Regioselective reduction of N-alkyl-3-sulfonyl glutarimides to δ-lactams. Formal synthesis of (±)-paroxetine and (±)-tacamonine

Article abstract of DOI:10.1016/j.tet.2003.09.076

A convenient method for the preparation of 4- or 5-substituted 3-sulfonyl-δ-lactams via regioselective reduction of N-alkyl-3-sulfonyl glutarimides is described. Formal synthesis of (±)-paroxetine and (±)-tacamonine is also reported.

Full text of DOI:10.1016/j.tet.2003.09.076

Tetrahedron 59 (2003) 9383–9387
Regioselective reduction of N-alkyl-3-sulfonyl glutarimides to
d-lactams. Formal synthesis of (6)-paroxetine and (6)-tacamonineq
Chung-Yi Chen,a Bo-Rui Chang,a Min-Ruei Tsai,a Meng-Yang Changb
,
*
and Nein-Chen Changa
,
*
aDepartment of Chemistry, National Sun Yat-Sen University, Kaohsiung 804, Taiwan, ROC
bDepartment of Applied Chemistry, National University of Kaohsiung, Kaohsiung 811, Taiwan, ROC
Received 19 August 2003; accepted 19 September 2003
Abstract—A convenient method for the preparation of 4- or 5-substituted 3-sulfonyl-d-lactams via regioselective reduction of N-alkyl-3-
sulfonyl glutarimides is described. Formal synthesis of (^)-paroxetine and (^)-tacamonine is also reported.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
the 3-sulfonyl and C-2 carbonyl. The sulfonyl group also
increased the electrophilicity of C-2 carbon. Regioselective
reduction of the C-6 carbonyl of glutarimide 1 was
accomplished by protection of the C-2 carbonyl as an
enolate5c (Scheme 1).
Six-membered nitrogen-containing heterocycles are abun-
dant in nature and exhibit diverse and important biological
properties.1 Alkaloids that contain the piperidine ring
continue to be the targets of extensive synthetic interest,
partly because there are many biologically active natural
products of this type.2 Accordingly, the development of a
general method for the preparation of piperidine derivatives
has been the subject of considerable synthetic efforts.3
d-Lactams have been generally regarded as the precursors of
the corresponding piperidines. It is well documented that
one of the most widely used methods for the construction of
the tetracyclic carbon skeleton of indole alkaloids is to
synthesize an appropriate d-lactam, which is then cyclized
to indole alkaloids via the Bischler–Napieralski reaction.
Herein, we report a convenient method for the preparation
of 4- or 5-substituted 3-sulfonyl-d-lactams from N-alkyl-3-
sulfonyl glutarimide 1.
Recently, we developed an efficient route to the unsym-
metrical glutarimides with a sulfonyl group at C-3 position.4,5
The feature of this approach is the utility of a sulfonyl group
to control subsequent regioselective functionalizations
that lead to a variety of hydroxy d-lactams with diverse
substituents.5 Regioselective reduction of C-2 carbonyl of
glutarimide 1 was accomplished with NaBH4.5a,b This was
attributed to the chelation of the reducing agent with both
Scheme 1. Regioselective reduction of N-alkyl-3-sulfonyl glutarimide 1 to
hydroxy lactam.
2. Results and discussion
2.1. Regioselective reduction of N-alkyl-3-sulfonyl
glutarimide 1 to d-lactam 5 with LiAlH4
q Supplementary data associated with this article can be found at doi:
10.1016/j.tet.2003.09.076
It was reported that reduction of glutarimides with NaBH4
or LiAlH4 yielded hydroxy lactams or over-reduced product
hydroxy amides.6 However, reduction of glutarimides
directly to d-lactams has never been achieved. We
discovered that treatment of glutarimide 1 with 1.2 equiv.
Keywords: glutarimide; d-lactam; regioselective reduction; paroxetine;
tacamonine.
*
Corresponding authors. Tel.: þ886-7-5252000x3913; fax: þ886-7-
5253913; e-mail: ncchang@mail.nsysu.edu.tw
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.09.076

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C.-Y. Chen et al. / Tetrahedron 59 (2003) 9383–9387
Scheme 2. Regioselective reduction of N-alkyl-3-sulfonyl glutarimide 1 with LiAlH4.
Et3N at 258C for 30 min followed by addition of 5 equiv. of
LiAlH4, the resulting mixture was further refluxed in THF
solution for 3 h, d-lactam 5 was obtained in good yields
(Scheme 2).
2.2. Formal synthesis of (6)-paroxetine
To demonstrate the synthetic utility of this methodology, the
efficient formal synthesis of (^)-paroxetine (8), which is
marketed as the hydrochloride Paxil/Seroxat, a selective
serotonin reuptake inhibitor, was reported. Reductive
desulfonylation of 5e with sodium amalgam in methanol
solution furnished 7 in good yield, which had been readily
converted into (^)-paroxetine (8) by Yu.8 The spectro-
scopic data for 7 were identical to those reported in the
literature (Scheme 3).
In order to examine the generality of this new method for the
preparation of d-lactam 5, several examples were tested; the
results are listed in Table 1. The regioselective reduction of
1 and the formation of d-lactam 5 could be rationalized by
the formation of enolate 4, which prevented the C-2
carbonyl group from LiAlH4 reduction. It is worth noting
that when reduction of 1 proceeded at rt (258C), hydroxy
lactam 3 was obtained exclusively. Nevertheless, when the
reaction mixture was heated to refluxing temperature in
THF solution, the corresponding d-lactam 5 was yielded as
the only product, presumably via B intermediate. Since
dianion intermediate C is more unstable compared with A
and B, the corresponding hydroxy amides (ring opening
products) were not observed at elevated temperature.
Table 1. Synthesis of 5 via regioselective LiAlH4 reduction
No.
1
R1
R2
R3
5 (yielda, %)
1
2
3
1a
1b
1c
Bn
Bn
Bn
H
Me
Ph
H
H
H
5a (75)
5b (86)
5c (78)
Scheme 3. Formal synthesis of (^)-paroxetine.
4
5
6
1d
1e
1f
Bn
H
H
H
5db (95)
5e (76)
5f (88)
Bn
4-FC6H4
2.3. Foral synthesis of (6)-tacamonine
PMB
Tacamonine (11), one of the few indole alkaloids of the
tacamane type, was isolated in 1984 from Tabernaemontana
eglandulosa,9 which possess vasodilator and hypotensive
activities. Lactam 10 has been converted to 11 in three
steps via Bischler–Napieralski cyclization.10 As shown in
7
8
1g
1h
Tryp
Tryp
H
H
H
Et
5g (85)
5h (83)
a
All yields were based on glutarimide 1.
The structure of 5d was confirmed by X-ray analysis (see Ref. 7).
b

C.-Y. Chen et al. / Tetrahedron 59 (2003) 9383–9387
9385
bath, and concentrated under reduced pressure. The residue
was diluted with water (5 mL) and extracted with ethyl
acetate (3£20 mL). The combined organic layers were
washed with brine, dried, filtered and evaporated. Purifi-
cation on silica gel (hexane/ethyl acetate¼4/1–2/1) pro-
duced products.
4.2.1. 3-Ethyl-1-[2-(1H-indol-3-yl)ethyl]-5-(toluene-4-
sulfonyl)piperidine-2,6-dione (1h). 82% Yield; mp 168–
1708C; 1H NMR (500 MHz, CDCl3) d 8.07 (brs, 0.7H), 8.04
(brs, 0.3H), 7.87 (d, J¼8.5 Hz, 0.7H), 7.72–7.63 (m, 2.3H),
7.36 (t, J¼8.0 Hz, 2.1H), 7.31 (t, J¼8.0 Hz, 0.9H), 7.18–
7.14 (m, 1H), 7.12–7.08 (m, 1H), 7.01 (d, J¼2.5 Hz, 0.7H),
6.95 (d, J¼2.5 Hz, 0.3H), 4.15–3.96 (m, 3H), 3.13–3.07
(m, 0.7H), 2.99–2.95 (m, 1.3H), 2.90–2.85 (m, 0.7H),
2.78–2.74 (m, 0.7H), 2.61–2.56 (m, 0.3H), 2.44 (s, 3H),
2.31–2.25 (m, 0.3H), 2.05–1.87 (m, 2H), 1.59–1.48 (m,
1H), 0.93 (t, J¼8.0 Hz, 2.1H), 0.90 (t, J¼8.0 Hz, 0.9H); 13C
NMR (125 MHz, CDCl3) d 173.15 (0.7C), 172.52 (0.3C),
165.01 (0.3C), 164.66 (0.7C), 145.72 (0.7C), 145.34 (0.3C),
136.07, 135.50 (0.3C), 135.01 (0.7C), 129.86, 129.57,
128.94, 127.52 (0.7C), 127.40 (0.3C), 122.35, 121.91,
119.34, 118.89, 112.34 (0.7C), 112.19 (0.3C), 111.06, 65.86
(0.7C), 65.70 (0.3C), 41.94, 41.25, 39.21, 23.84, 23.39
(0.3C), 23.24 (0.7C), 22.59 (0.7C), 22.46 (0.3C), 21.71
(0.7C), 21.69 (0.3C), 10.61 (0.3C), 10.46 (0.7C); IR
(CHCl3, cm21) 3025, 1667. Mass m/z (EI, 30 eV) 438
(Mþ, 8.26%), 143 (100%), 130 (76.27%); HRMS calcd for
C24H26O4N2S: 438.1613, found: 438.1617. Anal. calcd for
C24H26O4N2S: C, 65.73; H, 5.98; O, 14.59; N, 7.31, found:
C, 65.79; H, 5.96; O, 14.55; N, 7.28.
Scheme 4. Formal synthesis of (^)-tacamonine.
Scheme 4, following the same procedures as described in
the synthesis of 5e, the key intermediate 10 was obtained in 3
steps from 9 (61% overall yield). The spectroscopic data for
10 matched those reported in the literature.10a The present
work constitutes a formal synthesis of (^)-tacamonine (11).
3. Conclusion
In conclusion, we have developed a convenient method
for the preparation of substituted d-lactams in good yield.
We also successfully accomplished the formal synthesis of
(^)-paroxetine and (^)-tacamonine. Further application of
this methodology in the synthesis of other alkaloids is
currently underway in our laboratory.
4.3. Procedure of regioselective reduction of glutarimide
1 to d-lactam 5
A solution of glutarimides 1 (2.0 mmol) in THF (20 mL)
was added to a stirred solution of triethylamine (2.4 mmol)
in THF (10 mL). After the reaction mixture was stirred at rt
for 30 min, lithium aluminum hydride (10.0 mmol) was
added. The resulting mixture was refluxed for 3 h, quenched
with NH4Cl (1 mL) in an ice bath, filtered and then
concentrated under reduced pressure. The residue was
diluted with water (5 mL) and extracted with ethyl acetate
(3£20 mL). The combined organic layers were washed with
brine, dried, filtered and evaporated. Purification on silica
gel (hexane/ethyl acetate¼3/1–1/1) produced products.
4. Experimental
4.1. General
Before use, THF was distilled from a deep blue solution
resulting from sodium and benzophenone under nitrogen.
All reagents and solvents were obtained from commercial
sources and used without further purification. Thin layer
chromatography (TLC) analysis was performed with pre-
coated silica gel (60 f254 plates) and column chroma-
tography was carried out on silica (70–230 mesh). All
reactions were performed under an atmosphere of nitrogen
in dried (except those concerned with aqueous solutions)
spherical flasks and stirred with magnetic bars.
4.3.1. 1-Benzyl-3-(toluene-4-sulfonyl)piperidin-2-one
1
(5a). 75% Yield; H NMR (500 MHz, CDCl3) d 7.82 (d,
J¼7.5 Hz, 2H), 7.31–7.22 (m, 7H), 4.74 (d, J¼14.5 Hz,
1H), 4.43 (d, J¼14.5 Hz, 1H), 4.03 (t, J¼7.0 Hz, 1H), 3.37–
3.32 (m, 1H), 3.24–3.18 (m, 1H), 2.75–2.69 (m, 1H), 2.44
(s, 3H), 2.31–2.17 (m, 2H), 1.81–1.75 (m, 1H); 13C NMR
(125 MHz, CDCl3) d 162.01, 144.67, 136.67, 136.23,
129.46 (2C), 129.10 (2C), 128.67 (2C), 127.77 (2C),
127.50, 65.86, 50.56, 47.16, 22.08, 21.70, 20.39; IR
(CHCl3, cm21) 3027, 1662. Mass m/z (EI, 30 eV) 349
(Mþþ1, 3.66%), 91 (100%); HRMS calcd for C19H21O3NS:
343.1242, found: 343.1236.
4.2. Procedure of [313] cycloaddition to N-alkyl-3-
sulfonyl glutarimide 1
A solution of N-substituted-2-(toluene-4-sulfonyl) aceta-
mide (2.0 mmol) in THF (15 mL) was added to a rapidly
stirred suspension of sodium hydride (4.4 mmol, 60%) in
THF (10 mL). After the reaction mixture was stirred at rt
for 15 min, a solution of a,b-unsaturated ester (2.0 mmol)
in THF (10 mL) was added. The resulting mixture was
refluxed for 30 min, quenched with NH4Cl (1 mL) in an ice
4.3.2. 1-Benzyl-4-methyl-3-(toluene-4-sulfonyl)piperi-
1
din-2-one (5b). 86% Yield; H NMR (500 MHz, CDCl3)
d 7.78 (d, J¼8.5 Hz, 2H), 7.35–7.26 (m, 7H), 4.67 (d,

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C.-Y. Chen et al. / Tetrahedron 59 (2003) 9383–9387
J¼15.0 Hz, 1H), 4.52 (d, J¼15.0 Hz, 1H), 3.76 (d, J¼
4.0 Hz, 1H), 3.41–3.36 (m, 1H), 3.25–3.20 (m, 1H), 3.09–
3.05 (m, 1H), 2.44 (s, 3H), 2.39–2.33 (m, 1H), 1.57–1.50
(m, 1H), 1.19 (d, J¼7.5 Hz, 3H); 13C NMR (125 MHz,
CDCl3) d 161.82, 144.73, 136.40, 136.33, 129.49 (2C),
128.99 (2C), 128.67 (2C), 127.81 (2C), 127.52, 72.52,
CDCl3) d 7.80 (d, J¼8.5 Hz, 2H), 7.35 (d, J¼8.5 Hz, 2H),
7.18 (D, J¼8.5 Hz, 2H) 6.86 (d, J¼8.5 Hz, 2H), 4.62 (d, J¼
14.5 Hz, 1H), 4.51 (d, J¼3.0 Hz, 1H) 4.40 (d, J¼14.5 Hz,
1H), 4.01 (d, J¼7.5 Hz, 1H), 3.80 (s, 3H), 3.39–3.33 (m,
2H), 3.21–3.17 (m, 1H), 3.00–2.91 (m, 2H), 2.90–2.73 (m,
2H), 2.45 (s, 3H), 2.35–2.33 (m, 1H), 2.11–1.90 (m, 3H);
13C NMR (125 MHz, CDCl3) d 161.46, 159.31, 145.10,
136.46, 129.81 (2C), 129.50 (2C), 129.19 (2C), 128.42,
114.29 (2C), 68.93, 55.50, 50.30, 50.03, 44.00, 36.71, 29.34,
29.15, 25.57, 23.99, 21.98; IR (CHCl3, cm21) 3045, 1682.
Mass m/z (EI, 30 eV) 491 (Mþ, 1.28%), 336 (91.88%), 121
(100%); HRMS calcd for C24H29O4NS3: 491.1259, found:
491.1252.
50.77, 44.27, 27.67, 27.57, 21.71, 20.22; IR (CHCl3, cm21
)
3025, 1668. Mass m/z (EI, 30 eV) 358 (Mþþ1, 1.36%), 202
(100%), 91 (86.07%); HRMS calcd for C20H23O3NS:
357.1399, found: 357.1392.
4.3.3. 1-Benzyl-4-phenyl-3-(toluene-4-sulfonyl)piperi-
1
din-2-one (5c). 78% Yield; H NMR (500 MHz, CDCl3) d
7.77 (d, J¼8.0 Hz, 2H), 7.35–7.21 (m, 10H), 7.10 (d, J¼
7.0 Hz, 2H), 4.73 (d, J¼15.0 Hz, 1H), 4.56 (d, J¼15.0 Hz,
1H), 4.30–4.27 (m, 2H), 3.38–3.36 (m, 1H), 3.06–3.00 (m,
1H), 2.66–2.60 (m, 1H), 2.43 (s, 3H), 1.89–1.83 (m, 1H);
13C NMR (125 MHz, CDCl3) d 162.05, 144.83, 141.36,
136.28, 136.06, 129.47 (2C), 128.99 (2C), 128.80 (2C),
128.59 (2C), 127.97 (2C), 127.54, 127.18, 126.95 (2C),
4.3.7. 1-[2-(1H-Indol-3-yl)ethyl]-3-(toluene-4-sulfonyl)-
piperidin-2-one (5g). 85% Yield; 1H NMR (500 MHz,
CDCl3) d 8.35 (brs, 1H), 7.80 (d, J¼8.5 Hz, 2H), 7.58 (d,
J¼5.0 Hz, 1H), 7.33–7.30 (m, 3H), 7.16 (t, J¼7.5 Hz, 1H),
7.09 (t, J¼2.5 Hz, 1H), 7.05 (s, 1H), 3.96 (t, J¼6.0 Hz, 1H),
3.75–3.70 (m, 1H), 3.50–3.45 (m, 1H), 3.15–3.10 (m, 1H),
3.04–2.98 (m, 4H), 2.59–2.54 (m, 1H), 2.40 (s, 3H), 2.09–
2.07 (m, 2H); 13C NMR (125 MHz, CDCl3) d 161.54,
144.62, 136.25, 129.43 (2C), 128.99 (2C), 127.21, 122.62,
121.80, 119.15, 118.45, 112.38, 111.30, 65.80, 51.09, 49.08,
48.76, 22.85, 21.93, 21.62, 20.40; IR (CHCl3, cm21) 3052,
1688. Mass m/z (EI, 30 eV) 396 (Mþ, 1.35%), 143 (100%);
HRMS calcd for C22H24O3N2S: 396.1507, found: 396.1510.
70.59, 50.85, 44.00, 37.75, 28.57, 21.66; IR (CHCl3, cm21
)
3030, 1658. Mass m/z (EI, 30 eV) 420 (Mþþ1, 2.29%), 264
(95.59%), 91 (100%); HRMS calcd for C25H25O3NS:
419.1555, found: 419.1549.
4.3.4. 1-Benzyl-4-dimethoxymethyl-3-(toluene-4-sulfo-
1
nyl)piperidin-2-one (5d)7. 95% Yield; mp 96–988C; H
NMR (500 MHz, CDCl3) d 7.81 (d, J¼8.0 Hz, 2H), 7.40 (d,
J¼8.0 Hz, 2H), 7.34–7.27 (m, 5H), 4.61 (dd, J¼15.0,
4.0 Hz, 2H), 4.35 (d, J¼5.6 Hz, 1H), 4.13 (d, J¼2.5 Hz,
1H), 3.38 (s, 1H), 3.37 (s, 1H), 3.35 (t, J¼4.5 Hz, 1H),
3.28–3.23 (m, 2H), 2.46 (s, 3H), 2.36–2.31 (m, 1H), 1.87–
1.83 (m, 1H); 13C NMR (125 MHz, CDCl3) d 161.75,
144.71, 136.27, 136.22, 129.45, 128.93, 128.51, 127.80,
127.39, 104.88, 66.82, 54.96, 54.37, 50.75, 44.62, 34.83,
21.65, 20.73; IR (CHCl3, cm21) 3030, 2928. Mass m/z (EI,
30 eV) 418 (Mþþ1, 1.32%), 262 (58.37%), 91 (100%);
HRMS calcd for C22H27O5NS: 417.1610, found: 417.1604.
Single-crystal X-ray diagram: crystal of 5d was grown by
slow diffusion of ethyl acetate into a solution of 5d in
dichloromethane to yield colorless prism. The compound
crystallizes in the primitive orthorhombic crystal system,
4.3.8. 5-Ethyl-1-[2-(1H-indol-3-yl)ethyl]-3-(toluene-4-
sulfonyl)piperidin-2-one (5h). 83% Yield; mp 173–
1758C; H NMR (500 MHz, CDCl3) d 8.14 (brs, 1H), 7.82
1
(d, J¼8.5 Hz, 1H), 7.79 (d, J¼8.5 Hz, 1H), 7.61 (d, J¼
8.0 Hz, 0.5H), 7.57 (d, J¼8.0 Hz, 0.5H), 7.35–7.31 (m,
3H), 7.18 (t, J¼7.5 Hz, 1H), 7.12–7.08 (m, 1H), 7.02 (d,
J¼2.5 Hz, 1H), 4.05 (dd, J¼3.5, 7.5 Hz, 0.5H), 3.92 (dd,
J¼2.5, 4.5 Hz, 0.5H), 3.78–3.73 (m, 0.5H), 3.69–3.65 (m,
0.5H), 3.55–3.44 (m, 1H), 3.15–3.12 (m, 0.5H), 3.04–3.01
(m, 0.5H), 3.03–2.85 (m, 2H), 2.75 (t, J¼10.5 Hz, 1H),
2.44–2.39 (m, 0.5H), 2.42 (s, 3H), 2.27–2.24 (m, 0.5H),
1.96–1.89 (m, 0.5H), 1.68–1.61 (m, 1H), 1.53–1.48 (m,
0.5H), 1.30–1.14 (m, 2H), 0.82 (t, J¼7.5 Hz, 1.5H), 0.77 (t,
J¼7.5 Hz, 1.5H); 13C NMR (125 MHz, CDCl3) d 161.86
(0.5C), 161.51 (0.5C), 144.63 (0.5C), 144.50 (0.5C), 136.84
(0.5C), 136.61 (0.5C), 136.24, 129.46 (0.5C), 129.35
(0.5C), 129.17, 128.98, 127.26, 122.55 (0.5C), 122.36
(0.5C), 121.97 (0.5C), 121.93 (0.5C), 119.30 (0.5C), 119.28
(0.5C), 118.54, 112.62, 111.22 (0.5C), 111.20 (0.5C), 65.71
(0.5C), 65.54 (0.5C), 53.99 (0.5C), 53.80 (0.5C), 49.12
(0.5C), 49.01 (0.5C), 34.95, 31.58, 27.67 (0.5C), 27.42
(0.5C), 26.01 (0.5C), 26.00 (0.5C), 22.87 (0.5C), 22.82
(0.5C), 21.67, 11.00 (0.5C), 10.94 (0.5C); IR (CHCl3,
cm21) 3053, 1687. Mass m/z (EI, 30 eV) 424 (Mþ, 1.18%),
143 (100%); HRMS calcd for C24H28O3N2S: 424.1821,
found: 424.1817. Anal. calcd for C24H28O3N2S: C, 67.90;
H, 6.65; O, 11.31; N, 6.60, found: C, 67.93; H, 6.61; O,
11.25; N, 6.58.
˚
˚
space group P21/c (#14), a¼10.634(2) A, b¼24.581(4) A,
3
c¼8.383(2) A, V¼2133.1(7) A , Z¼4, dcalcd¼1.300 g/cm3,
˚
˚
F(000)¼888.00, 2u range 16(20.5–27.98).
4.3.5. 1-Benzyl-4-(4-fluorophenyl)-3-(toluene-4-sulfo-
nyl)piperidin-2-one (5e). 76% Yield; 1H NMR
(500 MHz, CDCl3) d 7.76 (d, J¼8.5 Hz, 2H), 7.34–7.29
(m, 7H), 7.09–7.06 (m, 2H), 6.97–6.93 (m, 2H), 4.68 (d,
J¼14.5 Hz, 1H), 4.59 (d, J¼14.5 Hz, 1H), 4.26–4.23 (m,
1H), 4.21 (d, J¼2.5 Hz, 1H), 3.42–3.38 (m, 1H), 3.07–3.02
(m, 1H), 2.62–2.56 (m, 1H), 2.44 (s, 3H), 1.86–1.81 (m,
1H); 13C NMR (125 MHz, CDCl3) d 161.96, 160.81,
145.00, 137.33, 136.16, 136.02, 129.55 (2C), 129.06 (2C),
128.68 (2C), 128.66, 128.59, 128.08 (2C), 127.70, 115.81,
115.63, 71.00, 50.99, 44.11, 37.41, 28.91, 21.71; IR (CHCl3,
cm21) 3021, 1616. Mass m/z (EI, 30 eV) 438 (Mþþ1,
6.47%), 282 (23.70%), 91 (100%); HRMS calcd for
C25H24O3NSF: 437.1461, found: 437.1464.
4.4. Procedure of reductive desulfonylation of 3-sulfonyl
lactam 5
6% Sodium amalgam (Na/Hg, 3.0 g) and sodium phosphate
(40 mg) were added to a stirred solution of 3-sulfonyl
lactam 5 (2.0 mmol) in methanol (5 mL), and vigorously
4.3.6. 1-Benzyl-4-[1,3]dithian-2-yl-3-(toluene-4-sulfo-
1
nyl)piperidin-2-one (5f). 88% Yield; H NMR (500 MHz,

C.-Y. Chen et al. / Tetrahedron 59 (2003) 9383–9387
9387
New York, 1985; Vol. 26, p 89. (b) Oefner, C.; Binggeli, A.;
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W.; Gruninger, F.; Guller, R.; Hirth, G.; Marki, H.; Mathews,
S.; Miller, M.; Ridley, R. G.; Stadler, H.; Viera, E.; Wilhelm,
M.; Winklr, F.; Wostl, W. Chem. Biol. 1999, 6, 127. (c) Viera,
E.; Binggeli, A.; Breu, V.; Bur, D.; Fischli, W.; Gu¨ller, R.;
stirred for 2 h at rt. The residue was filtered and washed with
methanol (2£10 mL). The combined organic layers were
concentrated to obtain the crude product. Purification on
silica gel (hexane/ethyl acetate¼2/1–1/1) produced
products.
4.4.1. 1-Benzyl-4-(4-fluorophenyl)piperidin-2-one (7).
1
90% Yield; H NMR (500 MHz, CDCl3) d 7.35–7.32 (m,
¨
¨
Hirth, G.; Marki, H. P.; Muller, M.; Oefner, C.; Stadler, H.;
Wilhelm, M.; Wostl, W. Bioorg. Med. Chem. Lett. 1999, 9,
1397. (d) Gu¨ller, R.; Binggeli, A.; Breu, V.; Bur, D.; Fischli,
W.; Hirth, G.; Jenny, C.; Kansy, M.; Montavon, F.; Mu¨ller,
M.; Oefner, C.; Stadler, H.; Vieira, E.; Wilhelm, M.; Wostl,
2H), 7.30–7.27 (m, 3H), 7.15 (dd, J¼5.0, 8.5 Hz 2H), 7.01
(t, J¼8.5 Hz, 2H), 4.74 (d, J¼14.5 Hz, 1H), 4.55 (d, J¼
14.5 Hz, 1H), 3.33–3.24 (m, 2H), 3.12–3.06 (m, 1H), 2.80
(ddd, J¼2.0, 5.5, 17.0 Hz, 1H), 2.55 (dd, J¼11.0, 17.0 Hz,
2H), 2.08–2.03 (m, 1H), 1.94–1.86 (m, 1H); 13C NMR
(125 MHz, CDCl3) d 169.04, 162.57, 139.05, 136.98,
128.60 (2C), 128.14 (2C), 127.93, 127.87, 127.44, 115.57,
115.41, 49.98, 46.19, 39.57, 37.94, 30.26; IR (CHCl3,
cm21) 3027, 1618. Mass m/z (EI, 30 eV) 283 (Mþ, 2.48%),
91 (100%); HRMS calcd for C18H18ONF: 283.1367, found:
283.1362.
¨
W.; Marki, P. Bioorg. Med. Chem. Lett. 1999, 9, 1403.
2. (a) Southon, I. W.; Buckingham, J. Dictionary of Alkaloids;
Chapman & Hall: London, 1989. (b) Daly, J. W. J. Nat. Prod.
1998, 61, 162.
3. (a) Yamaguchi, R.; Moriyasu, M.; Yoshioka, M.; Kawanisi,
M. J. Org. Chem. 1988, 53, 3507. (b) Comins, D. L.; Killpack,
M. O. J. Am. Chem. Soc. 1992, 114, 10973. (c) Midland,
M. M.; McLoughlin, J. I. Tetrahedron Lett. 1988, 29, 4653.
(d) Flann, C.; Malone, T. C.; Overman, L. E. J. Am. Chem.
Soc. 1987, 109, 6097. (e) Overman, L. E.; Sarkar, A. K.
Tetrahedron Lett. 1992, 33, 4103. (f) Castro, P.; Overman,
L. E.; Zhang, X.; Mariano, P. S. Tetrahedron Lett. 1993, 34,
5243. (g) de Kimpe, N.; Boelens, M.; Piqueru, J.; Baele, J.
Tetrahedron Lett. 1994, 35, 1925. (h) Yang, T. K.; Teng, T. F.;
Lin, J. Y.; Lay, T. Y. Tetrahedron Lett. 1994, 35, 3581.
(i) Francois, D.; Lallemand, M. C.; Selkti, M.; Tomas, A.;
Kunesch, N.; Husson, H. P. Angew. Chem., Int. Ed. Engl.
1998, 37, 104.
4.4.2. 5-Ethyl-1-[2-(1H-indol-3-yl)ethyl]piperidin-2-one
(10). 90% Yield; mp 147–1498C; 1H NMR (500 MHz,
CDCl3) d 8.22 (brs, 1H), 7.66 (d, J¼8.0 Hz, 1H), 7.35 (d,
J¼8.0 Hz, 1H), 7.18 (t, J¼7.5 Hz, 1H), 7.11 (t, J¼7.5 Hz,
1H), 7.04 (s, 1H), 3.70–3.59 (m, 2H), 3.17–3.14 (m, 1H),
3.03 (t, J¼7.5 Hz, 2H), 2.86 (t, J¼10.5 Hz, 1H), 2.50–2.45
(m, 1H), 2.38–2.31 (m, 1H), 1.85–1.81 (m, 1H), 1.58–1.54
(m, 1H), 1.38–1.32 (m, 1H), 1.28–1.22 (m, 2H), 0.83 (t,
J¼7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) d 169.94,
136.25, 127.51, 121.94, 121.92, 119.26, 118.75, 113.20,
111.13, 53.82, 48.39, 35.52, 31.62, 26.87, 26.01, 22.93,
11.29; IR (CHCl3, cm21) 3050, 1681. Mass m/z (EI, 30 eV)
424 (Mþ, 1.18%), 143 (100%); HRMS calcd for
C17H22ON2: 270.1732, found: 270.1729. Anal. calcd for
C17H22ON2: C, 75.52; H, 8.21; O, 5.92; N, 10.36, found: C,
75.68; H, 8.15; O, 5.90; N, 10.34.
4. (a) Chang, M. Y.; Chang, B. R.; Tai, H. M.; Chang, N. C.
Tetrahedron Lett. 2000, 41, 10273. (b) Chang, M. Y.; Chen,
S. T.; Chang, N. C. Tetrahedron 2002, 58, 5075.
5. (a) Chang, M. Y.; Chen, S. T.; Chang, N. C. Tetrahedron 2002,
58, 3623. (b) Hsu, R. T.; Cheng, L. M.; Chang, N. C.; Tai,
H. M. J. Org. Chem. 2002, 67, 5044. (c) Chang, B. R.; Chen,
C. Y.; Chang, N. C. Tetrahedron Lett. 2002, 43, 3233.
6. Wijnberg, J. B. P. A.; Schoemaker, H. E.; Speckamp, W. N.
Tetrahedron 1978, 34, 179.
5. Supplementary Material
7. CCDC 219521 contains the supplementary crystallographic
data for this paper. This data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax:
þ44-1223-336033; e-mail: deposit@ccdc.cam.ac.uk).
8. Yu, M. S.; Lantos, I.; Peng, Z. O.; Yu, J.; Cacchio, T.
Tetrahedron Lett. 2000, 41, 5647.
Experimental procedures and photocopies of spectral data
for 1h, 5a–5h, 7, 10 (1H NMR in CDCl3) were supported.
Acknowledgements
9. van Beek, T. A.; Verpoorte, R.; Baerheim Svendsen, A.
Tetrahedron 1984, 40, 737.
´
10. (a) Massiot, G.; Sousa Oliverira, F.; Levy, J. Bull. Soc. Chim.
Financial support from the National Science Council of the
Republic of China is gratefully acknowledged.
Fr. II 1982, 185. (b) Danieli, B.; Lesma, G.; Macecchini, S.;
Passarella, D.; Silvani, A. Tetrahedron: Asymmetry 1999, 10,
4057.
References
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