Enantiospecific formation of 3,6-dihydro-1H-pyridin-2-ones: Low-pressure palladium-catalysed decarboxylative carbonylation of 3-tosyl-5-vinyloxazolidin- 2-ones

Article abstract of DOI:10.1055/s-2005-924765

Palladium-catalysed decarboxylative carbonylation of 3-tosyl-5- vinyloxazolidin-2-ones 5 occurs at atmospheric pressure to give 1-tosyl-3,6-dihydro-1H-pyridin-2-ones 6. The reaction proceeds with no loss of enantiopurity and detosylation with sodium napht

Full text of DOI:10.1055/s-2005-924765

PAPER
227
Enantiospecific Formation of 3,6-Dihydro-1H-pyridin-2-ones:
Low-Pressure Palladium-Catalysed Decarboxylative Carbonylation
of 3-Tosyl-5-vinyloxazolidin-2-ones
E
nantiosp
u
ecific Forma
l
tion of
i
3,6-Dih
a
ydro-1
H
-
p
n
yridin-2-ones G. Knight,*a Iain M. Lawson,a Christopher N. Johnsonb
a
School of Natural Sciences, Chemistry, Bedson Building, University of Newcastle-Upon-Tyne, Newcastle-Upon-Tyne, NE1 7RU, UK
Fax +44(191)2227068; E-mail: J.G.Knight@ncl.ac.uk
GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW, UK
b
Received 16 September 2005
This paper is dedicated to Professor Steven Ley on the occasion of his 60th birthday.
rivative does not undergo carbonylation to give a lactam,
we turned our attention to carbonylation of the corre-
sponding N-tosyl derivative.
Abstract: Palladium-catalysed decarboxylative carbonylation of 3-
tosyl-5-vinyloxazolidin-2-ones 5 occurs at atmospheric pressure to
give 1-tosyl-3,6-dihydro-1H-pyridin-2-ones 6. The reaction pro-
ceeds with no loss of enantiopurity and detosylation with sodium
naphthalenide gives the title compounds in good yields.
Ibuka has reported that 3-tosyl-5-vinyloxazolidin-2-ones
undergo palladium-catalysed decarboxylation to give cis-
N-tosyl-2-vinylaziridines.7 In addition, Tanner has shown
that the palladium-catalysed carbonylation of N-tosyl-2-
vinylaziridines occurs under one atmosphere of carbon
monoxide to give b-lactams.8 Considering these reports, it
was envisaged that a low-pressure palladium-catalysed
decarboxylative carbonylation of N-tosyl-5-vinyloxazoli-
din-2-ones might result in the formation of b-lactams via
in situ formation of the corresponding aziridines. In this
article, we report that the palladium-catalysed decarboxy-
lative carbonylation of amino acid derived N-tosyl-5-vi-
nyloxazolidin-2-ones does indeed proceed under one
atmosphere of carbon monoxide but gives N-tosyl-3,6-di-
hydro-1H-pyridin-2-ones and not the expected b-lactams.
Key words: carbonylation, catalysis, palladium, cyclisation, lac-
tams
The use of transition metal mediated carbonylation
reactions has been shown to be a useful method for the
formation of a variety of functionalised heterocyclic com-
pounds.1 We have shown that 5-vinyloxazolidin-2-ones 1
undergo a stereospecific, palladium-catalysed decarboxy-
lative carbonylation to give 3,6-dihydro-1H-pyridin-2-
ones 22 (Scheme 1). Lactams such as 2 have been shown
to be useful intermediates in the synthesis of polyhydrox-
ylated piperidines,3 pumiliotoxins4 and (Z)-ethylenic
pseudodipeptides.5 Reduction of the necessary carbon
monoxide pressure from 60 atmospheres (Scheme 1)
would increase the synthetic utility of this carbonylation
reaction.
R
BrMg
t-BuOK, THF
0 °C, overnight
R
O
OH
NHBoc
THF, r.t., 2 h
NHBoc
3
4
R
PdCl2(PPh3)2,
EtOH,
CO (60 atm),
60 °C, 24 h
R
TsCl, NaH
DMF–THF
R
R
O
HN
HN
O
O
O
TsN
HN
–78 °C to r.t.,18 h
O
O
O
1
2
1
5
Scheme 1 High-pressure carbonylation of 5-vinyloxazolidin-2-ones.
Scheme 2 Synthesis of 3-tosyl-5-vinyloxazolidin-2-ones.
Placing a strongly electron withdrawing group on the ni-
trogen of the oxazolidinone was expected to activate it to-
wards decarboxylation which might facilitate the
carbonylation reaction. We recently reported the palladi-
um-catalysed cycloaddition of 3-tosyl-5,5-divinyloxazo-
lidin-2-ones to electron deficient alkenes, which involves
decarboxylation under mild conditions.6 Since we have al-
ready shown2a that a N-Boc-5-vinyloxazolidin-2-one de-
5-Vinyloxazolidin-2-ones 1a–d were prepared in two
steps, as previously reported,2a,3 from the corresponding
a-amino aldehydes 3 (Scheme 2) which, in turn, were
prepared either by Swern oxidation of N-Boc a-amino al-
cohols 3a–c (R = i-Pr, Bn, Ph) or by DIBAL-H reduction
of N-Boc a-amino methyl ester 3d (R = CH2OTBDMS).
Addition of vinyl magnesium bromide to the aldehydes
gave allylic alcohols 4 which were cyclised by treatment
with potassium tert-butoxide to give oxazolidinones 1. N-
Tosylation by reaction with sodium hydride and p-
toluenesulfonyl chloride gave 3-tosyl-5-vinyloxazolidin-
SYNTHESIS 2006, No. 2, pp 0227–0230
x
x
.
x
x
.2
0
0
5
Advanced online publication: 21.12.2005
DOI: 10.1055/s-2005-924765; Art ID: C09505SS
© Georg Thieme Verlag Stuttgart · New York
2-ones
5
in good yields. N-Tosylation of 1d
(R = CH2OTBDMS) was accompanied by removal of the

228
J. G. Knight et al.
PAPER
Table 1 Palladium-Catalysed Decarboxylative Carbonylation of
3-Tosyl-5-vinyloxazolidin-2-onesa
silicon-protecting group, giving N-tosyl vinyl oxazol-
idinone 5e (R = CH2OH). Reprotection of the alkoxy
group, to give 5d, was achieved by reaction with
TBDMSCl and imidazole in DMF.
Entry
Oxazolidinone
R
Yield of lactam 6 (%)b
1
2
3
4
5
5a
5b
5c
5d
5e
i-Pr
Bn
Ph
74
75
77
Attempted carbonylation of 3-tosyl-5-vinyloxazolidin-2-
one 5a (R = i-Pr) using the conditions reported for the car-
bonylative ring expansion of N-tosyl vinylaziridines8
[Pd2(dba)3·CHCl3 (20 mol%), PPh3 (160 mol%), CO (1
atm), benzene, r.t.] gave d-lactam 6a in 69% yield
(Scheme 3), with no b-lactam evident.9 Aggarwal report-
ed a single example of the unexpected carbonylation of an
N-sulfonyl-2-(b-trimethylsilylvinyl)aziridine to give a py-
ridin-2-one, but ascribed this result to the directing effect
of the silyl group.10
CH2OTBDMS 71
CH2OH
0c
a Conditions: Pd2(dba)3 (5 mol%), PPh3 (10 mol%), CO (1 atm),
benzene, 60 °C, 4 h.
b Isolated yield.
c No starting material was observed in the NMR spectrum of the
crude.
Pd2(dba)3⋅CHCl3
(20 mol%),
iPr
TsN
iPr
TsN
O
R
R
Ph3P (160 mol%),
CO (1 atm),
benzene, r.t.
69%
O
Na, C10H8
1,2-DME, –78 o
O
HN
TsN
C
5a
6a
O
O
6
2
Scheme 3 Carbonylation of 3-tosyl-5-vinyloxazolidin-2-ones.
Scheme 5 Detosylation of N-tosyl-3,6-dihydropyridin-2-ones.
Table 2 Detosylation of N-Tosyl-3,6-dihydropyridin-2-ones 6
Despite the absence of the b-lactam, formation of the d-
lactam 6a under an initial pressure of one atmosphere of
carbon monoxide was encouraging. Use of such a high
palladium loading (40 mol%) makes the process very
costly, and the high phosphine loading (160 mol%) hin-
ders purification of the product. In our recent investiga-
tion of the decarboxylative cycloaddition of N-tosyl-5,5-
divinyloxazolidin-2-ones,6 we found that Pd2(dba)3 (5
mol%) could be used successfully with a phosphine/Pd ra-
tio of 1:1 (i.e. 10 mol% of PPh3). We were pleased to find
that carbonylation of N-tosyl-5-vinyloxazolidin-2-ones
5a–d, under these conditions, in benzene at 60 °C, gave d-
lactams 6a–d in good yields (Scheme 4, Table 1, entries
1–4). Attempted carbonylation of 5e, bearing a free hy-
droxyl group, was unsuccessful (Table 1, entry 5).
Lactam 6
R
Yield of 2 (%)
6a
6b
6c
6d
i-Pr
84
87
75
81
Bn
Ph
CH2OTBDMS
TsCl, NaH
DMF–THF
HN
O
TsN
75%
O
–78 °C to r.t., 18 h
67%
O
O
(4R)-1a
(4R)-5a
Pd2(dba)3 (5 mol%),
Ph3P (10 mol%),
R
Pd2(dba)3,
PPh3,
benzene,
CO (1 atm),
60 °C, 4 h
R
PdCl2(PPh3)2,
EtOH,
CO (60 atm),
60 °C, 24 h
TsN
O
72%
TsN
CO (1 atm),
benzene, 60 °C
O
O
6
5
Scheme 4 Atmospheric pressure carbonylation of 3-tosyl-5-vinyl-
Na, C10H8
oxazolidin-2-ones.
HN
O
TsN
O
1,2-DME, –78 °C
88%
Holmes has reported the detosylation of N-tosyl e-lactams
in good yield using sodium naphthalenide.11 This method
was therefore applied to the detosylation of d-lactams
6a–d. A solution of sodium naphthalenide in DME was
added to each N-tosyl d-lactam 6a–d, producing detosyl-
ated d-lactams 2a–d in good yield (75–87%, Scheme 5
and Table 2).
(6R)-2a
(6R)-6a
Scheme 6 Formation of ent-2a by both low- and high-pressure
carbonylation routes.
The high-pressure carbonylation of 5-vinyloxazolidin-2-
ones 1 to give d-lactams 2 (Scheme 1) has been shown to
occur without loss of enantiomeric purity.2a In order to
demonstrate that this was also true in the N-tosyl series,
oxazolidinone (4R)-1a was synthesised from D-valine.
Synthesis 2006, No. 2, 227–230 © Thieme Stuttgart · New York

PAPER
Enantiospecific Formation of 3,6-Dihydro-1H-pyridin-2-ones
229
1 H, (CH3)2CH], 0.90 (d, J = 6.9 Hz, 3 H, (CH3)2CH), 0.76 [d, J =
6.9 Hz, 3 H, (CH3)2CH].
High pressure carbonylation [PdCl2(PPh3)2, CO (60 atm),
EtOH, 60 °C, 24 h] of (4R)-1a gave the corresponding lac-
tam (6R)-2a in good yield (72%). N-Tosylation of (4R)- 13C NMR (75 MHz, CDCl3): d = 152.4, 152.1, 145.7, 145.6, 136.3,
135.8, 134.8, 129.9, 129.4, 129.3, 128.9, 128.8, 121.5, 118.4, 81.4,
1a, followed by low-pressure carbonylation, and subse-
quent detosylation using sodium naphthalenide also gave
75.5, 67.6, 66.6, 31.1, 30.1, 21.8, 19.5, 19.3, 17.9, 17.5, 15.2
MS: m/z (%) = 310 (M+ + H, 0.1), 226 (19), 202 (22), 155 (100), 91
N-H lactam (6R)-2a (44% over three steps) (Scheme 6).
(70), 65 (13).
Analysis of (6R)-2a, formed both by the high- and low-
HRMS: m/z calcd for C15H19NO4S: 309.103480; found:
309.103480.
pressure carbonylation routes, by chiral gas
chromatography12 and comparison with (6S)-2a, showed
that each lactam was formed as a single enantiomer.
(4S,5RS)-4-(tert-Butyldimethylsilanyloxymethyl)-3-[(4-methyl-
benzene)sulfonyl]-5-vinyloxazolidin-2-one (5d)
TBDMSCl (92 mg, 1.35 mmol) was added at 0 °C to a stirred solu-
tion of (4S,5RS)-4-hydroxymethyl-3-[(4-methylbenzene)sulfonyl]-
5-vinyloxazolidin-2-one (5e; 200 mg, 0.67 mmol) in DMF (1 mL).
In conclusion, we have demonstrated that palladium-ca-
talysed decarboxylative carbonylation of N-tosyl-5-viny-
loxazolidin-2-ones 5 occurs under atmospheric pressure
of carbon monoxide to give the corresponding N-tosyl-
3,6-dihydropiperidin-2-ones 6 which may be detosylated
under mild conditions. The carbonylation/detosylation se-
quence occurs without loss of enantiomeric purity.
Imidazole (112 mg, 0.74 mmol) was then added to the solution and
the reaction was stirred at r.t. for 6 h. The mixture was then poured
into PE–EtOAc (1:1, 500 mL) and washed with H2O (3 × 100 mL).
The organic phase was dried (MgSO4), filtered and the solvent re-
moved under reduced pressure. Purification of the crude product by
column chromatography on silica gel (PE–EtOAc, 10:1) afforded
O-TBDMS, N-tosyl-protected vinyl oxazolidinone 5d as a cream
coloured solid (254 mg, 92%, 2:1 ratio of diastereoisomers).
1H NMR and 13C NMR spectra were recorded on a Brüker WM 300
and JEOL LA 500 machines at ambient temperature. GC was per-
formed on a Packard 427GC using a b-dextrin 120 column (20
m × 0.25 mm) and recorded on a Hitachi D2500 chromato integra-
tor. IR spectra were obtained on an ATI Mattson Genesis REV I
FTIR spectrometer. MS were recorded on a Micromass autospec M
and Kratos MS80 RF spectrometers. Elemental analyses were per-
formed on a Carlo Erba 1106 instrument. Petroleum ether (PE) used
had a bp range 40–60 °C.
IR (film): 2956, 1786, 1647, 1597, 1371, 1046 cm–1.
Major Diasteroisomer
1H NMR (300 MHz, CDCl3): d = 7.86 (m, 2 H, MeC6H4SO2), 7.27
(d, J = 8 Hz, 2 H, MeC6H4SO2), 5.64 (ddd, J = 6.5, 10.5, 17 Hz, 1
H, HC=CH2), 5.16–5.41 (m, 2 H, HC=CH2), 4.88 (m, 1 H, CHN),
4.02 (m, 1 H, CHO), 3.72 (m, 2 H, CH2OSi), 2.37 (s, 3 H,
CH3ArSO2), 0.94 [s, 9 H, (CH3C)3Si], –0.04 [s, 6 H, (CH3)2Si].
N-Tosyl-5-vinyloxazolidin-2-ones 5; General Procedure
To a stirred suspension of NaH (2 equiv) in a mixture of THF (1
mL⋅mmol–1 oxazolidinone) and DMF (2.5 mL⋅mmol–1 oxazolidin-
one) at 0 °C were added successively 5-vinyloxazolidin-2-one 1 (1
equiv) in THF (0.5 mL⋅mmol–1 oxazolidinone) and p-TsCl (1.3
equiv). Stirring was continued for 18 h at r.t., then the reaction was
quenched by the addition of a sat. solution of NH4Cl (1 mL⋅mmol–1
oxazolidinone) at –78 °C with vigorous stirring. The mixture was
extracted with Et2O (2 × 30 mL), and the extract was washed suc-
cessively with HCl (2 M, 30 mL), NaHCO3 (30 mL), H2O (30 mL),
dried (MgSO4) and the solvents removed under reduced pressure.
Purification by column chromatography on silica gel (PE–EtOAc,
10:1) afforded the N-tosyl-protected oxazolidinone 5.
Minor Diastereoisomer
1H NMR (300 MHz, CDCl3): d = 7.86 (m, 2 H, MeC6H4SO2), 7.27
(d, J = 8 Hz, 2 H, MeC6H4SO2), 5.95–6.05 (m, 1 H, HC=CH2),
5.16–5.41 (m, 2 H, HC=CH2), 4.92 (m, 1 H, CHN), 4.02 (m, 3 H,
CH2OSi, CHO), 2.37 (s, 3 H, CH3ArSO2), 0.94 [s, 9 H, (CH3C)3Si],
–0.04 [s, 6 H, (CH3)2Si].
13C NMR (75 MHz, CDCl3): d = 152.2, 145.9, 145.7, 136.0, 135.4,
133.9, 130.4, 130.3, 128.7, 128.6, 123.0, 119.1, 79.9, 71.8, 63.5,
63.0, 62.0, 60.4, 26.0, 25.8, 22.0, 21.4, 18.3, 18.0.
MS: m/z (%) = 411 (M+, 0.3), 396 (1.7), 354 (100), 280 (27), 229
(65), 149 (46), 91 (83), 73 (49), 43 (48).
HRMS: m/z calcd for C19H29NO5SSi: 411.152611; found:
411.153574.
(4S,5RS)-4-Isopropyl-3-[(4-methylbenzene)sulfonyl]-5-vinyl-
oxazolidin-2-one (5a)
(4S,5RS)-4-Isopropyl-5-vinyloxazolidin-2-one (1a; 2.408 g, 16
mmol) gave N-tosyl vinyl oxazolidinone 5a as white needles (4.144
g, 86%, 1.5:1 ratio of diastereoisomers).
IR (film): 2965, 1773, 1646, 1595, 1370 cm–1.
N-Tosyl-3,6-dihydropyridin-2-ones 6; General Procedure
A solution of N-tosyl-5-vinyloxazolidin-2-one 5 in benzene (9
mL⋅mmol–1 oxazolidinone) was placed in a glass flask fitted with a
Young’s tap under a N2 atmosphere. Pd2(dba)3 (5 mol%) and PPh3
(10 mol%) were weighed into a glass sample vial and dissolved in
benzene (1 mL⋅mmol–1 oxazolidinone). The catalyst solution was
injected into the flask and the flask was flushed with CO, sealed and
the reaction was heated at 60 °C and stirred for 4 h. The reaction
mixture was allowed to cool to r.t. and the solvent was removed un-
der reduced pressure. Lactam 6 was purified by flash column chro-
matography on silica (CH2Cl2).
Major Diastereoisomer
1H NMR (300 MHz, CDCl3): d = 7.86 (d, J = 8.4 Hz, 2 H,
MeC6H4SO2), 7.27 (d, J = 8.4 Hz, 2 H, MeC6H4SO2), 5.60–5.71
(ddd, J = 5.8, 10.4, 16.6 Hz, 1 H, HC=CH2), 5.14–5.23 (m, 2 H,
HC=CH2), 4.58–4.61 (m, 1 H, CHN), 4.01–4.03 (m, 1 H, CHO),
2.47 [s, 4 H, CH3ArSO2, (CH3)2CH], 0.90 (d, J = 6.9 Hz, 3 H,
(CH3)2CH), 0.76 [d, J = 6.9 Hz, 3 H, (CH3)2CH].
(6S)-3,6-Dihydro-6-isopropyl-1-[(4-methylbenzene)sulfo-
nyl]pyridin-2-one (6a)
(4S,5RS)-4-Isopropyl-3-[(4-methylbenzene)sulfonyl]-5-vinylox-
azolidin-2-one (5a; 200 mg, 0.646 mmol) afforded lactam 6a as a
white solid (140 mg, 74%).
Minor Diastereoisomer
1H NMR (300 MHz, CDCl3): d = 7.96 (d, J = 8.4 Hz, 2 H,
MeC6H4SO2), 7.27 (d, J = 8.4 Hz, 2 H, MeC6H4SO2), 5.81–5.92 (m,
1 H, HC=CH2), 5.34–5.46 (m, 2 H, HC=CH2), 4.91–4.96 (m, 1 H,
CHN), 4.37–4.40 (m, 1 H, CHO), 2.47 (s, 3 H, CH3ArSO2), 2.11 [m,
Mp 112–114 °C; [a]D21 +138.1 (c 1.5, CHCl3).
Synthesis 2006, No. 2, 227–230 © Thieme Stuttgart · New York

230
J. G. Knight et al.
PAPER
IR (KBr): 2964, 1695, 1596, 1350 cm–1.
Acknowledgment
1H NMR (500 MHz, CDCl3): d = 7.82 (d, J = 8.4 Hz, 2 H,
MeC6H4SO2), 7.21 (d, J = 8.4 Hz, 2 H, MeC6H4SO2), 5.83 (ddd,
J = 3.1, 5.5, 10.1 Hz, 1 H, HC=CHCH2), 5.77 (ddd, J = 2.1, 4.6,
10.1 Hz, 1 H, HC=CHCH2), 4.68 (m, 1 H, CHN), 2.94 (ddt, J =
22.3, 2.1, 3.1 Hz, 1 H, CHHC=O), 2.83 (ddd, J = 22.3, 4.6, 1.5 Hz,
1 H, CHHC=O), 2.45 [d sept, J = 4.6, 6.9 Hz, 1 H, (CH3)2CH], 2.34
(s, 3 H, CH3ArSO2), 0.97 [d, J = 7 Hz, 3 H, (CH3)2CH], 0.75 [d,
J = 6.7 Hz, 3 H, (CH3)2CH].
13C NMR (125 MHz, CDCl3): d = 168.6, 144.6, 136.5, 129.1, 129.0,
123.4, 123.1, 63.2, 35.0, 34.6, 21.6, 19.1, 15.1.
MS: m/z (%) = 293 (M+, 0.2), 250 (72), 186 (51), 156 (6), 91 (100),
65 (21), 41 (15).
We thank the EPSRC and GlaxoSmithKline for funding.
References
(1) (a) Mahadevan, V.; Getzler, Y. D. Y. L.; Coates, G. W.
Angew. Chem. Int. Ed. 2002, 41, 2781. (b) Khumtaveeporn,
K.; Alper, H. Acc. Chem. Res. 1995, 28, 414. (c) Ley, S. V.;
Cox, L. R.; Meek, G. Chem. Rev. 1996, 96, 423.
(2) (a) Knight, J. G.; Ainge, S. W.; Harm, A. M.; Harwood, S.
J.; Maughan, H. I.; Armour, D. R.; Hollinshead, D. M.; Jaxa-
Chamiec, A. A. J. Am. Chem. Soc. 2000, 122, 2944.
(b) Knight, J. G.; Tchabanenko, K. Tetrahedron 2002, 58,
6659.
(3) Knight, J. G.; Tchabanenko, K. Tetrahedron 2003, 59, 281.
(4) O’Mahoney, G.; Nieuwenhuyzen, M.; Armstrong, P.;
Stevenson, P. J. J. Org. Chem. 2004, 69, 3968.
(5) (a) Garro-Hélion, F.; Guibé, F. J. Chem. Soc., Chem.
Commun. 1996, 641. (b) Sauriat-Dorizon, H.; Guibé, F.
Tetrahedron Lett. 1998, 39, 6711. (c) Boucard, V.; Sauriat-
Dorizon, H.; Guibé, F. Tetrahedron 2002, 58, 7275.
(6) Knight, J. G.; Tchabanenko, K.; Stoker, P. A.; Harwood, S.
J. Tetrahedron Lett. 2005, 46, 6261.
HRMS: m/z calcd for C15H19NO3S: 293.108565; found:
293.109802.
Detosylation of Lactams 6; General Procedure
Naphthalene (394 mg, 3.07 mmol) and freshly cut Na (79 mg, 3.44
mmol) were suspended in DME (10 mL) and the mixture was soni-
cated until the solution began to turn dark green. The mixture was
then removed from the sonicator, cooled to 0 °C and stirred for a
further 2 h.
A stirred solution of N-tosyl-3,6-dihydropyridin-2-one 6 in DME (1
mL) was cooled to –65 °C and the previously prepared sodium
naphthelenide solution was added dropwise until the solution re-
mained dark green. The mixture was stirred at –65 °C for a further
30 min and then quenched by the slow addition of a sat. solution of
NH4Cl. The reaction was allowed to warm to r.t. over 30 min and
was then poured into H2O (20 mL). The mixture was then extracted
with CH2Cl2 (4 × 20 mL), the combined organic layers were dried
(MgSO4) and the solvents were removed under reduced pressure.
Purification by flash column chromatography on silica (PE–EtOAc,
1:1) gave d-lactam 2.
(7) Ibuka, T.; Mimura, N.; Aoyama, H.; Akaji, M.; Ohno, H.;
Miwa, Y.; Taga, T.; Nakai, K.; Tamamura, H.; Fujii, N. J.
Org. Chem. 1997, 62, 999.
(8) Tanner, D.; Somfai, P. Bioorg. Med. Chem. Lett. 1993, 3,
2415.
(9) The 1H NMR spectrum of the crude product mixture showed
no evidence of b-lactam formation (in particular, no signals
in the range 3.5–4 ppm for the azetidinone 3- and 4-protons);
see also ref. 8.
(10) Aggarwal, V. K.; Alonso, E.; Fang, G.; Ferrara, M.; Hynd,
G.; Porcelloni, M. Angew. Chem. Int. Ed. 2001, 40, 1433.
(11) Evans, P. A.; Holmes, A. B.; Russell, K. J. Chem. Soc.,
Perkin Trans. 1 1994, 3397.
(12) Gas chromatography analysis [138 °C, b-dextrin 120
column (20 m × 0.25 mm)] of (6R)-3,6-dihydro-6-
isopropyl-1H-pyridin-2-one (6R)-2a, formed by the direct
carbonylation of (4R)-1a, showed a single peak (tR 36.963
min). Likewise, analysis of (6R)-2a formed by deprotection
of the N-tosylpiperidinone (4R)-6a also showed only one
peak (tR 36.703 min), as did the analysis of the (S)-N-H
lactam (6S)-2a (tR 37.856 min). Analysis of a 1:4 mixture of
the enantiomers, (6R)-2a/(6S)-2a showed two peaks in a 1:4
ratio (37.747 min; 38.590 min).
(6S)-3,6-Dihydro-6-isopropyl-1H-pyridin-2-one (2a)2a
(6S)-3,6-Dihydro-6-isopropyl-1-[(4-methylbenzene)sulfonyl]pyri-
din-2-one (6a; 35 mg, 0.12 mmol) afforded d-lactam 2a as a white
solid (14 mg, 84%).
1H NMR (300 MHz, CDCl3): d = 6.40 (br s, 1 H, NH), 5.78–5.72
(m, 1 H, CH=CH), 5.61–5.56 (m, 1 H, CH=CH), 2.85 (m, 2 H,
CH2CO), 3.87 (br s, 1 H, CHN), 1.76 [d sept, J = 4.0, 6.7 Hz, 1 H,
(CH3)2CH], 0.87 [d, J = 6.7 Hz, 3 H, (CH3)2CH], 0.84 [d, J = 6.6
Hz, 3 H, (CH3)2CH].
13C NMR (75 MHz, CDCl3): d = 170.7, 123.9, 123.2, 59.7, 34.2,
31.9, 17.9, 17.3.
Synthesis 2006, No. 2, 227–230 © Thieme Stuttgart · New York