Addition of dienolates to sulfinimines. Stereoselective synthesis of dihydropyridones

Article abstract of DOI:10.1016/S0040-4020(01)00833-X

The vinylogous Mannich reaction of sulfinimines with dienolates was investigated. Lithium and trimethylsilyl enolates of ethyl 3-ethoxycrotonate reacted with enantiopure 10-isobornylsulfinimines to give derivatives of δ-aminoacids which were cyclised to 6-aryl substituted derivatives of 2(1H)-pyridinones. 6-Aryl substituted 2,4-piperidinediones with either (S) or (R) configuration were analogously obtained using lithium and TMS enolates of 2,2,6-trimethyl-1,3-dioxin-4-one.

Full text of DOI:10.1016/S0040-4020(01)00833-X

TETRAHEDRON
Pergamon
Tetrahedron57 +2001) 8385±8390
Addition of dienolates to sul®nimines.
Stereoselective synthesis of dihydropyridones
Robert KaweÎckip
Institute of Organic Chemistry, Polish Academy of Sciences, ul. Kasprzaka 44, PL-01-224 Warszawa, Poland
Received 20 April 2001; revised 10 July 2001; accepted 8 August 2001
AbstractÐThe vinylogous Mannich reaction of sul®nimines with dienolates was investigated. Lithium and trimethylsilyl enolates of ethyl
3-ethoxycrotonate reacted with enantiopure 10-isobornylsul®nimines to give derivatives of d-aminoacids which were cyclised to 6-aryl
substituted derivatives of 2+1H)-pyridinones. 6-Aryl substituted 2,4-piperidinediones with either +S) or +R) con®guration were analogously
obtained using lithium and TMS enolates of 2,2,6-trimethyl-1,3-dioxin-4-one. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
auxiliary is derived from 10-isobornylsul®nate which may
be recycled without loss of optical activity.8
Derivatives of piperidine are widely spread in nature,
mainly as alkaloids and insect defence substances.1 Most
of them show pronounced biological activity and are impor-
tant for the pharmaceutical industry. This is why the stereo-
selective synthesis of such compounds is of great interest.
Dihydropyridones are valuable starting materials for the
synthesis of natural piperidine derivatives.2 One of the
ways to obtain2+1 H)-pyridinones is the cycloaddition
reaction of Brassard's diene to imines. Several chiral
auxiliaries have been used to achieve good enantio-
selectivity of this reaction. Midland and coworkers used
derivatives of a-alkoxy imines which were prepared in
several steps from natural aminoacids.3 The ee of the
cycloadduct with Brassard's diene strongly depended on
the Lewis acid used and varied from 66% to greater than
98%. Waldman et al. applied imines obtained from alde-
hydes and valine tert-butyl esters.4 Appropriate dihydro-
pyridones were obtained with excellent stereoselectivities.
However, the removal of the chiral auxiliary was not
straightforward and was achieved in ®ve steps.
2. Results and discussion
All sul®nimines were prepared from appropriate 10-iso-
bornylsul®namides and aldehydes according to the
published procedure.8
The reactionof sul®nimines 1a±d with Brassard's diene 2
gave in the presence of Lewis acid dihydropyridones 3a±d
+Scheme 1). Several Lewis acids were tested, however, the
most ef®cient was BF3´Et2O. The progress of the reaction
was slow and usually 2±3 days were necessary to obtain
reasonable yields of the product. The enantioselectivity
observed was modest +Table 1). The presence of an acyclic
intermediate in the reaction mixture suggests that the
mechanism of dihydropyridone formation is stepwise.
The con®guration of the products was determined by
conversion of the dihydropyridone 3a into known
piperidone 6 +Scheme 2).9 Thus, 3a was hydrolysed to
piperidinedione 4a inhydrochloric acid and reacted with
ethanedithiol to give thioketal 5. The reductionwith
Raney nickel gave piperidinone 6 which had anopposite
optical rotationcompared to known+ R)-+1) enantiomer of
6. We assumed that the +S) con®guration at C-6 found in 3a
is the same inthe other 6-aryl substituted derivatives 3.
Chiral, non racemic sul®nimines have become important
starting materials for the synthesis of several derivatives
of amines, aminoacids, aminophosphonic acids, and
nitrogen heterocycles.5 Several optically active sul®nyl
group have beenprepared for this purpose of which the
most useful are p-toluenesul®nyl6 and t-butanesul®nyl.7 In
this paper we describe the use of optically active sul®ni-
mines in the reaction with silylated dienes as well as with
lithium dienolates leading to enantiomerically enriched
dihydropyridones and 2,4-piperidinediones. The chiral
We next turned our attention to the other O-silyl dienolate
i.e. 2,2-dimethyl-4-methylene-6-trimethylsilyloxy-4H-1,3-
dioxine 10 which can be easily obtained from ketene
acetone adduct 12.10 The reaction with sul®nimines was
carried out indichloromethane at 2708C and usually only
3±4 h were necessary to complete the reaction. The addition
of dienolate 10 to sul®nimines was preferably promoted by
Keywords: imines; Mannich reactions; piperidinones; sul®nyl compounds.
Tel.: 148-22-6323221; fax: 148-22-6326681; e-mail: rkaw@icho.edu.pl
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020+01)00833-X

8386
R. KaweÎcki / Tetrahedron 57 -2001) 8385±8390
Scheme 1.
Table 1. Addition of Brassard's diene to sul®nimines 1
of acids. The product possessed the same con®guration at
the C-6 carbonatom as inthe case of the reactionwith
Brassard's diene. However, the enantiomeric excess for
the same substrates 1a,b was much higher +Table 2). The
use of the 2-hydroxy substituted derivative of sul®nimine 1b
resulted ina decrease of the ee from 86 to 65% +entry 4)
showing that presence of a bulky trimethylsilyl group has an
important in¯uence on the stereoselectivity. However, the
con®guration at the sulfur atom plays a crucial role. The use
of +RS) diastereoisomer of sul®nimine resulted in almost
complete lack of enantioselectivity +entry 3 and 5). Zinc
tri¯ate did not catalyse the reaction. The use of Zn+OTf)2
followed by additionof TMSOTf gave the product with only
15% ee +entry 6).
Entry
R1
Lewis acid
Product
Yield +%)
ee +%)a
1
2
3
4
5
Ph
Ph
EtAlCl2
+2)-3ab
+2)-3a
+2)-3b
+2)-3c
+2)-3d
35
80
73
61
27
58
42
54
63
33
BF3´Et2O
BF3´Et2O
BF3´Et2O
BF3´Et2O
30-ClC6H4
30-NO2C6H4
40-MeOC6H4
Reactionwas carried out inCH 2Cl2 at rt for 2 days.
a
The enantiomeric excess of the product was determined by 1H NMR; see
Section3 for details.
Major enantiomer has +S) con®guration at C-6 +vide infra).
b
TMSOTf +1.3 equiv.). The reaction mixture contained
sul®namide which was hydrolysed during aqueous workup
and subsequently cyclised to 2,4-piperidinedione 4 in
MeOH±K2CO3 mixture +Scheme 3). 2,4-Piperidinediones
canbe easily converted to appropriate 4-ethoxy dihydro-
pyridones 3 in anhydrous ethanol solution in the presence
It was of great interest to compare the reactivity of
trimethylsilyl derivatives with lithium dienolates. The
dienolate obtained by deprotonation of ethyl 3-ethoxy
crotonate with LDA in THF reacted with sul®nimine at
Scheme 2.
Scheme 3.

R. KaweÎcki / Tetrahedron 57 -2001) 8385±8390
10 to sul®nimines promoted by Table 4. Additionof lithium dienolate of 12 to sul®nimines
8387
Table 2. Additionof silyl dieonlate
TMSOTf
Entry
Sul®nimine
Product
Yield +%)
ee +%)a
Entry
R1
R2
Sul®nimine Product Yield +%) ee +%)a
1
2
3
+SS)-1a
+SS)-1b
+SS)-1e
+1)-4a
+1)-4b
+2)-4e
41
23
41
87
75
91
1
2
3
4
5
6b
7
Ph
TMS +SS)-1a
+2)-4a
+2)-4b
+2)-4b
+2)-4b
+1)-4b
+1)-4b
'1)-4e
84
96
76
92
85
57
45
74
86
3
65
13
15
89
30-ClC6H4 TMS +SS)-1b
30-ClC6H4 TMS +RS)-7
30-ClC6H4
30-ClC6H4
30-ClC6H4
2-Furyl
H
H
H
+SS)-8
+RS)-9
+RS)-9
Reactiontemperature was 2308C except for entry 2 which was 2708C.
a
The enantiomeric excess of the product was determined by 1H NMR; see
Section3 for details.
TMS +SS)-1e
Reactionwas carried out inCH 2Cl2 at 2708C for 3 h.
a
The enantiomeric excess of the product was determined by 1H NMR; see
Section3 for details.
The additive +1 mol equiv.) of Zn+OTf)2 was used.
2308C and only the g-coupling product was observed in the
reaction mixture. It was converted to 2,4-piperidinedione in
a standard way. The ee of the product was similar to or
higher than that obtained with silyl dienolate 10 +Table 4).
However, the product possessed the opposite con®guration
at C-6.
b
Simple lithium and silyl enolates having the same geometry
give additionproducts to sul®nimines with opposite stereo-
chemistry.8 The reactions of dienolates of dioxinone 12
follow this rule. The same con®guration of the dihydro-
pyridone in the case of Brassard's diene and lithium 1,3-
diethoxy-1,3-butadienoate may result from the different
stereochemistry of the enolate.
The results presented here show that the vinylogous
Mannich reaction of sul®nimines serves as a useful method
for the preparation of 6-substituted enantiomerically
enriched dihydropyridones. The best results +up to 92%
ee) were obtained using the lithium enolate of 3-ethoxy
crotonate. The use of silyloxy or lithium derivatives of
ketene acetone adduct resulted in obtaining products with
either +S) or +R) con®guration at C-6 and similar ee +up to
91%).
Scheme 4.
Table 3. Addition of lithium 1,3-diethoxy-1,3-butadienoate to sul®nimines
Entry
Sul®nimine
Product
Yield +%)
ee +%)a
1
2
3
4
+SS)-1a
+SS)-1b
+SS)-1c
+SS)-1e
+2)-3a
+2)-3b
+2)-3c
+1)-3e
72
60
30
30
85
92
87
88
Reactionwas carried out inTHF at 2308C.
3. Experimental
3.1. General
a
The enantiomeric excess of the product was determined by 1H NMR; see
Section3 for details.
NMR spectra were recorded at 500 or 200 MHz +1H). All
spectra were referenced to residual solvent peak +chloro-
form 7.26 and 77.0 ppm for 1H an d13C, respectively).
THF was distilled from sodium inthe presence of sodium
benzophenone ketyl. CH2Cl2 was distilled from CaH2.
Brassard's diene11 and 2,2-dimethyl-4-methylene-6-
trimethylsilyloxy-4H-1,3-dioxine10 were prepared accord-
ing to standard procedure. Sul®nimines 1a,d were synthe-
sised as described.8 Sul®nimines 1b,c,e and 7±9 were
obtained by condensation of appropriate sul®namide8,12
with aldehydes using Ti+OEt)4 at rt.13 Melting points were
not corrected. The enantiomeric excess of the products was
determined by integration of the H-6 or the NH resonances
2308C to give sul®namides which were N-deprotected and
cyclised to dihydropyridones in ethanolic HCl solution
+Scheme 4). The major enantiomer of the product possessed
the +S) con®guration at C-6. The enantiomeric excess was
greater than85% +Table 3). Lowerign the temperature
below 2508C resulted informationof the
product.
a-coupling
Similar results were obtained using the lithium dienolate of
dioxinone 12 +Scheme 5). The reactionwas carried out at
1
in H NMR +500 MHz) spectra using +S) or +R)-t-butyl-
phenylphosphinothioic acid14 as chiral solvating agent.
3.1.1. '1S,2R,4R,SS)-7,7-Dimethyl-N-'3-chlorophenyl-
methylene)-2-trimethylsilyloxybicyclo[2.2.1]heptane-1-
methanesul®namide '1b). Yield 88%, colourless crystals,
20
mp 73±778C. [a]D ˆ280.5 +cˆ1.09, CHCl3). IR +KBr)
1601, 1088 cm21. H NMR +CDCl3) d 0.12 +s, 9H), 0.81
+s, 3H), 1.07 +s, 3H), 1.1±1.25 +m, 1H), 1.35 +m, 1H), 1.65±
1
Scheme 5.

8388
R. KaweÎcki / Tetrahedron 57 -2001) 8385±8390
1.9 +m, 5H), 2.25 +d, Jˆ12.9 Hz, 1H), 3.61 +d, Jˆ12.9 Hz,
1H), 4.09 +dd, Jˆ4.0, 6.7 Hz, 1H), 7.35±7.50 +m, 2H), 7.69
+dt, Jˆ1.6, 7.1 Hz, 1H), 7.89 +t, Jˆ1.6 Hz, 1H), 8.56 +s, 1H).
13C NMR +CDCl3) d 0.3, 20.1, 20.5, 27.4, 30.8, 42.1, 44.9,
48.9, 50.3, 57.3, 77.0, 127.8, 128.7, 130.1, 132.1, 135.0,
135.6, 159.7. HR LSIMS calcd for C20H3135ClNO2SSi
+M1H)1: 412.1533. Found: 412.1554.
3.2.3. 5,6-Dihydro-4-ethoxy-6-'3-nitrophenyl)-2'1H)-
pyridinone '3c). Colourless crystals, mp 144±1488C.
27
[a]D ˆ284.6 +cˆ2.26, CHCl3). IR +KBr) 1669, 1528,
1
1344 cm21. H NMR +CDCl3) d 1.35 +t, Jˆ7.0 Hz, 3H),
2.64 and 2.73 +ABMX, Jˆ15.7, 10.0, 6.0, 1.0 Hz, 2H),
3.91 +m, 2H), 4.86 +dd, Jˆ10.0, 6.0 Hz, 1H), 5.14 +s, 1H),
5.81 +br, 1H), 7.58 +t, Jˆ8.0 Hz, 1H), 7.73 +d, Jˆ8.0 Hz,
1H), 8.20 +ddd, Jˆ8.0, 2.0, 0.9 Hz, 1H), 8.24 +t, Jˆ2.0 Hz,
1H). 13C NMR +CDCl3) d 14.0, 35.9, 53.3, 64.3, 93.7, 121.3,
122.9, 129.8, 132.3, 143.3, 148.3, 167.2, 169.8. HRMS
calcd for C13H14N2O4: 262.0954. Found: 262.0961.
3.1.2. '1S,2R,4R,SS)-7,7-Dimethyl-N-'3-nitrophenyl-
methylene)-2-trimethylsilyloxybicyclo[2.2.1]heptane-1-
methanesul®namide '1c). Yield 86%, colourless crystals,
25
mp 92±938C. [a]D ˆ294.6 +cˆ0.76, CHCl3). IR +KBr)
1
1089, 1530, 1348, 1605 cm21. H NMR +CDCl3) d 0.12
3.2.4. 5,6-Dihydro-4-ethoxy-6-'4-methoxyphenyl)-2'1H)-
pyridinone '3d). Colourless crystals, mp 143±1478C.
+s, 9H), 0.81 +s, 3H), 1.08 +s, 3H), 1.1±1.25 +m, 1H), 1.4±
1.6 +m, 1H), 1.65±1.9 +m, 5H), 2.27 +d, Jˆ12.9 Hz, 1H),
3.65 +d, Jˆ12.9 Hz, 1H), 4.09 +dd, Jˆ6.6, 3.8 Hz, 1H), 7.68
+dd, Jˆ7.7, 8.2 Hz, 1H), 8.15 +dt, Jˆ7.7, 1.3 Hz, 1H), 8.35
+ddd, Jˆ8.2, 2.3, 1.1 Hz, 1H), 8.69 +s, 1H), 8.73 +dd, Jˆ2.3,
1.3 Hz, 1H). 13C NMR +CDCl3) d 0.3, 20.1, 20.4, 27.4, 30.8,
42.1, 44.8, 48.9, 50.3, 57.4, 77.0, 123.6, 126.4, 130.0, 134.9,
135.4, 148.6, 158.8. Anal. calcd for C20H30N2O4SSi: C,
56.84; H, 7.15; N, 6.63. Found: C, 56.87; H, 7.21; N, 6.67.
27
[a]D ˆ235.5 +cˆ1.12, CHCl3). IR +KBr) 3181,
1
1665 cm21. H NMR +CDCl3) d 1.32 +t, Jˆ7.2 Hz, 3H),
2.4±2.7 +m, 2H), 3.78 +s, 3H), 3.88 +m, 2H), 4.65 +dd,
Jˆ10.9, 5.9 Hz, 1H), 5.08 +s, 1H), 5.51 +br, 1H), 6.82±
6.93 +1/2 AA0XX0, 2H), 7.21±7.33 +1/2 AA0XX0, 2H). 13C
NMR +CDCl3) d 14.1, 36.8, 54.1, 55.2, 64.2, 93.5, 114.1,
127.4, 132.7, 159.3, 168.3, 169.6. HRMS calcd for
C14H17NO3 247.1208. Found: 247.1212.
3.1.3. '1S,2R,4R,SS)-7,7-Dimethyl-N-'2-furylmethylene)-
2-trimethylsilyloxybicyclo[2.2.1]heptane-1-methane-
3.2.5. 5,6-Dihydro-4-ethoxy-6-'2-furyl)-2'1H)-pyridi-
none '3e). Brownsolid, mp 84±87 8C. IR +KBr) 3208,
1670 cm21. H NMR +CDCl3) d 1.36 +t, Jˆ7.0 Hz, 3H),
20
sul®namide '1e). Yield 90%, oil, [a]D ˆ282.5 +cˆ1.32,
1
1
CHCl3). IR +neat) 1090, 1614 cm21. H NMR +CDCl3) d
2.73 and 2.80 +ABMX, Jˆ16.7, 8.8, 5.8 Hz, 2H), 3.92
+m, 2H), 4.78 +dd, Jˆ8.8, 5.8 Hz, 1H), 5.09 +s, 1H), 5.61
+br, 1H), 6.25 +d, Jˆ3.1 Hz, 1H), 6.34 +dd, Jˆ3.1, 1.8 Hz,
1H), 7.38 +d, Jˆ1.8 Hz, 1H). 13C NMR +CDCl3) d 14.0,
32.4, 47.8, 64.2, 93.6, 106.2, 110.3, 142.3, 153.1, 167.8,
169.1. HRMS calcd for C11H13NO3: 207.0895. Found:
207.0880.
0.07 +s, 9H), 0.77 +s, 3H), 1.03 +s, 3H), 1.0±1.1 +m, 1H),
1.4±1.8 +m, 6H), 2.22 +d, Jˆ12.8 Hz, 1H), 3.57 +d,
Jˆ12.8 Hz, 1H), 4.07 +dd, Jˆ4.0, 6.7 Hz, 1H), 6.53 +dd,
Jˆ1.8, 3.5 Hz, 1H), 6.97 +d, Jˆ3.5 Hz, 1H), 7.62 +d,
Jˆ1.8 Hz, 1H), 8.40 +s, 1H). 13C NMR +CDCl3) d 0.2,
20.1, 20.4, 27.4, 30.8, 42.2, 44.7, 48.9, 50.3, 57.3, 76.8,
112.4, 118.7, 146.6, 148.2, 150.5. Anal. calcd for
C18H29NO3SSi: C, 58.82; H, 7.95; N, 3.81. Found: C,
58.59; H, 7.91; N, 3.75.
3.3. Determination of con®guration of dihydropyridone
3a
3.2. General procedure for addition of Brassard's diene
to sul®nimines
3.3.1. 6-Phenyl-2,4-piperidinedione '4a). To the solution
of pyridone 3a +200 mg, 0.92 mmol) inacetone +4 mL) was
added 10% aqueous hydrochloric acid +1 mL) and the
mixture was stirred overnight at rt. The excess acetone
was evaporated and the residue was extracted with
CH2Cl2. Organic extracts were dried +MgSO4) and evapo-
rated to give pure 4a +166 mg, 95%) as colourless solid. Mp
To the solutionof sul®nimine
1 +0.53 mmol) inCH Cl2
2
+4 mL) was added dropwise borontri¯uoride etherate
+100 mg, 0.71 mmol) at 2508C. The mixture was stirred
for 10 minand the solutionof Brassard's diene +227 mg,
1.0 mmol) inCH 2Cl2 +0.7 mL) was added slowly. The
mixture was slowly warmed to rt and stirred for two days.
Phosphate buffer +pHˆ7) was added and reaction mixture
was extracted three times with CH2Cl2. Organic extracts
were dried +MgSO4) and evaporated. Resulted oil was
dissolved inCH 2Cl2 +3 mL) and treated with TFA
+0.2 mL). After 1 h the solutionwas enutralised with
26
1
164±1688C. [a]D ˆ248.2 +cˆ1.0, CHCl3). H NMR data
identical to reported.9 IR +KBr) 3424, 1718, 1672 cm21 13C
NMR +CDCl3) d 46.7, 47.1, 52.6, 125.9, 128.6, 129.2,
139.2, 169.1, 202.3.
.
3.3.2. 1-Aza-2-oxo-6-phenyl-10,30-dithiaspiro[5,4]decane
'5). To the solution of piperidinedione 4a +166 mg,
0.88 mmol) and ethanedithiol +106 mg, 1.13 mmol) in
CH2Cl2 +4 mL) was added zinc tri¯ate +383 mg,
1.05 mmol) and the reaction mixture was stirred under
re¯ux for 15 h. The mixture was cooled to rt and water
+4 mL) was added. Organic layer was separated and aqueous
phase was extracted three times with CH2Cl2. Combined
organic extracts were dried +MgSO4) and evaporated. The
residue was puri®ed by chromatography onsilica gel
+CH2Cl2 and EtOH, 15:1) to give colourless solid
saturated solutionof NaHCO and extracted with CH2Cl2.
3
Combined organic layers were dried +MgSO4) an
evaporated. The product was puri®ed by chromatography
onsilica gel +CH Cl2 and EtOH, 45:1, then 30:1).
d
2
3.2.1. 5,6-Dihydro-4-ethoxy-6-phenyl-2'1H)-pyridinone
'3a). Spectral data identical to previously reported.15
3.2.2. 6-'3-Chlorophenyl)-5,6-dihydro-4-ethoxy-2'1H)-
pyridinone '3b). Spectral data identical to previously
reported.15
25
+150 mg, 65%). [a]D ˆ123.5 +cˆ1.04, CHCl3). Spectral
data identical to reported.9

R. KaweÎcki / Tetrahedron 57 -2001) 8385±8390
8389
3.4. 6-Phenyl-2-piperidinone '6)
and basi®ed with saturated solution of NaHCO3. Organic
layer was separated and water phase was extracted with
CH2Cl2. Combined organic extracts were dried +MgSO4)
and evaporated. Resulting oil was dissolved in MeOH
+4 mL) and solid K2CO3 +ca. 200 mg) was added. The
suspension was stirred overnight at rt. MeOH was evapo-
rated at rt and the residue was dissolved in water +1.5 mL)
followed by acidi®cationwith 10% hydrochloric acid. The
mixture was extracted three times with CH2Cl2. Organic
extracts were treated with few drops of etheral solutionof
HCl and dried overnight over MgSO4. Evaporationof
solvents gave oil which was puri®ed by chromatography
To the solutionof thioketal 5 +140 mg, 0.53 mmol) in
ethanol +10 mL) was added freshly prepared Raney nickel
+W-2) and the mixture was re¯uxed for 80 min. The catalyst
was removed by decantation and washed several times with
EtOH. The combined extracts were ®ltered trough Celite.
Evaporationgave crystals which were puri®ed by chromato-
graphy onsilica gel +CH 2Cl2 and MeOH 50:1, then 20:1) to
22
give 62 mg +67%) of colourless crystals. [a]D ˆ226.7
+cˆ1.33, CHCl3). Lit16 value for +R) enantiomer [a]D
ˆ
20
173.6 +cˆ1.4, CHCl3). Spectral data identical to reported.9
onsilica gel +CH Cl2 and MeOH 45:1, then 30:1). Yield
2
3.4.1. '1S,2R,4R,RS)-7,7-Dimethyl-N-'3-chlorophenyl-
methylene)-2-trimethylsilyloxybicyclo[2.2.1]heptane-1-
92 mg +85%).
20
methanesul®namide '7). Yield 92%, oil. [a]D ˆ2122.8
3.6. General procedure for addition of lithium 1,3-
diethoxy-1,3-butadienoate to sul®nimines
+cˆ1.59, CHCl3). IR +®lm) 1603, 1089 cm21.1H NMR
+CDCl3) d 0.12 +s, 9H), 0.83 +s, 3H), 1.07 +s, 3H), 1.06±
1.18 +m, 1H), 1.44±1.61 +m, 1H), 1.63±1.91 +m, 5H), 2.71
and 3.19 +AB, Jˆ12.5 Hz, 2H), 3.98 +dd, Jˆ3.8, 7.0 Hz,
1H), 7.34±7.50 +m, 2H), 7.68 +dt, Jˆ1.7, 7.1 Hz, 1H) 7.83
+t, Jˆ1.7 Hz, 1H), 8.57 +s, 1H). 13C NMR +CDCl3) d 0.3,
20.1, 20.7, 27.3, 31.4, 42.1, 45.0, 48.8, 50.1, 58.4, 77.1,
127.6, 128.6, 130.1, 132.0, 135.0, 135.7, 159.0. HR
LSIMS calcd for C20H3135ClNO2SSi +M1H)1: 412.1533.
Found: 412.1546.
To the solutionof LDA prepared by additionof n-butyl-
lithium +1.6 M inhexane, 0.45 mL, 0.72 mmol) to the solu-
tionof diisopropylamien +73 mg, 0.72 mmol) inTHF
+3 mL) was added dropwise at 2708C solutionof ethyl
3-ethoxycrotonate +106 mg, 0.67 mmol) in THF +0.3 mL).
The reactionmixture was stirred for 2.5 h at 2708C, and
thenwarmed to 2308C. The solutionof sul®nimien
+168 mg, 0.45 mmol) inTHF +0.5 mL) was added and the
1a
reactionmixture was kept 3.5 h at 2308C. Saturated solu-
tionof NH Cl was added, and after warming to rt the
3.4.2. '1S,2R,4R,SS)-7,7-Dimethyl-N-'3-chlorophenyl-
methylene)-2-hydroxybicyclo[2.2.1]heptane-1-methane-
sul®namide '8). Yield 77%, colourless crystals, mp 110±
4
mixture was extracted with CH2Cl2. Combined extracts
were dried +MgSO4) and evaporated under vacuum. The
residue was dissolved inCH Cl2 and ethanolic solution of
20
1158C. [a]D ˆ128.4 +cˆ1.19, CHCl3). IR +KBr) 3469,
2
1
1606, 1085, 1055 cm21. H NMR +CDCl3) d 0.86 +s, 3H),
HCl was added +4.5 mL). The mixture was left at rt for 24 h
and evaporated. The residue was dissolved in CH2Cl2
+3 mL) and water +2 mL). The mixture was extracted
twice with CH2Cl2 and combined extracts were dried
+MgSO4) and evaporated. The chromatography on silica
gel +CH2Cl2 and MeOH 45: 1, and then 30: 1) gave 70 mg
+72%) of beige crystals.
1.08 +s, 3H), 1.2±1.45 +m, 1H), 1.6±1.95 +m, 6H), 2.78 and
3.41 +AB, Jˆ13.3 Hz, 2H), 3.51 +br, 1H), 4.03 +dd, Jˆ4.1,
7.2 Hz, 1H), 7.35±7.55 +m, 2H), 7.70 +dt, Jˆ1.6, 7.6 Hz,
1H), 7.81 +t, Jˆ1.6 Hz, 1H), 8.61 +s, 1H). 13C NMR +CDCl3)
d 19.9, 20.5, 27.6, 31.4, 39.3, 44.4, 49.1, 51.3, 56.8, 76.3,
127.5, 129.0, 130.4, 132.8, 135.0, 135.3, 161.4. HR LSIMS
calcd for C17H2235ClNO2SNa +M1Na)1: 362.0957. Found:
362.0956.
3.7. General procedure for preparation of 2,4-
piperidinediones from diketene±acetone adduct and
sul®nimines
3.4.3. '1S,2R,4R,RS)-7,7-Dimethyl-N-'3-chlorophenyl-
methylene)-2-hydroxybicyclo[2.2.1]heptane-1-methane-
sul®namide '9). Yield 70%, colourless crystals, mp 112±
To the solutionof LDA +1.0 mmol) inTHF +3 mL) prepared
as above, was added slowly at 2708C solution of dioxinone
12 +1.0 mmol) inTHF +0.5 mL). The dieonlate was
generated for 2 h at 2708C. The reactionmixture was
warmed to 2408C and the solution of sul®nimine 1a
+187 mg, 0.5 mmol) was added. The solutionwas stirred
for 3.5 h at 2308C and quenched with sat. solution of
NH4Cl. The mixture was extracted with CH2Cl2 and organic
extracts were evaporated. The residue was dissolved in
ethanolic solution of HCl +4 mL) and left for 1 h. The solu-
tionwas evaporated, dissolved inMeOH +5 mL) and K 2CO3
+ca. 200 mg) was added. The suspension was stirred for
24 h, evaporated and dissolved in H2O. The solutionwas
acidi®ed with 10% aqueous HCl solutionand extracted with
CH2Cl2. Combined extracts were dried +MgSO4) and evapo-
rated. The product was puri®ed by chromatography as
described above.
26
1138C. [a]D ˆ11.0 +cˆ1.06, CHCl3). IR +KBr) 3349,
1
1604, 1066 cm21. H NMR +CDCl3) d 0.87 +s, 3H), 1.05
+s, 3H), 1.1±1.3 +m, 1H), 1.5±1.9 +m, 6H), 2.95 and 3.07
+AB, Jˆ13.4 Hz, 2H), 3.54 +br, 1H), 4.15 +dd, Jˆ4.4,
7.6 Hz, 1H), 7.35±7.55 +m, 2H), 7.70 +dt, Jˆ1.6, 7.3 Hz,
1H) 7.90 +t, Jˆ1.6 Hz, 1H), 8.58 +s, 1H). 13C NMR +CDCl3)
d 19.9, 20.5, 27.3, 30.8, 38.6, 44.9, 48.5, 50.7, 57.2, 76.8,
128.0, 128.7, 130.2, 132.5, 135.2, 135.2, 160.7. Anal. calcd
for C17H22ClNO2S: C, 60.08; H, 6.52; N, 4.12; S, 9.43.
Found: C, 59.97; H, 6.68; N, 4.00; S, 9.63.
3.5. Typical procedure for addition of TMS-enol ether to
sul®nimines
To the solutionof sul®nimine 1a +165 mg, 0.49 mmol) and
TMS-enol ether 10 +178 mg, 0.83 mmol) inCH 2Cl2 +4 mL)
was added TMSOTf +180 mg, 0.81 mmol) at 2708C. The
reactionmixture was stirred at 2708C for 3 h followed by
additionof water +1.5 mL). The mixture was warmed to rt
3.7.1. 6-'3-Chlorophenyl)-2,4-piperidinedione '4b).
1
Yellowish solid, mp 102±1088C. IR +KBr) 1671 cm21. H

8390
R. KaweÎcki / Tetrahedron 57 -2001) 8385±8390
3. +a) Midland, M. M.; McLoughlin, J. I. Tetrahedron Lett. 1988,
29, 4653±4656. +b) Midland, M. M.; Koops, R. W. J. Org.
Chem. 1992, 57, 1158±1161.
NMR +CDCl3) d 2.75 and 2.91 +ABX, Jˆ4.8, 9.3, 16.0 Hz,
2H), 3.38 +s, 2H), 4.79 +ddd, Jˆ2.0, 4.8, 9.3 Hz, 1H), 6.20
+br, 1H), 7.18±7.23 +m, 1H), 7.31±7.34 +m, 1H), 7.35±7.39
+m, 2H). 13C NMR +CDCl3) d 46.6, 47.1, 52.2, 124.0, 126.2,
128.8, 130.5, 135.0, 141.3, 169.1, 201.5. HRMS calcd for
C11H1035ClNO2 223.0400. Found: 223.0390.
4. +a) Waldmann, H.; Braun, M.; Draeger, M. Angew. Chem., Int.
Ed. Engl. 1990, 29, 1460±1471. +b) Waldmann, H.; Braun,
M.; Draeger, M. Tetrahedron: Asymmetry 1991, 2, 1231±
1246.
3.7.2. 6-'2-Furyl)-2,4-piperidinedione '4e). Beige crystals,
5. +a) Davis, F. A.; Zhou, P.; Chen, B.-C. Chem. Soc. Rev. 1998,
27, 13±18. +b) Zhou, P.; Chen, B.-C.; Davis, F. A. Advances in
Sulfur Chemistry; Rayner, C. M., Ed.; JAI: Stamford, 2000;
Vol. 2, pp. 249±282.
1
mp 77±828C. IR +KBr) 3190, 1725, 1671 cm21. H NMR
+CDCl3) d 2.95 and 2.95 +ABX, Jˆ16.6, 5.5 Hz, 2H), 3.34
and 3.39 +AB, Jˆ19.2 Hz, 2H), 4.89 +m, 1H), 6.26 +d,
Jˆ3.3, 2.0 Hz, 1H), 6.35 +dd, Jˆ3.3, 2.0, 1H), 6.39 +br,
1H), 7.41 +m, 1H). 13C NMR +CDCl3) d 42.7, 46.3, 47.1,
107.0, 110.4, 143.0, 151.8, 169.1, 202.0. HRMS calcd for
C9H9NO3 179.0582. Found: 179.0577.
6. Davis, F. A.; Reddy, R. E.; Szewczyk, J. M.; Portonovo, P. S.
Tetrahedron Lett. 1993, 34, 6229±6232.
7. Cogan, D. A.; Liu, G.; Kim, K.; Backes, B. J.; Ellman, J. A.
J. Am. Chem. Soc. 1998, 120, 8011±8019.
8. KaweÎcki, R. J. Org. Chem. 1999, 64, 8724±8727.
9. Davis, F. A.; Chao, B.; Fang, T.; Szewczyk, J. M. Org. Lett.
2000, 2, 1041±1043.
Acknowledgements
10. Grunwell, J. R.; Karipides, A.; Wigal, C. T.; Heinzman, S. W.;
Parlow, J.; Surso, J. A.; Clayton, L.; Fleitz, F. J.; Daffner, M.;
Stevens, J. E. J. Org. Chem. 1991, 56, 91±95.
Financial support from the State Committee for Scienti®c
Research +grant 3T09A 02816) is gratefully acknowledged.
11. Savard, J.; Brassard, P. Tetrahedron Lett. 1979, 4911±4914.
12. KaweÎcki, R. Tetrahedron: Asymmetry 1999, 10, 4183±4190.
13. Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J. A.
J. Org. Chem. 1999, 64, 1278±1284.
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Â
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