Synthesis and reactions of sulfur-substituted indolizidinones

Article abstract of DOI:10.1016/j.tet.2011.05.086

An aza-Diels-Alder reaction product 2 was readily converted to a tetrahydropyridine derivative 6, but its N-benzyl group was unexpectedly difficult to cleave under various conditions. On the other hand, the N-tosyl α,β-unsaturated ester 14 was transformed

Full text of DOI:10.1016/j.tet.2011.05.086

Tetrahedron 67 (2011) 5395e5401
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Synthesis and reactions of sulfur-substituted indolizidinones
*
Shang-Shing P. Chou , Bing-Heng Lee, Cheng-Han Ni, Yu-Chou Lin
Department of Chemistry, Fu Jen Catholic University, New Taipei City 24205, Taiwan, ROC
a r t i c l e i n f o
a b s t r a c t
Article history:
An aza-DielseAlder reaction product 2 was readily converted to a tetrahydropyridine derivative 6, but its
N-benzyl group was unexpectedly difficult to cleave under various conditions. On the other hand, the
N-tosyl a,b-unsaturated ester 14 was transformed in one step by Mg/MeOH/Et3N to a thio-substituted
indolizidinone 3. This method was also extended to a methyl-substituted diene 16, which stereo-
selectively provided the cis-2,6-disubstitutedproduct 17. Further synthetic transformations yielded in-
dolizidinones 20e24, including a formal synthesis of the natural product monomorine I.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 31 March 2011
Received in revised form 13 May 2011
Accepted 20 May 2011
Available online 27 May 2011
Keywords:
Indolizidines
Aza-DielseAlder reaction
Indolizidinones
Monomorine I
1. Introduction
indolizidines.10 We have also completed a formal synthesis of
monomorine I,11 which is a trail pheromone of pharaoh’s ants.12
The piperidine ring is a common molecular fragment in both
natural and synthetic compounds with various biological activi-
ties.1,2 The aza-DielseAlder reaction is potentially one of the most
versatile and rapid routes to substituted piperidines.3 However,
most imines fail to participate in these [4þ2] cycloadditions. In
general, a strongly electron-withdrawing group, such as an acyl4 or
a sulfonyl group5,6 attached to the nitrogen or carbon of the imine is
needed.
We have previously reported effective aza-DielseAlder re-
actions of thio-substituted dienes with activated or unactivated
imines,7e9 simply by in situ preparation of the iminium salts from
amine hydrochlorides and aldehydes. For example, 2-phenylthio-
1,3-butadiene (1) can give the tetrahydropyridine derivative 2 in
good yield. We now report that although the attempted conversion
of compound 2 to the thio-substituted indolizidinone 3 failed under
various conditions (Scheme 1), the synthesis of compound 3 via an
N-tosyl analogue succeeded to afford the general structure of
2. Results and discussion
Compound 2 was successfully reduced to the alcohol 4 by lith-
ium aluminum hydride in THF (Scheme 2).13 Swern oxidation of
alcohol 4 gave smoothly the expected aldehyde 5, which decom-
posed significantly during purification by column chromatography.
Thus, after the Swern oxidation, the crude aldehyde 5 was directly
treated with (carbethoxymethylene)triphenylphosphorane in
CH2Cl2 at room temperature to give the
a,b-unsaturated ester 6
(E/Z¼20:1).
It was hoped that under catalytic hydrogenation conditions
compound 6 could be directly converted to the target molecule 3.
SPh
SPh
LiAlH4 (4 eq)
THF, rt, 1 h
Swern oxidation
OH
N
Bn
CO2Et
SPh
N
Bn
SPh
SPh
SPh
BnNH2•HCl
H
4 (93%)
2
HCOCO2Et
DMF, rt, 24 h
N
N
N
Bn
CO2Et
1
SPh
n-Bu
(+)-monomorine I
O
2 (89%)
Ph3P=CHCO2Et (2 eq)
CH2Cl2, rt, 12 h
3
O
Scheme 1.
N
CO2Et
N
Bn
Bn
6 (78%) E/Z = 20:1
5
* Corresponding author. Fax: þ886 2 29023209; e-mail address: chem1004@
Scheme 2.
mails.fju.edu.tw (S.-S.P. Chou).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.05.086

5396
S.-S.P. Chou et al. / Tetrahedron 67 (2011) 5395e5401
However, after varying the hydrogenation conditions (catalyst,
solvent, pressure of H2, reaction temperature, acidic medium, etc.),
the benzyl group of compound 6 could not be cleaved. The keto
ester 7 was obtained in 32% yield under a high pressure of hydrogen
in aqueous acid. In this reaction, the vinyl sulfide in compound 6
was hydrolyzed under the acidic condition, and the C]C of the
give the aza-DielseAlder product 12 in good yield. The ester 12 was
then reduced by lithium aluminum hydride to give alcohol 13.
Swern oxidation of alcohol 13 gave an unstable aldehyde, which
was further treated with (carbethoxymethylene)triphenylphos-
phorane in ClCH2CH2Cl at 75 ꢀC to give the
a,b-unsaturated ester 14
(E/Z¼20:1). Following a literature procedure,18 reaction of com-
pound 14 with magnesium in methanol gave compound 3 only in
22% yield. After trying different modifications, it was found that
addition of triethylamine to methanol improved the yield of
product 3e72%. Three distinguished steps were involved in this
reaction: cleavage of the tosyl group, reduction of the C]C bond,
and cyclization of the amino ester intermediate to the product 3.
Compound 3 was further oxidized to the sulfone 15. It is worth
mentioning that the oxidation reaction should be carried out at
a,b-unsaturated ester was reduced by hydrogen. It was speculated
that the thio group in compound 6 might poison the palladium
catalyst. Thus, compound 6 was first hydrolyzed by concentrated
HBr14 to give the ketone 8. Further reaction of compound 8 under
catalytic hydrogenation condition yielded only the C]C reduction
product 7 without cleaving the benzyl group. We also found that
treatment of compound 6 with sodium in liquid ammonia15 gave
the thio-cleaved alcohol 9 in 30% yield.
0
ꢀC, and no base should be added during the workup because
compound 15 was quite sensitive to base.
SPh
O
Having established a method for constructing the indolizidi-
none 3, we then wanted to apply it to the synthesis of some natural
products. Reaction of (E)-2-phenylthio-1,3-pentadiene (16)9 with
PTSI (10) under various conditions provided a different ratio and
yield of cis/trans product 17 (Table 1). Although the cis and trans
H2 (150 psi), cat. Pd/C
N
Bn
CO2Et aq. HCl, EtOH, 60 oC, 4.5 h
N
Bn
CO2Et
7 (32%)
6
O
SPh
Table 1
Synthesis of compound 17 from diene 16
conc. HBr
SPh
EtOH, 70 oC, 1.5 h
N
Bn
CO2Et
N
Bn
CO2Et
SPh
11 (1.1 equiv)
8 (65%)
N
CO2Et
6
(Table 1)
Ts
17
16
H2 (60 psi), cat. Pd(OH)2
EtOH, 60 oC, 4.5 h
7 (62%)
Entry
Reaction conditions
Yield of 17 (%)
cis/trans
SPh
1
2
3
4
5
6
Toluene, rt, 24 h
31
55
S.M.
36
28
55:45
62:38
d
Toluene, reflux, 20 h
95% EtOH, reflux, 24 h
DMF, rt, 12 h
CF3CH2OH, reflux, 20 h
CF3CH2OH, rt, 12 h
Na/NH3 (l), THF
-78 oC to -29 o
OH
C
69:31
87:13
79:21
N
Bn
CO2Et
N
Bn
74
9 (30%)
6
isomers of compound 17 could not be separated by column chro-
matography, their ratios were estimated from the 1H NMR spectra.
The reactions carried out in toluene (entries 1 and 2) shows that
higher temperature increased the yield of product 17 and the cis/
trans ratio. Using 95% EtOH as the solvent (entry 3), only unreacted
starting material was recovered. The reaction in DMF (entry 4) was
similar to that in toluene (entry 1). The highest cis/trans ratio of
compound 17 was obtained in refluxing CF3CH2OH (entry 5), but
the yield of product 17 was too low. The best reaction condition was
to carry out the reaction of diene 16 with imine 11 in CF3CH2OH at
room temperature (entry 6); the yield was highest and the ratio of
cis/trans ratio was about 4:1.
The cis/trans mixture of compound 17 was reduced directly by
lithium aluminum hydride in THF at room temperature to the al-
cohols 18a and 18b, which were separated by column chromatog-
raphy. The structure of compounds 18a and 18b was established by
X-ray crystallography (Fig. 1 and Fig. 2).19
Since the benzyl group of compound 6 was so unexpectedly
difficult to cleave, we turned to synthesize piperidine derivatives
with a more labile group attached to the nitrogen. A successful
synthesis of target molecule 3 is shown in Scheme 3. Following
a literature procedure,16,17 imine 11 prepared in situ from p-tolue-
nesulfonyl isocyanate (10, PTSI) was directly reacted with diene 1 to
SPh
HCOCO2Et, Tol
reflux, 36 h
1 (0.67 equiv)
TsN=C=O
TsN=CHCO2Et
Tol, reflux, 20 h
N
CO2Et
10
11
Ts
12 (77%)
SPh
SPh
1) Swern oxidation
LiAlH4 (8 eq)
THF, rt, 3 h
OH
2) Ph3P=CHCO2Et
ClCH2CH2Cl
N
CO2Et
N
Ts
Ts
75 oC, 9 h
14 (73%), E/Z = 20:1
13 (80%)
SPh
N
SO2Ph
SPh
SPh
SPh
Mg (20 eq)
MeOH/Et3N (10:1), rt, 5.5 h
mCPBA (3 eq)
CH2Cl2, 0 oC, 2 h
LiAlH4 (4 eq)
THF, rt, 1 h
+
OH
OH
N
N
CO2Et
N
N
Ts
17
Ts
Ts
O
O
18a (75%)
18b (18%)
3 (72%)
15 (79%)
Scheme 3.

S.-S.P. Chou et al. / Tetrahedron 67 (2011) 5395e5401
5397
compound 19 was successfully converted to the indolizidinone 20
by treatment with magnesium in MeOH/Et3N (10:1) at room tem-
perature. The cis-stereochemistry of compound 20 is clearly shown
by the X-ray crystal structure (Fig. 3).19
Fig. 1. X-ray crystal structure of compound 18a.
Fig. 3. X-ray crystal structure of compound 20.
Compound 20 was oxidized to the corresponding sulfone 21 by
the reaction with mCPBA. Further treatment of compound 21 with
6% sodium amalgam in a small amount of phosphoric acid20
resulted in the cleavage of the phenylsulfonyl group to give prod-
uct 22. On the other hand, the reaction of compound 20 with
concentrated HBr solution21 in 95% EtOH at 70 ꢀC gave the ketone
23 in excellent yield. The cis-stereochemistry of compound 23 is
clearly shown by the X-ray crystal structure (Fig. 4).19 Compound 20
also reacted with Raney nickel in refluxing 95% EtOH to afford the
bicyclic product 24, which has been converted to monomorine I.22
Fig. 2. X-ray crystal structure of compound 18b.
SPh
N
SO2Ph
N
mCPBA (2.5 eq)
6% Na/Hg, H3PO4
THF, reflux, 4 h
Swern oxidation of alcohol 18a gave an unstable aldehyde,
which was further treated with (carbethoxymethylene)triphenyl-
CH2Cl2, rt, 1.5 h
N
phosphorane in CH2Cl2 at room temperature to give the
saturated ester 19 (E/Z¼8:1). Without separating the E/Z isomers,
a,b-un-
O
O
O
22 (46%)
20
21 (71%)
O
N
SPh
SPh
SPh
excess conc. HBr
1) Swern oxidation
95% EtOH, 70 oC, 2 h
N
OH
2) Ph3P=CHCO2Et
CH2Cl2, rt, 12 h
N
Ts
18a
N
Ts
CO2Et
O
O
23 (93%)
20
19 (72%), E/Z = 8:1
SPh
N
SPh
Mg (30 eq)
H
Ra-Ni (10 eq)
95% EtOH, reflux, 4 h
N
N
MeOH/Et3N (10:1)
rt, 6 h
(ref. 20)
N
n-Bu
O
O
O
(+)-monomorine I
20
24 (63%)
20 (70%)

5398
S.-S.P. Chou et al. / Tetrahedron 67 (2011) 5395e5401
(1 M, 0.14 mL, 3.39 mmol) at room temperature. After stirring for
1 h, the solvent was removed under vacuum. Saturated NaCl so-
lution was then slowly added. The mixture was extracted three
times with ethyl acetate. The organic solution was dried (MgSO4)
and concentrated under reduced pressure to give the crude prod-
uct, which was purified by flash chromatography using ethyl ace-
tate/hexanes (1:5) as eluent to give compound 4 (246 mg, 93%) as
a yellow oil: IR (film) 3416, 3059, 3027, 2923, 1631, 1582, 1494, 1475,
1453, 1439, 1364, 1335, 1067, 1025, 999, 738, 698 cmꢁ1
;
1H NMR
(CDCl3, 300 MHz) 7.39e7.22 (10H, m), 5.88 (1H, br s), 3.75 (2H, s),
d
3.75e3.51 (1H, m), 3.48 (1H, dd, J¼5.4, 10.8 Hz), 3.37 (1H, br d,
J¼19.8 Hz), 3.16e3.10 (2H, m), 2.61 (1H, br s), 2.37 (1H, br d,
J¼18.0 Hz), 1.90 (1H, dd, J¼1.2, 18.0 Hz); 13C NMR (CDCl3, 75 MHz)
d
138.6, 133.5,131.5, 129.6, 129.2, 128.8, 128.5, 127.4, 127.3 (ꢂ2), 61.5,
57.9, 56.6, 47.5, 27.3; EI-MS (rel intensity) m/z 311 (Mþ, 0.26), 281
(38), 280 (100), 109 (21), 91 (99), 65 (22); EI-HRMS m/z calcd for
C19H21NOS 311.1344, found 311.1348.
4.1.2. (E)- and (Z)-1-Benzyl-2-[(2-ethoxycarbonyl)ethenyl]-4-(phe-
nylthio)-1,2,3,6-tetrahydropyridine (6). To
a solution of oxalyl
chloride (0.29 mL, 3.37 mmol) in CH2Cl2 (4 mL) at ꢁ78 ꢀC under
nitrogen was slowly added
a solution of DMSO (0.41 mL,
5.73 mmol) in CH2Cl2 (4 mL). The mixture was stirred for 5 min, and
then a solution of 4 (350 mg, 1.12 mmol) in CH2Cl2 (4 mL) was
added. After stirring for 30 min, another solution of Et3N (1.1 mL,
7.87 mmol) in CH2Cl2 (4 mL) was added. The mixture was slowly
warmed to room temperature, and stirred for another 20 min.
Water (15 mL) was added, and the mixture was extracted with
CH2Cl2. The organic solution was washed with aq K2CO3, dried
(MgSO4), and concentrated under vacuum. The 1H NMR of the
crude aldehyde product confirmed its structure, but since the al-
dehyde is quite unstable, it was then immediately dissolved in
CH2Cl2 (10 mL) and treated with (carbethoxymethylene)triphe-
nylphosphorane (780 mg, 2.25 mmol) at room temperature for
12 h. Saturated ammonium chloride solution was then added. The
mixture was extracted with CH2Cl2, washed with aq K2CO3, dried
(MgSO4), and evaporated under vacuum to give crude product 6.
Purification by flash chromatography using ethyl acetate/hexanes
(1:5) as eluent gave a mixture of (E)- and (Z)-6 (20:1, 333 mg, 78%)
as a yellow liquid. The mixture was used for the next step without
separation. IR (film) 3059, 3027, 2978, 2925, 2801, 1718, 1649, 1582,
1475, 1439, 1367, 1262, 1176, 1033, 742, 697 cmꢁ1; 1H NMR (CDCl3,
Fig. 4. X-ray crystal structure of compound 23.
3. Conclusions
Compound 6 was synthesized readily from compound 2 in good
yield. The N-benzyl group of compound 6 was unexpectedly diffi-
cult to cleave under various conditions. On the other hand, the
N-tosyl a,b-unsaturated ester 14 was converted in one step by Mg/
MeOH/Et3N to the thio-substituted indolizidinone 3. In this simple
procedure, three important transformations were accomplished:
cleavage of the N-tosyl group, reduction of the C]C bond, and
cyclization of the amino ester intermediate. We have also found
that the aza-DielseAlder reaction of imine 15 with methyl-
substituted diene 16 could be carried out under suitable condi-
tion to give stereoselectively the cis-product 17, which was further
transformed to indolizidinones 20e24. Compound 24 has been
used to synthesize the natural product monomorine I.
300 MHz) of (E)-16:
d
7.38e7.22 (10H, m), 7.01 (1H, dd, J¼8.4,
15.7 Hz), 5.90 (1H, d, J¼15.7 Hz), 5.89 (1H, s), 4.21 (2H, q, J¼6.9 Hz),
3.76 (1H, d, J¼13.2 Hz), 3.44 (1H, d, J¼13.5 Hz), 3.43 (1H, s), 3.22
(1H, dd, J¼2.7, 5.7 Hz), 3.09 (1H, dd, J¼2.7, 5.7 Hz). 2.47 (1H, br d,
J¼18.0 Hz), 2.16 (1H, br d, J¼18.0 Hz),1.30 (3H, t, J¼7.2 Hz); (Z)-6 has
4. Experimental section
4.1. General
some characteristic 1H NMR (CDCl3, 300 MHz) absorptions:
d 6.36
(1H, dd, J¼9.3, 11.7 Hz), 4.13e4.07 (2H, m), 1.22 (3H, t, J¼6.6 Hz); 13C
Melting points were determined with a SMP3 melting appara-
tus. Infrared spectra were recorded with a PerkineElmer 1600 or
100 series FTIR spectrometer. 1H and 13C NMR spectra were recor-
ded on a Bruker Avance 300 spectrometer operating at 300 and at
NMR (CDCl3, 75 MHz) of (E)-6: d 166.1, 146.6, 138.3, 133.5, 131.6
(ꢂ2), 129.1, 128.9, 128.7, 128.4, 127.7, 127.2, 123.6, 60.5, 58.9, 58.5,
50.5, 35.0, 14.3; EI-MS (rel intensity) m/z 379 (Mþ, 3), 271 (22), 270
(91), 91 (100); EI-HRMS m/z calcd for C23H25NO2S 379.1606, found
379.1610.
75 MHz, respectively. Chemical shifts (d) are reported in parts per
million (ppm) and the coupling constants (J) are given in Hertz.
High resolution mass spectra (HRMS) were measured with a mass
spectrometer Finnigan/Thermo Quest MAT 95XL. X-ray crystal
structures were obtained with an EnrafeNonius FR- 590 diffrac-
tometer (CAD4, Kappa CCD). Elemental analyses were carried out
with Heraeus Vario III-NCSH, Heraeus CHNeOeS-Rapid Analyzer or
Elementar Vario EL III. Flash column chromatographic purifications
were performed using Merck 60H silica gel.
4.1.3. 1-Benzyl-2-[2-(ethoxycarboyl)ethyl]-4-oxopiperidine (7). A so-
lution of 6 (100 mg, 0.26 mmol) in absolute ethanol (3 mL) was put in
a thick-walled glass bottle for high pressure hydrogenation. To this
were added 10% Pd/C (10 mg) and 5 M HCl (1 mL). Hydrogen
(150 psi) was filled into the reaction bottle, and the mixture was
stirred rapidly at 60 ꢀC for 4.5 h. After cooling to room temperature,
Celite was used to filter off the catalyst. The filtrate was then con-
centrated under vacuum to remove EtOH, and the residue was dis-
solved in ethyl acetate, dried (MgSO4), and evaporated to give crude
product, which was purified by flash chromatography using ethyl
acetate/hexanes (1:6) and 5% of Et3N as eluent to give product 7
4.1.1. 1-Benzyl-2-(hydroxymethyl)-4-(phenylthio)-1,2,3,6-tetrahydr-
opyridine (4). To a solution of 2 (300 mg, 0.85 mmol) in THF (5 mL)
under nitrogen was added dropwise a solution of LiAlH4 in THF

S.-S.P. Chou et al. / Tetrahedron 67 (2011) 5395e5401
5399
(24 mg, 32%) as a brown liquid: IR (film) 3062, 3030, 2960, 2362,
decompose the unreacted p-toluenesulfonyl isocyanate. The mix-
ture was extracted with ethyl acetate, dried (MgSO4), and concen-
trated under reduced pressure to give the crude product, which was
purified by flash chromatography using ethyl acetate/hexanes (1:6)
and 5% Et3N as eluent to give product 12 (2.18 g, 77%) as a light
yellow solid, mp 80e81 ꢀC; IR (film) 3054, 3026, 2980, 2940, 2912,
1739, 1339, 1291, 1195, 1163, 1098, 1027, 931, 814, 744, 732,
1728, 1707, 1452,1371, 1261, 1177, 1113,1028, 736, 699 cmꢁ1; 1H NMR
(CDCl3, 300 MHz)
d
7.38e7.27 (5H, m), 4.10 (2H, q, J¼7.2 Hz), 3.91
(1H, d, J¼13.5 Hz), 3.74 (1H, d, J¼13.5 Hz), 3.12e3.03 (2H, m),
2.83e2.75 (1H, m), 2.63 (1H, dd, J¼1.5, 5.1 Hz), 2.51e2.37 (3H, m),
2.32e2.23 (2H, m), 1.98e1.73 (2H, m),1.24 (3H, t, J¼7.2 Hz); 13C NMR
(CDCl3, 75 MHz)
d 209.3, 173.3, 139.0, 128.7, 128.5, 127.4, 60.5, 60.0,
56.3, 47.4, 44.1, 39.0, 30.6, 26.8, 14.3; EI-MS (rel intensity) m/z 289
(Mþ, 3), 188 (92), 91 (100); EI-HRMS m/z calcd for C17H23NO3
289.1678, found 289.1673.
692 cmꢁ1
;
1H NMR (CDCl3, 300 MHz)
d
7.67 (2H, d, J¼8.4 Hz),
7.29e7.22 (7H, m), 5.89 (1H, t, J¼1.7 Hz), 4.85 (1H, dd, J¼0.9, 6.6 Hz),
4.20 (1H, br d, J¼10.6 Hz), 4.07e3.95 (2H, m), 3.84 (1H, dd, J¼10.6,
7.0 Hz), 2.67 (1H, br d, J¼17.1 Hz), 2.52 (1H, d, J¼17.1 Hz), 2.42 (3H,
4.1.4. (E)- and (Z)-1-Benzyl-2-[2-(ethoxycarboyl)ethenyl]4-oxopip-
eridine (8). A mixture of 6 (250 mg, 0.66 mmol), concentrated HBr
(47e49%, 2.5 mL), and EtOH (5 mL) was heated at 75 ꢀC for 1.5 h
under nitrogen. After cooling to room temperature, the solvent was
removed under vacuum. To the residue was added slowly saturated
NaHCO3 solution. The mixture was extracted with CH2Cl2, dried
(MgSO4), and evaporated under vacuum. The crude product was
purified by flash chromatography using ethyl acetate/hexanes (1:7)
as eluent to give a mixture of (E)- and (Z)-8 (16:1, 123 mg, 65%) as
a yellow oil: IR (film) 3060, 3028, 2977, 2933, 2905, 2806,1720,1657,
s), 1.06 (3H, t, J¼7.2 Hz); 13C NMR (CDCl3, 75 MHz)
d 169.5, 143.5,
136.0, 132.7, 131.4, 129.5, 129.0, 128.4, 127.5, 127.2, 125.4, 61.3, 53.5,
43.3, 32.1, 21.5, 13.9; EI-MS (rel intensity) m/z 417 (Mþ, 0.12), 263
(22), 262 (100), 188 (69), 91 (62); EI-HRMS m/z calcd for
C21H23NO4S2 417.1068, found 417.1071.
4.1.7. 2-(Hydroxymethyl)-4-(phenylthio)-1-toluenesulfonyl-1,2,3,6-
tetrahydropyridine (13). To a solution of 12 (1.00 g, 2.39 mmol) in
THF (10 mL) under nitrogen was added dropwise a solution of
LiAlH4 in THF (1 M, 0.80 mL, 19.0 mmol) at room temperature. After
stirring for 2 h, the solvent was removed under vacuum. Saturated
NaCl solution was then slowly added. The mixture was extracted
three times with ethyl acetate. The organic solution was dried
(MgSO4) and concentrated under reduced pressure to give the
crude product, which was purified by flash chromatography using
ethyl acetate/hexanes (1:5) as eluent to give compound 13 as
a yellow solid (719 mg, 80%): mp 98.3e99.3 ꢀC; IR (film) 3495, 3056,
2920, 2854, 1636, 1596, 1581, 1474, 1438, 1396, 1326, 1250, 1161,
1103, 1061, 947, 815, 745, 733, 712, 694, 659 cmꢁ1; 1H NMR (CDCl3,
1649, 1453, 1368, 1252, 1177, 1029, 986, 736, 699 cmꢁ1
;
1H NMR
(CDCl3, 300 MHz) of (E)-8:
d
7.37e7.26 (5H, m), 6.81 (1H, dd, J¼8.1,
15.4 Hz), 5.98 (1H, d, J¼15.4 Hz), 4.21 (2H, q, J¼7.2 Hz), 3.97 (1H, d,
J¼13.5 Hz), 3.50e3.40 (1H, m), 3.32 (1H, d, J¼13.5 Hz), 3.10e3.04
(1H, m), 2.51e2.38 (5H, m), 1.30 (3H, t, J¼7.2 Hz); (Z)-8 has some
characteristic 1H NMR (CDCl3, 300 MHz) absorptions:
d 6.31 (1H, dd,
J¼9.0,11.7 Hz), 5.91 (1H, d, J¼11.7 Hz), 4.52 (2H, q, J¼7.2 Hz); 13C NMR
(CDCl3, 75 MHz) d 165.9,165.6,148.7,147.2,138.6,138.2,129.4,128.7,
128.5, 128.4, 128.2, 127.4, 127.3, 126.9, 123.8, 121.5, 63.2, 60.7, 60.4,
59.6, 59.2, 58.8, 49.8, 49.6, 46.1, 45.8, 41.2, 40.9, 14.3 (ꢂ2); EI-MS (rel
intensity) m/z 287 (Mþ, 2),196 (36), 91 (100); EI-HRMS m/z calcd for
C17H21NO3 287.1519, found 287.1521.
300 MHz)
d
7.70 (2H, d, J¼8.4 Hz), 7.30e7.16 (7H, m), 5.72 (1H, d,
J¼2.0 Hz), 4.28e4.17 (2H, m), 3.79 (1H, br d, J¼15.9 Hz), 3.63 (1H,
dd, J¼8.4, 11.1 Hz), 3.45 (1H, dd, J¼6.6, 11.1 Hz), 2.43 (3H, s),
2.22e2.11 (1H, m), 1.92 (1H, d, J¼17.4 Hz); 13C NMR (CDCl3, 75 MHz)
4.1.5. 1-Benzyl-2-(3-hydroxypropyl)-1,2,3,6-tetrahydropyridine
(9). To a solution of 6 (333 mg, 0.88 mmol) in THF (15 mL) at ꢁ78 ꢀC
was added liquid ammonia (35 mL) by condensing ammonia with
a dry ice condenser. Sodium (about 0.5 g) was cut into small pieces
and was quickly added. After stirring for 5 min, the solution turned
to dark blue. The reaction mixture was allowed to warm to ꢁ29 ꢀC,
and powdered ammonium chloride was added till the blue color
disappeared. The mixture was warmed to room temperature, and
the solvent was evaporated under vacuum. The residue was parti-
tioned between CH2Cl2 and water. The organic solution was dried
(MgSO4) and concentrated under vacuum to give crude product,
which was purified by flash chromatography using ethyl acetate/
hexanes (1:6) and 5% Et3N as eluent to give product 9 (60 mg, 30%)
as a light yellow oil: IR (film) 3402, 3026, 2924, 2859, 1652, 1602,
d 143.6, 137.1, 132.4, 131.9, 130.1, 129.8, 129.1, 127.7, 127.0, 123.0, 61.3,
53.1, 41.8, 29.0, 21.6; EI-MS (rel intensity) m/z 375 (Mþ, 0.32), 344
(82), 266 (40), 220 (61), 188 (65), 111 (28) 91 (100), 53 (20); EI-
HRMS m/z calcd for C19H21NO3S2 375.0963, found 375.0954.
4.1.8. (E)- and (Z)-2-[(2-Ethoxycarbonyl)ethenyl]-4-(phenylthio)-1-
toluenesulfonyl-1,2,3,6-tetrahydropyridine (14). Using a procedure
similar to that for the preparation of 6, compound 13 (540 mg,
1.44 mmol) gave product 14 (466 mg, 73% yield, E/Z¼20:1) as
a yellow solid. This mixture of E/Z products was washed several
times with small amounts of diethyl ether/hexanes (1:2) to give
pure (E)-14 (420 mg, 66%) as a white solid: mp 68.1e69.1 ꢀC; IR
(film) 3057, 2938, 2935, 2905, 2851, 1719, 1656, 1596, 1474, 1440,
1349, 1307, 1163, 1099, 1067, 1034, 981, 927, 815, 693 cmꢁ1; 1H NMR
1494, 1453, 1359, 1335, 1062, 1028, 1007, 732, 698 cmꢁ1
;
1H NMR
(CDCl3, 300 MHz)
d
7.67 (2H, d, J¼8.1 Hz), 7.3e7.23 (7H, m), 6.6 (1H,
(CDCl3, 300 MHz) 7.38e7.23 (5H, m), 5.83e5.77 (1H, m),
d
dd, J¼5.7, 15.9 Hz), 5.82 (1H, dd, J¼1.8, 15.9 Hz), 5.76 (1H, t,
J¼1.8 Hz), 4.84 (1H, t, J¼5.7 Hz), 4.21e4.13 (3H, m), 3.67 (1H, br d,
J¼16.8 Hz), 2.54 (1H, br d, J¼16.8 Hz) 2.43 (3H, s), 2.06 (1H, d,
5.58e5.53 (1H, m), 3.77e3.56 (4H, m), 3.18e3.0 (2H, m), 2.98e2.90
(1H, m), 2.30e2.24 (1H, m), 1.97e1.53 (6H, m); 13C NMR (CDCl3,
75 MHz)
d
138.5, 129.3, 128.5, 127.2, 124.8, 123.7, 63.1, 56.5, 54.4,
J¼16.8 Hz), 1.28 (3H, t, 6.9 Hz); 13C NMR (CDCl3, 75 MHz)
d 165.4,
46.4, 31.3, 30.3, 26.8; EI-MS (rel intensity) m/z 231 (Mþ, 2), 172
(100), 91 (68); EI-HRMS m/z calcd for C15H21NO 231.1623, found
231.1620.
143.7, 143.4, 136.2, 132.2, 131.9, 129.7, 129.5, 129.1, 127.7, 127.1, 123.6,
123.5, 60.5, 51.8, 42.2, 33.2, 21.4, 14.2; EI-MS (rel intensity) m/z 443
(Mþ, 3), 334 (87), 288 (69), 155 (25), 147 (16), 91 (100); EI-HRMS m/
z calcd for C23H25NO4S2 443.1225, found 443.1228.
4.1.6. Ethyl 4-(phenylthio)-1-toluenesulfonyl-1,2,3,6-tetrahydro-2-
pyridinecarboxylate (12). To a solution of ethyl glyoxylate (50% in
toluene, 2 mL, 10 mmol) in toluene (10 mL) was slowly added
p-toluenesulfonyl isocyanate (PTSI, 1.54 mL, 10 mmol). The mixture
was heated at reflux for 36 h under nitrogen to generate the imine
11. After cooling to room temperature, 2-phenylthio-1,3-butadiene
(1, 1.1 g, 6.73 mmol) was added. The reaction mixture was then
heated at reflux for 20 h. The solvent was removed under vacuum,
and to the residue was slowly added 5% aq NaOH (30 mL) to
4.1.9. 7-(Phenylthio)-1,2,3,5,8,8a-hexahydro-3-indolizinone
(3). A
mixture of 14 (300 mg, 0.68 mmol) and Mg (329 mg, 1.35 mmol) in
MeOH (10 mL) and triethylamine (1 mL) was stirred under nitrogen
at room temperature for 5.5 h. The solvent was evaporated under
vacuum to give crude product, which was purified by flash chro-
matography using ethyl acetate/hexanes (1:1) and 5% CH2Cl2 as
eluent to give 3 (119 mg, 72%) as a light yellow liquid: IR (film) 3054,
3030, 2954, 2924, 2852, 1683, 1672, 1653, 1456, 1437, 1418, 1364,

5400
S.-S.P. Chou et al. / Tetrahedron 67 (2011) 5395e5401
1264, 1023, 752, 692 cmꢁ1; 1H NMR (CDCl3, 300 MHz)
d
7.37e7.25
(42), 57 (72), 55 (77), 43 (66), 41 (64); FAB-HRMS m/z calcd for
20H23NO3S2 389.1119, found 389.1122. Compound trans-18b:
white solid, mp 87e88 ꢀC; IR (ATR, film) 3538, 3057, 2976, 2932,
1636, 1598, 1475, 1371, 1266, 1164 cmꢁ1 1H NMR (CDCl3,
300 MHz)
(5H, m), 5.87 (1H, dd, J¼2.7, 6.0 Hz), 4.37 (1H, ddd, J¼3.0, 3.3,
C
18.9 Hz), 3.74e3.66 (2H, m), 2.45e2.09 (5H, m), 1.72e1.58 (1H, m);
13C NMR (CDCl3, 75 MHz)
d
174.1, 132.3, 131.9, 130.6, 129.3, 127.7,
;
124.4, 53.9, 41.2, 37.0, 29.9, 25.0; EI-MS (rel intensity) m/z 246 (Mþ1
,
d
7.69 (2H, d, J¼8.1 Hz), 7.31e7.21 (5H, m), 7.15e7.12
12), 245 (M, 97), 136 (100), 108 (20); EI-HRMS m/z calcd for
C14H15NOS 245.0874, found 245.0881.
(2H, m), 5.75 (1H, dd, J¼1.8, 2.7 Hz), 4.78e4.74 (1H, m), 4.07e3.98
(1H, m), 3.81e3.71 (1H, m), 3.66e3.58 (1H, m), 3.20 (1H, dd,
J¼4.8, 9.9 Hz), 2.47 (3H, s), 1.81 (1H, dd, J¼3.9, 17.4 Hz), 1.67 (1H,
ddt, J¼17.4, 10.2, 1.8 Hz), 1.36 (3H, d, J¼6.9 Hz); 13C NMR (CDCl3,
4.1.10. 7-(Phenylsulfonyl)-1,2,3,5,8,8a-hexahydro-3-indolizinone
(15). To a solution of compound 3 (100 mg, 0.41 mmol) in CH2Cl2
(3 mL) at 0 ꢀC was added dropwise another solution of mCPBA (50%
in H2O, 0.42 g, 1.22 mmol) in CH2Cl2 (3 mL). The reaction mixture
was stirred at 0 ꢀC for another 2 h, and was then diluted with more
CH2Cl2. The solution was washed with saturated aqueous sodium
thiosulfate, dried (MgSO4), and concentrated under reduced pres-
sure. The residue was purified by flash chromatography using ethyl
acetate/hexanes (1:2) as eluent to give compound 15 (89 mg, 79%)
as a light yellow oil: IR (ATR, film) 3065, 2972, 2884, 2838, 2250,
1762,1680,1645,1583,1446,1421,1367,1305,1289,1214,1197,1149,
75 MHz)
d
143.6, 139.0, 132.3, 131.9, 130.9, 129.7 (ꢂ2), 129.1, 127.6,
126.7, 62.7, 56.1, 53.9, 30.0, 21.5, 20.7.
4.1.13. cis-(E)- and (Z)-1-Tosyl-2-[(2-ethoxycarbonyl)ethenyl]-6-
methyl-4-(phenylthio)-1,2,3,6-tetrahydropyridine (19). Using a pro-
cedure similar to that for the preparation of 6, compound 18a
(100 mg, 0.26 mmol) gave product 19 (85 mg, 72%; E/Z¼8:1) as
a yellow liquid. The E/Z mixture could be recrystallized from
CH2Cl2/hexanes to give pure E-19 as
98.6e99.5 ꢀC; IR (ATR, film) 3055, 2987, 1717, 1656, 1600, 1266,
1163 cmꢁ1 1H NMR (CDCl3, 300 MHz)
a white solid: mp
1091, 1071, 1022, 998, 981, 910, 815, 756, 720, 688 cmꢁ1
(CDCl3)
;
1H NMR
;
d
7.68 (2H, d, J¼8.4 Hz),
d
7.87e7.84 (2H, m), 7.69e7.54 (3H, m), 7.04 (1H, dd, J¼5.7,
7.32e7.20 (7H, m), 6.85 (1H, dd, J¼5.1, 15.9 Hz), 5.83 (1H, dd, J¼1.8,
15.9 Hz), 5.75 (1H, dd, J¼2.4, 3.3 Hz), 4.78e4.74 (1H, m), 4.53e4.49
(1H, m), 4.20 (2H, q, J¼7.2 Hz), 2.45 (3H, s), 2.15e1.98 (2H, m), 1.37
(3H, d, J¼7.2 Hz), 1.30 (3H, t, J¼7.2 Hz); 13C NMR (CDCl3, 75 MHz)
2.7 Hz), 4.60 (1H, dt, J¼20.4, 3.3 Hz), 3.78e3.60 (2H, m), 2.70 (1H, d,
J¼14.1 Hz), 2.43e2.31 (3H, m), 2.04e1.93 (1H, m), 1.74e1.65 (1H,
m); 13C NMR (CDCl3)
d 174.1, 138.4, 138.3, 133.7, 133.3, 129.4, 128.1,
52.7, 40.2, 30.2, 29.5, 24.7; FABMS (rel intensity) m/z 278 (MþþH,
3), 147 (21), 119 (21), 105 (25), 95 (39), 81 (52), 69 (70), 55 (100), 41
(93); FAB-HRMS m/z calcd for C14H15NO3S 277.0695, found m/z
277.0689.
d
165.9, 146.6, 143.6, 137.5, 132.2 (ꢂ2), 129.9, 129.4, 129.1, 128.4,
127.9, 126.9, 123.0, 60.6, 50.9, 50.8, 30.4, 23.6, 21.6, 14.3; ESI-MS
(rel intensity) m/z 458 (MþþH, 26), 348 (70), 302 (71), 282
(100); ESI-HRMS m/z calcd for C24H27NO4S2 457.1367, found
457.1372.
4.1.11. cis- and trans-Ethyl 2-methyl-4-(phenylthio)-1-tosyl-1,2,5,6-
tetrahydro-6-pyridinecarboxylate (17). Using a procedure similar
to that for the preparation of 12, except that the reaction was carried
out in CF3CH2OH at room temperature for 12 h. Compound 16
(500 mg, 2.84 mmol) gave product 17 (906 mg, 74%) as an in-
separable liquid of cis/trans isomers (79:21): IR (film) 3055, 2980,
2933,1738,1597,1582,1475,1440,1338,1305,1196,1162,1100,1025,
4.1.14. cis-5-Methyl-7-(phenylthio)-1,2,3,5,8,8a-hexahydro-3-
indolizinone (20). Using a procedure similar to that for the prepa-
ration of 3, compound 19 (100 mg, 0.22 mmol) gave product 20
(40 mg, 70%) as a white solid: mp 112e114 ꢀC; IR (ATR, film) 3054,
2986, 2870, 1683, 1406, 1266 cmꢁ1 1H NMR (CDCl3, 300 MHz)
;
d
7.35e7.28 (5H, m), 5.84 (1H, dd, J¼2.4, 3.6 Hz), 4.19 (1H, br s), 3.59
958, 867, 745, 722, 692 cmꢁ1
;
13C NMR (CDCl3, 75 MHz)
d
170.4,170.3,
(1H, ddq, J¼2.1, 3.9, 6.0 Hz), 2.39e2.31 (3H, m), 2.25e2.11 (2H, m),
143.5, 143.3, 138.9, 137.4, 132.5 (ꢂ2), 132.0, 131.9, 131.7, 129.7, 129.4,
129.2, 129.1, 129.0, 128.8, 128.1, 127.7, 127.5, 127.1 (ꢂ2), 61.6, 61.5,
56.4, 52.8, 52.0, 50.7, 32.1, 29.1, 21.8 (ꢂ2), 21.5 (ꢂ2),14.0,13.9; EI-MS
(rel intensity) m/z 431 (Mþ, 0.39), 416 (12), 358 (16), 322 (12), 277
(14), 276 (100), 202 (42), 188 (29), 91 (28); EI-HRMS m/z calcd for
C22H25NO4S2 431.1225, found 431.1229. The cis-17 has some char-
1.62e1.52 (1H, m), 1.48 (3H, d, J¼6.6 Hz); 13C NMR (CDCl3, 75 MHz)
d
175.7, 133.2, 131.7, 131.6, 129.5, 129.3, 127.6, 56.9, 49.6, 36.7, 31.4,
26.4, 20.4; EI-MS (rel intensity) m/z 259 (20), 245 (17), 244 (100),
150 (94), 134 (19); EI-HRMS m/z calcd for C15H17NOS 259.1031,
found 259.1025. Anal. Calcd for C15H17NOS: C, 69.46; H, 6.61; N,
5.40; S, 12.36. Found: C, 69.36; H, 6.43; N, 5.33; S, 12.66.
acteristic absorptions: 1H NMR (CDCl3, 300 MHz)
d 7.70 (2H, d,
J¼8.4 Hz), 7.30e7.23 (7H, m), 5.73 (1H, t, J¼3.3 Hz), 4.84 (1H, dd,
J¼6.6, 1.5 Hz), 4.56e4.47 (1H, m), 4.22e4.11 (2H, m), 2.57 (1H, d,
J¼17.1 Hz), 2.42 (3H, s), 2.20e2.10 (1H, m),1.33 (3H, d, J¼7.2 Hz),1.19
(3H, t, J¼6.3 Hz). The trans-17 has some characteristic absorptions:
4.1.15. cis-5-Methyl-7-(phenylsulfonyl)-1,2,3,5,8,8a-hexahydro-3-
indolizinone (21). Using a procedure similar to that for the prepa-
ration of 15, compound 20 (100 mg, 0.39 mmol) gave product 21
(80 mg, 71%) as a white solid: mp 130.4e131.4 ꢀC; IR (ATR, film)
1H NMR (CDCl3, 300 MHz)
d
5.77 (1H, dd, J¼1.5, 2.1 Hz), 4.70 (1H, t,
3054, 2987, 2927, 1727, 1604, 1551, 1422, 1266 cmꢁ1
;
1H NMR
J¼4.9 Hz), 4.56e4.47 (1H, m), 4.22e4.11 (2H, m), 2.65e2.64 (2H, m),
1.27 (3H, d, J¼6.6 Hz), 1.21 (3H, t, J¼6.9 Hz).
(CDCl3, 300 MHz) d 7.88e7.86 (2H, m), 7.69e7.55 (3H, m), 6.96 (1H,
dd, J¼3.0, 3.6 Hz), 4.33 (1H, br s), 3.45 (1H, ddq, J¼2.4, 3.6, 6.6 Hz),
2.65 (1H, ddd, J¼15.9, 3.6,1.5 Hz), 2.40e2.31 (2H, m), 2.25e2.17 (1H,
m), 2.11e2.01 (1H, m), 1.66e1.51 (1H, m), 1.57 (3H, d, J¼6.6 Hz); 13C
4.1.12. 1-Tosyl-2-(hydroxymethyl)-6-methyl-4-(phenylthio)-1,2,3,6-
tetrahydropyridine (18). Using a procedure similar to that for the
preparation of 4, compound 17 (50 mg, 0.12 mmol) gave product
cis-18a (34 mg, 75%) and trans-18b (8 mg, 18%). Compound cis-
18a: white solid, mp 91.3e92.3 ꢀC; IR (ATR, film) 3533, 3055,
NMR (CDCl3, 75 MHz) d 175.7, 139.6, 138.7, 136.9, 133.8, 129.5, 128.1,
55.8, 49.0, 31.2, 30.6, 26.2, 19.0; EI-MS (rel intensity) m/z 291 (Mþ,
8), 276 (50), 150 (100), 125 (60), 84 (37), 67 (16), 17 (19); EI-HRMS
m/z calcd for C15H17NO3S 291.0929, found 291.0932.
2984, 2932, 1644, 1598, 1476, 1334, 1266, 1163 cmꢁ1
(CDCl3, 300 MHz)
;
1H NMR
d
7.67 (2H, d, J¼8.1 Hz), 7.31e7.17 (7H, m),
4.1.16. cis-5-Methyl-1,2,3,5,8,8a-hexahydro-3-indolizinone (22). To
a solution of compound 21 (40 mg, 0.14 mmol) in dried THF (4 mL)
was added 6% sodium amalgam (1.4 mmol) and two drops of
concentrated phosphoric acid. The mixture was heated at reflux
for 4 h. Upon cooling the mixture was filtered through Celite,
rinsed with ethyl acetate, and evaporated under vacuum. The
residue was purified by flash chromatography using ethyl acetate/
hexanes (1:2 to 1:1) to give product 22 (9 mg, 46%) as a colorless
5.77e5.75 (1H, m), 4.55e4.50 (1H, m), 4.09 (1H, tt, J¼7.8, 3.9 Hz),
3.66e3.59 (1H, m), 3.50e3.42 (1H, m), 2.45 (3H, s), 1.95 (1H, br s),
1.92e1.86 (2H, m), 1.44 (3H, d, J¼6.9 Hz); 13C NMR (CDCl3,
75 MHz)
d
143.7, 137.5, 132.6, 131.9, 130.0, 129.2, 128.7 (ꢂ2), 127.8,
126.9, 63.2, 52.9, 50.4, 28.0, 24.4, 21.7; FABMS (rel intensity) m/z
390 (MþþH, 18), 358 (40), 234 (54), 214 (85), 155 (41), 154 (100),
137 (58), 136 (100), 91 (82), 88 (44), 77 (52), 73 (43), 69 (60), 67

S.-S.P. Chou et al. / Tetrahedron 67 (2011) 5395e5401
5401
liquid: IR (ATR, film) 2985, 2936, 1681, 1651, 1457, 1409, 1377,
1266 cmꢁ1 1H NMR (CDCl3, 300 MHz)
tensity) m/z 138 (15), 124 (15), 110 (100), 104 (25), 91 (26), 84 (24),
55 (15), 41 (16); EI-HRMS m/z calcd for C9H15NO 153.1154, found
153.1151.
;
d
5.79 (1H, ddt, J¼9.9, 6.6,
1.5 Hz), 5.66 (1H, dt, J¼9.9, 3.3 Hz), 4.11 (1H, br m), 3.50 (1H, ddq,
J¼2.1, 3.9, 6.0 Hz), 2.38e2.29 (3H, m), 2.22e2.16 (1H, m),
2.06e1.96 (1H, m), 1.66e1.51 (1H, m), 1.46 (3H, d, J¼6.6 Hz); 13C
Acknowledgements
NMR (CDCl3, 75 MHz)
d 176.2, 131.1, 122.8, 55.8, 48.7, 32.1, 31.3,
26.9, 20.5; EI-MS (rel intensity) m/z 151 (Mþ, 54), 138 (28), 136
(100), 108 (50), 96 (21), 84 (43), 68 (29), 67 (21); EI-HRMS m/z
calcd for C9H13NO 151.0997, found 151.0991.
Financial support of this work by the National Science Council of
the Republic of China is gratefully acknowledged (NSC 94-2113-M-
030-005, 95-2113-M-030-002, and 97-2113-M-030-001-MY3).
4.1.17. cis-5-Methyl-1,2,3,5,8,8a-hexahydro-3,7-indolizinedione
(23). To a solution of compound 20 (50 mg, 0.19 mmol) in 95%
EtOH (4 mL) was added dropwise a 50% HBr (3 mL). The mixture
was heated at 70 ꢀC under nitrogen for 2 h. The solvent and excess
HBr solution were removed under vacuum, and saturated sodium
bicarbonate was slowly added. The solution was extracted with
CH2Cl2, dried (MgSO4), and evaporated under vacuum. The crude
product was purified by flash chromatography using ethyl acetate
as eluent to give product 23 (30 mg, 93%) as a white solid: mp
91.2e92.2 ꢀC; IR (ATR, film) 2986, 2873, 2904, 2832, 1723, 1683,
References and notes
1. Rubiralta, M.; Giralt, E.; Diez, E. Piperidine, Structure, Preparation, Reactivity and
Synthetic Applications of Piperidine and Its Derivatives; Elsevier: Amsterdam,1991.
2. Daly, J. W.; Garraffo, H. M.; Spande, T. F. In The Alkaloids; Cordell, G. A., Ed.;
Academic: New York, NY, 1993; Vol. 43, p 185.
3. Boger, D. L.; Weinreb, S. M. Hetero DielseAlder Methodology in Organic Synthesis;
Academic: Orlando, 1987.
4. Weinreb, S. M. Acc. Chem. Res. 1985, 18, 16e21.
5. Sisko, J.; Weinreb, S. M. Tetrahedron Lett. 1989, 30, 3037e3040.
6. Birkinshaw, T. N.; Tabor, A. B.; Holmes, A. B.; Kaye, P.; Mayne, P. M.; Raithby, P. R.
J. Chem. Soc., Chem. Commun. 1988, 1599e1601.
7. Chou, S. S. P.; Hung, C. C. Synth. Commun. 2001, 31, 1097e1104.
8. Chou, S. S. P.; Hung, C. C. Synth. Commun. 2002, 32, 3119e3126.
9. Chou, S. S. P.; Chen, K. W. Synth. Commun. 2004, 34, 4573e4582.
10. For a recent review, see: Michael, J. P. Nat. Prod. Rep. 2008, 25, 139e165.
11. For a recent synthesis, see Toyooka, N.; Zhou, D.; Nemoto, H. J. Org. Chem. 2008,
73, 4575e4577 and references cited therein.
12. Ritter, F. J.; Rotgans, I. E. M.; Talman, E.; Vierwiel, P. E. J.; Stein, F. Experientia
1973, 29, 530e531.
13. Angle, S. R.; Henry, R. M. J. Org. Chem. 1997, 62, 8549e8552.
14. Kurihara, T.; Tanno, H.; Takemura, S.; Harusawa, S.; Yoneda, R. J. Heterocycl.
Chem. 1993, 70, 643e652.
1457, 1417, 1377, 1266 cmꢁ1
;
1H NMR (CDCl3, 300 MHz)
d
4.25e4.09 (2H, m), 2.84 (1H, dd, J¼15.9, 6.6 Hz), 2.75 (1H, dd,
J¼18.3, 3.6 Hz), 2.49e2.26 (5H, m), 1.64 (1H, m), 1.32 (3H, d,
J¼6.6 Hz); 13C NMR (CDCl3, 75 MHz)
d 207.0, 174.1, 54.6, 46.7, 44.9,
44.8, 31.4, 27.3, 21.9; FABMS (rel intensity) m/z 168 (MþþH, 37),
166 (10), 102 (100), 84 (10); FAB-HRMS m/z calcd for C9H13NO2
167.0946, found 167.0947.
15. Amat, M.; Llor, N.; Hidalgo, J.; Bosch, J. J. Org. Chem. 2003, 68, 1919e1928.
16. Hamley, P.;Holmes, A. B.; Kee, A.;Ladduwahetty, T.;Smith,D.F. Synlett1991, 29e30.
17. Baillarge, M.; Le Goffic, F. Synth. Commun. 1987, 17, 1603e1606.
18. Goodenough, K. M.; Moran, W. J.; Raubo, P.; Harrity, J. P. A. J. Org. Chem. 2005,
70, 207e213.
19. Crystallographic data (excluding structure factors) for compounds 18a, 18b, 20,
and 23 in this paper have been deposited with the Cambridge Crystallographic
Data Centre as supplementary publication CCDC 819071 (compound 18a),
819070 (compound 18b), 819073 (compound 20), and 819072 (compound 23).
Copies of the data can be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK (fax: þ44 (0) 1223 336033 or e-mail:
deposit@ccdc.cam.ac.uk).
20. Chou, S. S. P.; Sun, C. M. Tetrahedron Lett. 1990, 31, 1035e1038.
21. Chou, S. S. P.; Chung, Y. C.; Chen, P. A.; Chiang, S. L.; Wu, C. J. J. Org. Chem. 2011,
76, 692e695.
22. Pattenden, L. C.; Adams, H.; Smith, S. A.; Harrity, J. P. A. Tetrahedron 2008, 64,
2951e2961.
4.1.18. cis-5-Methyl-1,2,3,5,6,7,8,8a-octahydro-3-indolizinone
(24). A mixture of compound 20 (50 mg, 0.19 mmol) and a W-2
Ra-Ni (198 mg) in 95% EtOH (3 mL) was heated at reflux under
nitrogen for 4 h. The solid was filtered off with Celite, washed with
methanol, and the solvent was evaporated under vacuum in an ice
bath. The crude product was purified by flash chromatography
using ethyl acetate/hexanes (1:2 to 1:1) as eluent to give product
24 (19 mg, 63%) as a colorless liquid. The spectral data were
identical with the literature report:22 IR (ATR, film) 2987, 1638,
1422, 1265 cmꢁ1 1H NMR (CDCl3, 300 MHz)
; d 3.33e3.27 (2H, m),
2.35e2.28 (2H, m), 2.17e2.05 (1H, m), 1.87e1.79 (2H, m),
1.70e1.60 (4H, m), 1.58e1.18 (4H, m); 13C NMR (CDCl3, 75 MHz)
d
175.7, 59.4, 52.6, 33.9, 32.7, 32.0, 25.7, 23.0, 20.0; EI-MS (rel in-