dimethylamine (40% aq, 4 equiv)
Et2NH (10 equiv)
DMF, r.t., 1 h
THF, 90 °C, 6 h
DMF, r.t., 1 h
DMF, r.t., 20 h
DMF, r.t., 3.5 h
DMF, r.t., 1 h
DMF, r.t., 5 h
DMF, r.t., 24 h
CH3CN, r.t., 70 min
THF, 0 °C, 1.5 h
76
65
3
Pyrrolidine (1.5 equiv)
N-methylaniline (4 equiv)
Sodium acetate (2 equiv)
NaNO2 (2 equiv)
78
4
65
5
79
6
21
7
KF (10 equiv)
89
8
KI (10 equiv)
no reaction
9
1-(1-Pyrrolidino)cyclohexene (2 equiv)
Acetylacetone (4 equiv), LDA (4.4 equiv)
35
74
10
Scheme 9
Scheme 8
Table 5 N-Desulfonylation of Lactams
Table 6 N-Desulfonylation and Tandem Alkylation of Lactam 3a
Entry Com- R1
pound
R2
Product Yield
(%)
Entry
R
Reagent/Condition
Product Yield
(%)
1
2
3
4
5
6
7
8
3a
3d
3e
6
SPh
H
9a
9b
9c
9d
9e
9f
92
98
95
87
84
80
77
81
1
2
3
4
5
6
Me
t-BuOK (4 equiv), MeI (4 10a
equiv), r.t., 1.5 h
82
69
90
84
90
87
SPh
Me
Allyl
Bn
t-BuOK (8 equiv), Allyl- 10b
Br (8 equiv), r.t., 4 h
SPh
4-Pentenyl
SO2Ph
Bn
H
H
H
H
H
t-BuOK (4 equiv), BnBr 10c
(4 equiv), r.t., 1.5 h
7a
7b
7g
7h
Bz
t-BuOK (16 equiv), BzCl 10d
(16 equiv), r.t., 6 h
Me
CH(CO2Me)2
CH2CO2Me
9g
9h
Ac
t-BuOK (8 equiv), AcCl
10e
(8 equiv), r.t., 30 min
CO2Me
t-BuOK (4 equiv), MeO- 10f
COCl (4 equiv), r.t., 2 h,
reflux, 3 h
We have also found that following the treatment of lactam
3a with Bu3SnH/AIBN, direct addition of a mixture of t-
BuOK and RX gave the N-substituted products 10
(Scheme 9 and Table 6). In most cases, the yields are fair-
ly good since alkyl or acyl isocyanates do not undergo the
aza-Diels–Alder reactions with thio-substituted dienes,
the preparation of compounds 10 via this process consti-
tutes an efficient way of constructing these molecules.
7
8
Cbz
t-BuOK (4 equiv), CbzCl 10g
(8 equiv), r.t., 24 h, Tol,
reflux, 8 h
65
24
Acryloyl t-BuOK (4 equiv),
H2C=CHCOCl (4 equiv),
r.t., 3 h
10h
In summary, we have carried out the first aza-Diels–Alder
reactions of arylsulfonyl isocyanates with thio-substituted
1,3-dienes via the 3-sulfolene precursors 1 to give the cy-
clized products 3 with complete control of chemo- and re-
gioselectivity. The cyclized products 3a and 5 could
further undergo reactions with nucleophiles and bases to
give useful heterocyclic compounds. The N-tosyl group of
the cyclic products could also be selectively replaced by
hydrogen or another substituent.
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Tetrahydro-2-pyridinones via aza-Diels–Alder Reactions
2455
Infrared spectra were recorded with an FT-IR spectrometer Analect
1H NMR: = 2.69 (2 H, t, J = 6.3 Hz), 4.08 (2 H, t, J = 6.3 Hz), 5.14
(1 H, s), 7.38–7.60 (8 H, m), 8.02 (2 H, d, J = 7.8 Hz).
1
RFX–65. H and 13C NMR spectra were measured for samples in
CDCl3 with an FT-NMR spectrometer Bruker AC–300 at 300 MHz
and 75 MHz, respectively, 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. Melting points were mea-
sured with an apparatus Mel-Temp, and were uncorrected. The sil-
ica gel used for flash column chromatography was made by Merck
(60 H). All reagents were of reagent grade and toluene was distilled
from CaH2 before use.
13C NMR: = 29.7, 43.9, 114.1, 127.3, 128.3, 128.5, 129.8, 130.3,
133.4, 135.1, 138.9, 160.3, 161.5.
FAB-MS (relative intensity) m/z: 346 (M++H, 100), 77 (10).
FAB-HRMS (NBA) (m/z): calcd for C17H15NO3S2, 345.0493;
found, 346.0565 (M++H).
1-[(4-Chlorophenyl)sulfonyl]-4-(phenylthio)-5,6-dihydro-2-
pyridinone (3c)
Pale yellow solid (144 mg, 38%); mp 151–152 °C.
aza-Diels–Alder Reactions of Thio-substituted 1,3-Dienes with
Arylsulfonyl Isocyanates; General Procedure
IR (film): 3088, 3055, 2922, 2888, 1672, 1583, 1474, 1361, 1294,
1211, 1169, 1133, 1090, 901, 758, 673 cm–1.
1H NMR: = 2.70 (2 H, t, J = 6.3 Hz), 4.07 (2 H, t, J = 6.3 Hz), 5.14
(1 H, s), 7.41–7.47 (7 H, m), 7.95 (2 H, d, J = 6.8 Hz).
13C NMR: = 29.8, 44.0, 114.0, 127.3, 128.9, 130.0, 130.5, 135.2,
137.4, 140.2, 138.9, 160.7, 161.5.
FAB-MS (relative intensity) m/z: 382 (42), 381 (21), 380 (M++H,
A mixture of the 3-sulfolene 1 (226 mg, 1 mmol), the isocyanate (5
mmol) and a catalytic amount of hydroquinone (10 mg, 0.1 mmol)
was heated under N2 in toluene (4 mL) at 110 °C for 4.5 h. If a high-
er temperature was needed, a sealed tube was used. The solvent was
removed under vacum and to the reaction mixture was added a 5%
aqueous NaOH solution (50 mL). This was extracted with CH2Cl2
(30 mL 3), and the organic solution was dried (Na2SO4) and
evaportated. The crude product was purified by silica gel column
chromatography using hexane–EtOAc (8:1 4:1) with 5–10% of
NEt3 (except for making 2a) as the eluent.
100), 154 (11), 131 (11).
FAB-HRMS (NBA) (m/z): calcd for C18H17NO3S2 , 379.0104;
found, 380.0184 (M++H).
1-[(4-Methylphenyl)sulfonyl]-4-(phenylthio)-3,6-dihydro-2-
pyridinone (2a)
White or pale yellow solid (185 mg, 51% yield); mp 66–68 °C.
6-Methyl-1-[(4-methylphenyl)sulfonyl]-4-(phenylthio)-5,6-
dihydro-2-pyridinone (3d)
Pale yellow solid (126 mg, 81%); mp 100–102 °C.
IR (film): 3058, 2922, 1691, 1595,1474, 1461, 1440, 1386, 1356,
1293, 1257, 1187, 1167, 1146, 1088, 853, 705, 690 cm–1.
IR (film): 3055, 2977, 2928, 1671, 1595, 1381, 1352, 1319, 1224,
1166, 1090, 945, 705, 682 cm–1.
1H NMR: = 2.41 (3 H, s), 3.02 (2 H, d, J = 3.4 Hz), 4.50 (2 H, dd,
J = 7.3, 3.4 Hz), 5.80 (1 H, br s), 7.29–7.37 (7 H, m), 7.92 (2 H, d,
J = 8.2 Hz).
13C NMR: = 21.5, 37.8, 47.5, 118.8, 128.6, 128.8, 129.1, 129.3,
129.4, 130.4, 133.1, 135.5, 145.1, 166.1.
EIMS (relative intensity) m/z: 359 (M+, 15), 295 (28), 250 (36), 205
(17), 204 (94), 187 (13), 186 (93), 176 (18), 161 (34), 155 (36), 149
(11), 147 (24), 135 (15), 110 (12), 109 (34), 94 (10), 91 (100), 77
(10), 67 (11), 65 (34), 39 (13).
1H NMR: = 1.39 (3 H, d, J = 6.5 Hz), 2.30 (1 H, d, J = 17.1 Hz),
2.39 (3 H, s), 3.05 (1 H, dd, J = 17.1, 4.6 Hz), 4.96–5.01 (1 H, m),
5.16 (1 H, br s), 7.27 (2 H, d, J = 8.0 Hz), 7.39–7.46 (5 H, m), 7.93
(2 H, d, J = 8.0 Hz).
13C NMR: = 19.5, 21.5, 35.9, 50.7, 113.3, 127.5, 128.8, 129.0,
129.9, 130.3, 135.2, 136.7, 144.3, 157.2, 160.6.
EI-MS (relative intensity) m/z: 373 (M+, 1), 311 (7), 310 (22), 309
(100), 308 (15), 295 (12), 294 (61), 200 (53), 155 (12), 147 (17),
133 (34), 109 (26), 91 (79), 89 (12), 77 (11), 67 (17), 65 (34), 39
(15).
EI-HRMS (m/z): calcd for C18H17NO3S2, 359.0650; found,
359.0650.
FAB-HRMS (NBA) (m/z): calcd for C19H19NO3S2, 373.0806;
found, 373.0788.
1-[(4-Methylphenyl)sulfonyl]-4-(phenylthio)-5,6-dihydro-2-
pyridinone (3a)
White or pale yellow solid (2.555 g, 71%); mp 105–106 °C.
6-(4-Pentenyl)-1-[(4-methylphenyl)sulfonyl]-4-(phenylthio)-
5,6-dihydro-2-pyridinone (3e)
Pale yellow solid (162 mg, 70%); mp 114–115 °C.
IR (film): 3058, 2922, 2877, 1672, 1593, 1357, 1294, 1209, 1167,
1089, 900, 705, 688 cm-1.
1H NMR: = 2.38 (3 H, s), 2.67 (2 H, t, J = 6.3 Hz), 4.06 (2 H, t,
J = 6.3 Hz), 5.13 (1 H, s), 7.27 (2 H, d, J = 8.2 Hz), 7.38–7.45 (5 H,
m), 7.88 (2 H, d, J = 8.2 Hz).
13C NMR: = 21.4, 29.5, 43.8, 113.9, 127.1, 128.2, 129.1, 129.8,
130.2, 135.1, 135.7, 144.4, 160.2, 161.5.
FAB-MS (relative intensity) m/z: 360 (M++H, 100), 295 (3), 204
IR (film): 3071, 2924, 2859, 1670, 1595, 1440, 1347, 1223, 1185,
1166, 1088, 908, 886, 814, 751, 704, 691, 677, 659, 544 cm–1.
1H NMR: = 1.42–1.49 (2 H, m), 1.71–1.79 (2 H, m), 2.06–2.13 (2
H, m), 2.39 (3 H, s), 2.46 (1 H, d, J = 17.3 Hz), 2.94 (1 H, dd,
J = 17.3, 3.7 Hz), 4.76–4.83 (1 H, m), 4.99–5.06 (2 H, m), 5.15 (1
H, br s), 5.72–5.86 (1 H, m), 7.26 (2 H, d, J = 8.1 Hz), 7.41–7.43 (5
H, m), 7.91 (2 H, d, J = 8.1 Hz).
13C NMR: = 21.5, 25.5, 32.4, 33.0, 33.1, 55.0, 113.7, 115.2, 127.5,
128.9, 129.0, 129.9, 130.3, 135.2, 136.7, 137.8, 144.3, 157.2, 160.8.
(6), 155 (11), 91 (21), 55 (12).
FAB-HRMS (NBA) (m/z): calcd for C18H17NO3S2, 359.0650;
FAB-MS (relative intensity) m/z: 428 (M++H, 100), 294 (10), 204
(10), 155 (11), 91 (19).
found, 360.0690 (M++H).
1-(Phenylsulfonyl)-4-(phenylthio)-5,6-dihydro-2-pyridinone
(3b)
Pale yellow solid (347 mg, 50%); mp 103–104 °C.
FAB-HRMS (NBA) (m/z): calcd for C23H25NO3S2, 427.1276,
428.1349 (M++H).
Anal. Calcd for C23H25NO3S2: C, 64.61; H, 5.89. Found: C, 64.30;
H, 5.96.
IR (film): 3069, 2930, 2887, 1681, 1591, 1474, 1447, 1358, 1294,
1211, 1170, 1132, 1089, 902, 751, 731, 688, 662 cm–1.
Synthesis 2001, No. 16, 2450–2462 ISSN 0039-7881 © Thieme Stuttgart · New York

2456
S.-S. P. Chou, C.-C. Hung
PAPER
1-[(4-Methylphenyl)sulfonyl]-4,5-bis(phenylthio)-5,6-dihydro-
2-pyridinone (3f)
13C NMR: = 14.9, 21.5, 33.0, 40.7, 62.7, 114.6, 127.4, 129.4,
129.9, 130.3, 135.2, 139.0, 143.8, 160.2, 160.4, 162.9.
Pale yellow solid (337 mg, 72%); mp 162–164 °C.
FABMS (relative intensity) m/z: 400 (M++H, 100), 244 (12), 229
(23), 217 (13), 95 (13), 91 (29), 83 (12), 81 (13), 71 (11), 69 (19),
67 (12), 57 (23), 55 (27), 43 (20), 41 (17).
IR (film): 3057, 2921, 2871, 1673, 1581, 1474, 1454, 1439, 1378,
1356, 1321, 1283, 1224, 1168, 1089, 915, 751, 683 cm–1.
1H NMR = 2.36 (3 H, s), 3.84–3.93 (2 H, m), 4.49 (1 H, dd,
J = 12.6, 2.8 Hz), 5.18 (1 H, s), 7.25 (2 H, d, J = 8.2 Hz), 7.31–7.44
(8 H, m), 7.56–7.59 (2 H, m), 7.95 (2 H, d, J = 8.2 Hz).
FAB-HRMS (m/z): calcd for C21H21NO3S2, 399.0963; found,
400.1039 (M++H).
3-Methyl-1-[(4-methylphenyl)sulfonyl]-4-(phenylthio)-5,6-
dihydro-2-pyridinone (3j)
Pale yellow brown solid (90 mg, 53%); mp 142–143 °C.
13C NMR: = 21.3, 47.7, 48.2, 116.0, 127.2, 128.5, 128.9, 129.0,
129.2, 129.8, 130.2, 132.1, 134.2, 135.2, 135.7, 144.4, 159.0, 160.1.
EIMS (relative intensity) m/z: 467 (M+, 9), 403 (51), 295 (23), 294
(82), 293 (29), 292 (51), 284 (27), 155 (41), 147 (47), 109 (58), 91
(100), 65 (50).
IR (film): 3057, 2922, 1671, 1596, 1473, 1439, 1383, 1355, 1305,
1250, 1167, 1099, 975, 861, 813, 750, 733, 704, 674, 615, 568, 544
cm–1.
1H NMR: = 1.93 (3 H, s), 2.32 (2 H, t, J = 6.3 Hz), 2.41 (3 H, s),
3.91 (2 H, t, J = 6.3 Hz), 7.30 (2 H, d, J = 8.2 Hz), 7.41–7.45 (5 H,
m), 7.89 (2 H, d, J = 8.2 Hz).
EI-HRMS (m/z): calcd for C24H21NO3S3, 467.0684; found,
467.0683.
1-(Phenylsulfonyl)-4,5-bis(phenylthio)-5,6-tetrahydro-2-
pyridinone (3g)
Colorless viscous liquid (329 mg, 73%).
13C NMR: = 13.2, 21.5, 29.3, 43.3, 124.0, 128.4, 129.2, 129.3,
129.5, 129.6, 135.0, 136.1, 144.4, 151.0, 162.3.
IR (film): 3059, 2924, 2871, 1681, 1581, 1474, 1448, 1359, 1321,
1282, 1224, 1170, 1089, 914, 884, 750, 735, 688 cm–1.
AB-MS (relative intensity) m/z: 374 (M++H, 100), 309 (9), 219 (9),
218 (8), 91 (9), 57 (10), 55 (9).
1H NMR: = 3.85& ndash;3.90 (1 H, m), 3.94 (1 H, d, J = 3.1 Hz),
4.51 (1 H, dd, J = 13, 3.1 Hz), 5.18 (1 H, s), 7.36–7.61 (13 H, m),
8.07 (2 H, dd, J = 7.5, 1.4 Hz).
13C NMR: = 47.8, 48.3, 115.9, 127.2, 128.4, 128.5, 129.0, 129.3,
129.9, 130.3, 132.1, 133.5, 134.3, 135.2, 138.8, 159.3, 160.2.
FAB-HRMS (NBA) (m/z): calcd for C19H19NO3S2, 373.0806; found
374.0889, (M++H).
Anal. Calcd for C19H19NO3S2: C, 61.10; H, 5.13. Found: C, 61.15;
H, 5.19.
1-[(4-Methylphenyl)sulfonyl]-4-(phenylsulfonyl)-5,6-dihydro-
2-pyridinone (5)
EIMS (relative intensity) m/z: 453 (M+, 18), 389 (34), 284 (22), 281
(22), 280 (88), 279 (28), 278 (54), 202 (22), 147 (40), 141 (46), 109
(32), 77 (100), 51 (20).
To a solution of 3a (225 mg, 0.626 mmol) in CH2Cl2 at 0 °C was
added a solution of mCPBA (50%, 540 mg, 1.565 mmol). After stir-
ring at r.t.for 90 min, the mixture was diluted with CH2Cl2 (30 mL).
This was washed with sequentially with 5% Na2S2O3 (30 mL 2)
and 5% aq. NaHCO3 (30 mL 2). The organic solution was then
dried (Na2SO4) and evaporated to give pure product (240 mg, 98%).
EI-HRMS (m/z): calcd for C23H19NO3S3, 453.0527; found,
453.0522.
1-[(4-Chlorophenyl)sulfonyl]-4,5-bis(phenylthio)-5,6-dihydro-
2-pyridinone (3h)
Pale yellow liquid (227 mg, 47%).
White solid; mp 152–153 °C.
IR (film): 3067, 2924, 2877, 1693, 1595, 1447, 1362, 1323, 1307,
1169, 1156, 1129, 1087, 1016, 884, 732, 704, 687 cm–1.
1H NMR: = 2.40 (3 H, s), 2.69 (2 H, t, J = 6.4 Hz), 4.07 (2 H, t,
J = 6.4 Hz), 6.52 (1 H, s), 7.30 (2 H, d, J = 8.1 Hz), 7.55–7.61 (2 H,
m), 7.69 (1 H, t, J = 7.2 Hz), 7.84-7.88 (4 H, m).
13C NMR: = 21.5, 23.5, 43.7, 127.1, 128.5, 128.6, 129.4, 129.7,
134.7, 134.8, 136.6, 145.3, 154.2, 160.9.
FAB-MS (relative intensity) m/z: 392 (M++H, 88), 165 (10), 155
(70), 154 (16), 152 (10), 139 (25), 136 (26), 91 (100), 89 (25), 77
(35).
IR (film): 3059, 2923, 2871, 1674, 1583, 1475, 1361, 1280, 1225,
1170, 1091, 915, 759, 735, 691 cm–1.
1H NMR: = 3.85–3.90 (1 H, m), 3.94 (1 H, d, J = 3.1 Hz), 4.50 (1
H, dd, J = 13.1, 3.1 Hz), 5.18 (1 H, s), 7.37–7.49 (10 H, m), 7.57–
7.61 (2 H, m), 8.02 (2 H, dd, J = 6.8, 1.8 Hz).
13C NMR: = 47.9, 48.3, 115.8, 127.2, 128.7, 129.1, 129.4, 130.0,
130.2, 130.5, 132.1, 134.3, 135.3, 137.2, 140.2, 159.8, 160.2.
EIMS (relative intensity) m/z: 487 (M+, 14), 423 (32), 316 (19), 314
(63), 312 (36), 284 (21), 177 (17), 175 (46), 147 (47), 113 (33), 111
(100), 109 (78), 77 (16), 75 (23), 65 (23).
FAB-HRMS (NBA) (m/z): calcd for C18H17NO5S2, 391.0548;
EI-HRMS (m/z): calcd for C23H18ClNO3S3, 487.0137; found:
487.0132.
found, 392.0634, (M++H).
Anal. Calcd for C18H17NO5S2: C, 55.23; H, 4.38. Found: C, 54.80;
H, 4.19.
5-[(4-Methylphenyl)sulfonyl]-8-(phenylthio)-5-
azaspiro[3.5]non-7-en-6-one (3i)
Pale yellow liquid (48 mg, 58%).
General Procedure for the Reaction of Lactams 3a and 5 with
Grignard or Organolithium Reagents
IR (film): 3059, 2955, 1681, 1595, 1578, 1493, 1474, 1440, 1413,
1356, 1285, 1258, 1222, 1164, 1127, 1090, 966, 947, 852, 837, 814,
752, 705, 694, 667, 642, 561, 548 cm–1.
1H NMR: = 1.65–1.76 (2 H, m), 2.07–2.16 (2 H, m), 2.41 (3 H, s),
2.52–2.62 (2 H, m), 2.88 (2 H, br s), 5.29 (1 H, s), 7.30 (2 H, d,
J = 8.2 Hz), 7.42–7.49 (5 H, m), 7.97 (2 H, d, J = 8.2 Hz).
To a solution of 3a (210 mg, 0.58 mmol) in anhyd THF (5.8 mL) at
r.t. was added dropwise MeLi (1.6 mL, 2.34 mmol, 1.5 M in Et2O)
and the resulting solution was stirred for 1 h. The reaction mixture
was poured into sat. NH4Cl solution and was extracted with CH2Cl2.
The organic solution was dried (Na2SO4) and evaporated. The crude
product was purified by silica gel column chromatography using
hexane–EtOAc (8:1 2:1) with 5–10% of Et3N as the eluent.
Synthesis 2001, No. 16, 2450–2462 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Tetrahydro-2-pyridinones via aza-Diels–Alder Reactions
2457
6,6-Dimethyl-1-[(4-methylphenyl)sulfonyl]-4-(phenylthio)-
1,2,3,6-tetrahydropyridine (6a)
13C NMR: = 21.4, 30.8, 41.0, 79.3, 126.2, 127.1, 127.3, 127.5,
128.3, 129.1, 129.4, 131.9, 133.5, 137.1, 140.2, 140.3, 143.0, 146.8.
Pale yellow liquid (143 mg, 66%).
FAB-MS (relative intensity) m/z: 498 (M++H, 30), 327 (23), 218
(10), 217 (27), 206 (15), 205 (66), 184 (75), 183 (17), 178 (10), 177
(13), 167 (13), 155 (63), 149 (36), 105 (100), 102 (11), 91 (45), 77
(18).
IR (film): 3070, 2971, 2926, 1475, 1439, 1323, 1157, 1094, 814,
744, 691, 662 cm–1.
1H NMR: = 1.40 (6 H, s), 2.41 (3 H, s), 2.62 (2 H, t, J = 6.0 Hz),
3.12 (2 H, d, J = 6.0 Hz), 5.95 (1 H, s), 7.19–7.28 (7 H, m), 7.73 (2
H, d, J = 8.0 Hz).
FAB-HRMS (m/z): calcd for C30H27NO2S2, 497.1483; found,
498.1556 (M++H).
13C NMR: = 21.4, 30.0, 31.6, 41.0, 72.1, 126.8, 127.1, 128.9,
129.4, 130.6, 132.2, 134.3, 137.0, 142.9, 143.5.
EIMS (relative intensity) m/z: 373 (M+, 2), 358 (5), 265 (14), 264
(74), 205 (13), 203 (12), 184 (26), 178 (16), 177 (13), 155 (74), 110
(18), 109 (27), 108 (13), 92 (15), 91 (100), 77 (13), 65 (39), 59 (15),
43 (27).
6,6-Diallyl-1-[(4-methylphenyl)sulfonyl]-4-(phenylthio)-1,2,3,6-
tetrahydropyridine (6e)
Colorless liquid (169 mg, 91%).
IR (film): 3072, 2976, 2925, 1475, 1438, 1322, 1304, 1157, 1094,
918, 814, 745, 691, 663 cm–1.
1H NMR: = 2.33 (4 H, d, J = 6.3 Hz), 2.41 (3 H, s), 2.60 (2 H, t,
J = 5.9 Hz), 3.12 (2 H, t, J = 5.9 Hz), 5.09-5.18 (4 H, m), 5.73–5.87
(3 H, m), 7.20–7.28 (7 H, m), 7.72 (2 H, d, J = 7.9 Hz).
EI-HRMS (m/z): calcd for C20H23NO2S2, 373.1170; found:
373.1172.
6,6-Dibutyl-1-[(4-methylphenyl)sulfonyl]-4-(phenylthio)-
1,2,3,6-tetrahydropyridine (6b)
13C NMR: = 21.3, 30.3, 41.1, 46.4, 75.8, 119.6, 127.1, 128.9,
129.4, 129.4, 131.2, 132.7, 133.9, 134.0, 137.1, 139.6, 142.9.
Pale yellow solid (166 mg, 60%); mp 93–95 °C.
EI-MS (relative intensity) m/z: 425 (M+, 0.1), 403 (10), 402 (43),
360 (10), 232 (10), 231 (69), 219 (30), 189 (15), 184 (51), 177 (45),
163 (24), 155 (88), 110 (16), 109 (18), 91 (100), 77 (12), 69 (26), 67
(18), 65 (29), 41 (40), 39 (16)
IR (film): 2954, 2931, 2860, 1467, 1439, 1323, 1157, 1094, 813,
744, 691, 662 cm–1.
1H NMR: = 0.89 (6 H, t, J = 6.8 Hz), 1.25–1.41 (8 H, m), 1.53 (4
H, t, J = 7.6 Hz), 2.41 (3 H, s), 2.61 (2 H, t, J = 5.9 Hz), 3.13 (2 H,
t, J = 5.9 Hz), 5.73 (1 H, s), 7.19–7.24 (5 H, m), 7.27 (2 H, d, J = 8.1
Hz), 7.74 (2 H, d, J = 8.1 Hz).
EI-HRMS (m/z): calcd for C24H27NO2S2, 425.1483; found,
425.1470.
1-[(4-Methylphenyl)sulfonyl]-4-(phenylthio)-1,2,3,6-
tetrahydro-pyridine (6f)
13C NMR: = 13.9, 21.3, 22.9, 25.9, 30.3, 41.0, 42.5, 77.4, 126.8,
127.1, 128.9, 129.4, 130.9, 132.8, 134.6, 137.2, 141.4, 142.8.
To a solution of 3a (194 mg, 0.54 mmol) in anhyd THF (5.8 mL) at
r.t. was added LiAlH4 (95%, 13 mg, 0.34 mmol). After stirring for
5 h, saturated NaCl solution was slowly added, and was extracted
with CH2Cl2. The organic solution was dried (Na2SO4) and evapo-
rated. The crude product was purified by silica gel column chroma-
tography using hexane–EtOAc (8:1 2:1) with 5–10% of Et3N as
the eluent.
EIMS (relative intensity) m/z: 457 (M+, 3), 418 (28), 248 (12), 247
(71), 235 (43), 209 (23), 184 (42), 177 (11), 163 (28), 155 (79), 110
(11), 92 (10), 91 (100), 85 (88), 65 (13), 57 (32), 41 (15).
EI-HRMS (m/z): calcd for C26H35NO2S2, 457.2109; found,
457.2104.
6,6-Dibenzyl-1-[(4-methylphenyl)sulfonyl]-4-(phenylthio)-
1,2,3,6-tetrahydropyridine (6c)
Pale yellow solid (100 mg, 68%); mp 116–117 °C.
White solid (42 mg, 23%); mp 91–93 °C.
IR (film): 3055, 2922, 2850, 1596, 1474, 1439, 1339, 1304, 1239,
1165, 1099, 1057, 1023, 945, 815, 745, 719, 692, 651, 595 cm–1.
1H NMR: = 2.29 (2 H, br s), 2.43 (3 H, s), 3.21 (2 H, t, J = 5.6 Hz),
3.67 (2 H, d, J = 3.1 Hz), 5.74 (1 H, t, J = 3.1 Hz), 7.26–7.33 (7 H,
m), 7.66 (2 H, d, J = 8.2 Hz).
13C NMR: = 21.4, 29.7, 43.3, 45.7, 123.5, 127.5, 127.6, 129.1,
129.6, 131.6, 131.8, 132.7, 133.5, 143.6.
EIMS (relative intensity) m/z: 345 (M+, 10), 326 (23), 316 (9), 266
IR (film): 3059, 3027, 2922, 2860, 1598, 1494, 1474, 1453, 1439,
1322, 1304, 1235, 1156, 1119, 1032, 1023, 814, 744, 701, 662, 566,
550 cm–1.
1H NMR: = 1.98 (2 H, t, J = 6.0 Hz), 2.40 (3 H, s), 2.76 (2 H, t,
J = 6.0 Hz), 2.87 (2 H, d, J = 13.5 Hz), 2.94 (2 H, d, J = 13.5 Hz),
5.79 (1 H, s), 6.98-7.00 (2 H, m), 7.17–7.30 (15 H, m), 7.50 (2 H, d,
J = 8.2 Hz).
(13), 251 (8), 237 (16), 236 (100), 217 (22).
13C NMR: = 21.4, 29.5, 40.8, 48.5, 77.6, 126.8, 127.1, 128.1,
128.8 (x2), 129.4, 130.7, 131.6, 133.5, 134.0, 136.2, 136.8, 137.9,
142.8.
EI-HRMS (m/z): calcd for C18H19NO2S2, 345.0857; found,
345.0852.
FAB-MS (relative intensity) m/z: 526 (M++H, 40), 452 (12), 355
(27), 281 (18), 269 (10), 184 (27), 155 (47), 91 (100).
6,6-Dibenzyl-1-[(4-methylphenyl)sulfonyl]-4-(phenylsulfonyl)-
1,2,3,6-tetrahydropyridine (6g)
Pale yellow liquid (89 mg, 33%).
FAB-HRMS (m/z): calcd for C32H31NO2S2, 525.1796; found,
526.1884 (M++H).
IR (film): 3060, 3028, 2922, 1598, 1494, 1446, 1453, 1439, 1324,
1291, 1148, 1121, 1092, 1023, 814, 733, 704, 688, 662, 616, 569,
550 cm–1.
1H NMR: = 2.03 (2 H, t, J = 6.7 Hz), 2.39 (3 H, s), 2.54 (2 H, t,
J = 6.7 Hz), 2.97 (4 H, s), 6.97 (1 H, s), 7.15 (10 H, br s), 7.24 (3 H,
d, J = 8.1 Hz), 7.36–7.44 (2 H, t, J = 7.4 Hz), 7.51 (2 H, d, J = 7.4
Hz), 7.57 (2 H, d, J = 8.1 Hz).
13C NMR: = 21.4, 25.8, 41.8, 47.9, 77.8, 126.8, 126.9, 127.8,
128.2, 129.0, 129.4, 130.4, 133.1, 135.4, 136.9, 138.6, 138.9, 143.0,
145.4.
1-[(4-Methylphenyl)sulfonyl]-6,6-diphenyl-4-(phenylthio)-
1,2,3,6-tetrahydropyridine (6d)
Pale yellow liquid (236 mg, 95%).
IR (film): 3057, 3026, 2924, 2860, 1597, 1582, 1491, 1474, 1446,
1326, 1304, 1158, 1120, 1093, 1022, 1001, 813, 747, 701, 666, 634,
550 cm–1.
1H NMR: = 2.40 (3 H, s), 2.42 (2 H, t, J = 6.2 Hz), 3.06 (2 H, t,
J = 6.2 Hz), 6.52 (1 H, s), 7.22–7.34 (17 H, m), 7.65 (2 H, d, J = 8.0
Hz).
Synthesis 2001, No. 16, 2450–2462 ISSN 0039-7881 © Thieme Stuttgart · New York

2458
S.-S. P. Chou, C.-C. Hung
PAPER
FAB-MS (relative intensity) m/z: 558 (M++H, 57), 484 (25), 364
(10), 184 (22), 155 (38), 154 (18), 137 (10), 136 (15), 107 (10), 102
(26), 92 (10), 91 (100), 77 (11), 57 (10), 55 (11).
13C NMR: = 21.5, 28.4, 42.9, 43.9, 120.8, 127.1, 128.4, 128.7,
128.9 (x 2), 129.2, 135.9, 144.5, 158.8, 163.2.
FAB-MS (relative intensity) m/z: 342 (M++H, 100), 155 (16), 102
FAB-HRMS (m/z): calcd for C32H31NO4S2, 557.1694; found,
(14), 91 (38).
558.1780 (M++H).
FAB-HRMS (NBA) (m/z): calcd for C19H19NO3S, 341.1086; found,
342.1173 (M++H).
1-[(4-Methylphenyl)sulfonyl]-6,6-diphenyl-4-(phenylsulfonyl)-
1,2,3,6-tetrahydropyridine (6h)
Yellow liquid (247mg, 94%).
4-Methyl-1-[(4-methylphenyl)sulfonyl]-5,6-dihydro-2-
pyridinone (7b)
IR (film): 3060, 3028, 2926, 1597, 1492, 1446, 1326, 1303, 1152,
1091, 1074, 814, 749, 732, 700, 662, 554 cm–1.
1H NMR: = 2.37 (3 H, s), 2.67 (2 H, t, J = 7.0 Hz), 3.03 (2 H, t,
J = 7.0 Hz), 7.19 (2 H, d, J = 7.8 Hz), 7.26 (11 H, br s), 7.41 (2 H,
d, J = 7.6 Hz), 7.51–7.57 (3 H, m), 7.65 (2 H, d, J = 7.8 Hz).
13C NMR: = 21.3, 26.7, 42.0, 80.0, 126.4, 126.9, 127.8, 127.9,
128.4, 129.1, 129.4, 133.3, 136.6, 138.3, 138.6, 143.0, 144.6, 146.5.
FAB-MS (relative intensity) m/z: 530 (M++H, 16), 388 (12), 217
(18), 206 (19), 205 (100), 184 (54), 183 (17), 167 (13), 155 (53),
139 (12), 118 (19), 105 (55), 102 (22), 91 (41), 77 (22).
White solid (120 mg, 90%); mp 104–106 °C.
IR (film): 2924, 1685, 1593, 1386, 1351, 1312, 1167, 1090, 952,
899, 706, 691 cm–1.
1H NMR: = 1.94 (3 H, s), 2.41 (3 H, s), 2.46 (2 H, t, J = 6.4 Hz),
4.03 (2 H, t, J = 6.4 Hz), 5.63 (1 H, s), 7.30 (2 H, d, J = 8.1 Hz), 7.91
(2 H, d, J = 8.1 Hz).
13C NMR: = 21.5, 22.8, 30.3, 43.7, 120.6, 128.4, 129.2, 136.1,
144.4, 156.6, 163.2.
FAB-MS (relative intensity) m/z 267 (16), 266 (M++H, 100), 155
(16), 91 (28), 81 FAB-HRMS (NBA) (m/z): calcd for C13H15NO3S,
265.0773; found, 266.0854 (M++H).
FAB-HRMS (NBA) (m/z): calcd for C30H27NO4S2. 529.1381;
found, 530.1456 (M++H).
4-Butyl-1-[(4-methylphenyl)sulfonyl]-5,6-dihydro-2-
pyridinone (7c)
Colorless liquid (111 mg, 91%).
6,6-Diallyl-1-[(4-methylphenyl)sulfonyl]-4-(phenylsulfonyl)-
1,2,3,6-tetrahydropyridine (6i)
Colorless liquid (177 mg, 88%).
IR (film): 2956, 2930, 2871, 1685, 1638, 1596, 1492, 1466, 1380,
1353, 1289, 1227, 1168, 1126, 1089, 934, 900, 862, 814, 706, 691,
640, 545 cm–1.
IR (film): 3073, 2977, 2925, 1446, 1325, 1303, 1157, 1081, 997,
920, 814, 737, 689, 662 cm–1.
1H NMR: = 2.36 (4 H, d, J = 7.3 Hz), 2.40 (3 H, s), 2.65 (2 H, t,
J = 6.7 Hz), 3.06 (2 H, t, J = 6.7 Hz), 5.10 (4 H, d, J = 12.2 Hz),
5.65–5.79 (2 H, m), 6.83 (1 H, s), 7.27 (2 H, d, J = 8.0 Hz), 7.46–
7.51 (2 H, m), 7.59 (1 H, d, J = 7.1 Hz), 7.69 (2 H, d, J = 8.0 Hz),
7.76 (2 H, d, J = 7.2 Hz).
13C NMR: = 21.3, 26.2, 42.3, 45.7, 76.2, 120.0, 127.0, 127.9,
129.1, 129.5, 131.8, 133.3, 136.9, 138.8, 138.9, 143.1, 146.0.
EIMS (relative intensity) m/z: 457 (M+, 0.1), 435 (9), 434 (37), 274
(11), 184 (34), 155 (70), 125 (23), 109 (13), 92 (10), 91 (100), 77
(15), 67 (16), 65 (15), 41 (27), 39 (10).
1H NMR; = 0.89 (3 H, t, J = 7.1 Hz), 1.24–1.48 (4 H, m), 2.19 (2
H, t, J = 7.1 Hz), 2.41 (3 H, s), 2.46 (2 H, t, J = 6.5 Hz), 4.01 (2 H,
t, J = 6.5 Hz), 5.61 (1 H, s), 7.30 (2 H, d, J = 8.1 Hz), 7.91 (2 H, d,
J = 8.1 Hz).
13C NMR: = 13.6, 21.5, 22.1, 28.5, 28.9, 36.1, 43.8, 119.4, 128.3,
129.2, 136.0, 144.4, 160.7, 163.4.
EIMS (relative intensity) m/z: 307 (M+, 4), 244 (17), 243 (100), 242
(30), 120 (62), 119 (41), 91 (36), 82 (20), 65 (18), 41 (18), 39 (15),
27 (12).
EI-HRMS (m/z): calcd for C16H21NO3S, 307.1242; found,
EI-HRMS (m/z): calcd for C24H27NO4S2, 457.1381; found,
307.1265.
457.1353.
4-Azido-1-[(4-methylphenyl)sulfonyl]-5,6-dihydro-2-
pyridinone (7e)
General Procedure for the Reaction of Lactams 3a and 5 with
Organocopper Reagents
To a solution of 5 (255 mg, 0.65 mmol) in DMF (6.5 mL) at 0 °C
was added NaN3 (51 mg, 0.72 mmol) and. The reaction mixture was
stirred for 0.5 h and was poured into saturated NaCl solution and
was extracted with CH2Cl2. The organic solution was dried
(Na2SO4) and evaporated. The crude product was purified by silica
gel column chromatography using hexane–EtOAc (8:1 2:1) with
5–10% of Et3N as the eluent.
To a mixture of CuI (382 mg, 2 mmol) in anhyd THF (5 mL) at
–78 °C was added dropwise BnMgCl (1 mL, 2 mmol, 2 M in THF)
and the solution was stirred for 0.5 h. To the mixture was added a
solution of 3a (180 mg, 0.5 mmol) in THF (5 mL) at –78 °C and
stirred for 8 h. The reaction mixture was poured into saturated
NH4Cl solution and was extracted with CH2Cl2. The organic solu-
tion was dried (Na2SO4) and evaporated. The crude product was pu-
rified by silica gel column chromatography using hexane–EtOAc
(4:1 2:1) with 5–10% of Et3N as the eluent.
White solid (145 mg, 76%); mp 106–108 °C (decomp).
IR (film): 3066, 2922, 2113, 1676, 1617, 1376, 1352, 1312, 1204,
1166, 1089, 705, 688 cm–1.
1H NMR: = 2.42 (3 H, s), 2.56 (2 H, t, J = 6.3 Hz), 4.08 (2 H, t,
J = 6.3 Hz), 5.49 (1 H, s), 7.31 (2 H, d, J = 8.2 Hz), 7.91 (2 H, d,
J = 8.2 Hz).
4-Benzyl-1-[(4-methylphenyl)sulfonyl]-5,6-dihydro-2-
pyridinone (7a)
White solid (156 mg, 91%); mp 71–72 °C.
13C NMR: = 21.5, 27.3, 43.0, 107.6, 128.4, 129.3, 135.8, 144.7,
156.1, 162.7.
FAB-MS (relative intensity) m/z: 293 (M++H, 15), 267 (23), 265
IR (film): 3060, 3027, 2923, 1685, 1637, 1596, 1494, 1466, 1453,
1420, 1376, 1353, 1319, 1290, 1229, 1185, 1167, 1120, 1089, 940,
814, 705, 691, 641, 543 cm–1.
1H NMR: = 2.41 (3 H, s), 2.41–2.43 (2 H, m), 3.48 (2 H, s), 3.97
(2 H, t, J = 6.5 Hz), 5.62 (1 H, s), 7.10 (2 H, d, J = 7.4 Hz), 7.24–
7.33 (5 H, m), 7.90 (2 H, d, J = 8.3 Hz).
(46), 237 (13), 155 (74), 139 (26), 91 (100), 77 (14), 70 (18).
FAB-HRMS (NBA) m/z: calcd for C12H12N4O3S, 292.0630; found,
293.0721 (M++H).
Synthesis 2001, No. 16, 2450–2462 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Tetrahydro-2-pyridinones via aza-Diels–Alder Reactions
2459
1-[(4-Methylphenyl)sulfonyl]-6-oxo-1,2,3,6-tetrahydro-4-
pyridinyl cyanide (7f)
A similar procedure was used as for 7e.
1-[(4-Methylphenyl)sulfonyl]-2-pyridinone (8)
To a solution of 5 (185 mg, 0.47 mmol) in DMF (4.6 mL) at r.t. was
added pyrrolidine (50 mg, 0.7 mmol). After stirring for 1 h, the re-
action mixture was poured into saturated NaCl solution and was ex-
tracted with CH2Cl2. The organic solution was dried (Na2SO4) and
evaporated. The crude product was purified by silica gel column
chromatography using hexane–EtOAc (8:1 2:1) with 5–10% of
Et3N as the eluent.
Pale yellow solid (80 mg, 93%); mp 123–124 °C.
IR (film): 3072, 2923, 2852, 2255, 2224, 1689, 1595, 1355, 1314,
1170, 1088, 911, 814, 705, 688 cm–1.
1H NMR: = 2.44 (3 H, s), 2.75 (2 H, t, J = 6.4 Hz), 4.13 (2 H, t,
J = 6.4 Hz), 5.40 (1 H, s), 7.34 (2 H, d, J = 8.2 Hz), 7.91 (2 H, d,
J = 8.2 Hz).
13C NMR: = 21.6, 27.1, 43.3, 115.3, 126.1, 128.6, 129.5, 134.8,
135.3, 145.5, 160.0.
FAB-MS (relative intensity) m/z: 277 (M++H, 32), 155 (32), 136
(23), 107 (20), 105 (20), 97 (25), 95 (35), 93 (21), 91 (63), 85 (22),
83 (37), 81 (43), 79 (27), 77 (24), 73 (22), 71 (41), 69 (71), 67 (42),
57 (100), 55 (86), 43 (71), 41 (60), 29 (20).
Pale yellow solid (92 mg, 78%); mp 128–130 °C.
IR (film): 2924, 1685, 1593, 1386, 1351, 1312, 1167, 1090, 952,
899, 706, 691 cm–1.
1H NMR: = 2.43 (3 H, s), 6.22–6.27 (1 H, m), 6.40 (1 H, d, J = 9.3
Hz), 7.27–7.31 (1 H, m), 7.34 (2 H, d, J = 8.3 Hz), 7.99 (2 H, d,
J = 8.3 Hz), 8.08 (1 H, dd, J = 7.4, 1.7 Hz).
13C NMR: = 21.6, 106.1, 123.4, 129.4, 129.8, 131.6, 133.4, 141.0,
146.1, 160.0.
EI-MS (relative intensity) m/z: 250 (18), 249 (M+, 3), 186 (19), 185
(100), 184 (85), 157 (45), 156 (12), 155 (27), 91 (73), 65 (16), 39
(22).
FAB-HRMS (NBA) (m/z): calcd for C13H12N2O3S, 276.0569;
found, 277.0666 (M++H).
Dimethyl 2-{1-[(4-Methylphenyl)sulfonyl]-6-oxo-1,2,3,6-
tetrahydro-4-pyridinyl}malonate (7g)
EI-HRMS (m/z): calcd for C12H11NO3S, 249.0460; found,
To a mixture of NaH (71 mg, 1.5 mmol) in anhyd THF (5 mL) at
0 °C was added dimethyl malonate (0.11 mL, 1 mmol) and was
stirred for 0.5 h. To the mixture was added a solution 5 (194 mg, 0.5
mmol) in THF (5 mL) at –78 °C. The solution was slowly warmed
to r.t. The reaction mixture was poured into saturated ammonium
chloride solution and was extracted with CH2Cl2. The organic solu-
tion was dried (Na2SO4) and evaporated. The crude product was pu-
rified by silica gel column chromatography using hexane–EtOAc
(8:1 4:1) with 5–10% of NEt3 as the eluent.
249.0464.
Anal. Calcd for C12H11NO3S: C, 57.82; H, 4.45. Found: C, 57.81; H,
4.64.
General Procedure for Desulfonylation of Lactams
To a mixture of the lactam (0.50 mmol) and AIBN (0.10 mmol) in
degassed toluene (10 mL) was added Bu3SnH (1.1 mmol). This was
heated at reflux under N2 for 2 h. During this period another two
portions of AIBN (0.10 mmol each) were added in 30 min interval.
The solvent was then evaporated under vacuum and the crude prod-
uct was purified by silica gel column chromatography using hex-
ane–EtOAc (2:1 1:1) with 5–10% of NEt3 as the eluent to give the
desulfonylated product.
Colorless liquid (119 mg, 63%).
IR (film): 2955, 1738, 1690, 1435, 1354, 1305, 1210, 1187, 1168,
1126, 1089, 706, 690 cm–1.
1H NMR: = 2.42 (3 H, s), 2.69 (2 H, t, J = 6.3 Hz), 3.76 (6 H, s),
4.06 (2 H, t, J = 6.3 Hz), 4.26 (1 H, s), 5.81 (1 H, s), 7.31 (2 H, d,
J = 8.2 Hz), 7.91 (2 H, d, J = 8.2 Hz).
13C NMR: = 21.4, 27.2, 43.9, 53.0, 57.3, 124.7, 128.3, 129.2,
135.5, 144.7, 149.4, 162.1, 166.0.
EIMS (relative intensity) m/z: 381 (M+, 0.2), 318 (16), 317 (83), 316
(43), 294 (14), 226 (10), 198 (10), 186 (16), 170 (14), 166 (11), 155
(16), 139 (10), 138 (18), 120 (27), 119 (30), 91 (100), 89 (10), 65
(35), 59 (42).
4-(Phenylthio)-5,6-dihydro-2-pyridinone (9a)
While solid (95 mg, 92%); mp 112–113 °C.
IR (film): 3298, 3203, 3073, 3043, 2922, 2851, 1667, 1591, 1479,
1439, 1409, 1339, 1244, 1210, 1125, 1013, 839, 768, 748, 706, 691,
639 cm–1.
1H NMR: = 2.51 (2 H, t, J = 6.7 Hz), 3.44 (2 H, t, J = 6.7 Hz), 5.27
(1 H, s), 6.25 (1 H, br s), 7.43–7.51 (5 H, m).
13C NMR: = 28.8, 39.5, 114.5, 128.1, 129.7, 129.9, 135.2, 155.6,
166.0.
EI-HRMS (m/z): calcd for C17H19NO7S, 381.0882; found,
381.0887.
FAB-MS (relative intensity) m/z: 206 (M++H, 100), 204 (11), 77
(3), 39 (3), 30 (8).
Ethyl 2-{1-[(4-Methylphenyl)sulfonyl]-6-oxo-1,2,3,6-
tetrahydro-4-pyridinyl}acetate (7h)
A similar procedure was used as for 7g.
FAB-HRMS (NBA) (m/z): calcd for C11H11NOS, 205.0561; found,
206.0641 (M++H).
Colorless liquid (47 mg, 35%).
Anal. Calcd for C11H11NOS: C, 64.36; H, 5.40. Found: C, 64.22; H,
5.50.
IR (film): 2981, 2924, 1733, 1686, 1595, 1466, 1353, 1286, 1214,
1186, 1168, 1125, 1089, 1028, 959, 893, 814, 706, 690 cm–1.
1H NMR: = 1.26 (3 H, t, J = 7.1 Hz), 2.42 (3 H, s), 2.59 (2 H, t,
J = 6.4 Hz), 3.21 (2 H, s), 4.06 (2 H, t, J = 6.4 Hz), 4.15 (2 H, q,
J = 7.1 Hz), 5.73 (1 H, s), 7.31 (2 H, d, J = 8.3 Hz), 7.91 (2 H, d,
J = 8.3 Hz).
13C NMR: = 14.0, 21.5, 28.8, 41.6, 43.8, 61.4, 123.1, 128.4, 129.3,
135.8, 144.7, 151.7, 162.7, 168.7.
FAB-MS (relative intensity) m/z: 338 (M++H, 100), 155 (34), 139
6-Methyl-4-(phenylthio)-5,6-dihydro-2-pyridinone (9b)
While solid (63 mg, 98%); mp 180–181 °C.
IR (film): 3183, 3053, 2962, 2926, 1666, 1586, 1474, 1444, 1403,
1333, 1305, 1102, 1022, 838, 810, 777, 754, 704, 692, 608, 541,
509, 498 cm–1.
1H NMR: = 1.23 (3 H, d, J = 6.3 Hz), 2.31–2.41 (2 H, m), 3.67–
3.75 (1 H, m), 5.24 (1 H, s), 6.61 (1 H, br s), 7.39–7.48 (5 H, m).
13C NMR: = 20.6, 36.3, 46.6, 114.1, 128.2, 129.7, 129.8, 135.2,
154.7, 166.2.
(13), 102 (34), 91 (58), 57 (12), 41 (12), 39 (10), 29 (12).
FAB-HRMS (NBA) (m/z): calcd for C16H19NO5S, 337.0984; found,
FAB-MS (relative intensity) m/z: 220 (M++H, 100), 219 (21), 218
(25), 204 (14), 177 (9), 154 (9), 136 (9), 44 (10).
338.1051 (M++H).
Synthesis 2001, No. 16, 2450–2462 ISSN 0039-7881 © Thieme Stuttgart · New York

2460
S.-S. P. Chou, C.-C. Hung
PAPER
Dimethyl 2-(6-Oxo-1,2,3,6-tetrahydro-4-pyridinyl)malonate
FAB-HRMS (m/z): calcd for C12H13NOS, 219.0718; found,
220.0801 (M++H).
(9g)
Light yellow liquid (32 mg, 77%).
6-(4-Pentenyl)-4-(phenylthio)-5,6-dihydro-2-pyridinone (9c)
Pale yellow solid (58 mg, 95%); mp 126–127 °C.
IR (film): 3245, 2955, 2922, 2855, 1735, 1678, 1624, 1482, 1436,
1371, 1320, 1274, 1202, 1152, 1106, 1020, 1000, 750 cm–1.
IR (film): 3185, 3072, 2936, 2852, 1654, 1584, 1472, 1459, 1402,
1341, 910, 850, 754, 691, 500 cm–1.
1H NMR: = 1.41–1.62 (4 H, m), 2.03–2.09 (2 H, m), 2.28–2.50 (2
H, m), 3.55–3.61 (1 H, m), 4.95–5.03 (2 H, m), 5.26 (1 H, s), 5.69–
5.83 (1 H, m), 6.25 (1 H, br s), 7.40–7.50 (5 H, m).
13C NMR: = 24.4, 33.2, 34.2, 34.5, 50.7, 114.3, 115.0, 128.2,
129.7, 129.8, 135.2, 137.8, 154.6, 165.9.
FABMS (relative intensity) m/z: 274 (M++H, 100), 272 (15), 204
1H NMR: = 2.52 (2 H, t, J = 6.9 Hz), 3.46 (2 H, td, J = 6.9, 2.5
Hz), 3.77 (6 H, s), 4.27 (1 H, s), 5.88 (1 H, s), 6.18 (1 H, br s).
13C NMR: = 26.1, 39.6, 53.0, 58.0, 124.9, 146.1, 165.7, 166.7.
FAB-MS (relative intensity) m/z: 228 (M++H, 100), 136 (11), 95
(10), 91 (11), 81 (13), 69 (20), 67 (14), 57 (20), 55 (30), 43 (21), 41
(22).
FAB-HRMS (NBA) (m/z): calcd for C10H13NO5, 227.0794; found,
228.0884 (M++H).
(18), 98 (8).
FAB-HRMS (NBA) (m/z):calcd for C16H19NOS, 273.1187; found,
Ethyl 2-(6-Oxo-1,2,3,6-tetrahydro-4-pyridinyl)acetate (9h)
Light yellow liquid (33 mg, 81%).
274.1268 (M++H).
IR (film): 3246, 2980, 2933, 1731, 1676, 1624, 1481, 1334, 1250,
1211, 1177, 1151, 1106, 1027, 749 cm–1.
1H NMR: = 1.27 (3 H, t, J = 7.1 Hz), 2.41 (2 H, t, J = 6.9 Hz), 3.22
(2 H, s), 3.45 (2 H, td, J = 6.9, 2.6 Hz), 4.17 (2 H, q, J = 7.1 Hz),
5.80 (1 H, s), 6.44 (1 H, br s).
13C NMR: = 14.0, 27.6, 39.4, 42.1, 61.1, 122.7, 148.1, 166.5,
169.3.
FAB-MS (relative intensity) m/z: 184 (M++H, 100), 183 (10), 182
4-(Phenylsulfonyl)-,5,6-dihydro-2-pyridinone (9d)
White solid (103 mg, 87%); mp 157–159 °C.
IR (film): 3227, 3056, 3073, 2921, 1674, 1620, 1480, 1445, 1345,
1309, 1155, 1089, 996, 755, 686, 649, 584, 560 cm–1.
1H NMR: = 2.56 (2 H, td, J = 6.7, 1.2 Hz), 3.47 (2 H, td, J = 6.7,
2.6 Hz), 6.63 (1 H, d, J = 1.2 Hz), 6.77 (1 H, br s), 7.60 (2 H, t,
J = 7.4 Hz), 7.71 (1 H, t, J = 7.4 Hz), 7.91 (1 H, t, J = 7.4 Hz).
13C NMR: = 22.3, 39.4, 127.4, 128.5, 129.6, 134.4, 137.2, 151.8,
164.0.
FAB-MS (relative intensity) m/z:238 (M++H, 100), 236 (9), 154
(24), 138 (12), 111 (16), 110 (13), 55 (13), 41 (10).
FAB-HRMS (NBA) (m/z): calcd for C9H13NO3,183.0895; found,
184.0985 (M++H).
(19), 137 (15), 136 (17).
FAB-HRMS (NBA) (m/z): calcd for C11H11NO3S, 237.0460; found,
General Procedure for N-Desulfonylation and Tandem
Alkylation of Lactam 3a
238.0539 (M++H).
The same general procedure was used as for the preparation of 9 ex-
cept for the following. After compound 3a was reacted with
Bu3SnH/AIBN at reflux for 2 h, the reaction mixture was cooled to
r.t. The alkyl halide or the acyl chloride (2.0 mmol) and t-BuOK
(2.0 mmol) were then added sequentially. The reaction conditions
as shown in Table 6 were followed. The solvent was then removed
under vacuum. The crude product was purified by silica gel column
chromatography using hexane–EtOAc (4:1 1:1) with 5–10% of
Et3N as the eluent.
Anal. Calcd for C11H11NO3S: C, 55.68; H, 4.67. Found: C, 55.64; H,
4.68.
4-Benzyl-5,6-dihydro-2-pyridinone (9e)
White solid (69 mg, 84%); mp. 124–125 °C.
IR (film): 3218, 3060, 3024, 2944, 2843, 1666, 1623, 1600, 1483,
1450, 1403, 1372, 1337, 1139, 997, 870, 753, 701, 667, 618 cm–1,
1H NMR: = 2.23 (2 H, t, J = 7.1 Hz), 3.35 (2 H, td, J = 7.1, 2.5
Hz), 3.49 (2 H, s), 5.69 (1 H, s), 6.47 (1 H, br s), 7.15–7.33 (5 H, m).
13C NMR: = 27.3, 39.4, 43.2, 120.4, 126.8, 128.6, 128.9, 136.8,
155.1, 167.2.
1-Methyl-4-(phenylthio)-5,6-dihydro-2-pyridinone (10a)
Light yellow solid (90 mg, 82%); mp 78–80 °C.
IR (film): 3055, 2927, 2855, 1649, 1593, 1489, 1439, 1399, 1350,
1332, 1279, 1246, 1200, 1147, 1064, 1023, 999, 969, 926, 853, 769,
750, 705, 692, 646 cm–1.
1H NMR: = 2.53 (2 H, t, J = 7.0 Hz), 2.94 (3 H, s), 3.42 (2 H, t,
J = 7.0 Hz), 5.33 (1 H, s), 7.39–7.48 (5 H, m).
FAB-MS (relative intensity) m/z: 188 (M++H, 100), 186 (13), 91
(10), 81 (10), 69 (15), 67 (11), 57 (16), 55 (25), 43 (18), 41 (17).
FAB-HRMS (NBA) (m/z): calcd for C12H13NO, 187.0997; found,
188.1072 (M++H).
13C NMR: = 28.8, 34.1, 47.4, 115.8, 128.5, 129.7, 129.8, 135.1,
152.6, 164.0.
4-Methyl-5,6-dihydro-2-pyridinone (9f)
White solid (42 mg, 80%); mp 112–113 °C.
FAB-MS (relative intensity) m/z: 220 (M++H, 100), 218 (19), 44(8),
42 (4).
IR (film): 2932, 2855, 1676, 1623, 1482, 1449, 1379, 1362, 1336,
1154, 1109, 995, 856, 748 cm–1.
1H NMR: = 1.96 (3 H, s), 2.28 (2 H, t, J = 7.1 Hz), 3.41 (2 H, td,
J = 7.1, 2.6 Hz), 5.69 (1 H, s), 6.76 (1 H, br s).
FABHRMS (NBA) (m/z): calcd for C12H13NOS, 219.0718; found,
220.0799 (M++H).
13C NMR: = 22.9, 29.0, 39.2, 119.8, 152.9, 167.4.
Anal. Calcd for C12H13NOS: C, 65.72; H, 5.97. Found: C, 65.45; H,
6.13.
FAB-MS (relative intensity) m/z: 112 (M++H, 100), 110 (10), 109
(10), 107 (10), 105 (11), 95 (20), 93 (14), 91 (15), 83 (15), 81 (27),
79 (13), 71 (12), 69 (28), 67 (19), 57 (27), 55 (41), 43 (27), 41 (26).
1-Allyl-4-(phenylthio)-5,6-dihydro-2-pyridinone (10b)
Light yellow liquid (85 mg, 69%).
FAB-HRMS (NBA) (m/z): calcd for C8H9NO, 111.0684; found,
IR (film): 3075, 2925, 2835, 1649, 1593, 1474, 1440, 1415, 1352,
1336, 1296, 1242, 1215, 1178, 1088, 1068, 1024, 993, 971, 922,
853, 767, 749, 705, 692 cm–1.
112.0754 (M++H).
Synthesis 2001, No. 16, 2450–2462 ISSN 0039-7881 © Thieme Stuttgart · New York

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Tetrahydro-2-pyridinones via aza-Diels–Alder Reactions
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1H NMR: = 2.51 (2 H, t, J = 6.9 Hz), 3.38 (2 H, t, J = 6.9 Hz), 3.99
(2 H, d, J = 5.8 Hz), 5.14–5.20 (2 H, m), 5.35 (1 H, s), 5.69–5.82 (1
H, m), 7.38–7.51 (5 H, m).
13C NMR: = 28.9, 44.5, 48.4, 115.6, 117.2, 128.4, 129.7, 129.8,
133.2, 135.1, 152.9, 163.6.
13C NMR: = 29.0, 43.6, 53.6, 115.1, 127.4, 129.8, 130.1, 135.1,
154.4, 159.6, 161.8.
FAB-MS (relative intensity) m/z: 264 (M++H, 100), 232 (47), 206
(6), 91 (5), 77 (5);.
FAB-HRMS (m/z): calcd for C13H13NO3S, 263.0616; found,
FABMS (relative intensity) m/z:246 (M++H, 100), 245 (7), 244
264.0701 (M++H).
(23), 70 (17), 41 (15).
Benzyl 6-oxo-4-(phenylthio)-1,2,3,6-tetrahydro-1-pyridinecar-
boxylate (10g)
Pale yellow liquid (111 mg, 65%).
FABHRMS (NBA) (m/z): calcd for C12H13NOS, 245.0874; found,
246.0958 (M++H).
1-Benzyl-4-(phenylthio)-5,6-dihydro-2-pyridinone (10c)
Pale yellow liquid (133 mg, 90%).
IR (film): 3060, 3031, 2940, 2890, 1761, 1711, 1689, 1595, 1379,
1318, 1288, 1204, 1158, 1098, 1025, 939, 856, 771, 749, 694 cm–1.
IR (film): 3059, 2928, 2922, 2855, 1645, 1592, 1493, 1474, 1439,
1355, 1314, 1242, 1151, 1124, 1086, 1074, 1027, 968, 853, 749,
731, 695, 596 cm–1.
1H NMR: = 2.44 (2 H, t, J = 6.7 Hz), 3.31 (2 H, t, J = 6.7 Hz), 4.57
1H NMR: = 2.55 (2 H, t, J = 6.1 Hz), 3.97 (2 H, t, J = 6.1 Hz), 5.27
(2 H, s), 5.33 (1 H, s), 7.32–7.47 (10 H, m).
13C NMR: = 29.2, 43.7, 68.3, 115.4, 127.6, 127.8, 128.1, 128.4,
129.9, 130.3, 135.2, 135.4, 153.8, 159.5, 162.0.
(2 H, s), 5.40 (1 H, s), 7.22–7.50 (10 H, m).
13C NMR: = 28.8, 44.4, 49.2, 115.4, 127.2, 127.8, 128.3, 129.3,
129.7, 130.6, 135.1, 137.3, 152.9, 163.7.
FAB-MS (relative intensity) m/z: 340 (M++H, 65), 296 (16), 232
(14), 91 (100), 57 (14), 55 (13), 43 (10), 41 (11).
FAB-HRMS (NBA) (m/z): calcd for C19H17NO3S, 339.0929; found,
FAB-MS (relative intensity) m/z: 296 (M++H, 100), 295 (9), 294
340.1006 (M++H).
(17), 91 (44).
1-Acryloyl-4-(phenylthio)-5,6-dihydro-2-pyridinone (10h)
Pale yellow liquid (31 mg, 24%).
FAB-HRMS (NBA) m/z: calcd for C18H17NOS, 295.1031; found,
296.1111 (M++H).
IR (film): 3058, 2955, 2927, 1676, 1593, 1403, 1380, 1315, 1215,
1191, 1015, 936, 855, 750, 691 cm–1.
1-Benzoyl-4-(phenylthio)-5,6-dihydro-2-pyridinone (10d)
Pale yellow solid (130 mg, 84%); mp 134–136 °C.
1H NMR: = 2.60 (2 H, td, J = 6.4, 0.8 Hz), 4.03 (2 H, t, J = 6.4
Hz), 5.34 (1 H, d, J = 0.8 Hz), 5.71 (1 H, dd, J = 10.3, 1.7 Hz), 6.36
(1 H, dd, J = 16.7, 1.7 Hz), 7.02 (1 H, dd, J = 16.7, 10.3 Hz), 7.45–
7.53 (5 H, m).
IR (film): 3058, 2928, 2888, 1676, 1590, 1466, 1440, 1379, 1307,
1215, 1176, 1114, 1048, 1023, 987, 935, 855, 795, 772, 750, 729,
702, 691, 639 cm–1
1H NMR: = 2.73 (2 H, t, J = 6.3 Hz), 4.03 (2 H, t, J = 6.3 Hz), 5.30
(1 H, s), 7.33–7.56 (10 H, m).
13C NMR: = 29.2, 41.4, 114.8, 127.5, 128.2, 130.0, 130.4, 131.5,
135.3, 161.5, 164.0, 168.4.
13C NMR: = 29.4, 43.3, 114.5, 127.5, 127.9, 128.2, 130.0, 130.4,
131.4, 135.3, 136.1, 161.2, 163.9, 173.5.
FAB-MS (relative intensity) m/z: 310 (M++H, 45), 309 (4), 308 (4),
FAB-MS (relative intensity) m/z: 260 (M++H, 100), 259 (13), 257
(10), 206 (58), 204 (19), 197 (11), 189 (11), 174 (20), 154 (18), 137
(12), 136 (19), 114 (24), 91 (11), 77 (11), 55 (25.
106 (9), 105 (100), 77 (14).
FAB-HRMS (m/z): calcd for C14H13NO2S, 259.0667; found,
260.0738 (M++H).
FAB-HRMS (NBA) (m/z): calcd for C18H16NO2S, 309.0823; found,
310.0896 (M++H).
Acknowledgement
1-Acetyl-4-(phenylthio)-5,6-dihydro-2-pyridinone (10e)
Pale yellow liquid (112 mg, 90%).
Financial support of this work by the National Science Council of
the Republic of China is gratefully acknowledged (NSC 89-2113-
M-030-005).
IR (film): 3055, 2922, 2855, 1678, 1594, 1368, 1312, 1273, 1217,
1151, 1062, 1025, 982, 933, 855, 749, 691 cm–1.
1H NMR: = 2.50 (3 H, s), 2.55 (2 H, t, J = 6.3 Hz), 4.01 (2 H, t,
J = 6.3 Hz), 5.32 (1 H, s), 7.44–7.53 (5 H, m).
13C NMR: = 27.0, 29.1, 40.8, 115.0, 127.6, 129.9, 130.3, 135.3,
160.9, 163.9, 172.9.
FAB-MS (relative intensity) m/z: 248 (M++H, 100), 247 (9), 246
(9), 207 (10), 206 (70), 205 (11), 204 (25), 102 (10), 77 (11), 43
(15).
References
(1) Weinreb, S. M.; Staib, R. R. Tetrahedron 1982, 38, 3087.
(2) Boger, D. L. Chem. Rev. 1986, 86, 781.
(3) Boger, D. L.; Weinreb, S. M. Hetero Diels-Alder
Methodology in Organic Synthesis; Academic Press:
Orlando, 1987.
(4) Weinreb, S. M. Acc. Chem. Res. 1985, 18, 16.
(5) Loven, R. P.; Speckamp, W. N.; Zunnebeld, W. A.
Tetrahedron 1975, 31, 1717.
FAB-HRMS (NBA) (m/z): calcd for C13H13NO2S, 247.0667; found,
248.0739 (M++H).
(6) Birkinshaw, T. N.; Tabor, A. B.; Holmes, A. B.; Kaye, P.;
Mayne, P. M.; Raithby, P. R. J. Chem. Soc., Chem. Commun.
1988, 1599; and references cited therein.
(7) Sisko, J.; Weinreb, S. M. Tetrahedron Lett. 1989, 30, 3037.
(8) To the best of knowledge, there was only one report that a
diene underwent an aza-Diels-Alder reaction with tolyl
isocyanate: Barluenga, J.; Aznar, F.; Fernandez, M.
Tetrahedron Lett. 1995, 36, 6551.
Methyl 6-oxo-4-(phenylthio)-1,2,3,6-tetrahydro-1-pyridinecar-
boxylate (10f)
Pale yellow solid (114 mg, 87%); mp 88–90 °C.
IR (film): 3057, 3002, 2952, 2850, 1763, 1714, 1682, 1595, 1474,
1439, 1388, 1321, 1206, 1096, 1025, 941, 855, 773, 752, 705, 692,
637, 505 cm–1.
1H NMR: = 2.57 (2 H, t, J = 6.1 Hz), 3.84 (3 H, s), 3.98 (2 H, t,
J = 6.1 Hz), 5.33 (1 H, s), 7.42–7.51 (5 H, m).
Synthesis 2001, No. 16, 2450–2462 ISSN 0039-7881 © Thieme Stuttgart · New York

2462
S.-S. P. Chou, C.-C. Hung
PAPER
(9) For the reaction of an aza-diene reacting with the C=N bond
of tosyl isocyanate, see: Saito, T.; Kimura, H.; Chonan, T.;
Soda, T.; Karakasa, T. J. Chem. Soc., Chem. Commun. 1997,
1013.
(17) Chou, S. S. P.; Sun, C. M.; Wey, S. J. Synth. Commun. 1989,
19, 1593.
(18) Chou, S. S. P.; Liang, P. W. J. Chin. Chem. Soc. 2000, 47,
83; and references cited therein.
(10) Ulrich, H. Chem. Rev. 1965, 65, 369.
(11) Arbuzov, B. A.; Zobova, N. N. Synthesis 1974, 461.
(12) Takaki, K.; Okamura, A.; Ohshiro, Y.; Agawa, T. J. Org.
Chem. 1978, 43, 402.
(13) Gompper, R.; Heinemann, U. Angew. Chem., Int. Ed. Engl.
1980, 19, 463.
(14) Chou, T. S.; Tso, H. H. Org. Prep. Proc. Int. 1989, 21, 259.
(15) Chou, T. S.; Chou, S. S. P. J. Chin. Chem. Soc. 1992, 39,
625.
(16) Chou, S. S. P.; Liou, S. Y.; Tsai, C. Y.; Wang, A. J. J. Org.
Chem. 1987, 52, 4468.
(19) For a preliminary result, see: Chou, S. S. P.; Hung, C. C.
Tetrahedron Lett. 2000, 41, 8323.
(20) Hopkins, P. B.; Fuchs, P. L. J. Org. Chem. 1978, 43, 1208.
(21) Chou, T. S.; Lee, S. J.; Peng, M. L.; Sun, D. J.; Chou, S. S.
P. J. Org. Chem. 1988, 53, 3027.
(22) Chou, S. S. P.; Wey, S. J. J. Org. Chem. 1990, 52, 1270.
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(25) Parsons, A. F.; Pettifer, R. M. Tetrahedron Lett. 1996, 37,
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Synthesis 2001, No. 16, 2450–2462 ISSN 0039-7881 © Thieme Stuttgart · New York