Methylenation and oxidation of chiral non-racemic 2-piperidones: Reactivity of a new 3-oxolactam

Article abstract of DOI:10.1055/s-1999-3393

The preparation of (R)-N-(2-hydroxy-1-phenylethyl)-3- methylenepiperidin-2-one (2) and (R)-N-(2-hydroxy-1-phenylethyl)piperidine- 2,3-dione (3) from the (R)-phenylglycinol-derived lactam 1 is described. We have also studied the reactivity of 3-oxolactam 3, and a series of functionalized derivatives has been prepared.

Full text of DOI:10.1055/s-1999-3393

258
PAPER
Methylenation and Oxidation of Chiral Non-Racemic 2-Piperidones:
Reactivity of a New 3-Oxolactam
Pilar Forns,a M. Montserrat Fern‡ndez,a Anna Diez,*a Mario Rubiralta,a Marie Pierre Cherrier,b Martine Bonin,b
Jean-Charles Quirionb
a Laboratori de Qu’mica Orgˆnica, Facultat de Farmˆcia, Universitat de Barcelona, 08028-Barcelona, Spain
Fax: +34(93)4021896; E-mail: adiez@farmacia.far.ub.es
b Laboratoire de Chimie ThŽrapeutique, FacultŽ des Sciences Pharmaceutiques et Biologiques, UniversitŽ RenŽ Descartes (Paris V), 4,
Avenue de lÕObservatoire, 75270 Paris CŽdex 06, France
Received 22 May 1998; revised 17 July 1998
Abstract: The preparation of (R)-N-(2-hydroxy-1-phenylethyl)-3-
methylenepiperidin-2-one (2) and (R)-N-(2-hydroxy-1-phenyleth-
yl)piperidine-2,3-dione (3) from the (R)-phenylglycinol-derived
lactam 1 is described. We have also studied the reactivity of 3-
oxolactam 3, and a series of functionalized derivatives has been pre-
pared.
Key words: 3-methylenelactam, 3-oxolactam, 3-hydroxylactam,
(R)-(Ð)-phenylglycinol, WadsworthÐEmmons Reaction
Scheme 1
Methylene lactam 2 was characterized by a molecular
In our earlier work, we investigated the reactivity of the
enolate of chiral lactam 1 for the preparation of some 3-
substituted piperidines.1Ð3 During this study we encoun-
tered difficulties in introducing functionalized electro-
philes. In order to circumvent this problem, we now
describe the synthesis of 3-methylenelactam 2 and the
oxolactam 3. These new derivatives can be used as build-
ing blocks for the synthesis of more complex piperidine
molecules: 3-methylenelactam 2 is a suitable substrate for
conjugate addition in analogy with our previous work on
the preparation of indole alkaloids from lactam 4,4 and ox-
olactam 3 is a precursor of C-3 and/or C-4 functionalized
piperidines, as shown by the studies on its reactivity.
peak at m/z 231 in its mass spectrum, a double bond ab-
sorption in the IR spectrum at 1592 cmÐ1, the presence of
two olefin doublets (JAB = 2 Hz) at d = 5.35 and 6.28 in
1
the H NMR spectrum, and a methylene carbon at d =
122.6 in the 13C NMR spectrum. The chloromethyllactam
5 was obtained as a single isomer, which we assumed had
an S configuration according to the model we proposed
1
previously.1 In its H and 13C NMR spectra, the chloro-
methyllactam 5 showed a multiplet at d = 4.05Ð4.20 cor-
responding to the exocyclic methylene protons, and the
methine and methylene carbons at d = 43.8 (C-3) and 46.8
(CH2Cl).
Simultaneously, methylenation of lactam 1 to give 3-
methylenelactam 2 was attempted by transformation of 3-
oxolactam 3 by a Wittig-type reaction8 or using Lombar-
do's method.9 In addition, we intended to use oxolactam 3
for further functionalization on positions C-3 and C-4.
The direct oxidation of a six-membered lactam to the cor-
responding 3-oxolactam has been described recently by
forming the enolate with LDA and quenching with oxy-
gen.10,11 Before that, Meyers had prepared a five-mem-
bered chiral 3-oxolactam by oxidative cleavage of a
dithioacetal.12 Because of our experience in using StorkÕs
method13 to transform dithiane rings into carbonyls,4b,14
we planned to prepare the 3-oxolactam 3 from the dime-
thyldithioacetal precursor 8. Thus, reaction of lactam 1
with methyl methanethiolsulfonate was conducted in di-
verse experimental conditions as summarized in the Ta-
ble. When we used sec-BuLi at Ð78¡C, a mixture of
lactams 7a,b was obtained in only very low yield (Entry
1). Use of a larger excess of base and electrophile im-
proved the yield moderately, and the proportion of thio-
ethers 7a and 7b after column chromatography was 6:4
The synthesis of methylene lactam 2 from lactam 1 was
first attempted through an elimination of the products of
both hydroxymethylation followed by tosylation,5 and
reaction with Eschenmoser's salt followed by quater-
nization.6 Since these methods were unsuccessful, we
tried the direct methylenation of lactam 1 to obtain 2.
Thus, treatment of lactam 1 with sec-BuLi in the pres-
ence of hexamethylphosphoramide (HMPA) and 4• mo-
lecular sieves, followed by addition of excess CH2BrCl,
yielded the 3-methylenelactam 2 together with a small
proportion of the intermediate 3-chloromethyl lactam 57
(Scheme 1).
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Methylenation and Oxidation of Chiral Non-Racemic 2-Piperidones
259
(de 20%). In contrast, with LDA as the base at 0¡C (Mey-
ers conditions), compounds 7 were obtained in 73% yield,
with the diastereomeric excess increased to 80% (Entry
3). However, under these conditions the formation of
dithioacetal 8 was already observed, in 13% yield. A sec-
ond addition of base and nucleophile to the reaction medi-
um, followed by stirring at room temperature, gave
exclusively the dithioacetal 8 in 74% yield (Entry 4). Ox-
idation of dithioacetal 8 with (CF3COO)2IPh in 90:10 ac-
etonitrile/H2O12 provided the expected piperidin-2,3-dione
3 in 77% yield, as white crystals (Scheme 2). The struc-
ture assignment was confirmed by the analytical data, and
in particular by the presence of two distinct carbonyl sig-
nals in the 13C NMR spectrum at d = 159.0 (lactam) and
191.7 (ketone).
Scheme 3
tride)at room temperature. In this case only isomer 9a was
obtained as a solid after column chromatography (silica
gel) in 18% yield. The structure of isomer 9a was con-
firmed by X-ray crystallography as the expected (aR,3R)
isomer (Figure).
Scheme 2
We then performed a series of experiments to verify that
the 3-oxo group of compound 3 reacted as an independent
ketone function. This allowed us to prepare a series of de-
rivatives with potential synthetic applicabilities.
Figure ORTEP representation of the 3-hydroxylactam 9a
The third kind of reaction we were interested in was the
Wittig-type, for preparation of not only 3-methylene lac-
tam 2 but also of the conjugated esters accessible from 3
by a WadsworthÐEmmons reaction.17 When compound 3
was reacted with methylenetriphenylphosphonium ylide18
the starting substrate was partially recovered together
with unidentified decomposition products. The same re-
sult was obtained by treatment of lactam 3 with CH2I2 in
the presence of Zn and AlCl3 (Lombardo's method).9a,19
We had tried unsuccessfully to prepare hydroxylactams 9
by electrophilic hydroxylation using DavisÕ oxaziri-
dines.15 However, treatment of oxolactam 3 with NaBH4
yielded an unseparable 2:116 C3-diastereomeric mixture
of hydroxylactams 9a,b in 98% yield (Scheme 3). Both
hydroxylactams were characterized by their C-3 methine
carbon, which appeared at d = 68.3 for 9a (major isomer)
and at d = 68.0 for 9b in the 13C NMR spectrum of the
mixture. In the 1H NMR spectrum, both isomers presented
the 3-H signal masked under the multiplet at d = 4.10Ð
4.25 that corresponds to the b-protons.
Treatment of oxolactam 3 in 1,2-dimethoxyethane (DME)
with 2 equivalents of methylenetriphenylphosphonium
ylide provided a mixture of (Z)-10a and (E)-10b. Howev-
er, the excess phosphonoacetate had to be removed by mi-
In order to improve the steric outcome of the reduction we
tried using lithium tri-sec-butylborohydride (L-Selec-
Table Effects of Base and Temperature on the Formation of Compounds 7 and 8
Entry
Temp
(¡C)
Base
(equiv)
Electrophile
(equiv)
Yield (%)
7a + 7b
Ratio
Yield (%)
8
of 7a:7ba
1
2
3
4
Ð78
Ð78
0
sec-BuLi (3.5)
sec-BuLi (7)
LDA (3.5)
3
6
11
27
73
0
60:40
60:40
90:10
Ð
Ð
Ð
13
74
2.5
3, then 3
0, then 25
LDA (3, then 3.5)
a Determined by 1H NMR spectral analysis.
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260
P. Forns et al.
PAPER
experiments were performed on a Varian XL-500 instrument
(500 MHz). Unless otherwise noted, NMR spectra were registered
in CDCl3, and chemical shifts are expressed in parts per million (δ)
relative to internal TMS. IR spectra were recorded on a Nicolet FT-
IR spectrophotometer. Mass spectra were determined on a Hewlett-
Packard 5988A mass spectrometer, either by chemical ionization
(CIMS) or electronic impact (EIMS). Flash column chromatogra-
phy was carried out on silica gel 60 (40Ð63 mm, SDS). TLC was
performed on silica gel 60 (F254, Macherey-Nagel) and developed
with the solvent described in each case for flash chromatography.
The spots were located by UV light and Draggendorf or hexachlo-
roplatinate reagent. Purification of reagents and solvents was effect-
ed according to standard methods. Prior to concentration under
reduced pressure, all extracts were dried (Na2SO4). Microanalyses
were performed on a Carlo Erba 1106 analyzer by the Departament
de Qu’mica Orgˆnica i Biol˜gica CID, Barcelona. The X-ray anal-
ysis of compound 9a was performed at the Faculty of Pharmacy of
the UniversitŽ de Paris V, Paris.
crodistillation, following which we observed the presence
of a third compound, 11 (10a:10b:11 = 6:1:1.8). Pip-
eridinone 11 was the result of the double bond isomeriza-
tion under the distillation conditions (Scheme 4).
Subsequent column chromatography yielded pure 10a
and a mixture of 10b and 11. The most characteristic 1H
NMR datum of compounds 10 was the narrow triplet (J =
1 Hz) corresponding to the exocyclic olefin proton, which
resonated at d = 6.00 in the major Z isomer and at d = 7.00
in the minor E-isomer. In contrast, compound 11 showed
the 4-H olefin proton at d = 6.40 and a singlet at d = 3.30
due to the exocyclic methylene protons.
(αR)-N-(2-Hydroxy-1-phenylethyl)-3-methylenepiperidin-2-
one (2)
To a solution of lactam 1 (718 mg, 3.27 mmol) in anhyd THF
(20 mL) containing 4• molecular sieves (5 g) was added sec-BuLi
(1.3M, 7.5 mL, 8.25 mmol) at Ð78¡C under a N2 atmosphere, and
the mixture was stirred for 15 min. HMPA (1.4 mL, 8.25 mmol) was
then added at Ð60¡C, immediately followed by CH2BrCl (1.1 mL,
16.35 mmol), and the mixture was stirred for 3 h at Ð40¡C. The re-
action was quenched by the addition of sat. aq NH4Cl solution
(20 mL) and the product was extracted with EtOAc. The organic ex-
tracts were dried and evaporated to give a pale brown oil which was
chromatographed (EtOAc/hexane, 7:3) to separate the 3-methyl-
enelactam 2 and 3-chloromethyllactam 5.
Scheme 4
3-Methylenelactam 2
Yield 61%; white solid; [a]D Ð137.7 (c = 0.5, CHCl3); mp 104Ð
In order to diminish the amount of phosphonoacetate
needed and to facilitate the purification, we protected the
hydroxy group of 3 by reaction with TBDMSCl under the
standard conditions. The silyl ether 12 was then submitted
to the WadsworthÐEmmons reaction with one equivalent
of the ylide in dioxane and the conjugated esters 13a,b
were obtained. In this case, direct purification of the reac-
tion mixture by column chromatography allowed the iso-
lation of the pure isomers, and the diastereoselection was
improved to 13a:13b = 9:1 (52% total yield).
106¡C (EtOAc).
IR (CHCl3): n = 3450Ð3350, 1651, 1592 cmÐ1.
1H NMR (CDCl3/TMS): d = 1.55Ð1.95 (m, 3 H, 5-H and OH), 2.45Ð
2.65 (m, 2 H, 4-H), 3.03 (ddd, 1 H, J = 12, 8, 4 Hz, 6-HA), 3.30 (ddd,
1 H, J = 12, 7, 4 Hz, 6-HB), 4.10Ð4.30 (m, 2 H, CH2OH), 5.35 (d, 1
H, J = 2 Hz, =CHA), 5.85 (dd, 1 H, J = 9, 5 Hz, a-H), 6.28 (d, 1 H,
J = 2 Hz, =CHB), 7.20Ð7.55 (m, 5 H, C6H5).
13C NMR (CDCl3/TMS): d = 23.0 (C-5), 29.6 (C-4), 44.0 (C-6),
58.9 (C-a), 61.5 (C-b), 122.6 (=CH2), 127.7 and 128.6 (Ph-o, Ph-m,
Ph-p), 136.9 and 137.6 (Ph-i and C-3), 165.8 (C-2).
EI-MS: m/z (%) = 231 (M+, 0.1), 213 (M+ Ð H2O, 19), 200 (100).
Anal. Calcd for C14H17NO2: C, 72.79; H, 7.42; N, 6.06. Found: C,
72.72; H, 7.34; N, 5.93.
a
( R,3R)-3-Chloromethyl-N-(2-hydroxy-1-phenylethyl)piperi-
din-2-one (5)
Yield 7%.
In summary we have described the preparation of com-
pounds 2 and 3 as the first examples of a family of C-3
functionalized lactams and show that the C-3 position of
compound 3 reacts as a classical carbonyl group. The re-
activity of these compounds to synthesize asymmetric C-
4 substituted piperidines is under investigation.
1H NMR (CDCl3/TMS): d = 1.65Ð2.02 (m, 4 H, 4-H and 5-H),
2.80Ð2.95 (m, 2 H, 3-H and 6-HA), 3.10Ð3.22 (m, 1 H, 6-HB), 3.70
(br s, 1 H, OH), 3.80 (dd, 1 H, J = 12, 2 Hz, CHAOH), 4.05 (dd, 1
H, J = 12, 9 Hz, CHBOH), 4.06Ð4.20 (m, 2 H, CH2Cl), 5.85 (dd, 1H,
J = 9, 2 Hz, a-H), 7.20Ð7.40 (m, 5 H, C6H5).
13C NMR (CDCl3/TMS): d = 21.6 (C-5), 24.2 (C-4), 43.8 (C-3),
43.9 (C-6), 46.7 (CH2Cl), 58.9 (C-a), 61.4 (C-b), 127.7, 128.5 and
128.6 (Ph-o, Ph-m, and Ph-p), 136.4 (Ph-i), 170.9 (C-2).
Melting points were determined in a capillary tube on a BŸchi ap-
paratus. Optical rotations were measured with a Perkin-Elmer 241
polarimeter, at 23¡C. 1H and 13C NMR spectra were recorded on a
Varian Gemini-200 instrument (200 MHz) and 2D NMR COSY
EI-MS: m/z (%) = 269 (M+ + 1.5, 0.2), 267 (M+ Ð 0.5, 0.6), 249 (27),
200 (100).
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Methylenation and Oxidation of Chiral Non-Racemic 2-Piperidones
261
In the absence of molecular sieves (aR,3S,2'RS)-N-(2-hydroxy-1-
phenylethyl)-3-(2-methylbut-1-yl)piperidin-2-ones (6a,b) were
also formed besides the lactams 2 and 5.
1H NMR (pure 6a, CDCl3/TMS, 500 MHz): d = 0.89 (t, 3 H, J = 7
Hz, CH3CH2), 0.92 (d, 3 H, J = 7 Hz, CH3CH), 1.0Ð51.55 (m, 4 H,
5-H and 3'-H), 1.65Ð2.00 (m, 4 H, 2'-H and 1'-HA), 2.40Ð2.51 (m, 1
H, 1'-HB), 2.87 (ddd, 1 H, J = 12, 8, 5 Hz, 6-HA), 3.15Ð3.25 (m, 2
H, 6-HB and 3-H), 4.10Ð4.20 (br s, 2 H, CH2OH), 5.70 (t, 1 H, J =
6 Hz, a-H), 7.20Ð7.40 (m, 5 H, C6H5).
13C NMR (1:1 mixture of 6a:b, CDCl3/TMS): d = 11.0 and 11.5*
(CH3CH2), 18.1* and 19.7 (CH3CH), 21.4 (C-5), 25.7* and 26.4
(CH3CH2), 28.0 and 30.4* (C-4), 31.5* and 31.6 (CH3CH), 39.1*
and 39.6 (CH2CH), 39.7 (C-3), 44.0 and 44.1* (C-6), 59.3 and 59.4*
(C-a), 62.2 (C-β), 127.7, 127.8, and 128.6 (Ph-o, Ph-m, and Ph-p),
136.9 (Ph-i), 175.6 (C-2).
at 0¡C the manipulation was repeated by adding LDA (1.2 M,
3.7 mL, 4.47 mmol) and MeSSO2Me (0.46 mL, 4.48 mmol), and the
mixture was stirred at r.t. for 2 h. The reaction was quenched by the
addition of aq NH4Cl solution (20 mL) and the product was extracted
with EtOAc. The organic extracts were dried and evaporated to yield
a brown oil, which after column chromatography (EtOAc/hexane,
6:4) furnished the dithioacetal 8 (74%) as a pale yellow solid; [a]D
Ð96.1 (c = 0.88, CHCl3); mp 100.0Ð100.3¡C (EtOAc/hexane).
1H NMR (CDCl3/TMS): d = 1.92 (m, 2 H, 5-H), 2.17 and 2.19 (2 s,
3 H each, SCH3), 2.20Ð2.30 (m, 2 H, 4-H), 2.55 (t, 1 H, J = 6 Hz,
OH), 3.02 and 3.27 (2 dt, 1 H each, J =12, 6 Hz, 6-H), 4.05Ð4.20 (m,
2 H, CH2OH), 5.67 (dd, 1 H, J = 9, 6 Hz, a-H), 7.20Ð7.40 (m, 5 H,
C6H5).
13C NMR (CDCl3/TMS): d = 12.9 and 13.1 (SCH3), 20.1 (C-5), 34.9
(C-4), 43.9 (C-6), 50.0 (C-3), 59.6 (C-a), 61.8 (C-b), 127.6, 127.8,
and 128.8 (C6H5), 169.5 (C-2).
EI-MS: m/z (%) = 289 (M+, 0,1), 258 (100).
CI-MS: m/z = 312 (M+ + 1), 340 (M+ + 29).
(αR,3RS)-N-(2-Hydroxy-1-phenylethyl)-3-methylsulfanylpipe-
ridin-2-ones (7a,b)
Anal. Calcd for C15H21NO2S2: C, 57.84; H, 6.79; N, 4.49. Found: C,
57.34; H, 6.77; N, 4.48.
To a solution of the lactam 1 (82 mg, 0.375 mmol) in anhyd THF
(4 mL) under N2 atmosphere was added LDA (1.4M, 1.31 mmol,
858 mL) at 0¡C. The mixture was stirred for 25 min. MeSSO2Me
(0.75 mmol, 97 mL) was added and the mixture was stirred at 0¡C
for 30 min. The reaction was quenched by adding satd aq NH4Cl so-
lution (2 mL) and the crude was extracted with EtOAc. The organic
extracts were dried and evaporated to yield a brown oil which was
chromatographed. On elution with EtOAc/hexane (80:20) dithioac-
etal 8 (13%, see below) was obtained. Elution with EtOAc gave
pure methylsulfanyllactam 7b (7%) and EtOAc/MeOH (95:5) as
eluent afforded the isomer 7a (66%).
(αR)-N-(2-Hydroxy-1-phenylethyl)piperidine-2,3-dione (3)
To a solution of 8 (533 mg, 1.71 mmol) in MeCN/H2O (9:1, 70 mL)
was added (CF3CO2)2IPh (3.42 mmol, 1.84 g) and the mixture was
stirred at r.t. for 3 h. The reaction was quenched by the addition of
aq sat. NaHCO3 and extracted with CH2Cl2. The organic extracts
were dried and evaporated to afford a pale yellow oil which was
chromatographed (CH2Cl2/MeOH, 95:5) to obtain the oxolactam 3
(77%) as a white solid; [a]D Ð169.0 (c = 0.51, CHCl3); mp 167¡C
(EtOAc).
IR (CHCl3): n = 3367, 1736, 1673 cmÐ1.
7a: white solid; [a]D Ð171.4 (c = 0.78, CHCl3); mp 126Ð127¡C
(EtOAc).
IR (CHCl3): n = 3345, 1620 cmÐ1.
1H NMR (CDCl3): d = 1.70Ð1.80 (m, 1 H, 5-HA), 1.85Ð2.00 (m, 2
H, 5-HB and 4-HA), 2.20Ð2.30 (m, 1 H, 4-HB), 2.35 (s, 3 H, SCH3),
2.84 (dd, 1 H, J = 7, 4 Hz, OH), 3.00 (dt, 1 H, J = 12, 6 Hz, 6-HA),
3.19 (ddd,1 H, J = 12, 8, 4 Hz, 6-HB), 3.45 (t, 1 H, J = 5,1Hz, 3-HA),
4.05Ð4.25 (m, 2 H, b-H), 5.75 (dd, 1 H, J = 12 and 4 Hz, a-H), 7.20Ð
7.40 (m, 5 H, C6H5).
1H NMR (DMSO-d6/TMS): d = 1.90Ð2.10 (m, 2 H, 5-H), 2.65 (t, 2
H, J = 7 Hz, 4-H), 3.16Ð3.30 (m, 1 H, 6-HA), 3.50Ð3.62 (m, 1 H, 6-
HB), 4.10Ð4.22 (m, 2 H, CH2OH), 5.00 (t, 1 H, J = 6 Hz, OH), 5.85
(dd, 1 H, J = 9, 5 Hz, a-H), 7.20Ð7.40 (m, 5 H, C6H5).
13C NMR (DMSO-d6/TMS): d = 21.6 (C-5), 38.1 (C-4), 42.9 (C-6),
59.2 (C-a), 60.9 (C-b), 127.7, 128.2, and 128.8 (Ph), 135.7 (Ph-i),
159.0 (C-2), 191.7 (C-3).
CI-MS: m/z = 234 (M++1).
13C NMR (CDCl3/TMS): d = 16.4 (CH3), 20.5 (C-5), 27.8 (C-4),
43.5 (C-6), 45.9 (C-3), 58.9 (C-a), 61.8 (C-b), 127.6, 127.8 and
128.6 (Ph-o, Ph-m, and Ph-p), 136.7 (Ph-i), 171.2 (C-2).
Anal. Calcd for C13H15NO3: C, 66.93; H, 6.48; N, 6.00. Found: C,
66.51, H, 6.51; N, 5.88.
3-Hydroxy-N-(2-hydroxy-1-phenylethyl)piperidin-2-ones
(9a,b)
CI-MS: m/z = 266 (M++1).
Anal. Calcd for C14H19NO2S: C, 63.36; H, 7.21; N, 5.27; S, 12.08.
Found : C, 63.46; H, 7.28; N, 5.34; S, 12.06.
Method A: To a solution of 3 (100mg, 0.42 mmol) in anhyd THF
(5 mL) at 0¡C was added NaBH4 (75 mg, 6.81 mmol) portionwise.
After 2 h at r.t., H2O was added (3 mL) and the mixture was extract-
ed with CH2Cl2. The organic extracts were dried and evaporated to
give a 2:1 diastereomeric mixture of the unseparable alcohols 9a/9b
(98%).
7b: [a]D Ð35.0 (c = 0.48, CHCl3).
1H NMR (CDCl3/TMS,300 MHz): d = 1.57Ð1.70 (m, 1 H, 5-HA),
1.80Ð2.20 (m, 3 H, 4-H and 5-HB), 2.32 (s, 3 H, SCH3), 3.00 (dt, 1
H, J = 12, 6 Hz, 6-HA), 3.10 (br s, 1 H, OH), 3.29 (dt, 1 H, J = 12,
6 Hz, 6-HB), 3.45 (t, 1 H, J = 6 Hz, 3-H), 4.13 (d, 2 H, J = 9 Hz, b-
H), 5.71 (t, 1 H, J = 9 Hz, a-H), 7.20Ð7.40 (m, 5 H, C6H5).
13C NMR (CDCl3/TMS): d = 16.0 (SCH3), 20.8 (C-5), 27.4 (C-4),
43.4 (C-6), 46.0 (C-3), 59.3 (C-a), 61.7 (C-b), 127.6 (Ph-o and Ph-
p), 128.6 (Ph-m), 136.7 (Ph-i), 170.9 (C-2). 5:5)
Method B: To a solution of 3 (86 mg, 0.37 mmol) in anhyd THF
(5mL) cooled at Ð78¡C was added slowly L-Selectride (1 M,
0.74 mL, 0.74 mmol). The mixture was stirred for 2 h at Ð78¡C and
for 1 h at r.t. To quench the reaction THF (5 mL), HOAc (1.5 mL),
and H2O (2 mL) were added. The aqueous phase was extracted with
EtOAc (3 × 5 mL). The organic layers were dried and evaporated,
and the residue was chromatographed (EtOAc) to yield 9a (19%).
(αR)-N-(2-Hydroxy-1-phenylethyl)-3,3-dimethyldisulfanylpip-
eridin-2-one (8)
To a solution of the lactam 1 (280 mg, 1.28 mmol) in anhyd THF
(25 mL), at 0¡C under N2 atmosphere was added LDA (1.2 M,
3.7 mL, 4.47 mmol) at 0¡C under a N2 atmosphere. After stirring
for 30 min, MeSSO2Me (0.46 mL, 4.48 mmol) was added. After 1 h
IR (CHCl3): n = 3017, 1677 cmÐ1.
1H NMR (CDCl3/TMS): d = 1.60Ð2.00 (m, 3 H, 5-H and 4-HA),
2.20Ð2.30 (m, 1 H, 4-HB), 2.98Ð3.10 (m, 1 H, 6-HA), 3.20Ð3.30 (m,
1 H, 6-HB), 4.10Ð4.25 (m, 3 H, 3-H and b-H), 5.65 (dd, 1 H, J = 8,
6 Hz, a-H), 7.20Ð7.50 (m, 5 H, C6H5).
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P. Forns et al.
PAPER
13C NMR (CDCl3/TMS): d = 20.0 (C-5), 28.1 (C-4), 43.1(C-6),
59.1 (C-a), 61.3 (C-b), 68.3 (C-3), 127.5, 127.7, and 128.7 (C6H5),
138.7(Ph-i), 174.0 (C-2).
(αR)-N-(2-tert-Butyldimethylsilyloxy-1-phenylethyl)-3-(ethoxy-
carbonylmethylene)piperidin-2-ones (13a,b)
To a suspension of NaH (55%, 15 mg, 0.325 mmol) in dioxane
(1.5 mL) was added triethylphosphonoacetate (65 mL, 0.325 mmol).
When the mixture was clear, a solution of silylated lactam 12 (113
mg, 0.325 mmol) in dioxane (2 mL) was added. The mixture was
stirred for 3 h at r.t. The reaction was quenched by the addition of
sat. aq NaHCO3 solution and extracted with EtOAc. The organic ex-
tracts were dried and evaporated and the residue was flash chro-
matographed. On elution with cyclohexane, isomer (E)-13b (5%)
was isolated pure and elution with cyclohexane/EtOAc (80:20)
gave isomer (Z)-13a.
CI-MS: m/z = 236 (M++1), 264 (M++29).
X-Ray Crystallography of Lactam 9a
Crystal data : C13H15NO3. Mw = 233.27. A suitable crystal was in-
vestigated on a Siemens P3 diffractometer [l(Mo Ka radiation) =
0.71069 •, graphite monochromator]. Orthorhombic, space group
P212121, Z = 4, a = 7.832 (4) •, b = 8.975 (9) •, c = 16.801 (9) •,
dc = 1.31 g.cmÐ3; F(000) = 496, m = 0.87 mmÐ1. 1668 reflections up
to 2q = 55û of which 667 with F =3s(F) were kept in refinement cal-
culations. The structure was solved by direct methods using
SHELXS8620 and refined by the full matrix least squares based on
F with CRYSTALS.21 All non-hydrogen atoms were located in dif-
ference Fourier maps and refined at observed positions with aniso-
tropic temperature factors. Convergence was reached at R = Σ(FoÐ
Fc)/ΣFo= 0.041. Molecular graphics are from CAMERON.22
(Z)-13a: yield 47%; [a]D Ð100.0 (c = 1.2, CHCl3).
IR (film): n = 1715, 1680 cmÐ1.
1H NMR (CDCl3/TMS): d = 0.10 (s, 6 H, SiCH3), 0.80 (s, 9 H,
CCH3), 1.30 (t, J = 7 Hz, 3 H, CH3CH2), 1.60Ð1.80 (m, 2 H, 5-H),
2.40Ð2.50 (m, 2 H, 4-H), 2.90Ð3.05 (m, 1 H, 6-HA), 3.20Ð3.35 (m,
1 H, 6-HB), 4.00Ð4.10 (m, 2 H, b-H), 4.30 (q, 2 H, J = 7 Hz, CH2O),
5.75Ð5.80 (m 1 H, a-H), 5.95 (s, 1 H, =CH), 7.20Ð7.40 (m, 5 H,
C6H5).
13C NMR (CDCl3/TMS): d = 1.0 and 1.3 (SiCH3), 13.9 (CH2CH3),
17.9(CCH3), 25.7 (C-5), 29.7 (C-4), 43.8 (C-6), 56.6 (C-a), 60.7,
and 61.9 (C-b and CH2O), 126.8, 127.8, and 128.2 (C6H5), 135.8
(Ph-i), 137.4 (=CH), 162.6 (CO2Et), 167.9 (C-2).
(αR)-3-(Ethoxycarbonylmethylene)-N-(2-hydroxy-1-phenyl-
ethyl)piperidin-2-one (10)
To a suspension of NaH (55%, 40 mg, 0.903 mmol) in DME (3 mL)
was added triethyl phosphonoacetate (179 mL, 0.903 mmol). When
the mixture was clear, a solution of 3 (100 mg, 0.43 mmol) in warm
DME (3 mL) was added and the mixture was refluxed for 2 h. After
cooling to r.t., sat. aq NH4Cl (5 mL) was added and the aqueous
phase was extracted with CH2Cl2. The organic extracts were dried
and evaporated. The excess of triethylphosphonoacetate was re-
moved from the residue by distillation (155Ð160¡C/8Ð9 Torr). The
crude product was chromatographed (EtOAc) to isolate isomer (E)-
10a (5%) and a mixture of (Z)-10b and 11 (45%).
CI-MS: m/z = 418 (M++1).
(E)-13b: [a]D Ð55.0 (c = 1.3, CHCl3).
IR (film): n = 1715, 1682 cmÐ1.
1H NMR (CDCl3/TMS): d = 0.00 (s, 6 H, SiCH3), 0.80 (s, 9 H,
CCH3), 1.30 (t, 3 H, J = 7 Hz, CH2CH3), 1.50Ð1.80 (m, 3 H, 5-H and
4-HA), 2.90Ð3.00 (m, 1 H, 4-HB), 3.00Ð3.15 (m, 1 H, 6-HA), 3.30Ð
3.50 (m, 1 H, 6-HB), 4.00Ð4.17 (m, 2 H, b-H), 4.20 (q, 2 H, J = 7 Hz,
CH2O), 5.85 (dd, 1 H, J = 9, 7 Hz, a-H), 7.00 (br s, 1 H, =CH), 7.20Ð
7.40 (m, 5 H, C6H5).
13C NMR (CDCl3/TMS): d = Ð0.05 (SiCH3), 14.1 (CH2CH3), 22.3
(CCH3), 25.7 (C-5), 29.6 (C-4), 43.6 (C-6), 58.0 (C-a), 60.2, and
61.8 (C-b and CH2O), 123.7 (C-3), 127.5, 127.9, and 128.4 (C6H5),
137.1 (=CH), 161.0 (CO2Et), 167.0 (C-2).
Isomer (E)-10b
1H NMR (CDCl3/TMS, 200 MHz): d = 1.30 (t, 3 H, J = 7 Hz, CH3),
1.70Ð1.98 (m, 2 H, 5-H), 2.50Ð2.63 (m, 1 H, 4-HA), 3.00Ð3.20 (m,
2 H, 4-HB and 6-HA), 3.20Ð3.40 (m, 1 H, 6-HB), 4.05Ð4.35 (m, 4 H,
b-H and CH2O), 5.90 (dd, 1 H, J = 8, 7 Hz, a-H), 7.02 (br s, 1 H,
W1/2 = 8 Hz, =CH), 7.20Ð7.40 (br s, 5 H, C6H5).
13C NMR (CDCl3/TMS): d = 16.2 (CH3), 24.0 (C-5), 35.6 (C-4),
41.5 (C-6), 58.7 (C-a), 62.2 and 62.3 (C-b and CH2O), 126.8, 127.7
and 128.5 (C6H5), 135.9 (Ph-i), 136.5 (=CH), 163.5 (CO2Et), 171.5
(C-2).
CI-MS: m/z = 418 (M++1).
CI-MS: m/z = 304 (M++1).
Acknowledgement
Anal. Calcd for C17H21NO4: C, 67.32; H, 6.93; N, 4.62. Found: C,
67.01; H, 7.03; N, 4.62.
Support for this research has been provided by the CIRIT
(Generalidad de Catalunya) through grants QFN95-4703 and
1995SGR-00429, and by the Ministerio de Educaci—n y Ciencia
through grant HF-312B. M.-P. Cherrier thanks ADIR (Servier) for
Þnancial support.
(αR)-N-[2-(tert-Butyldimethylsilyloxy)-1-phenylethyl]piperi-
dine-2,3-dione (12)
To a solution of 3 (231 mg, 0.991 mmol) in anhyd DMF (2.5 mL)
and imidazole (135 mg, 1.98 mmol) was added a solution of TB-
DMSCl (135 mg, 1.24 mmol) in DMF (1 mL). The mixture was
stirred overnight at r.t. and quenched with brine (4 mL). The aque-
ous phase was extracted with Et2O, and the organic extracts were
dried and evaporated, to give an oil which was chromatographed
(EtOAc/cyclohexane, 2:8 to 1:1) to yield 12 (52%); [a]D Ð26.0 (c =
0.1, MeOH).
1H NMR (CDCl3/TMS): d = 0.10 (2 s, 6 H, SiCH3), 0.90 (s, 9 H,
CCH3), 2.00Ð2.10 (m, 2 H, 5-H), 2.70Ð2.80 (m, 2 H, 4-H), 3.30 (m,
1 H, 6-HA), 3.55 (m, 1 H, 6-HB), 4.20 (m, 2 H, β-H), 5.80 (t, 1 H, J
= 5 Hz, a-H), 7.20Ð7.50 (m, 5 H, C6H5).
References
(1) Micouin, L.; Bonin, M.; Cherrier, M.-P.; Mazurier, A.; To-
mas, A.; Quirion, J.-C.; Husson, H.-P. Tetrahedron 1996, 52,
7719.
(2) (a) Micouin, L.; Quirion, J.-C.; Husson, H.-P. Synthetic Com-
mun. 1996, 26, 1605.
(b) Micouin, L.; Varea, T.; Riche, C.; Chiaroni, A.; Quirion,
J.-C.; Husson, H.-P. Tetrahedron Lett. 1994, 35, 2529.
(3) Rodriguez, R.; Estiarte, M.A.; Diez, A.; Rubiralta, M.; Colell,
A.; Garcia-Ruiz, C.; Fern‡ndez-Checa, J.-C. Tetrahedron
1996, 52, 7727.
13C NMR (CDCl3/TMS): d = 0.0 (SiCH3), 21.9 (CCH3), 25.7 (C-5),
38.4 (C-4), 43.5 (C-6), 57.9 (C-a), 61.4 (C-b), 127.6, 127.9, and
128.6 (C6H5), 138.4 (Ph-i), 158.0 (C-2), 191.8 (C-3).
(4) (a) Micouin, L.; Diez, A.; L—pez, I.; Rubiralta, M.; Quirion,
J.-C.; Husson, H.-P. Tetrahedron Lett. 1995, 36, 1693Ð1696.
CI-MS: m/z = 348 (M+ + 1).
Synthesis 1999, No. 2, 258–263 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Methylenation and Oxidation of Chiral Non-Racemic 2-Piperidones
263
(b) For the synthesis of Aspidosperma alkaloids from a non-
chiral 3-methylenelactam, see: Forns, P.; Diez, A.; Rubiralta,
M. J. Org. Chem. 1996, 61, 7882.
(b) Takai, K.; Hotta, Y.; Oshima, K.; Nozaki, H. Tetrahedron
Lett. 1978, 2417.
(10) Li, W.; Hanau, C.E.; d'Avignon, A.; Moeller, K.D. J. Org.
(5) (a) Roush, W.R.; d'Ambra, T.E. J. Am. Chem. Soc. 1983, 105,
1058.
Chem 1995, 60, 8155.
(11) Moeller, K.D.; Li, W. J. Am. Chem. Soc. 1996, 118, 10106.
(12) Meyers, A.I.; Sturgess, M.A. Tetrahedron Lett. 1988, 29,
5339.
(b) De Clercq, P.; Vanderwalle, M. J. Org. Chem. 1977, 42,
3477.
(6) (a) Danishefsky, S.; Schuda, P.F.; Kitahara, T.; Etheredge,
S.J. J. Am. Chem. Soc. 1977, 99, 6066.
(13) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 287.
(14) Forns, P.; Diez, A.; Rubiralta, M.; Solans, X.; Font-Bardia, M.
Tetrahedron 1996, 52, 3563.
(b) Roberts, J.L.; Borromeo, P.S.; Poulter, C.D. Tetrahedron
Lett. 1977, 1621.
(15) (a) Davis, F.A.; Chen, B.-C. J. Org. Chem. 1993, 58, 1751.
(b) Davis, F.A.; Chen, B.-C. Chem. Rev. 1992, 92, 919.
(16) The proportion was determined from the 1H NMR analysis.
(17) Diez, A.; Vila, C.; Sinibaldi, M.-E.; Troin, Y.; Rubiralta, M.
Tetrahedron Lett. 1993, 34, 733.
(7) In the absence of molecular sieves, lactams 2 and 5 were ob-
tained in variable yields, together with compound 6. Com-
pound 6 proved to be a mixture of only two diastereomers
(a,b), identified by a molecular peak at m/z 289, and by the
presence of two methyl groups and two methine carbons for
each isomer in the spectral data of the mixture. Conjugate ad-
dition of sec-BuLi on methylenelactam 2 would presumably
lead to the formation of the four possible isomers;2b therefore,
compounds 6a,b were assigned as the C-2' epimers resulting
from the attack of sec-BuLi as a nucleophile on chlorolactam
5. This also indicated that the variable yields we were obtain-
ing resulted from the competition of the SN2 reaction versus
the elimination.
(18) Hasan, I.; Marinelli, E.R.; Chang Lin, L.C.; Fowler, F.W.;
Levy, A.B. J. Org. Chem. 1981, 46, 157.
(19) Lombardo, L. Tetrahedron Lett. 1982, 23, 4293.
(20) Sheldrick, G. M. (1985). SHELXS86. Program for solution of
Crystal Structures. University of Gšttingen, Germany.
(21) Watkin, D. J., Carruthers J. R. & Betteridge P. W.,
CRYSTALS-User Guide, Chemical Crystallography Labora-
tory, University of Oxford, England, 1985.
(22) Pearce, L. J., Watkin, D. J. & Prout, C. K., CAMERON : A
Program for Plotting Molecular Structures, Chemical Crystal-
lography Laboratory, University of Oxford, England, 1992.
(8) For a review, see: Krief, A. Tetrahedron 1980, 36, 2531.
(9) (a) Hakan, K.; Thielmann, M.; Thielmann, T.; Winterfeldt, E.
Tetrahedron 1987, 43, 2035.
Synthesis 1999, No. 2, 258–263 ISSN 0039-7881 © Thieme Stuttgart · New York