Regioselective reduction of N-alkyl-3-sulfonyl glutarimides. Synthesis of 3,4-dihydro-3-tosylpyridin-2-ones

Article abstract of DOI:10.1016/S0040-4039(02)00446-X

Treatment of N-alkyl-3-sulfonyl glutarimides (1) with sodium hydride and then lithium aluminum hydride could give regioselective reduced hydroxy piperidones (5) which were further dehydrated to 3,4-dihydro-3-tosylpyridin-2-ones (6) in the presence of boro

Full text of DOI:10.1016/S0040-4039(02)00446-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3233–3235
Regioselective reduction of N-alkyl-3-sulfonyl glutarimides.
Synthesis of 3,4-dihydro-3-tosylpyridin-2-ones
Bo-Rui Chang, Chung-Yi Chen and Nein-Chen Chang*
Department of Chemistry, National Sun Yat-Sen University, Kaohsiung 804, Taiwan, ROC
Received 22 January 2002; revised 25 February 2002; accepted 1 March 2002
Abstract—Treatment of N-alkyl-3-sulfonyl glutarimides (1) with sodium hydride and then lithium aluminum hydride could give
regioselective reduced hydroxy piperidones (5) which were further dehydrated to 3,4-dihydro-3-tosylpyridin-2-ones (6) in the
presence of boron trifluoride. © 2002 Elsevier Science Ltd. All rights reserved.
N-Acyliminium ion has been used intensively in the
synthesis of alkaloids and compounds with potential
biological activities.1 It is well known that hydroxy
piperidone is a reasonable precursor of N-acyliminium
ion.2 Therefore, the regioselective reduction of asymmet-
rically substituted cyclic imide to their corresponding
hydroxy piperidones became an interesting topic in
natural products synthesis3 and has been studied for
decades. Nevertheless, it is unlikely that one soon will be
able to make reliable predictions on the regiochemical
outcome of reduction of more complex imide systems.4
exclusively C-2 carbonyl group reduced product 2
(Scheme 1). In the course of our study toward the
synthesis of alkaloids, we needed C-6 carbonyl group
reduced hydroxy piperidone 5. Herein, we reported a
general and mild route for the preparation of 5.
As shown in Scheme 2, a mixture of glutarimide 1 and
1.2 equivalent of sodium hydride in THF was allowed to
react at 25°C for 5 min, then 2 equivalent of LiAlH4 was
added in one portion and further stirred for 0.5–1.0 h.
After normal a workup procedure, various hydroxy
piperidones 5 were obtained with reduction occurring
exclusively at the C-6 position. To confirm these results,
hydroxy piperidones 5 were treated with boron tri-
fluoride, the corresponding dehydration products 6 were
produced in good yields (Scheme 2).
Recently, we developed an efficient route to the unsym-
metrical glutarimides with sulfonyl group at C-3 posi-
tion.5 We further discovered that treatment of 1 with
sodium borohydride at −10°C in methanol solution gave
R1
R1
TolO2S
O
R2
O
TolO2S
O
R2
O
+
N
2
6
N
R3O
Bn
Bn
1
R1
R1
TolO2S
R2
O
TolO2S
HO
R2
O
NaBH4 / MeOH
-10 oC
BF3-Et2O
N
N
Bn
Bn
2
3
Scheme 1.
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00446-X

3234
B.-R. Chang et al. / Tetrahedron Letters 43 (2002) 3233–3235
R1
R1
TolO2S
O
R2
O
TolO2S
O
R2
O
1) LAH / THF
2) NH4Cl-H2O
NaH
THF
N
N
Bn
4
Bn
1
R1
R1
TolO2S
O
R2
TolO2S
O
R2
BF3-Et2O
CH2Cl2, 0 oC
N
OH
N
Bn
Bn
5
6
Scheme 2.
Several examples were examined and the results are
listed in Table 1. Regioselective reduction of 1 could
be rationalized by the formation of enolate 4, which
prevented the C-2 carbonyl group from LiAlH4
reduction.
Desulfonation of 5b and 5d using sodium amalgam in
methanol furnished the corresponding hydroxy lactam
7b and 7d, respectively. In general, these products
cannot be obtained by direct reduction of the corre-
sponding unsymmetrical glutarimides 9.6 It was
reported that unsymmetrical glutarimides 9 seem to
be preferentially reduced at the less hindered carbonyl
group4b to furnish 10 (Scheme 3). The structures of
7b and 7d were further confirmed by transformation
to the corresponding elimination enamides 8b and 8d,
respectively.
Table 1. Synthesis of 6 via regioselective LiAlH4 reduction
of 1a,b,c7
Entry
R1
R2
Yield of 6 (%)
a
b
c
-H
-H
-H
-H
-H
-CH3
-C2H5
86
85
88
86
In conclusion, we have developed general ways of
regioselective reduction of unsymmetical 3-sulfonyl
glutarimides. The application of these results in
indolizidines, quinolizidines, isoquinolines and indole
alkaloids synthesis is currently underway in our labo-
ratory.
d
e
f
g
h
j
-H
-H
-CH3
-Ph
-Ph
-Bn
-H
-H
-H
80
90
90
90
85
Acknowledgements
The authors would like to thank the National Science
Council of the Republic of China for financial sup-
port.
a All the yields were based on glutarimides 1.
b The structures of 6b and 6d were confirmed by X-ray analysis.
c Selected NMR spectral data for 6a, 6b, 6e, 6f, 6j, see Ref. 8.
R
R
TolO2S
O
R
BF3-Et2O
Na-Hg / MeOH
CH2Cl2, 0 oC
O
N
OH
O
N
N
OH
Bn
Bn
Bn
8b R=CH3(95%)
8d R=Allyl (91%)
5b R=CH3
5d R=Allyl
7b R=CH3(90%)
7d R=Allyl (84%)
R
[ H ]
R
R
[ H ]
O
N
OH
O
N
H
9
O
HO
N
O
H
H
11
10
Scheme 3.

B.-R. Chang et al. / Tetrahedron Letters 43 (2002) 3233–3235
3235
References
solution (1 mL) and extracted with AcOEt (3×20 mL). The
organic layers were washed with brine (2×10 mL), dried
with anhydrous MgSO4, filtered and evaporated. Without
purification, crude 5a was treated with boron trifluoride
(cat.) in 20 mL of CH2Cl2 for 1 day, water (20 mL) was
then added. After extraction with CH2Cl2 (2×20 mL), the
organic layers were washed with brine (2×10 mL), dried
with anhydrous MgSO4, filtered and evaporated. The
crude product was purified by flash chromatography (hex-
ane/AcOEt=4/1) to afford dehydration product 6a (293
mg, 86%).
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1
8. Selected spectral data of 6a: H NMR (500 MHz, CDCl3):
l 7.72 (d, J=8.5 Hz, 2H), 7.35–7.26 (m, 7H), 5.95 (dd,
J=8.0, 3.0 Hz, 1H), 5.15–5.12 (m, 1H), 4.70 (d, J=15.0
Hz, 1H), 4.61 (d, J=15.0 Hz, 1H), 4.05 (dd, J=8.0, 3.0
Hz, 1H), 3.21 (ddd, J=19.0, 5.0, 3.0 Hz, 1H), 2.88–2.81
1
(m, 1H), 2.42 (s, 3H); 6b: H NMR (500 MHz, CDCl3): l
7.73 (d, J=8.0 Hz, 2H), 7.35–7.26 (m, 7H), 5.66 (s, 1H),
4.65 (d, J=15.0 Hz, 1H), 4.57 (d, J=15.0 Hz, 1H), 4.05
(dd, J=8.0, 3.0 Hz, 1H), 3.01 (dd, J=18.5, 3.0 Hz, 1H),
2.83 (dd, J=18.5, 8.0 Hz, 1H), 2.43 (s, 3H), 1.72 (s, 3H);
6e: 1H NMR (500 MHz, CDCl3): l 7.71 (d, J=8.0 Hz,
2H), 7.37–7.23 (m, 12H), 6.21 (d, J=2.5 Hz, 1H), 4.72 (s,
2H), 4.20 (dd, J=8.0, 3.5 Hz, 1H), 3.59 (dd, J=18.0, 3.5
Hz, 1H), 3.25 (ddd, J=18.0, 8.0, 2.5 Hz, 1H), 2.42 (s, 3H);
6f: 1H NMR (500 MHz, CDCl3): l 7.67 (d, J=8.5 Hz,
2H), 7.35–7.23 (m, 10H), 7.134 (d, J=7.0 Hz, 2H), 5.75 (d,
J=1.0 Hz, 1H), 4.69 (d, J=15.0 Hz, 1H), 4.59 (d, J=15.0
Hz, 1H), 4.00 (dd, J=8.5, 3.5 Hz, 1H), 3.34 (S, 2H), 2.96
(dd, J=18.5, 3.5 Hz, 1H), 2.70 (dd, J=18.5, 1.0 Hz, 1H),
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7. Standard procedure: A solution of 1a (357 mg, 1.0 mmol)
in THF (10 mL) was added to a rapidly stirred suspension
of sodium hydride (60% dispersion in mineral oil, 1.2
mmol). After the reaction mixture was stirred at room
temperature for 5 min, 2.0 mmol of LiAlH4 was then
added and the resulting reaction mixture was stirred for
1.0 h, quenched with a saturated ammonium chloride
1
2.42 (s, 3H); 6j: H NMR (500 MHz, CDCl3): l 7.72 (d,
J=8.0 Hz, 2H), 7.39–7.30 (m, 7H), 7.00–6.97 (m, 2H),
6.92–6.88 (m, 2H), 6.21 (d, J=7.5 Hz, 1H), 5.31 (dd,
J=7.5, 6.5 Hz, 1H), 4.88 (d, J=14.5 Hz, 1H), 4.57 (d,
J=6.5 Hz, 1H), 4.54 (d, J=14.5 Hz, 1H), 4.00 (s, 1H),
1
2.44 (s, 3H); 8b: H NMR (500 MHz, CDCl3): l 7.31–7.21
(m, 5H), 5.74 (s, 1H), 4.63 (s, 2H), 2.56 (t, J=8.0 Hz, 2H),
2.22 (t, J=8.0 Hz, 2H), 1.65 (s, 3H).