Stereoselective synthesis of 3,4-trans-disubstituted γ-lactams by cerium(IV) ammonium nitrate mediated radical cyclization of cinnamamides

Article abstract of DOI:10.1055/s-2007-965981

A facile synthesis of 3,4-trans-disubstituted γ-lactams was developed, consisting of the radical cyclization of cinnamamides mediated by cerium(IV) ammonium nitrate. The single-electron-transfer (SET) reaction of the methoxystyrenyl moiety mediated by cer

Full text of DOI:10.1055/s-2007-965981

PAPER
1179
Stereoselective Synthesis of 3,4-trans-Disubstituted g-Lactams by Cerium(IV)
Ammonium Nitrate Mediated Radical Cyclization of Cinnamamides
Stereoselective
Sy
i
nthesis
j
of 3,4-
a
trans-Disub
y
stitute
d
g
-LactamsNair,* Kishor Mohanan, Tachapully D. Suja, Akkattu T. Biju
Organic Chemistry Section, Regional Research Laboratory (CSIR), Trivandrum 695019, India
Fax +91(471)2491712; E-mail: vijaynair_2001@yahoo.com
Received 9 January 2007; revised 31 January 2007
addition to carbon–carbon multiple bonds resulting in
Abstract: A facile synthesis of 3,4-trans-disubstituted g-lactams
was developed, consisting of the radical cyclization of cinnam-
amides mediated by cerium(IV) ammonium nitrate. The single-
electron-transfer (SET) reaction of the methoxystyrenyl moiety me-
diated by cerium(IV) ammonium nitrate gives rise to a cation radi-
cal, whose cyclization followed by reaction with oxygen and
methanol generates 3,4-trans-disubstituted g-lactams.
novel carbon–heteroatom bond-forming reactions were
also developed in our laboratory.4
Although cerium(IV) ammonium nitrate is well known to
mediate numerous intermolecular transformations of syn-
thetic importance,5 its utility in intramolecular cyclization
reactions6 remained largely unexplored until our recent
investigations along this direction opened up a stereose-
lective route to substituted tetrahydrofurans and cyclo-
pentanes.7 The reactions were rationalized as occurring
via the intramolecular interception of cation radicals gen-
erated by the cerium(IV) ammonium nitrate mediated
single-electron-transfer (SET) reaction of styrenic double
bonds by suitably positioned C=C bonds and further oxi-
dation (Scheme 1). Subsequently, it was found that
epoxypropyl cinnamyl ethers and (cinnamyl) (epoxypro-
pyl)amines on reaction with cerium(IV) ammonium ni-
trate afford tetrahydropyran and piperidine derivatives,
respectively.8
Key words: cerium(IV) ammonium nitrate, intramolecular cycliza-
tion, cinnamamides, single electron transfer, g-lactams
Cerium (IV) salts have found widespread use as one-elec-
tron oxidants for organic compounds.1 During our decade-
long investigations on cerium(IV) ammonium nitrate
(CAN) mediated transformations, a number of interesting
carbon–carbon bond-forming reactions such as the syn-
thesis of dihydrofurans by the oxidative addition of 1,3-
dicarbonyl compounds to nonactivated alkenes2 and the
formation of tetralin derivatives by the dimerization of
substituted styrenes3 were uncovered. In addition to this,
cerium(IV) ammonium nitrate mediated oxidation of soft
anions to the corresponding radicals and their subsequent
Against the backdrop of the literature presented above,
and in view of the importance of g-lactam derivatives,9 it
(MeO)n
(MeO)n
(MeO)n
Ce(IV)
X
I
X
X
II
III
O2, MeOH
X = O, C(CO2Me)2
(MeO)n
O
MeO
X
IV
Scheme 1 Cerium(IV) ammonium nitrate mediated intramolecular cyclization
SYNTHESIS 2007, No. 8, pp 1179–1184
x
x
.
x
x
.2
0
0
7
Advanced online publication: 12.03.2007
DOI: 10.1055/s-2007-965981; Art ID: Z00607SS
© Georg Thieme Verlag Stuttgart · New York

1180
V. Nair et al.
PAPER
was decided to apply the SET process to N-cinnamyl-4- from both synthetic and mechanistic standpoints. It is an-
methoxy-N-propylcinnamamide (1a) (Scheme 2), as the ticipated that the mild reaction conditions and experimen-
formation of substituted g-lactams was anticipated. In a tal simplicity of the process will make its application to
pilot experiment, 1a was treated with cerium(IV) ammo- the synthesis of a variety of g-lactam derivatives attrac-
nium nitrate in methanol (Scheme 2). The reaction afford- tive.
ed the 3,4-disubstituted g-lactam derivative as a separable
mixture of diastereomers 2a and 2a¢ in 61% yield.
OMe
OMe
OMe
OMe
i
OMe
62%
i
O
O
O
N
N
MeO
O
Pr
Pr
O
3
4
O
N
N
Pr
Pr
Scheme 3 Cerium(IV) ammonium nitrate mediated cyclization of
4-methoxy-N-prenyl-N-propylcinnamamide. Reagents and condi-
tions: (i) CAN (2.5 equiv), O2, MeOH, 2 h.
1a
2a + 2a'
Scheme 2 Cerium(IV) ammonium nitrate mediated cyclization of
N-cinnamyl-4-methoxy-N-propylcinnamamide. Reagents and condi-
tions: (i) CAN (2.5 equiv), O2, MeOH, r.t., 2 h, 61% (1:1 dr).
Table 1 Synthesis of 3,4-trans-Disubstituted g-Lactams by
Cyclization of the Corresponding Cinnamamides Mediated by
Cerium(IV) Ammonium Nitratea
The structures of the products were assigned by spectro-
scopic analysis. In the IR spectrum of isomer 2a, the lac-
tam and the benzoyl carbonyl stretching resonances were
centered at 1686 cm–1. In the 1H NMR spectrum, the ben-
zylic proton resonated as a doublet at d = 4.83 (J = 4.2
Hz). The aromatic and benzylic methoxy protons resonat-
ed as singlets at d = 3.70 and 3.30 respectively. In the 13C
NMR spectrum, the peaks at d = 198.4 and 172.4 were
diagnostic for the benzoyl and lactam carbonyl groups,
Starting material
Product
Yieldb (%)
MeO
MeO
MeO
54
O
O
N
O
N
Pr
Pr
2b
respectively. All other signals agreed with the assigned 1b
structure.
OMe
OMe
OMe
OMe
MeO
MeO
The isomer 2a¢ also showed the benzoyl and the lactam
carbonyl stretching together, centered at 1682 cm–1. In the
1H NMR spectrum, the benzylic proton resonated as a
doublet at d = 4.89 (J = 2.4 Hz). The methoxy groups on
the phenyl ring and the benzylic position were discernible
as singlets at d = 3.73 and 3.32, respectively. In the 13C
NMR spectrum, the benzoyl and lactam carbonyl signals
were visible at d = 198.5 and 172.6 respectively.
46
56
56
MeO
O
O
O
N
N
Pr
Pr
1c
2c
OMe
OMe
The stereochemical arrangement of the substituents at po-
sitions 3 and 4 in 2a and 2a¢ was assigned trans by analo-
gy with the corresponding five-membered carbocycles
and heterocycles previously reported from our laborato-
ry.7,10
MeO
O
O
O
N
The reaction was found to be general with various meth-
oxy-substituted N-propyl- and N-benzylcinnamamides,
and the corresponding g-lactams were isolated in moder- 1d
ate to good yields, as shown in Table 1.
N
Pr
Pr
2d
OMe
OMe
MeO
MeO
Gratifyingly, 4-methoxy-N-prenyl-N-propylcinnamamide
(3) also afforded the expected g-lactam derivative 4 in
62% yield (Scheme 3). It is noteworthy that only a single
diastereomer formed in this case.
O
MeO
In summary, the cerium(IV) ammonium nitrate mediated
oxidative intramolecular cyclization of N-cinnamyl-N-
propylcinnamamides led to the facile synthesis of 3,4-
trans-disubstituted g-lactams. The reaction is attractive
O
O
N
N
Pr
Pr
1e
2e
Synthesis 2007, No. 8, 1179–1184 © Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of 3,4-trans-Disubstituted g-Lactams
1181
Table 1 Synthesis of 3,4-trans-Disubstituted g-Lactams by
Cyclization of the Corresponding Cinnamamides Mediated by
Cerium(IV) Ammonium Nitratea (continued)
THF (10 mL) was added dropwise to a suspension of NaH (0.072 g,
3 mmol) in anhyd THF (10 mL) at reflux temperature and the mix-
ture was stirred for 10 min. Then a soln of cinnamyl bromide (0.275
g, 1.5 mmol) in THF (10 mL) was added, and the mixture was
stirred overnight. THF was removed by distillation on a rotary evap-
orator under reduced pressure, and the residue was diluted with H2O
(10 mL). The mixture was extracted with CH2Cl2 (3 × 10 mL),
washed with brine (10 mL), and dried (Na2SO4). Removal of the
solvent followed by purification of the residue by column chroma-
tography (silica gel, hexanes–EtOAc) afforded the pure products
1a–h.
Starting material
Product
Yieldb (%)
54 (1.5:1)
OMe
OMe
MeO
MeO
MeO
O
Pyrrolidin-2-ones 2a–i and 4 by Oxidative Cyclization of Cin-
namamides 1a–i and 3 Mediated by Cerium(IV) Ammonium
Nitrate; General Procedure
O
N
O
N
Pr
Pr
2f
MeO
A soln of CAN (685 mg, 1.25 mmol) in MeOH (15 mL) was added
dropwise to a stirred soln of cinnamamide 1a–i or 3 (0.5 mmol) in
MeOH (10 mL) under an O2 atmosphere. The stirring was continued
until consumption of the amide was complete as confirmed by TLC
(2 h). The solvent was removed by distillation on a rotary evapora-
tor under reduced pressure, and the residue was diluted with H2O
(10 mL). The mixture was extracted with CH2Cl2 (3 × 10 mL). The
combined organic extract was washed with H2O (10 mL) and brine
(10 mL) and dried (Na2SO4). Removal of the solvent on a rotary
evaporator followed by purification of the residue by column chro-
matography (silica gel, hexanes–EtOAc) gave diastereomeric mix-
tures of the corresponding 3,4-trans-disubstituted g-lactams 2a–i
and 4.
1f
MeO
MeO
MeO
48
MeO
O
O
N
O
N
Pr
Pr
1g
2g
OMe
OMe
MeO
MeO
4-Benzoyl-3-[methoxy(4-methoxyphenyl)methyl]-1-propylpyr-
rolidin-2-one (2a)
Isomer 1
50 (1.4:1)
MeO
O
O
O
N
N
Colorless solid; mp 138–140 °C.
Pr
Pr
IR (KBr): 3656, 2935, 2834, 1686, 1607, 1512, 1445, 1249, 1101,
1034 cm–1.
2h
1h
OMe
OMe
2i
1H NMR (300 MHz, CDCl3): d = 8.06 (d, J = 7.8 Hz, 2 H), 7.61–
7.57 (m, 1 H), 7.48 (t, J = 7.5 Hz, 2 H), 7.30–7.26 (m, 2 H), 6.86 (d,
J = 8.4 Hz, 2 H), 4.83 (d, J = 4.2 Hz, 1 H), 4.04–4.00 (m, 1 H), 3.81
(s, 3 H), 3.49 (t, J = 7.8 Hz, 1 H), 3.32 (s, 3 H), 3.30–3.27 (m, 1 H),
3.17–3.07 (m, 1 H), 3.02–2.95 (m, 1 H), 2.57 (t, J = 8.7 Hz, 1 H),
1.38 (q, J = 7.5 Hz, 2 H), 0.97 (t, J = 7.5 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 198.4, 172.4, 158.9, 135.5, 133.4,
131.3, 128.8, 128.7, 127.9, 127.0, 114.0, 113.8, 108.0, 80.6, 57.7,
55.0, 48.7, 44.3, 38.6, 28.0, 20.4, 11.2.
62 (1:1)
MeO
O
O
O
N
N
Ph
Ph
1i
2i
HRMS (EI): m/z calcd for C23H27NO4: 381.1940; found: 381.1932.
a Reagents and conditions: CAN (2.5 equiv), O2, MeOH, 2 h.
b Yields of isolated products; dr values are given in parentheses.
Isomer 2
Colorless solid; mp 110–112 °C.
IR (KBr): 2968, 2878, 1682, 1610, 1510, 1450, 1295, 1250, 1024,
834 cm–1.
Melting points were recorded on a Büchi melting point apparatus
and are uncorrected. NMR spectra were recorded at 300 MHz (1H)
and 75 MHz (13C) on a Bruker Avance DPX-300 MHz NMR spec-
trometer. IR spectra were recorded on a Bomem MB Series FT-IR
spectrophotometer. HRMS (EI) (at 5000 resolution) was carried out
on a JEOL JMS 600H mass spectrometer. Gravity column chroma-
tography was performed on silica gel (100–200 mesh) with hex-
anes–EtOAc mixtures as eluents. Solvents were distilled prior to
use. CAN used for the reactions was purchased from Aldrich, and
used without purification.
1H NMR (300 MHz, CDCl3): d = 7.51–7.45 (m, 2 H), 7.31–7.27 (m,
3 H), 7.13 (d, J = 8.7 Hz, 2 H), 6.71 (d, J = 8.4 Hz, 1 H), 4.89 (s, 1
H), 4.24–4.17 (m, 1 H), 3.73 (s, 3 H), 3.65 (t, J = 9.3 Hz, 1 H), 3.32
(s, 3 H), 3.29–3.17 (m, 4 H), 1.59 (q, J = 7.2 Hz, 2 H), 0.95 (t, J =
7.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 198.5, 172.6, 158.4, 133.4, 130.9,
129.6, 128.9, 113.7, 81.4, 56.6, 55.0, 49.0, 46.7, 28.2, 21.6, 11.3.
HRMS (EI): m/z calcd for C23H27NO4: 381.1940; found: 381.1940.
N-Cinnamyl(methoxy)-N-propylcinnamamides 1a–h; General
Procedure
The methoxy-N-propylcinnamamides were obtained by conversion
of the appropriate methoxycinnamic acids into the corresponding
mixed anhydrides by use of ClCO2Me and Et3N and then treatment
with PrNH2. A soln of the thus-formed amide (1 mmol) in anhyd
4-Benzoyl-3-[methoxy(2-methoxyphenyl)methyl]-1-propylpyr-
rolidin-2-one (2b)
Colorless viscous liquid.
IR (thin film): 3068, 2963, 2933, 1686, 1595, 1485, 1275, 1240,
1100, 1025, 749 cm–1.
Synthesis 2007, No. 8, 1179–1184 © Thieme Stuttgart · New York

1182
V. Nair et al.
PAPER
1H NMR (300 MHz, CDCl3): d = 7.44–7.12 (m, 7 H), 6.76 (t, J =
6.9 Hz, 2 H), 5.18 (d, J = 2.4 Hz, 1 H), 4.09–4.05 (m, 1 H), 3.91–
3.85 (m, 1 H), 3.74–3.58 (m, 6 H), 3.43–3.31 (m, 5 H), 1.58 (q, J =
7.4 Hz, 2 H), 0.96 (t, J = 7.4 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 198.1, 171.8, 159.7, 133.9, 134.4,
134.3, 129.6, 128.9, 128.4, 126.5, 112.8, 81.3, 57.9, 53.1, 46.5,
44.3, 38.9, 28.0.
13C NMR (75 MHz, CDCl3): d = 198.1, 171.9, 161.6, 148.8, 136.2,
130.1, 129.1, 128.9, 128.7, 127.9, 126.3, 118.9, 84.7, 57.3, 55.9,
47.9, 46.5, 37.2, 29.7, 21.4, 11.5.
HRMS (EI): m/z calcd for C24H29NO5: 411.2046; found: 411.2012.
Isomer 2
Colorless viscous liquid.
HRMS (EI): m/z calcd for C23H27NO4: 381.1940; found: 381.1975.
IR (thin film): 3054, 2942, 2914, 2842, 1686, 1600, 1510, 1450,
1266, 1014, 1024, 704 cm–1.
4-Benzoyl-3-[methoxy(3,4,5-trimethoxyphenyl)methyl]-1-pro-
pylpyrrolidin-2-one (2c)
Isomer 1
1H NMR (300 MHz, CDCl3): d = 7.58–7.48 (m, 4 H), 7.31–7.25 (m,
2 H), 6.82–6.79 (m, 1 H), 6.70–6.64 (m, 1 H), 4.88 (d, J = 2.2 Hz, 1
H), 4.25–4.22 (m, 1 H), 3.94–3.85 (m, 1 H), 3.80 (s, 3 H), 3.69–3.62
(m, 2 H), 3.60 (s, 3 H), 3.39–3.10 (m, 6 H). 1.62–1.55 (m, 2 H),
0.98–0.93 (m, 3 H).
13C NMR (75 MHz, CDCl3): d = 198.7, 173.0, 159.2, 148.8, 139.9,
136.2, 130.9, 128.8, 128.0, 127.3, 119.1, 85.0, 55.1, 50.4, 46.3,
45.8, 39.7, 28.5, 20.8, 10.9.
Colorless viscous liquid.
IR (thin film): 3072, 2932, 2862, 1686, 1600, 1515, 1424, 1266,
1112, 1034 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.00 (d, J = 8.1 Hz, 2 H), 7.60 (d,
J = 6.40 Hz, 2 H), 7.48 (t, J = 7.6 Hz, 3 H), 6.58 (s, 2 H), 4.84 (d,
J = 3.8 Hz, 1 H), 4.00–3.66 (m, 12 H), 3.35 (s, 3 H), 3.28–2.99 (m,
3 H), 2.83–2.79 (m, 1 H) 1.59–1.52 (m, 2 H), 1.00–0.94 (m, 3 H).
HRMS (EI): m/z calcd for C24H29NO5: 411.2046; found: 411.2041.
13C NMR (75 MHz, CDCl3): d = 197.8, 173.0, 159.1, 158.5, 139.9,
136.2, 130.3, 128.6, 128.0, 127.2, 126.2, 114.2, 113.8, 84.0, 56.8,
55.0, 46.3, 39.4.
4-Benzoyl-3-[(2,4-dimethoxyphenyl)(methoxy)methyl]-1-pro-
pylpyrrolidin-2-one (2f)
Isomer 1
Colorless viscous liquid.
HRMS (EI): m/z calcd for C25H31NO4: 441.5168; found: 441.5162.
IR (thin film): 2968, 2943, 1685, 1600, 1515, 1450, 1265, 1145,
1100 cm–1.
Isomer 2
Colorless viscous liquid
1H NMR (300 MHz, CDCl3): d = 8.00 (d, J = 7.3 Hz, 2 H), 7.61–
7.52 (m, 3 H), 6.89–6.74 (m, 3 H), 4.79 (d, J = 4.2 Hz, 1 H), 4.01–
3.93 (m, 1 H), 3.81 (s, 3 H), 3.75 (s, 3 H), 3.56–3.52 (m, 2 H), 3.33
(s, 3 H), 3.10–3.01 (m, 2 H), 2.59 (t, J = 9.4 Hz, 1 H), 1.39–1.31 (m,
2 H), 0.85 (t, J = 7.3 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 198.2, 173.0, 159.1, 139.9, 136.2,
130.3, 128.5, 128.1, 127.9, 126.9, 114.3, 113.5, 111.2, 110.9, 108.9,
84.0, 57.2, 55.0, 46.3, 45.8, 39.4, 21.3, 11.6.
IR (thin film): 3068, 2962, 2934, 2874, 2842, 1683, 1595, 1510,
1450, 1266, 1024, 1014, 704 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.61–7.52 (m, 4 H), 7.28–7.21 (m,
2 H), 6.79–6.69 (m, 1 H), 6.65–6.54 (m, 1 H), 4.81 (d, J = 2.2 Hz, 1
H), 4.18–4.12 (m, 1 H), 3.94–3.85 (m, 1 H), 3.83 (s, 6 H), 3.80 (s, 3
H), 3.69–3.62 (m, 2 H), 3.60 (s, 3 H), 3.39–3.10 (m, 6 H).
13C NMR (75 MHz, CDCl3): d = 197.7, 172.4, 159.2, 135.7, 134.5,
132.4, 129.9, 128.7, 128.1, 127.6, 112.8, 80.4, 55.9, 54.5, 46.9,
45.5, 37.5, 28.9, 21.1, 11.3.
HRMS (EI): m/z calcd for C24H29NO5: 411.2046; found: 411.2054.
Isomer 2
Colorless viscous liquid.
HRMS (EI): m/z calcd for C25H31NO4: 441.5168; found: 441.5160.
3-[Methoxy(4-methoxyphenyl)methyl]-4-(1-naphthoyl)-1-pro-
pylpyrrolidin-2-one (2d)
Colorless viscous liquid.
IR (thin film): 2935, 2847, 1688, 1605, 1438, 1364, 1209 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.59–7.46 (m, 4 H), 7.30 (t, J =
7.5 Hz, 2 H), 6.94–6.80 (m, 3 H), 4.88 (s, 1 H), 4.27–4.20 (m, 1 H),
3.92–3.71 (m, 5 H), 3.69–3.60 (m, 5 H), 3.35 (s, 3 H), 3.34–3.21 (m,
2 H), 1.63–1.56 (m, 2 H), 1.00–0.96 (m, 3 H).
IR (thin film): 2972, 2937, 1689, 1670, 1600, 1515, 1470, 1260,
1179, 1079, 1034 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.00 (d, J = 7.8 Hz, 1 H), 7.86 (d,
J = 7.8 Hz, 1 H), 7.80–7.77 (m, 2 H), 7.49–7.43 (m, 3 H), 7.33 (d,
J = 6.9 Hz, 1 H), 7.00 (d, J = 8.4 Hz, 1 H), 6.48 (d, J = 8.4 Hz, 2 H),
4.88 (s, 1 H), 4.28–4.21 (m, 2 H), 3.71–3.51 (m, 6 H), 3.40–3.33 (m,
4 H), 1.66–1.51 (m, 2 H), 1.00–0.95 (m, 3 H).
13C NMR (75 MHz, CDCl3): d = 198.3, 172.8, 158.6, 136.1, 133.0,
128.8, 128.2, 127.5, 114.7, 103.0, 80.7, 69.4, 57.7, 53.4, 52.3, 48.5,
46.8, 38.4, 20.4, 11.7.
HRMS (EI): m/z calcd for C24H29NO5: 411.2046; found: 411.2034.
13C NMR (75 MHz, CDCl3): d = 202.2, 172.4, 158.7, 133.7, 132.4,
131.0, 128.1, 127.8, 126.9, 125.7, 124.0, 113.9, 80.5, 57.8, 54.8,
48.6, 44.4, 41.9, 20.4, 11.1.
4-Benzoyl-3-[(2,3-dimethoxyphenyl)(methoxy)methyl]-1-pro-
pylpyrrolidin-2-one (2g)
Colorless viscous liquid.
IR (thin film): 2921, 2840, 1685, 1600, 1512, 1249, 1169 cm–1.
4-Benzoyl-3-[(3,4-dimethoxyphenyl)(methoxy)methyl]-1-pro-
pylpyrrolidin-2-one (2e)
Isomer 1
Colorless viscous liquid.
1H NMR (300 MHz, CDCl3): d = 7.81 (d, J = 7.8 Hz, 2 H), 7.56–
7.24 (m, 3 H), 6.99–6.97 (m, 2 H), 6.72–6.69 (m, 1 H), 4.89 (d, J =
5.1 Hz, 1 H), 4.11–4.05 (m, 1 H), 3.84–3.71 (m, 8 H), 3.42–3.19 (m,
7 H), 1.62–1.47 (m, 2 H), 1.00–0.94 (m, 3 H).
13C NMR (75 MHz, CDCl3): d = 198.2, 170.8, 161.2, 159.2, 133.8,
133.0, 128.5, 128.1, 117.0, 112.3, 109.9, 108.1, 81.2, 55.3, 54.8,
53.2, 52.5, 48.7, 43.2, 38.3, 20.1, 11.3.
IR (thin film): 3072, 2943, 2921, 2854, 2812, 1683, 1595, 1510,
1450, 1266, 1014, 1024, 704 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.02 (d, J = 7.4 Hz, 2 H), 7.67–
7.46 (m, 3 H), 6.95–6.82 (m, 3 H), 4.83 (d, J = 3.9 Hz, 1 H), 4.03–
3.99 (m, 1 H), 3.83 (s, 3 H), 3.77 (s, 3 H), 3.56–3.51 (m, 2 H), 3.33
(s, 3 H), 3.30–3.01 (m, 2 H), 2.69 (t, J = 9.2 Hz, 1 H), 1.41–1.34 (m,
2 H), 0.89 (t, J = 7.3 Hz, 3 H).
HRMS (EI): m/z calcd for C24H29NO5: 411.2046; found: 411.2032.
Synthesis 2007, No. 8, 1179–1184 © Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of 3,4-trans-Disubstituted g-Lactams
1183
4-Benzoyl-3-[(2,5-dimethoxyphenyl)(methoxy)methyl]-1-pro-
pylpyrrolidin-2-one (2h)
Isomer 1
13C NMR (75 MHz, CDCl3): d = 198.4, 172.0, 159.4, 135.6, 135.5,
133.4, 129.8, 128.9, 128.7, 127.9, 113.8, 81.4, 56.9, 55.1, 47.9,
46.5, 38.9, 28.0.
Colorless viscous liquid.
DEPT-135, CH2 negative: d = 47.9, 46.5.
IR (thin film): 2943, 1686, 1595, 1480, 1345, 1165, 1094, 1004
cm–1.
HRMS (EI): m/z calcd for C24H29NO5: 429.1940; found: 429.1954.
1H NMR (300 MHz, CDCl3): d = 7.91 (d, J = 7.7 Hz, 2 H), 7.62 (t,
J = 7.2 Hz, 2 H), 7.53–7.48 (m, 3 H), 7.27–7.21 (m, 1 H), 4.82 (d,
J = 3.1 Hz, 1 H), 4.12–3.97 (m, 1 H), 3.92 (s, 3 H), 3.69 (s, 3 H),
3.55–3.49 (m, 4 H), 3.35–3.25 (m, 5 H), 1.56 (t, J = 7.3 Hz, 2 H),
0.93 (q, J = 7.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 198.1, 172.3, 158.5, 135.4, 133.4,
131.2, 128.8, 127.5, 127.1, 112.1, 80.3, 57.5, 53.9, 48.8, 46.7, 41.2,
26.0, 21.3, 11.3.
3-(4-Methoxybenzoyl)-4-(1-methoxy-1-methylethyl)-1-propyl-
pyrrolidin-2-one (4)
Colorless viscous liquid.
IR (thin film): 2972, 2937, 1689, 1670, 1600, 1515, 1470, 1260,
1179, 1079, 1034 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.12 (d, J = 8.8 Hz, 2 H), 6.95 (d,
J = 8.8 Hz, 2 H), 4.54 (d, J = 7.0 Hz, 1 H), 3.89–3.78 (m, 5 H), 3.46–
3.15 (m, 7 H), 1.59–1.55 (m, 2 H), 1.13 (s, 3 H), 1.02 (s, 3 H), 0.94
(t, J = 1.9 Hz, 3 H).
HRMS (EI): m/z calcd for C24H29NO5: 411.2046; found: 411.2065.
13C NMR (75 MHz, CDCl3): d = 198.1, 172.5, 161.3, 132.0, 127.8,
126.5, 117.0, 109.2, 108.7, 80.1, 55.8, 54.3, 53.8, 48.3, 44.1, 38.2,
21.6, 20.1, 11.1.
Isomer 2
Colorless viscous liquid.
IR (thin film): 3022, 2942, 2840, 1687, 1640, 1602, 1512, 1256
cm–1.
HRMS (EI): m/z calcd for C19H27NO4: 333.1940; found: 333.1938.
1H NMR (300 MHz, CDCl3): d = 7.49–7.37 (m, 4 H), 7.31–7.27 (m,
2 H), 7.00–6.89 (m, 3 H), 4.83 (d, J = 2.3 Hz, 1 H), 4.25–4.18 (m, 1
H), 3.92–3.71 (m, 5 H), 3.71–3.63 (m, 5 H), 3.34 (s, 3 H), 3.35–3.21
(m, 2 H), 1.63–1.56 (m, 2 H), 1.00–0.96 (m, 3 H).
13C NMR (75 MHz, CDCl3): d = 198.1, 171.7, 159.7, 133.6, 132.4,
128.8, 128.1, 127.1, 113.2, 80.5, 56.1, 54.3, 46.9, 43.1, 37.1, 27.0,
21.8, 11.3.
Acknowledgment
Financial assistance from the Council of Scientific and Industrial
Research (CSIR), Government of India, is acknowledged. The au-
thors also thank Mrs. Saumini Mathew for recording NMR spectra
and Mrs. S. Viji for mass spectral analysis.
HRMS (EI): m/z calcd for C24H29NO5: 411.2046; found: 411.2034.
References
4-Benzoyl-1-benzyl-3-[methoxy(4-methoxyphenyl)methyl]pyr-
rolidin-2-one (2i)
Isomer 1
Colorless solid; mp 86–88 °C.
(1) (a) Imamoto, T. Lanthanide Reagents in Organic Synthesis;
Academic Press: London, 1994. (b) Hwu, J. R. Curr. Sci.
2001, 81, 1043. (c) Ho, T.-L.; Paquette, L. A. Encyclopedia
of Reagents for Organic Synthesis; Wiley: Chichester, 1995,
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Prabhakaran, J. Chem. Soc. Rev. 1997, 127. (c) Nair, V.;
Treesa, P. M.; Maliakal, D.; Rath, N. P. Tetrahedron 2001,
57, 7705.
IR (KBr): 2935, 2834, 1686, 1607, 1512, 1445, 1249, 1101, 1034
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.99 (d, J = 7.2 Hz, 2 H), 7.46 (t,
J = 7.7 Hz, 2 H), 7.29–7.20 (m, 5 H), 6.94 (t, J = 3.6 Hz, 2 H), 6.82
(d, J = 8.7 Hz, 2 H), 4.88 (d, J = 4.1 Hz, 1 H), 4.45 (d, J = 14.9 Hz,
1 H), 4.15 (d, J = 15.0 Hz, 1 H), 4.09–4.01 (m, 1 H), 3.81 (s, 3 H),
3.68 (t, J = 4.3 Hz, 1 H), 3.30 (s, 3 H), 3.15–3.10 (m, 1 H), 2.66 (t,
J = 9.2 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 198.3, 172.2, 159.8, 136.1, 135.5,
133.0, 128.6, 128.5, 127.5, 116.5, 113.8, 80.8, 57.7, 55.1, 53.4,
48.5, 46.8, 38.4.
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DEPT-135, CH2 negative: d = 48.5, 46.8.
HRMS (EI): m/z calcd for C24H29NO5: 429.1940; found: 429.1940.
Isomer 2
Colorless solid; mp 74–76 °C.
IR (KBr): 3063, 2834, 1681, 1612, 1512, 1454, 1263, 1182, 1034
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.49–7.47 (m, 2 H), 7.46 (t, J =
7.7 Hz, 2 H), 7.34–7.24 (m, 6 H), 6.72 (d, J = 8.6 Hz, 2 H), 4.96 (d,
J = 2.5 Hz, 1 H), 4.75 (d, J = 14.9 Hz, 1 H), 4.31 (d, J = 15.0 Hz, 1
H), 4.22–4.19 (m, 1 H), 3.72 (s, 3 H), 3.54 (t, J = 9.2 Hz, 1 H), 3.35
(s, 3 H), 3.30–3.27 (m, 1 H), 3.21–3.16 (dd, J = 5.8 Hz, J = 3.9 Hz,
1 H).
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Rath, N. P. Chem. Commun. 2001, 1682. (b) Nair, V.;
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Synthesis 2007, No. 8, 1179–1184 © Thieme Stuttgart · New York

1184
V. Nair et al.
PAPER
(10) The difference between the coupling constants for the
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(b) Nair, V.; Mohanan, K.; Suja, T. D.; Suresh, E.
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Tetrahedron 1982, 38, 2687. (b) Nilsson, B. M.; Ringdahl,
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936.
benzylic protons in 2a (4.2 Hz) and 2a¢ (2.4 Hz) indicates
that the isomeric pair 2a and 2a¢ differs only in the relative
stereochemistry of the methoxy group at the benzylic
position.
Synthesis 2007, No. 8, 1179–1184 © Thieme Stuttgart · New York