Synthesis of 6-substituted tetrahydropyridinones and cyclization to indolizidine and quinolizidine structures

Article abstract of DOI:10.1016/S0040-4039(03)01096-7

3-Sulfolenes 1 with various substituents at C-2 underwent [4+2] cycloaddition reactions with p-toluenesulfonyl isocyanate to give the teterahydropyridinones 4. Through N-detosylation and Hg(II)-mediated electrophilic addition/intramolecular cyclization of

Full text of DOI:10.1016/S0040-4039(03)01096-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4653–4655
Synthesis of 6-substituted tetrahydropyridinones and cyclization
to indolizidine and quinolizidine structures
Shang-Shing P. Chou,* Hao-Chieh Chiu and Chia-Cheng Hung
Department of Chemistry, Fu Jen Catholic University, Taipei, Taiwan 242, ROC
Received 26 March 2003; revised 24 April 2003; accepted 25 April 2003
Abstract—3-Sulfolenes 1 with various substituents at C-2 underwent [4+2] cycloaddition reactions with p-toluenesulfonyl
isocyanate to give the teterahydropyridinones 4. Through N-detosylation and Hg(II)-mediated electrophilic addition/intramolecu-
lar cyclization of 4e and 4f, the indolizidine and quinolizidine compounds 7a/7b and 8 were synthesized, respectively. © 2003
Elsevier Science Ltd. All rights reserved.
The piperidine ring is among the most abundant molec-
ular fragments in both natural and synthetic com-
pounds with various biological activities.1 The
aza-Diels–Alder reaction is one of the most versatile
routes to substituted piperidines.2–7 In general, the use
of strongly electron-deficient imines is a prerequisite.
We have also used this method to synthesize some
thio-substituted piperidine derivatives.8,9
reaction21–25 with p-toluenesulfonyl isocyanate (PTSI)
to give the cyclized products 4. The results are summa-
rized in Table 1.
Table 1. Aza-Diels–Alder reactions of 3-sulfolenes 1 with
PTSI
Although arylsulfonyl isocyanates have an electron-
deficient CꢀN moiety, their aza-Diels–Alder reactions
with dienes were rarely reported10–12 because the [2+2]
cycloaddition or electrophilic substitution predomi-
nates.13–15 We have recently reported the first aza-
Diels–Alder reactions of thio-substituted dienes with
arylsulfonyl isocyanates to give the cyclized products
with complete control of chemo- and regioselectiv-
ity.16,17 We now describe the extension of this reaction
to the synthesis of many 6-substituted tetra-
hydropyridinones. Two of these compounds are further
converted to the indolizidine and quinolizidine struc-
tures, which are important natural products.18
Entry
Compound 1
Product
Yield (%)
1
2
3
4
5
6
7
8
1a R=H
1b R=Me
1c R=Et
1d R=CH2CHꢀCH2
1e R=(CH2)2CHꢀCH2
1f R=(CH2)3CHꢀCH2
1g R=(CH2)2CH2Cl
1h R=CH2Ph
1i R=(CH2)3
4a
4b
4c
4d
4e
4f
4g
4h
4i
71a
81a
80
74
79
70a
70
71
9
10
11
58
1j R=(CH2)4
1k R=(CH2)5
4j
5b
19b
38c
a Results reported in Ref. 17.
Thio-substituted 3-sulfolenes 119,20 can undergo in situ
thermal desulfonylation and [4+2] cycloaddition
b 2j (12%) and 5a (35%) were also obtained.
c 2k (21%) was also obtained.
Keywords: thio-substituted 3-sulfolenes; aza-Diels–Alder reactions; Hg(II) ions; quinolizidines; indolizidines.
* Corresponding author. Fax: 886 2 29028073; e-mail: chem1004@mails.fju.edu.tw
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01096-7

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S.-S. P. Chou et al. / Tetrahedron Letters 44 (2003) 4653–4655
The desulfonylation of 3-sulfolenes 1 was carried out in
refluxing toluene in the presence of NaHCO3 (1 equiv.)
to remove the sulfur dioxide generated, and a catalytic
amount of hydroquinone (HQ) to prevent polymeriza-
tion of the dienes 2. The in situ generated dienes 2
would then react with PTSI (5 equiv.) to give the
cycloaddition products 3, which upon treatment with
acid or base gave the more stable conjugated products
4. By comparing the yields of entries 1–8, it can be seen
that varying the carbon number of the side chain or
having a terminal double bond or a chlorine substituent
does not affect the efficiency of the cycloaddition. How-
ever, 3-sulfolene 1i (entry 9) containing a spiro butane
moiety gave a slightly lower yield of product 4i. The
steric effect of the spiro pentane (entry 10) was even
greater so that only a low yield of cyclization product 4j
was obtained together with some unreacted diene 2j
and isomerized 2-sulfolene 5a. In the case of 3-sulfolene
1k (entry 11) containing a spiro hexane moiety, only the
diene 2k and isomerized 2-sulfolene 5b were obtained.
Comparing entries 1–2, greater amounts of Hg(OAc)2
leads to higher yield of product 7. Using the more
reactive mercuric trifluoroacetate, Hg(OTFA)2, the
yield was much higher (compare entry 3 with entry 1).
When these reactions were carried out at room temper-
ature (entries 1–3), the diastereomeric ratios of prod-
ucts 7a/7b were 1:1. Although these two isomers could
not be separated by column chromatography, the ratio
1
of these two isomers was determined by H NMR. The
NOESY spectrum of product 7b showed cross signals
between the methyl group and the hydrogen at the ring
junction, thus establishing its stereochemistry. We also
In order to synthesize the indolizidine and quinolizidine
bicyclic compounds, we used Parsons’ method of
Bu3SnH/AIBN to cleave the N-tosyl group of amides.26
The lactams 6a–c were obtained in high yield.
found that the amount of cis-7a decreases at lower
temperature and increases at higher temperature (com-
pare entries 3–6). Theoretical calculation28 shows that
cis-7a has a slightly lower energy (6.9977 kcal/mol)
than trans-7b (7.0977 kcal/mol). This means that cis-7a
is the thermodynamic product. On the other hand,
trans-7b is the kinetic product.
We investigated Harding’s method27 of using Hg(II) ion
to facilitate the synthesis of indolizidines and quino-
lizidines from lactams 6b–c. The results are summarized
in Table 2.
The Hg(OAc)2-mediated cyclization of 6c gave only a
single product trans-8, albeit in low yield (entry 7).
Increasing the amount of Hg(OAc)2 improved the yield
to 40% (entry 8). However, using Hg(OTFA)2 gave
product 8 in very good yield (entry 9). The structure of
8 was confirmed by its NOESY spectrum, which
showed cross signals between the methyl group and the
hydrogen at the ring junction. Therefore, the cycliza-
Table 2. Mercuric ion-promoted cyclization of 6b and 6c
Entry
6
Conditiona
Yield (%)
(cis:trans)b
1
2
3
4
5
6
7
8
9
6b
6b
6b
6b
6b
6b
6c
6c
6c
Hg(OAc)2 (1.2 equiv.), CH3CN, rt, 24 h
Hg(OAc)2 (2.4 equiv.), CH3CN, rt, 24 h
Hg(OTFA)2 (1.2 equiv.), CH3CN, rt, 24 h
Hg(OTFA)2 (1.2 equiv.), CH3CN, 0°C, 12 h
Hg(OTFA)2 (1.2 equiv.), CH3CN, −25 to −15°C, 12 h
Hg(OTFA)2 (1.2 equiv.), CH3CN, reflux, 3 h
Hg(OAc)2 (1.2 equiv.), CH3CN, rt, 24 h
Hg(OAc)2 (2.4 equiv.), CH3CN, rt, 24 h
Hg(OTFA)2 (1.2 equiv.), CH3CN, rt, 24 h
7a/7b (60)
7a/7b (76)
7a/7b (88)
7a/7b (78)
7a/7b (75)
7a/7b (74)
8 (18)
(1:1)
(1:1)
(1:1)
(5:6)
(4:6)
(6:4)
8 (40)
8 (84)
a After the reaction of 6b or 6c with Hg(II) reagent, the resulting solution was treated with NaBH4 (3 equiv.)/3 M NaOH in CH3CN at room
temperature for 2 h.
b The diastereomeric ratio of cis:trans was determined by 1H NMR.

S.-S. P. Chou et al. / Tetrahedron Letters 44 (2003) 4653–4655
4655
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In summary, we have synthesized many 6-substituted
tetrahydropyridinones 4 from the aza-Diels–Alder reac-
tions of 3-sulfolenes 1 with p-toluenesulfonyl isocya-
nate. We have also successfully converted the
cycloaddition products 4e and 4f to the indolizidine and
quinolizidine compounds 7a/7b and 8 with the media-
tion of Hg(II) ions.
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Acknowledgements
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25. Chou, S. S. P.; Tsao, H. J.; Lee, C. M.; Sun, C. M. J.
Financial support of this work by the National Science
Council of the Republic of China is gratefully acknowl-
edged (NSC 90-2113-M-030-009).
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28. The minimized steric energy is calculated by the program
CS Chem3D using MM2 and its default parameter.
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