Efficient synthesis of 4,5-disubstituted-3-toluenesulfonyl glutarimides. Application to the formal synthesis of mappicine ketone

Article abstract of DOI:10.1002/jccs.200800064

Various 4,5-disubstituted-3-sulfonyl glutarimides 3 were synthesized from α-sulfonyl acetamide 1 and ethyl α,β-disubstituted acrylate esters 2 via stepwise facile [3+3] annulation in moderate yield. The synthesis of pyridin-2-one 9, a key intermediate for mappicine ketone (4) synthesis, was also reported.

Full text of DOI:10.1002/jccs.200800064

Journal of the Chinese Chemical Society, 2008, 55, 431-434
431
Efficient Synthesis of 4,5-Disubstituted-3-toluenesulfonyl Glutarimides.
Application to the Formal Synthesis of Mappicine Ketone
Yung-Sheng Wanga (
Ching-Han Linb* (
), Nein-Chen Changa* (
) and Huo-Mu Taib (
),
)
aDepartment of Chemistry, National Sun Yat-Sen University, Kaohsiung, Taiwan 804, R.O.C.
bDepartment of Applied Chemistry, Chia-Nan University of Pharmacy and Science,
Tainan 717, Taiwan, R.O.C.
Various 4,5-disubstituted-3-sulfonyl glutarimides 3 were synthesized from a-sulfonyl acetamide 1
and ethyl a,b-disubstituted acrylate esters 2 via stepwise facile [3+3] annulation in moderate yield. The
synthesis of pyridin-2-one 9, a key intermediate for mappicine ketone (4) synthesis, was also reported.
Keywords: Ethyl a,b-disubstituted acrylate esters; [3+3] Annulation; Mappicine ketone.
INTRODUCTION
Table 1. Reaction of a-toluenesulfonylacetamide 1 and ethyl
a,b-disubstituted acrylate esters 2
Glutarimides possess various biological activities.1
Therefore, the preparation of these cyclic imides has at-
tracted considerable attention from organic chemists.2 Pre-
viously, we reported an efficient route to N-benzyl-3-sul-
fonyl-4 or 5-substituted glutarimides 3 via stepwise [3+3]
cycloaddition of N-benzyl a-sulfonylacetamide 1 with
a,b-unsaturated esters 2. We then further converted 3 to
various six-membered nitrogen containing heterocycles
and alkaloids3 (Shceme I). In this paper, we extended the
results to the synthesis of N-benzyl-4,5-disubstituted-3-
sulfonyl glutarimides. Synthetic study toward mappicine
ketone (4)4 (Fig. 1) is also reported.
R2
R2
TolO2S
O
TolO2S
O
R3
O
+
NaH
R3
THF, 55oC
NH
R1
N
R1
CO2Et
2
1
3
Product 5
Entry
R3
R1
R2
(yield %)
3a (71)a
3b (40)b
3c (43)b
1
2
3
4
Bn
Bn
Bn
CH3
CH3
CH3
CH(OCH3)2
CH2CH3
CH3
CH(OCH3)2
CH2OBn
3d (81)a
PMB
a. a mixture of two stereoisomers
b. one stereoisomer
Shceme I
sired glutarimide 3a was isolated as a mixture in 71% yield.
Encouraged by this result, various ethyl a,b-disubstituted
acrylate esters 2 were examined. The corresponding trisub-
stituted glutarimides 3 were obtained in moderate yield.
The scope of the reaction appears to be limited to
dialkyl a,b-disubstituted acrylic acid ethyl esters. It is
worth noting that entries 2 and 3 gave low yields. In the re-
actions of b-aryl-a-alkyl or b,b-disubstituted acrylic acid
R2
R2
TolO2S
O
TolO2S
O
R3
O
+
NaH
R3
alkaloides
NH
R1
N
R1
CO2Et
2
1
3
RESULTS AND DISCUSSION
Synthesis of 4,5-dimethyl-3-toluenesulfonyl glutar-
imide 3a
O
N
We first investigated the reaction of 1 with ethyl
tiglate. Amixture of N-benzyl a-sulfonylacetamide 1 and 3
equiv of sodium hydride in THF was allowed to react at
room temperature for 10 min, then 4 equiv of ethyl tiglate
was added in one portion and the solution was further
stirred at 55 °C for 12 hours. After general workup, the de-
N
O
Mappicine ketone (4)
Fig. 1

432 J. Chin. Chem. Soc., Vol. 55, No. 2, 2008
Wang et al.
ethyl esters, no desired glutarimides were obtained. The
presence of large substituent(s) at the b-position in ester
might account for the results.
tory.
EXPERIMENTAL
General
Preparation of pyridin-2-one 9, a key intermediate
for the synthesis of mappicine ketone (4)
Before use, THF was distilled from a deep blue solu-
tion resulting from sodium and benzophenone under nitro-
gen. All reagents and solvents were obtained from com-
mercial sources and used without further purification. Thin
layer chromatography (TLC) analysis was performed with
precoated silica gel (60 f254 plates) and column chroma-
tography was carried out on silica (70~230 mesh). All reac-
tions were performed under an atmosphere of nitrogen in
dried (except those concerned with aqueous solutions)
spherical flasks and stirred with magnetic bars. Organic
layers were dried with anhydrous magnesium sulfate be-
fore concentration in vacuo.
To demonstrate the synthetic utility of these results,
the synthesis of pyridin-2-one 9, the key intermediate for
mappicine ketone synthesis,4a was investigated. As de-
picted in Scheme II, regioselective reduction of 3d with ex-
cess sodium borohydride in methanol-tetrahydrofuran
(1:2) at -20 °C furnished hydroxy lactam 5. Without purifi-
cation, lactam 5 was treated with methanol in the presence
of BF3-Et2O to afford methoxy lactam 6 in 80% yield (two
steps from 3d). Removal of the benzyl protection in 6 with
hydrogen gas at 1 atm in the presence of palladium catalyst
obtained alcohol 7 in 95% yield. Oxidation of the primary
alcohol in 7 with PCC furnished the corresponding alde-
hyde 8 in 85% yield. Base promoted double elimination of
8 with DBU afforded pyridin-2-one 9. Pyridin-2-one 9 has
been converted to mappicine ketone (4).4a
General procedure to 4,5-disubstituted-3-toluene-
sulfonyl glutarimides (3a)-(3d)
A solution of a-toluenesulfonyl acetamide 1 (1.0
mmole) in THF (20 mL) was added to a rapidly stirred sus-
pension of sodium hydride (60% dispersion in mineral oil,
3.0 mmole). After the reaction mixture was stirred at room
temperature for 10 minutes, 4.0 mmole of a,b-unsaturated
esters 2 was then added to the suspension mixture. The
mixture was stirred at 55 °C for 12 h, quenched with water
(5 mL) and extracted with AcOEt (3 ´ 20 mL). The organic
layers were washed with brine, dried with anhydrous
MgSO4, filtered and evaporated. The residue was purified
by column chromatography on silica gel (elution with hex-
ane/ethyl acetate = 4:1) to give 4,5-disubstituted-3-tolu-
enesulfonyl glutarimides 3.
For 3a: 71% Yield; colorless oil; 1H NMR (500 MHz,
CDCl3): d) 7.61-7.46 (d, J = 8.5 Hz, 2H), 7.36-7.20 (m,
7H), 5.05-4.82 (dd, J = 14 Hz, 14 Hz, 2H), 3.94-3.92 (m,
1H), 3.63-3.58 (m, 1H), 3.15-3.10 (m, 1H), 2.76-2.69 (m,
1H), 2.45-2.43 (s, 3H), 1.50 (d, J = 7 Hz, 3H), 1.35 (d, J =
6.5 Hz, 3H). Ratio = 1:1.5 base one d) 7.59: d) 7.46. LRMS
m/z (ESI, M++1, 2.5e +0.6): 386. HRMS (ESI) calcd for
C21H24NO4S (M+ +1) 386.1426, found 386.1424.
Scheme II
OBn
OBn
O
TolO2S
O
TolO2S
HO
NaBH4, MeOH
-20oC
BF3-Et2O, MeOH
80%
N O
PMB
N
PMB
( 2 steps from 3d)
3d
5
OBn
OH
TolO2S
MeO
H2, Pd/C
95%
PCC
85%
TolO2S
MeO
N O
PMB
N O
PMB
6
7
H
O
H
O
O
N
ref. 4g
TolO2S
MeO
DBU, toluene
reflux, 86%
N
N
PMB
O
N
PMB
O
O
Mappicine ketone (4)
8
9
1
For 3b: 40% Yield; pale yellow oil; H NMR (500
MHz, CDCl3): d) 7.58 (d, J = 8.5 Hz, 2H), 7.33-7.22 (m,
7H), 4.99 (d, J = 14 Hz, 1H), 4.89 (d, J = 14 Hz, 1H), 4.37
(s, 1H), 4.21 (d, J = 3.5 Hz, 1H), 3.38 (s, 3H), 3.06 (d, J =
3.5 Hz, 1H), 2.81 (q, J = 8 Hz, 1H), 2.44 (s, 3H), 1.66 (d, J =
8 Hz, 3H). 13C NMR (125 MHz, CDCl3): d) 174.24,
164.63, 145.31, 136.61, 135.38, 129.72 (2C), 128.92 (2C),
128.64 (2C), 128.11 (2C), 127.18, 107.29, 65.14, 59.34,
CONCLUSION
In summary, we have successfully generated 4,5-di-
substituted 3-toluenesulfonyl glutarimides via a one pot
procedure. This methodology has proved to be applicable
for the synthesis of mappicine ketone (4). Further applica-
tion of these results in the synthesis of camptothecin and
other related alkaloids is currently underway in our labora-

Synthesis toward Glutarimides and Mappicine Ketone
J. Chin. Chem. Soc., Vol. 55, No. 2, 2008 433
55.93, 43.95, 37.68, 35.94, 21.72, 18.92. IR (CHCl3, cm-1):
2401, 2305, 1676, 1552. LRMS m/z (EI, 30 eV): 445
(1.7%), 290 (58.15%), 91 (94.02%), 75 (100%). HRMS
(FAB) calcd for C23H27NO6S (M++1) 446.1644, found
446.1637.
J = 8.0 Hz, 2H), 7.36-7.20 (m, 7H), 7.16 (d, J = 8.0 Hz, 2H),
6.87 (d, J = 8.5 Hz, 2H), 4.50 (d, J = 14.5 Hz, 1H), 4.48 (d, J
= 1 Hz, 1H), 4.33 (q, J = 5.5 Hz, 2H), 4.17 (d, J = 14.5 Hz,
1H), 3.81-3.77 (m, 4H), 3.47-3.40 (m, 2H), 2.74-2.68 (m,
4H), 2.41 (s, 3H), 2.22 (m, 1H), 1.22 (d, J = 7.0 Hz, 3H).
13C NMR (125 MHz, CDCl3): d 173.9, 159.1, 145.1, 137.9,
134.5, 130.8, 129.9, 129.2, 128.8, 128.4, 128.3, 127.6,
127.5, 113.7, 85.9, 72.7, 69.5, 63.5, 55.6, 55.2, 50.3, 39.0,
34.7, 21.7, 13.1. IR (CHCl3, cm-1): 2305, 1603. LRMS m/z
(EI, 30 eV): 537 (0.25%), 121 (100%), 91 (94%).
1
For 3c: 43% Yield; pale yellow oil; H NMR (500
MHz, CDCl3): d) 7.67 (d, J = 9 Hz, 2H), 7.34-7.20 (m, 7H),
4.98 (d, J = 14.5 Hz, 1H), 4.91 (d, J = 14.5 Hz, 1H), 4.43 (s,
1H), 4.18 (d, J = 3 Hz, 1H), 3.39 (s, 3H), 3.23 (d, J = 1.5 Hz,
1H), 3.18 (s, 3H), 2.58 (t, J = 3 Hz, 1H), 2.44 (s, 3H),
2.19-2.01 (m, 2H), 1.11 (t, J = 7.5 Hz, 3H). 13C NMR (125
MHz, CDCl3): d) 173.56, 164.63, 145.17, 136.64, 136.12,
129.69 (2C), 128.89 (2C), 128.42 (2C), 128.06 (2C),
127.08, 107.67, 64.62, 56.43, 55.86, 43.70, 43.36, 34.88,
25.61, 21.68, 12.14. IR (CHCl3, cm-1): 1672. LRMS m/z
(FAB): 460 (1.07%), 272 (54.3%), 91 (100%), 75 (90.73%).
HRMS (FAB) calcd for C24H30NO6S (M++1) 460.1794,
found 460.1787.
4-Hydroxymethyl-6-methoxy-1-(4-methoxybenzyl)-3-
methyl-5-(toluene-4-sulfonyl)-piperidine-2-one (7)
To a solution of methoxy lactam 6 (451 mg, 0.84
mmol) in 15 mL of MeOH was added a catalytic amount of
Pd/C, and the reaction mixture was stirred under hydrogen
overnight. After filtration of the catalyst, the solution was
extracted with CH2Cl2 and washed with water. The organic
layer was washed with brine, dried over MgSO4, and con-
centrated under reduced pressure. The crude residue was
subjected to flash silica gel chromatography (elution with
hexane/ethyl acetate 2:1) to give 338 mg (90%) of 7, pale
yellow oil. 1H NMR (500 MHz, CDCl3): d 7.66 (d, J = 8 Hz,
2H), 7.35 (d, J = 8 Hz, 2H), 7.28 (d, J = 8 Hz, 2H), 6.87 (d, J
= 8 Hz, 2H), 5.06 (d, J = 14.5 Hz, 1H), 4.87 (d, J = 1 Hz,
1H), 4.12 (d, J = 14.5 Hz, 1H), 3.80 (s, 3H), 3.77 (dd, J =
3.5, 1 Hz, 1H), 3.60 (d, J = 3.5 Hz, 1H), 2.75 (s, 3H), 2.67
(m, 1H), 2.46 (s, 3H), 2.23 (m, 1H), 1.26 (d, J = 7 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d 173.73, 159.20, 145.51,
134.33, 130.82 (2C), 130.12 (2C), 129.27, 128.77 (2C),
113.81 (2C), 85.64, 64.13, 62.86, 55.81, 55.25, 50.46,
40.43, 34.32, 21.70, 13.34. IR (CHCl3, cm-1): 2253, 1672.
LRMS m/z (EI, 30 eV): 447 (5.54%), 260 (26.67%), 121
(100%). HRMS (EI, 30 eV) calcd for C23H29NO6S (M+)
447.1713, found 447.1710.
1
For 3d: 81% Yield; pale yellow oil; H NMR (500
MHz, CDCl3): d) 7.45 (d, J = 8.5 Hz, 2H), 7.36-7.24 (m,
7H), 7.18 (d, J = 7.5 Hz, 2H), 6.80 (d, J = 8.5 Hz, 2H),
4.90-4.74 (m, 2H), 4.41 (d, J = 6 Hz, 2H), 4.22 (d, J = 3.5
Hz, 1H), 3.77 (s, 3H), 3.68-3.53 (m, 2H), 2.87-2.83 (m,
1H), 2.73-2.68 (m, 1H), 2.45 (s, 3H), 1.52 (d, J = 7.5 Hz,
3H). LRMS m/z (ESI, M++1, 2.5e+0.6): 522. HRMS (ESI)
calcd for C29H32NO6S (M+ +1) 522.1950, found 522.1953.
4-Benzyloxymethyl-6-methoxy-1-(4-methoxybenzyl)-3-
methyl-5-(toluene-4-sulfonyl)-piperidine-2-one (6)
A suspension of sodium borohydride (8.0 mmole)
and glutarimides 1 (1.5 mmole) in THF (30 mL) and metha-
nol (15 mL) was stirred for 2 h at -20 °C. After saturated
aqueous sodium bicarbonate was added to destroy the ex-
cess reduction agent at this temperature, organic solvents
were removed under reduced pressure. The residue was ex-
tracted with dichloromethane, and the combined organic
extracts were washed with brine, dried, filtered, and con-
centrated to afford 5. Without further purification, boron
trifloride diethyl etherate (0.5 mL) was added to a solution
of crude 5 in MeOH (20 mL) at 0 °C and stirred at this tem-
perature for 30 min. The reaction mixture was quenched
with saturated aqueous sodium bicarbonate. The layers
were separated, and the aqueous layer was extracted with
dichloromethane. The combined organic layers were washed
with brine, dried, filtered, and concentrated. The residue
was purified by column chromatography on silica gel (elu-
tion with hexane/ethyl acetate 2:1) to give methoxy lactam
6, pale yellow oil. 1H NMR (500 MHz, CDCl3): d) 7.54 (d,
2-Methoxy-1-(4-methoxybenzyl)-5-methyl-6-oxo-3-
(toluene-4-sulfonyl)-piperidine-4-carbaldehyde (8)
A solution of 7 (551 mg, 1.23 mmole) in CH2Cl2 (15
mL) was added to a mixture of PCC (317 mg, 1.47 mmole)
and Celite in CH2Cl2 (10 mL). The reaction mixture was
stirred overnight at room temperature, then filtered over a
short pad of silica gel with (hexane/ethyl acetate 4:1) to
provide 466 mg (85%) of aldehyde 8, pale yellow oil. 1H
NMR (500 MHz, CDCl3): d 9.54 (s, 1H), 7.64 (d, J = 8.5
Hz, 2H), 7.36 (d, J = 8 Hz, 2H), 7.29 (d, J = 8.5 Hz, 2H),
6.88 (d, J = 8 Hz, 2H), 4.98 (d, J = 14.5 Hz, 1H), 4.91 (d, J =
1.5 Hz, 1H), 4.27 (d, J = 14.5 Hz, 1H), 4.10 (dd, J = 5, 1.5
Hz, 1H), 3.81 (s, 3H), 2.94-2.77 (m, 2H), 2.77 (s, 3H), 2.46

434 J. Chin. Chem. Soc., Vol. 55, No. 2, 2008
Wang et al.
(s, 3H), 1.40 (d, J = 7 Hz, 3H). 13C NMR (125 MHz,
CDCl3): d 197.76, 171.85, 159.28, 145.84, 133.68, 130.85
(2C), 130.25 (2C), 130.00, 128.74 (2C), 113.86 (2C),
85.01, 62.06, 55.71, 55.24, 50.34, 49.47, 34.53, 21.70,
14.22. IR (CHCl3, cm-1): 2253, 1676. LRMS m/z (FAB):
446 (1.41%), 121 (100%). HRMS (FAB) calcd for
C23H28NO6S (M++1) 446.1637, found 446.1622.
Trans. 1 1988, 639. (e) Kim, M. H.; Patel, D. V. Tetrahedron
Lett. 1994, 35, 5603. (f) Robin, S.; Zhu, J.; Galons, H.;
Pham-Huy, C.; Claude, J. R.; Tomas, A.; Viossat, B. Tetra-
hedron: Asymmetry 1995, 6, 1249. (g) Zhu, J.; Pham-Huy,
C.; Lemoine, P.; Tomas, A.; Galons, H. Heterocycles 1996,
43, 1923.
3. Chang, M. Y.; Chang, B. R.; Tai, H. M.; Chang, N. C. Tetra-
hedron Lett. 2000, 41, 10273.
4. For recent examples of the synthesis of mappicine ketone,
see: (a) Comins, D. L.; Saha, J. K. J. Org. Chem. 1996, 61,
9623. (b) Josien, H.; Gurran, D. P. Tetrahedron 1997, 53,
8881. (c) Boger, D. L.; Hong, J. J. Am. Chem. Soc. 1998,
120, 1218. (d) Yadav, J. S.; Sarkar, S.; Chandrasekhar, S.
Tetrahedron 1999, 55, 5449. (e) Greene, A. E.; Leue, S.;
Genisson, Y.; Mekouar, K. J. Org. Chem. 2000, 65, 5212. (f)
Ciufolini, M. A.; Bouchu, D.; Rousset, L.; Penlou, S.;
Narkunan, K.; Carles, L. J. Org. Chem. 2002, 67, 4304. (g)
Lin, C. H.; Tsai, M. R.; Wang, Y. S.; Chang, N. C. J. Org.
Chem. 2003, 68, 5688.
1-(4-Methoxybenzyl)-3-methyl-2-oxo-1,2-dihydropyri-
dine-4-carbaldehyde (9)
To a solution of aldehyde 8 (750 mg, 1.67 mmole) in
15 mL toluene was added DBU (1 mL, 6.70 mmol). The re-
action mixture was stirred at 90 °C for 8 hrs, quenched with
NaHCO3 (25 mL) and extracted with AcOEt (3 ´ 20 mL).
The organic layers were washed with brine, dried with an-
hydrous MgSO4, filtered and evaporated. The residue was
purified by column chromatography on silica gel (elution
with hexane/ethyl acetate = 2:1) to provide 369 mg (86%)
of pyridine-2-one 9, pale yellow oil. 1H NMR (500 MHz,
CDCl3): d 10.39 (s, 1H), 7.28-7.24 (m, 3H), 6.87 (d, J = 8.5
Hz, 2H), 6.52 (d, J = 7.0 Hz, 1H), 5.09 (s, 2H), 3.79 (s, 3H),
2.51 (s, 3 H). 13C NMR (125 MHz, CDCl3): d 190.8, 163.5,
159.5, 139.2, 135.2, 134.2, 129.8 (2C), 127.8, 114.3 (2C),
101.7, 55.2, 52.4, 11.0. IR (CHCl3, cm-1): 1701, 1619.
LRMS m/z (EI, 30 eV): 257 (20.39%), 121 (100%), 91
(32.55%). HRMS (EI, 30 eV) calcd for C15H15NO3 (M+)
257.1052, found 257.1052.
5. (a) We have performed the following chemistries on 3; only
one isomer was obtained in each case which indicated that
each pair of stereoisomers of product 3 were C-3 epimer. The
configuration of 10a was elucidated by NOESY studies.
There is no NOE effect between two methyl groups.
R
R
3
Ts
Ts
1) NaBH4
N
Bn
O
O
N
Bn
O
2) BF3-Et2O
10
3
10a R = CH3
10b R = CH2OBn
ACKNOWLEDGMENTS
(b) For 10a: 85% yield; pale yellow oil; 1H NMR (500 MHz,
CDCl3): d 7.70 (d, J = 8.5 Hz, 2H), 7.36-7.22 (m, 8H), 4.83
(d, J = 15 Hz, 1H), 4.68 (d, J = 15 Hz, 1H), 2.47 (q, J = 7.5
Hz, 1H), 2.42 (s, 3H), 2.36 (q, J = 7.5 Hz, 1H), 0.98 (d, J =
7.5 Hz, 3H), 0.84 (d, J = 7.5 Hz, 3 H). 13C NMR (125 MHz,
CDCl3): d 171.88, 144.13, 136.98 (2C), 136.16, 129.74,
128.90, 128.08, 127.75, 127.51, 121.64, 49.79, 43.14, 33.89,
21.53, 18.88, 15.99. LRMS m/z (EI, 30 eV): 369 (11.57%),
91 (100%). HRMS calcd for C21H23NO3S 369.1399, found
369.1393. IR (CHCl3, cm-1): 2305, 1603. For 10b: 86%
Financial support from the National Science Council
of the Republic of China is gratefully acknowledged.
Received July 18, 2007.
REFERENCES AND NOTES
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1
yield; pale yellow oil; H NMR (500 MHz, CDCl3): d 7.66
(d, J = 8.5 Hz, 2H), 7.38 (s, 1H), 7.33-7.18 (m, 12H), 4.81 (d,
J = 15 Hz, 1H), 4.58 (d, J = 15 Hz, 1H), 4.30 (s, 2H), 3.40
(dd, J = 9.5, 3.5 Hz, 1H), 3.29 (dd, J = 9.5, 3.5 Hz, 1H), 2.86
(q, J = 7.5 Hz, 1H), 2.42-2.41 (m, 4H), 0.86 (d, J = 7.5 Hz,
3H). 13C NMR (125 MHz, CDCl3): d 172.00, 144.03, 139.23,
137.71, 137.11, 136.07, 129.70 (2C), 128.77 (2C), 128.32
(2C), 127.88 (2C), 127.63 (2C), 127.62 (2C), 127.55 (2C),
115.88, 73.17, 70.82, 49.71, 40.13, 39.10, 21.55, 16.63.
LRMS m/z (EI, 30 eV): 476 (2.75%), 91 (100%). HRMS
(FAB) calcd for C28H30NO4S (M++1) 476.1894, found
476.1900. IR (CHCl3, cm-1): 1695, 1647.
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