A convenient synthesis and cytotoxic evaluation of N-unsubstituted α-methylene-γ-lactams

Article abstract of DOI:10.1016/j.tet.2008.04.090

Chemoselective reduction of 3-aryl-2-diethoxyphosphoryl-4-nitroalkanoates provided the corresponding α-diethoxyphosphoryl-γ-lactams in completely diastereoselective manner. The products were shown to be useful substrates for the synthesis of mono-β-substituted and β,γ-disubstituted α-methylene-γ-lactams. Cytotoxicity of these compounds was evaluated.

Full text of DOI:10.1016/j.tet.2008.04.090

Tetrahedron 64 (2008) 6307–6314
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A convenient synthesis and cytotoxic evaluation of N-unsubstituted
a-methylene-
g
-lactams
,
a
b
b
Henryk Krawczyk a , qukasz Albrecht , Jakub Wojciechowski , Wojciech M. Wolf ,
*
c
c
_
´
Urszula Krajewska , Marek Rozalski
a
_
´ ´
Institute of Organic Chemistry, Technical University (Politechnika), 90-924 Łodz, Zeromskiego 116, Poland
Institute of General and Ecological Chemistry, Technical University (Politechnika), 90-924 Ło´dz, Zeromskiego 116, Poland
Department of Pharmaceutical Biochemistry, Medical University of Ło´dz, Muszynskiego 1, 90-151 Łodz, Poland
b
c
_
´
´
´
´ ´
a r t i c l e i n f o
a b s t r a c t
Article history:
Chemoselective reduction of 3-aryl-2-diethoxyphosphoryl-4-nitroalkanoates provided the correspond-
Received 22 February 2008
Received in revised form 8 April 2008
Accepted 24 April 2008
ing
to be useful substrates for the synthesis of mono-
lactams. Cytotoxicity of these compounds was evaluated.
a
-diethoxyphosphoryl-
g
-lactams in completely diastereoselective manner. The products were shown
b
-substituted and -disubstituted -methylene-
b
,
g
a
g-
Available online 29 April 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
a
a
-Diethoxyphosphoryl-
g-lactams
-Methylene- -lactams
g
Horner–Wadsworth–Emmons reaction
Diastereoselective synthesis
1. Introduction
Our preliminary studies revealed that the method consisting
of chemoselective reduction of 2-diethoxyphosphoryl-4-nitro-
alkanoates followed by lactamization and Horner–Wadsworth–
a
-Methylene-
occurring -methylene-
of -methylene- -lactams has received a considerable attention as
a consequence of the proven biological properties of this structural
motif.1–3 The N-substituted
-methylene- -lactams are readily
g
-lactams serveas isostericanalogsof the naturally
a
g-lactones. In the recent years, the synthesis
Emmons reaction of the resulting
with formaldehyde provides a useful tool for the synthesis of
-substituted -methylene-
-lactams.17 The method would sig-
a-diethoxyphosphoryl-g-lactams
a
g
g
a
g
a
g
nificantly benefit from the availability of substituted 2-diethoxy-
phosphoryl-4-nitroalkanoates. Recently, we have developed a new,
general route for diastereoselective synthesis of 3-aryl-2-diethoxy-
phosphoryl-4-nitroalkanoates 1 and 2.18 It becomes evident that
alkanoates of this type are suitable intermediates to access various
available by addition of various organometallic reagents derived
from 2-(bromomethyl)acrylates to aldimines.4–9 Other alternative
approaches involve alkylation of dianions derived from secondary
methacrylamides with aldehydes and subsequent cyclization of the
resulting
a
-methylene-
g
-hydroxyamides,10 regioselective addition
N-unsubstituted
that variety of
-diethoxyphosphoryl-
a
-methylene-
-monosubstituted and
-lactams 5 and 6 can be prepared in a
g
-lactams. In this paper, we report
of primary amines to (E)-1-alkyl-2,3-dimethoxycarbonyl butadi-
enes11 as well as regioselective ring-opening reactions of N-tosyl-
aziridines with aniline.12 To the best of our knowledge, the Michael
addition of nitroalkanes to acetates of Baylis–Hillman adducts
followed by chemoselective reduction and lactamization of
the resulting 2-alkylidene-4-nitroalkanoates is the only method for
a
b
g
b,g-disubstituted
a
completely diastereoselective manner from the corresponding
nitroalkanoates 1 and 2, respectively. We also demonstrate that
the resulting
converted to
a
-diethoxyphosphoryl-
g-lactams 5 and 6 can be
a
-methylene- -lactams 11 and 12, respectively, thus
g
the synthesis of N-unsubstituted
a
-alkylidene-
g
-lactams.13 The N-
providing a new approach to this class of compounds. Moreover, we
tested selected lactams 11 and 12 for their cytotoxic activity against
human leukemia cell lines.
unsubstituted -methylene-
a
g-lactams are also of particular interest
for the systematic study of their biological activity14 and from
a synthetic point of view.14–16 However, no general syntheses were
disclosed in the literature and therefore the development of new
efficient routes to these derivatives is of great importance.
2. Results and discussion
Nitroalkanoates 1 and 2 were obtained according to the pre-
* Corresponding author. Fax: þ48 42 6365530.
E-mail address: henkrawc@p.lodz.pl (H. Krawczyk).
viously reported procedure.18 The chemoselective reduction of the
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.04.090

6308
H. Krawczyk et al. / Tetrahedron 64 (2008) 6307–6314
O
O
(EtO)2P
NH
b
Ar
O
O
(EtO)2P
COOt-Bu
NO2
(3R*,4S*)-5a-d
(EtO)2P
COOt-Bu
NH2
a
Ar
Ar
R
O
O
R
(EtO)2P
NH
(2R*,3R*)-1a-d R = H
1c de = 48%
Ar
CH3
3a-d R=H
4a-d R=CH3
1d de = 48%
(3R*,4S*,5S*)-6a-d
(2R*,3R*,4R*)-2a-d R = CH3
Scheme 1. Reagents and conditions: (a) NiCl2$6H2O (2 equiv), NaBH4 (10 equiv), CH3OH, rt, 1 h; (b) Na2CO3 (3 equiv), CH3OH,
D, 4 h.
nitro group of 4-nitrobutanoates 1 by sodium borohydride in the
presence of NiCl2$6H2O19–23 afforded the expected 4-amino-
butanoates 3 accompanied by the corresponding
phosphoryl- -lactams 5. The aminobutanoates 3 were completely
converted into the -diethoxyphosphoryl- -lactams 5 by simple
a-diethoxy-
g
a
g
heating in methanol in the presence of Na2CO3. Reduction of
4-nitropentanoates 2 under the same conditions provided directly
a
-diethoxyphosphoryl-g-lactams 6 as the only products. In all the
cases, reactions proceeded in a completely diastereoselective
manner leading to the formation of lactams 5 and 6 as single
diastereoisomers (Scheme 1, Table 1).
The trans relative stereochemistry at the stereogenic centers C-3
and C-4 of lactams 6 was assigned on the basis of 1H and 13C NMR
3
data.24–26 The observed values of the coupling constants JPH4
¼
3
3
18.0–18.4 Hz, JH3H4¼9.3–9.5 Hz, and JPC5¼10.7–11.1 Hz clearly
proved the trans arrangement of the phosphoryl and aryl groups.
However, spectroscopic studies did not allow us to assign un-
ambiguously the relative stereochemistry at C-4 and C-5 stereo-
genic centers (3JH3H4¼6.9–7.1 Hz). This was established by single
crystal X-ray analysis of the N-Boc lactam 8c, which unequivocally
confirmed the trans relationship between the phosphoryl and aryl
groups, as well as aryl and methyl groups (Fig. 1) and allowed us to
Figure 1. The crystal structure of N-Boc lactam 8c. Both ethoxy groups at phosphorus
exhibit orientational disorder. Each of the respective atoms was refined in two partially
occupied positions. The picture shows sites for which the occupation factors were
0.64(2) as for O6, C18, C19, and 0.69(1) for O7, C20, and C21. For clarity, the less
occupied positions are not shown. Displacement ellipsoids are drawn at the 50%
probability level.
of preparation and the structural similarity, we by analogy also
assigned trans stereochemistry between the phosphoryl and aryl
groups in the lactams 5a–d.
assign the relative configuration 3R
*
,4S
*
,5S to the obtained prod-
*
ucts 6a–d. In the structure 8c, the pyrrolidinone five membered
ring adopts an envelope conformation with N, C1, C2, and C3 atoms
almost coplanar and C4 situated at the flap. The three lowest ring
asymmetry parameters27 are C2(C1)¼0.49(4), Cs(N–C1)¼5.70(4),
and Cs(C4)¼6.10(4)ꢀ. The 4-methoxyphenyl group is placed in
a sterically favored perpendicular position in respect to the pyrro-
lidinone fragment. In the crystal, symmetrically equivalent phenyl
rings are located too far from one another for the stacking
interactions.
These findings provided clear evidence that the reduction of 4-
nitropentanoates 2 proceeded with complete diastereocontrol and
the formation of the 4-aminopentanoates 4 followed by their ring
closure occurred with epimerization giving the lactams 6 as ther-
modynamically more stable trans diastereoisomers, exclusively.
Unfortunately, the spectra of the lactams 5a–d could not be inter-
preted so unequivocally. Therefore, taking into account the method
With the desired
hand, we turned our attention to their effective transformation into
the corresponding -methylene- -lactams 11 and 12, respectively
a-diethoxyphosphoryl-g-lactams 5 and 6 in
a
g
(Scheme 2, Table 1). Our initial attempts to obtain the lactams 11
and 12 by Horner–Wadsworth–Emmons reaction with formalde-
hyde under previously reported conditions17,28 indicated that the
products are accompanied by their N-hydroxymethyl derivatives.
The problem was eventually solved by protection of the amide ni-
trogen by Boc group. N-Boc a-diethoxyphosphoryl-g-lactams 7 and
8 were generated by treatment of the respective lactams 5 and 6
with Boc2O in the presence of catalytic DMAP. Notably, all the N-Boc
lactams 7 and 8 were obtained as single diastereoisomers. The
N-Boc lactams 7 and 8 displayed similar values of the coupling
constants to those observed for N-unprotected lactams 5 and 6.
Table 1
a
-Diethoxyphosphoryl-
g
-lactams 5, 6, N-Boc
a
-diethoxyphosphoryl-g-lactams 7, 8, N-Boc a-methylene-g-lactams 9, 10, and a-methylene-g-lactams 11, 12 prepared
Ar
Yield (%)
5 (R¼H)
6 (R¼CH3)
7 (R¼H)
8 (R¼CH3)
9 (R¼H)
10 (R¼CH3)
11 (R¼H)
12 (R¼CH3)
a
b
c
4-Br–C6H4–
4-CH3–C6H4–
4-CH3O–C6H4–
3,4-(OCH2O)–C6H3–
70
84
67
73
88
69
82
72
98
91
92
91
94
87
94
95
51
74
87
89
67
68
80
80
73
82
51
82
79
62
81
81
d

H. Krawczyk et al. / Tetrahedron 64 (2008) 6307–6314
6309
O
O
O
O
O
O
(EtO)2P
(EtO)2P
a
c
b
N
Boc
NH
NH
N
Boc
Ar
Ar
Ar
Ar
R
R
R
R
11a-d R=H
9a-d R=H
(2R*,3S*)-10a-d R=CH3
(3R*,4S*)-7a-d R=H
(3R*,4S*)-5a-d R=H
(4R*,5S*)-12a-d R=CH3
(3R*,4S*,5S*)-8a-d R=CH3
(3R*,4S*,5S*)-6a-d R=CH3
Scheme 2. Reagents and conditions: (a) Boc2O (1.2 equiv), DMAP (0.25 equiv), CH2Cl2, rt, 3 h; (b) t-BuOK (1.2 equiv), THF, rt, 0.5 h; then HCHO (5 equiv), THF, rt, 1 h; (c) CF3COOH/
CH2Cl2 (1:2), rt, 1 h.
Table 2
(diethoxyphosphoryl)-4-nitrobutanoates 1a–d and tert-butyl 3-
Cytotoxic activity of compounds 11a,d and 12a,b
aryl-2-(diethoxyphosphoryl)-4-nitropentanoates 2a–d were pre-
pared according to the literature procedure.18
a
Compound
Cytotoxicity IC50
HL-60
(mM)
NALM-6
4.2. General procedure for the preparation of 4-aryl-3-
(diethoxyphosphoryl)pyrrolidin-2-ones 5a–d
11a
11d
12a
12b
548.9ꢂ29.6
524.1ꢂ47.4
515.7ꢂ47.6
537.8ꢂ39.3
2.9ꢂ0.1
433.6ꢂ39.2
515.2ꢂ19.4
439.2ꢂ40.8
445.8ꢂ33.9
0.7ꢂ0.3
To
a
stirred solution of tert-butyl 3-aryl-2-(diethoxy-
(4 mmol) in MeOH (40 mL),
Carboplatin
phosphoryl)-4-nitrobutanoate
1
a
IC50, 50% inhibitory concentration represents the mean from dose response
curves of at least three experiments.
NiCl2$6H2O (1.90 g, 8 mmol) was added at room temperature. After
stirring for 10 min, NaBH4 (1.52 g, 40 mmol) was added in small
portions. The resulting mixture was stirred for 1 h at room tem-
perature and filtered through a pad of CeliteÒ. The solid material
was thoroughly washed with MeOH. Methanol was removed under
reduced pressure, the residue was dissolved in CHCl3 (30 mL), and
washed with NaHCO3 (15 mL). The water layer was extracted with
CHCl3 (15 mL), combined organic layers were dried over MgSO4,
and the solvent was evaporated under reduced pressure. The oily
residue was dissolved in MeOH (20 mL) and Na2CO3 (1.27 g,
12 mmol) was added. The resulting mixture was heated at reflux for
4 h. After that time, methanol was removed under reduced pres-
sure, the residue was dissolved in CHCl3 (30 mL), washed with
water (2ꢁ15 mL), dried over MgSO4, and evaporated. Evaporation
of the solvent under reduced pressure afforded a crude product,
which was purified by column chromatography (eluent: CHCl3/
MeOH 97:3).
The Horner–Wadsworth–Emmons reaction of the N-Boc-
diethoxyphosphoryl- -lactams and with excess para-
formaldehyde in the presence of t-BuOK afforded the corresponding
-methylene- -lactams 9 and 10, respectively. Free -methylene-g-
a-
g
7
8
a
g
a
lactams were regenerated from the N-Boc derivatives 9 and 10 by
treatment with CF3COOH. All the obtained lactams 11 and 12 were
isolated as crystalline solids in high yield.
Because of their potential biological activity as isosteric analogs
of a-methylene-g-lactones, selected lactams 11 and 12 were eval-
uated for their cytotoxic activity against HL-60 and NALM-6 human
leukemia cell lines.29 Obtained results (Table 2) are expressed as
IC50 values, which are the concentrations (mM) required to inhibit
tumor cell proliferation by 50% after 48 h of exposure of the cells to
a tested compound. Carboplatin was used as a reference compound.
As can be seen from Table 2, cytotoxicities of the tested lactams
11a,d and 12a,b are higher against NALM-6 cell line than against
HL-60 cell line. Disappointingly, all IC50 values are greater than 400
and are well over the range of compounds, which can be considered
4.2.1. (3R
*
,4S )-4-(4-Bromophenyl)-3-(diethoxyphosphoryl)-
*
pyrrolidin-2-one (5a)
Yield 1.05 g, 70%, white solid, mp 113–115 ꢀC; IR (CCl4): 1704,
highly potent according to Kupchan’s classification (IC50<15 m
M).30
1480, 1368, 1312, 1264, 1180, 1096, 1056, 1024; 31P NMR (CDCl3):
3
4
d
¼22.8; 1H NMR (CDCl3):
¼1.25 (dt, 3H, JHH¼7.1 Hz, JHP¼0.5 Hz,
d
CH3CH2OP),1.30 (dt, 3JHH¼7.1 Hz, 4JHP¼0.5 Hz, CH3CH2OP), 2.99 (dd,
1H, 3JHH¼5.5 Hz, 3JHP¼22.9 Hz, PCH), 3.37–3.41 (m, 1H, CHAr), 3.87–
4.04 (m, 2H, CH2N), 4.05–4.26 (m, 4H, 2ꢁCH3CH2OP), 7.26 (s, 1H,
3. Conclusions
In summary, motivated by the lack of an efficient method for the
preparation of N-unsubstituted -methylene- -lactams and their
potential cytotoxic activity, we have developed a simple and highly
diastereoselective method for the synthesis of -diethoxy-
phosphoryl- -lactams from the corresponding 3-aryl-2-diethoxy-
phosphoryl-4-nitroalkanoates. As demonstrated, the former can
be conveniently transformed into -methylene- -lactams. Target
NH), 7.29–7.37 (m, 4H, 4ꢁCHAr); 13C NMR (CDCl3):
d
¼172.2 (d,
a
g
2JCP¼1.6 Hz), 142.3 (d, JCP¼7.4 Hz), 128.6 (2ꢁ), 127.0, 126.5 (2ꢁ),
3
2
2
3
a
62.7 (d, JCP¼6.3 Hz), 62.0 (d, JCP¼6.7 Hz), 48.9 (d, JCP¼6.9 Hz),
1
2
3
g
48.5 (d, JCP¼147.1 Hz), 41.7 (d, JCP¼1.5 Hz), 16.0 (d, JCP¼3.2 Hz),
3
15.9 (d, JCP¼3.2 Hz). Anal. Calcd for C14H19BrNO4P: C, 44.70; H,
a
g
5.09; N, 3.72. Found: C, 44.58; H, 5.00; N, 3.61.
compounds displayed very weak cytotoxic activity.
4.2.2. (3R
*
,4S )-3-(Diethoxyphosphoryl)-4-(4-methylphenyl)-
*
4. Experimental
4.1. General
pyrrolidin-2-one (5b)
Yield 1.05 g, 84%, white solid, mp 122–124 ꢀC; IR (CCl4): 1701,
1455,1372,1315,1291,1163,1122,1016; 31P NMR (CDCl3):
d
¼22.9; 1H
3
NMR (CDCl3):
d
¼1.25 (t, 3H, JHH¼7.1 Hz, CH3CH2OP), 1.32 (t, 3H,
3
NMR spectra were recorded on a Bruker DPX 250 instrument at
250.13 MHz for 1H, 62.9 MHz for 13C, and 101.3 MHz for 31P NMR
using tetramethylsilane as internal standard and 85% H3PO4 as
external standard. The multiplicity of carbons was determined by
DEPT experiments. IR spectra were measured on a Specord M80
(Zeiss) instrument. Elemental analyses were performed on a Per-
kin–Elmer PE 2400 analyzer. Melting points were determined in
open capillaries and are uncorrected. tert-Butyl 3-aryl-2-
3JHH¼7.1 Hz, CH3CH2OP), 2.33 (s, 3H, CH3Ar), 2.96 (dd, 1H, JHH
¼
4.7 Hz, 3JHP¼22.7 Hz, PCH), 3.34–3.40 (m, 1H, CHAr), 3.86–4.01 (m,
2H, CH2N), 4.02–4.26 (m, 4H, 2ꢁCH3CH2OP), 5.74 (s, 1H, NH), 7.15 (s,
4H, 4ꢁCHAr); 13C NMR (CDCl3):
d
¼172.3,139.4 (d, 3JCP¼7.4 Hz),136.6,
2
2
129.2 (2ꢁ), 126.4 (2ꢁ), 62.7 (d, JCP¼6.2 Hz), 62.1 (d, JCP¼6.6 Hz),
3
1
49.0 (d, JCP¼6.3 Hz), 48.6 (d, JCP¼141.6 Hz), 41.4, 20.7, 16.0 (d,
3JCP¼2.2 Hz), 16.0 (d, JCP¼3.0 Hz). Anal. Calcd for C15H22NO4P: C,
3
57.87; H, 7.12; N, 4.50. Found: C, 57.68; H, 7.00; N, 4.61.

6310
H. Krawczyk et al. / Tetrahedron 64 (2008) 6307–6314
4.2.3. (3R
*
,4S
*
)-3-(Diethoxyphosphoryl)-4-(4-methoxyphenyl)-
4.3.2. (3R
*
,4S
*
,5S )-3-(Diethoxyphosphoryl)-5-methyl-4-
*
pyrrolidin-2-one (5c)
(methylphenyl)pyrrolidin-2-one (6b)
Yield 877 mg, 67%, white solid, mp 97–99 ꢀC; IR (CCl4): 1704,
Yield 898 mg, 69%, white solid, mp 137–138 ꢀC; IR (CCl4): 1704,
1516, 1480, 1368, 1312, 1296, 1248, 1180, 1048, 1032; 31P NMR
1520, 1440, 1372, 1336, 1312, 1256, 1184, 1160, 1052, 1016; 31P NMR
3
3
(CDCl3):
d
¼23.0; 1H NMR (CDCl3):
d
¼1.25 (t, 3H, JHH¼7.1 Hz,
(CDCl3):
d
¼23.1; 1H NMR (CDCl3):
d
¼1.15 (t, 3H, JHH¼7.1 Hz,
3
3
CH3CH2OP), 1.31 (t, 3H, JHH¼7.5 Hz, CH3CH2OP), 2.94 (dd, 1H,
CH3CH2OP), 1.23 (t, 3H, JHH¼7.1 Hz, CH3CH2OP), 1.28 (d, 3H,
3JHH¼4.9 Hz, JHP¼22.9 Hz, PCH), 3.31–3.35 (m, 1H, CHAr), 3.80
3JHH¼6.2 Hz, CH3CH), 2.34 (s, 3H, CH3Ar), 3.12 (dd, 1H, 3JHH¼9.3 Hz,
3
3
3
(s, 3H, CH3OAr), 3.84–4.03 (m, 2H, CH2N), 4.06–4.25 (m, 4H,
2JHP¼22.7 Hz, PCH), 3.34 (ddd, 1H, JHH¼9.3, 6.9 Hz, JHP¼18.4 Hz,
3
3
2ꢁCH3CH2OP), 6.36 (s, 1H, NH), 6.87 (d, 2H, JHH¼8.8 Hz,
CHAr), 3.69 (dq, 1H, JHH¼6.2, 6.9 Hz, CHN), 3.92–4.04 (m, 2H,
2ꢁCHAr), 7.20 (d, 2H, JHH¼8.8 Hz, 2ꢁCHAr); 13C NMR (CDCl3):
CH3CH2OP), 4.05–4.22 (m, 2H, CH3CH2OP), 6.34 (s, 1H, NH), 7.15 (s,
3
2
3
3
d
¼172.2 (d, JCP¼2.3 Hz), 158.4, 134.4 (d, JCP¼7.6 Hz), 127.6 (2ꢁ),
4H, 4ꢁCHAr); 13C NMR (CDCl3):
d
¼171.2, 137.6 (d, JCP¼3.1 Hz),
2
2
2
113.9 (2ꢁ), 62.7 (d, JCP¼6.3 Hz), 62.0 (d, JCP¼6.3 Hz), 54.9,
136.6, 127.2 (2ꢁ), 129.1 (2ꢁ), 62.5 (d, JCP¼6.2 Hz), 61.8 (d,
1
3
2
3
2
48.6 (d, JCP¼141.8 Hz), 49.0 (d, JCP¼7.0 Hz), 41.0 (d, JCP¼1.3 Hz),
2JCP¼6.7 Hz), 57.3 (d, JCP¼10.7 Hz), 50.4 (d, JCP¼2.5 Hz), 49.2 (d,
3
3
3
3
16.0 (d, JCP¼5.9 Hz), 15.9 (d, JCP¼5.9 Hz). Anal. Calcd for
15H22NO5P: C, 55.04; H, 6.77; N, 4.28. Found: C, 55.23; H, 6.63;
1JCP¼147.2 Hz), 20.7, 20.2, 15.9 (d, JCP¼6.3 Hz), 15.81 (d, JCP
¼
C
6.3 Hz). Anal. Calcd for C16H24NO4P: C, 59.07; H, 7.44; N, 4.31.
Found: C, 59.25; H, 7.59; N, 4.42.
N, 4.18.
4.2.4. (3R
*
,4S
*
)-3-(Diethoxyphosphoryl)-4-(3,4-methylene-
4.3.3. (3R
*
,4S
*
,5S )-3-(Diethoxyphosphoryl)-4-(methoxyphenyl)-5-
*
dioxyphenyl)pyrrolidin-2-one (5d)
methylpyrrolidin-2-one (6c)
Yield 996 mg, 73%, white solid, mp 95–97 ꢀC; IR (CCl4): 1697,
Yield 1.12 g, 82%, white solid, mp 118–120 ꢀC; IR (CCl4): 1704,
1441, 1245, 1036, 1015; 31P NMR (CDCl3):
d
¼22.9; 1H NMR (CDCl3):
1612, 1516, 1440, 1376, 1336, 1304, 1256, 1180, 1120, 1016; 31P NMR
3
3
3
d
¼1.29 (t, 3H, JHH¼7.0 Hz, CH3CH2OP), 1.31 (t, 3H, JHH¼7.0 Hz,
(CDCl3):
d
¼23.4; 1H NMR (CDCl3):
d
¼1.15 (dt, 3H, JHH¼7.1 Hz,
3
3
3
4
CH3CH2OP), 2.92 (dd, 1H, JHH¼5.6 Hz, JHP¼22.9 Hz, PCH), 3.32–
4JHP¼0.5 Hz, CH3CH2OP), 1.24 (dt, 3H, JHH¼7.1 Hz, JHP¼0.5 Hz,
3
3.38 (m, 1H, CHAr), 3.83–3.93 (m, 2H, CH2N), 4.04–4.26 (m, 4H,
CH3CH2OP), 1.28 (d, 3H, JHH¼6.1 Hz, CH3CH), 3.09 (dd, 1H,
2
3
2ꢁCH3CH2OP), 5.95 (s, 2H, CH2O2), 6.21 (s, 1H, NH), 6.74–6.77 (m,
3JHH¼9.5 Hz, JHP¼22.7 Hz, PCH), 3.33 (ddd, 1H, JHH¼9.5, 7.0 Hz,
3H, 3ꢁCHAr); 13C NMR (CDCl3):
d
¼172.2 (d, JCP¼2.6 Hz), 148.0,
3JHP¼18.3 Hz, CHAr), 3.67 (dq, 1H, JHH¼6.1, 7.0 Hz, CHN), 3.80 (s,
2
3
146.7, 136.4 (d, 3JCP¼8.0 Hz), 120.0, 108.3, 106.9, 101.0, 63.1 (d, 2JCP
¼
3H, CH3OAr), 3.91–4.07 (m, 2H, CH3CH2OP), 4.08–4.23 (m, 2H,
2
3
6.4 Hz), 62.3 (d, JCP¼6.8 Hz), 49.0 (d, JCP¼6.7 Hz), 48.8
(d, 1JCP¼141.2 Hz), 41.7 (d, 2JCP¼1.6 Hz), 16.2 (d, 3JCP¼3.5 Hz), 16.1 (d,
3JCP¼3.4 Hz). Anal. Calcd for C15H20NO6P: C, 52.79; H, 5.91; N, 4.10.
Found: C, 52.91; H, 6.03; N, 4.18.
CH3CH2OP), 6.10 (s, 1H, NH), 6.87 (d, 2H, 3JHH¼8.7 Hz, 2ꢁCHAr), 7.18
(d, 2H, JHH¼8.7 Hz, 2ꢁCHAr); 13C NMR (CDCl3):
d
¼171.2, 158.6,
3
3
2
132.6 (d, JCP¼2.6 Hz), 128.4 (2ꢁ), 113.8 (2ꢁ), 62.6 (d, JCP¼6.1 Hz),
2
3
2
61.8 (d, JCP¼6.6 Hz), 57.3 (d, JCP¼11.1 Hz), 55.0, 50.1 (d, JCP
¼
1
3
1.9 Hz), 49.2 (d, JCP¼147.1 Hz), 20.1, 16.0 (d, JCP¼6.4 Hz), 15.9 (d,
3JCP¼6.4 Hz). Anal. Calcd for C16H24NO5P: C, 56.30; H, 7.09; N, 4.10.
Found: C, 56.17; H, 6.97; N, 4.01.
4.3. General procedure for the preparation of 4-aryl-3-
(diethoxyphosphoryl)-5-methylpyrrolidin-2-ones
6a–d
4.3.4. (3R
*
,4S
*
,5S )-3-(Diethoxyphosphoryl)-5-methyl-4-(3,4-
*
To
a
stirred solution of tert-butyl 3-aryl-2-(diethoxy-
(4 mmol) in MeOH (40 mL),
methylenedioxyphenyl)pyrrolidin-2-one (6d)
phosphoryl)-4-nitropentanoate
2
Yield 1.02 g, 72%, white solid, mp 155–157 ꢀC; IR (CCl4): 1704,
NiCl2$6H2O (1.90 g, 8 mmol) was added at room temperature. After
stirring for 10 min, NaBH4 (1.52 g, 40 mmol) was added in small
portions. The resulting mixture was stirred for 1 h at room tem-
perature and filtered through a pad of CeliteÒ. The solid material
was thoroughly washed with MeOH. Methanol was removed under
reduced pressure, the residue was dissolved in CHCl3 (30 mL), and
washed with NaHCO3 (15 mL). The water layer was extracted with
CHCl3 (2ꢁ15 mL) and combined organic layers were dried over
MgSO4. Evaporation of the solvent under reduced pressure afforded
a crude product, which was purified by column chromatography
(eluent: CHCl3/MeOH 97:3).
1488, 1440, 1372, 1312, 1252, 1184, 1040, 1016; 31P NMR (CDCl3):
3
d
¼22.9; 1H NMR (CDCl3):
d
¼1.19 (t, 3H, JHH¼7.1 Hz, CH3CH2OP),
3
3
1.25 (t, 3H, JHH¼7.1 Hz, CH3CH2OP), 1.28 (d, 3H, JHH¼6.1 Hz,
3
2
CH3CH), 3.10 (dd, 1H, JHH¼9.3 Hz, JHP¼22.9 Hz, PCH), 3.30 (ddd,
3
3
3
1H, JHH¼9.3, 7.1 Hz, JHP¼18.4 Hz, CHAr), 3.66 (dq, 1H, JHH¼6.1,
7.1 Hz, CHN), 3.94–4.10 (m, 2H, CH3CH2OP), 4.11–4.23 (m, 2H,
CH3CH2OP), 5.96 (s, 2H, CH2O2), 6.74–6.79 (m, 3H, 3ꢁCHAr); 13C
2
3
NMR (CDCl3):
d
¼170.9 (d, JCP¼1.7 Hz), 147.6, 146.4, 134.3 (d, JCP¼
2
3.2 Hz), 120.8, 107.9, 107.3, 100.8, 62.5 (d, JCP¼6.2 Hz), 61.7 (d,
2JCP¼6.7 Hz), 57.1 (d, JCP¼10.8 Hz), 50.5 (d, JCP¼2.3 Hz), 49.1 (d,
1JCP¼147.1 Hz), 20.1, 15.9 (d, 3JCP¼6.0 Hz), 15.8 (d, 3JCP¼6.0 Hz). Anal.
Calcd for C16H22NO6P: C, 54.08; H, 6.24; N, 3.94. Found: C, 53.93; H,
6.10; N, 3.81.
3
2
4.3.1. (3R
*
,4S
*
,5S )-4-(Bromophenyl)-3-(diethoxyphosphoryl)-5-
*
methylpyrrolidin-2-one (6a)
Yield 1.37 g, 88%, white solid, mp 108–110 ꢀC; IR (CCl4): 1708,
4.4. General procedure for the preparation of
tert-butyl 4-aryl-3-(diethoxyphosphoryl)-2-oxo
pyrrolidine-1-carboxylates 7a–d or tert-butyl 4-(aryl)-3-
(diethoxyphosphoryl)-5-methyl-2-oxopyrrolidine-
1-carboxylates 8a–d
1548, 1496, 1440, 1372, 1312, 1248, 1164, 1028; 31P NMR (CDCl3):
d
3
¼23.1; 1H NMR (CDCl3):
d
¼1.14 (t, 3H, JHH¼7.1 Hz, CH3CH2OP),
3
3
1.21 (t, 3H, JHH¼7.1 Hz, CH3CH2OP), 1.29 (d, 3H, JHH¼6.2 Hz,
3
2
CH3CH), 3.17 (dd, 1H, JHH¼9.4 Hz, JHP¼22.5 Hz, PCH), 3.36 (ddd,
1H, 3JHH¼9.4, 7.0 Hz, 3JHP¼18.0 Hz, CHAr), 3.72 (dq, 1H, 3JHH¼6.2 Hz,
7.0 Hz, CHN), 3.91–4.04 (m, 2H, CH3CH2OP), 4.05–4.24 (m, 2H,
To a solution of the corresponding lactam 5 or 6 (3 mmol) in
CH2Cl2 (15 mL), Boc2O (785 mg, 3.6 mmol) and DMAP (92 mg,
0.75 mmol) were added. The resulting mixture was left at room
temperature for 3 h and then washed with 3% aqueous solution of
KHSO4 (10 mL) and water (10 mL), and dried over MgSO4. Evapo-
ration of the solvent under reduced pressure afforded a crude
product, which was purified by column chromatography (eluent:
CHCl3/acetone 95:5).
CH3CH2OP), 7.04 (s, 1H, NH), 7.24–7.31 (m, 4H, 4ꢁCHAr); 13C NMR
3
(CDCl3):
d
¼171.2, 140.6 (d, JCP¼3.0 Hz), 128.5 (2ꢁ), 127.4 (2ꢁ),
2
2
127.1, 62.7 (d, JCP¼6.2 Hz), 61.9 (d, JCP¼6.7 Hz), 57.2 (d,
3JCP¼10.9 Hz), 50.9 (d, JCP¼2.4 Hz), 49.2 (d, JCP¼147.4 Hz), 20.2,
2
1
3
3
16.0 (d, JCP¼6.9 Hz), 15.8 (d, JCP¼6.3 Hz). Anal. Calcd for
C
15H21BrNO4P: C, 46.17; H, 5.42; N, 3.59. Found: C, 46.31; H, 5.57;
N, 3.69.

H. Krawczyk et al. / Tetrahedron 64 (2008) 6307–6314
6311
4.4.1. (3R
*
,4S
*
)-tert-Butyl 4-(4-bromophenyl)-3-(diethoxy-
3JHH¼7.1 Hz, CH3CH2OP),1.52 (d, 3H, 3JHH¼6.1 Hz, CH3CH),1.54 (s, 9H,
C(CH3)3), 3.17 (dd,1H, 3JHH¼7.0 Hz, 2JHP¼24.8 Hz, PCH), 3.34 (ddd,1H,
3JHH¼7.0, 4.9 Hz, 3JHP¼19.0 Hz, CHAr), 3.95–4.11 (m, 3H, CH3CH2OP,
phosphoryl)-2-oxopyrrolidine-1-carboxylate (7a)
Yield 1.40 g, 98%, white solid, mp 87–89 ꢀC; IR (CCl4): 1788, 1748,
1456, 1368, 1308, 1160, 1056; 31P NMR (CDCl3):
d
¼20.9; 1H NMR
CHN), 4.12–4.29 (m, 2H, CH3CH2OP), 7.21–7.30 (m, 4H, 4ꢁCHAr); 13
C
3
4
(CDCl3):
d
¼1.21 (dt, 3H, JHH¼7.1 Hz, JHP¼0.6 Hz, CH3CH2OP), 1.31
NMR (CDCl3):
d
¼167.8, 149.3, 141.8 (d, 3JCP¼7.6 Hz), 128.8 (2ꢁ), 127.3
(dt, 3H,3JHH¼7.1 Hz,4JHP¼0.5 Hz,CH3CH2OP),1.53(s, 9H,C(CH3)), 3.18
(dd, 1H, 3JHH¼6.1 Hz, 2JHP¼23.7 Hz, PCH), 3.71–3.89 (m, 2H, CHAHBN,
CHAr), 4.05–4.11 (m, 2H, CH3CH2OP), 4.17–4.27 (m, 3H, CH3CH2OP,
(2ꢁ), 126.7, 83.1, 63.4 (d, 2JCP¼6.5 Hz), 62.0 (d, 2JCP¼6.9 Hz), 60.8 (d,
3JCP¼7.0 Hz), 50.4 (d, JCP¼141.8 Hz), 45.8, 27.7, 20.3, 16.0 (d,
1
3JCP¼6.2 Hz), 15.8 (d, 3JCP¼6.2 Hz). Anal. Calcd for C20H29BrNO6P: C,
CHAHBN), 7.21–7.39 (m, 4H, 4ꢁCHAr); 13C NMR (CDCl3):
d¼166.2 (d,
48.99; H, 5.96; N, 2.86. Found: C, 49.13; H, 6.08; N, 3.02.
2JCP¼2.8 Hz), 149.4, 141.5 (d, JCP¼8.0 Hz), 129.0 (2ꢁ), 127.6, 126.6
3
2
2
(2ꢁ), 83.3, 63.6 (d, JCP¼6.5 Hz), 62.4 (d, JCP¼6.9 Hz), 52.6 (d,
3JCP¼6.2 Hz), 50.8 (d, 1JCP¼139.8 Hz), 37.8 (d, 2JCP¼2.2 Hz), 27.9, 16.2
(d, 3JCP¼6.2 Hz), 16.0 (d, 3JCP¼6.2 Hz). Anal. Calcd for C19H27BrNO6P:
C, 47.91; H, 5.71; N, 2.94. Found: C, 47.77; H, 5.55; N, 2.80.
4.4.6. (3R
*
,4S
*
,5S )-tert-Butyl 3-(diethoxyphosphoryl)-5-methyl-4-
*
(4-methylphenyl)-2-oxopyrrolidine-1-carboxylate (8b)
Yield 1.11 g, 87%, white solid, mp 93–95 ꢀC; IR (CCl4): 1784, 1724,
1368, 1300, 1256, 1160, 1024; 31P NMR (CDCl3):
d
¼21.3; 1H NMR
3
(CDCl3):
d
¼1.21 (t, 3H, JHH¼7.1 Hz, CH3CH2OP), 1.31 (t, 3H,
4.4.2. (3R
*
,4S
*
)-tert-Butyl 3-(diethoxyphosphoryl)-4-(4-methyl-
3JHH¼7.1 Hz, CH3CH2OP),1.52 (d, 3H, 3JHH¼6.2 Hz, CH3CH),1.54 (s,1H,
C(CH3)3), 2.34 (s, 3H, CH3Ar), 3.16 (dd,1H, 3JHH¼6.8 Hz, 2JHP¼24.7 Hz,
PCH), 3.30 (ddd,1H, 3JHH¼6.8, 4.8 Hz, 3JHP¼18.7 Hz, CHAr), 3.95–4.16
(m, 3H, CH3CH2OP, CHN), 4.17–4.23 (m, 2H, CH3CH2OP), 7.09–7.18 (m,
phenyl)-2-oxopyrrolidine-1-carboxylate (7b)
Yield1.12 g, 91%, yellowoil;IR (CCl4):1780,1724,1512,1360,1308,
1252, 1032; 31P NMR (CDCl3):
d
¼21.4; 1H NMR (CDCl3):
¼1.22 (dt,
d
3H, 3JHH¼7.1 Hz, 4JHP¼0.4 Hz, CH3CH2OP), 1.31 (dt, 3H, 3JHH¼7.1 Hz,
4H, 4ꢁCHAr); 13C NMR (CDCl3):
d
¼167.9 (d, 2JCP¼1.1 Hz),149.3,138.9
4JHP¼0.4 Hz, CH3CH2OP), 1.52 (s, 9H, C(CH3)3), 2.33 (s, 3H, CH3Ar),
(d, JCP¼6.4 Hz), 137.0 (2ꢁ), 129.4 (2ꢁ), 126.5, 83.0, 63.3 (d,
3
3
2
2
3
3.16 (dd, 1H, JHH¼5.8 Hz, JHP¼23.7 Hz, PCH), 3.68–3.86 (m, 2H,
CHAHBN, CHAr), 4.02–4.14 (m, 2H, CH3CH2OP), 4.18–4.30 (m, 3H,
CH3CH2OP, CHAHBN), 7.10–7.17 (m, 4H, 4ꢁCHAr); 13C NMR (CDCl3):
2JCP¼6.4 Hz), 62.0 (d, JCP¼6.8 Hz), 61.0 (d, JCP¼7.0 Hz), 50.4
1
2
(d, JCP¼142.1 Hz), 45.3 (d, JCP¼1.1 Hz), 27.7, 20.7, 20.3, 16.0 (d,
3JCP¼6.2 Hz), 15.8 (d, JCP¼6.2 Hz). Anal. Calcd for C21H32NO6P: C,
3
2
3
d
¼167.7 (d, JCP¼1.7 Hz), 149.1, 138.2 (d, JCP¼8.1 Hz), 136.8, 129.2
59.28; H, 7.58; N, 3.29. Found: C, 59.42; H, 7.70; N, 3.41.
2
2
(2ꢁ), 126.2 (2ꢁ), 82.8, 63.2 (d, JCP¼6.5 Hz), 62.0 (d, JCP¼6.8 Hz),
52.5 (d, 3JCP¼6.1 Hz), 50.5 (d, 1JCP¼139.7 Hz), 37.2, 27.5, 20.6, 15.9 (d,
4.4.7. (3R
*
,4S
*
,5S )-tert-Butyl 3-(diethoxyphosphoryl)-4-(4-
*
3JCP¼6.1 Hz), 15.7 (d, JCP¼6.3 Hz). Anal. Calcd for C20H30NO6P: C,
methoxyphenyl)-5-methyl-2-oxopyrrolidine-1-carboxylate (8c)
3
58.39; H, 7.35; N, 3.40. Found: C, 58.52; H, 7.47; N, 3.49.
Yield 1.24 g, 94%, white solid, mp 88–90 ꢀC; IR (CCl4): 1784,1724,
1512,1368,1300,1252,1156,1032; 31P NMR (CDCl3):
d
¼21.6; 1H NMR
3
4.4.3. (3R
*
,4S
*
)-tert-Butyl 3-(diethoxyphosphoryl)-4-(4-methoxy-
(CDCl3):
d
¼1.28 (t, 3H, JHH¼7.1 Hz, CH3CH2OP), 1.33 (t, 3H,
3
phenyl)-2-oxopyrrolidine-1-carboxylate (7c)
3JHH¼7.1 Hz, CH3CH2OP), 1.52 (d, 3H, JHH¼6.2 Hz, CH3CH), 1.56 (s,
3
2
Yield 1.18 g, 92%, white solid, mp 72–75 ꢀC; IR (CCl4): 1788, 1720,
9H, C(CH3)3), 3.15 (dd, 1H, JHH¼7.1 Hz, JHP¼24.7 Hz, PCH), 3.31
(ddd,1H, 3JHH¼7.1, 5.2 Hz, 3JHP¼18.9 Hz, CHAr), 3.82 (s, 3H, CH3OAr),
4.13–4.31 (m, 3H, CH3CH2OP, CHN), 4.11–3.97 (m, 2H, CH3CH2OP),
6.87 (d, 2H, 3JHH¼8.7 Hz, 2ꢁCHAr), 7.17 (d, 2H, 3JHH¼8.7 Hz, 2ꢁCHAr);
1512,1368, 1312,1252,1156, 1032; 31P NMR (CDCl3):
d
¼21.0; 1H NMR
3
4
(CDCl3):
d
¼1.23 (dt, 3H, JHH¼7.0 Hz, JHP¼0.5 Hz, CH3CH2OP), 1.32
(dt,3H,3JHH¼7.0 Hz, 4JHP¼0.5 Hz, CH3CH2OP),1.52(s, 9H, C(CH3)), 3.14
3
2
(dd, 1H, JHH¼6.1 Hz, JHP¼23.7 Hz, PCH), 3.47–3.50 (m, 2H, CH2N),
3.66–3.72 (m, 1H, CHAr), 3.80 (s, 3H, CH3OAr), 4.01–4.12 (m, 2H,
CH3CH2OP), 4.15–4.29 (m, 2H, CH3CH2OP), 6.87 (d, 2H, 3JHH¼8.8 Hz,
13C NMR (CDCl3):
d
¼167.9, 158.7, 149.3, 133.7 (d, 3JCP¼6.2 Hz), 127.8
(2ꢁ),114.1 (2ꢁ), 83.1, 63.4 (d, 2JCP¼6.5 Hz), 62.0 (d, 2JCP¼6.9 Hz), 61.0
(d, 3JCP¼7.3 Hz), 55.0, 50.5 (d, 1JCP¼142.3 Hz), 45.1, 27.7, 20.2,16.0 (d,
2ꢁCHAr), 7.16 (d, 2H, 3JHH¼8.8 Hz, 2ꢁCHAr);13C NMR (CDCl3):
d¼167.8
3JCP¼6.2 Hz), 15.9 (d, JCP¼6.2 Hz). Anal. Calcd for C21H32NO7P: C,
3
(d, 2JCP¼2.3 Hz), 158.7, 149.2, 133.3 (d, 3JCP¼8.0 Hz), 127.5 (2ꢁ), 114.1
57.13; H, 7.31; N, 3.17. Found: C, 57.00; H, 7.16; N, 3.04.
2
2
(2ꢁ), 83.1, 63.4 (d, JCP¼6.5 Hz), 62.2 (d, JCP¼6.5 Hz), 55.0, 52.7 (d,
3JCP¼6.4 Hz), 50.8(d,1JCP¼139.6 Hz),37.0(d, 2JCP¼1.7 Hz), 27.7, 16.1 (d,
4.4.8. (3R
*
,4S
*
,5S )-tert-Butyl 3-(diethoxyphosphoryl)-5-methyl-4-
*
3JCP¼6.2 Hz), 15.9 (d, JCP¼6.2 Hz). Anal. Calcd for C20H30NO7P: C,
(3,4-methylenedioxyphenyl)-2-oxopyrrolidine-1-carboxylate (8d)
3
56.20; H, 7.07; N, 3.28. Found: C, 56.42; H, 7.19; N, 3.39.
Yield 1.29 g, 95%, white solid, mp 99–101 ꢀC; IR (CCl4): 1784,1724,
1368, 1304, 1252, 1160, 1040; 31P NMR (CDCl3):
d
¼21.2; 1H NMR
3
4.4.4. (3R
*
,4S
*
)-tert-Butyl 3-(diethoxyphosphoryl)-4-(3,4-
(CDCl3):
d
¼1.28 (t, 3H, JHH¼7.1 Hz, CH3CH2OP), 1.32 (t, 3H,
methylenedioxyphenyl)-2-oxopyrrolidine-1-carboxylate (7d)
3JHH¼7.1 Hz, CH3CH2OP),1.50 (d, 3H, 3JHH¼6.2 Hz, CH3CH),1.54 (s, 9H,
C(CH3)3), 3.10(dd,1H,3JHH¼6.9 Hz, 2JHP¼24.8 Hz, PCH), 3.25 (ddd,1H,
3JHH¼6.9, 4.9 Hz, 3JHP¼19.1 Hz, CHAr), 3.98–4.15 (m, 3H, CH3CH2OP,
CHN), 4.16–4.27 (m, 2H, CH3CH2OP), 5.96 (s, 2H, CH2O2), 6.68 (dd,1H,
Yield 1.21 g, 91%, white solid, mp 70–72 ꢀC; IR (CCl4): 1788, 1720,
1368, 1304, 1248, 1164, 1041; 31P NMR (CDCl3):
d
¼21.2; 1H NMR
3
4
(CDCl3):
d
¼1.25 (dt, 3H, JHH¼7.0 Hz, JHP¼0.2 Hz, CH3CH2OP), 1.33
3 4
(dt, 3H, JHH¼7.1 Hz, JHP¼0.5 Hz, CH3CH2OP), 1.53 (s, 9H, C(CH3)),
3JHH¼8.6 Hz, 4JHH¼1.8 Hz, CHAr), 6.70 (d,1H, 4JHH¼1.8 Hz, CHAr), 6,76
3
2
3
3.11 (dd, 1H, JHH¼5.6 Hz, JHP¼23.6 Hz, PCH), 3.66–3.81 (m, 2H,
CH2N), 4.04–4.30 (m, 5H, CHAr, 2ꢁCH3CH2OP), 5.96 (s, 2H, CH2O2),
(d, 1H, JHH¼8.6 Hz, CHAr); 13C NMR (CDCl3):
d¼167.7 (d,
3
2JCP¼1.8 Hz), 149.2, 147.9, 146.7, 135.5 (d, JCP¼6.4 Hz), 120.0, 108.2,
106.7,100.9, 83.0, 63.3 (d, 2JCP¼6.5 Hz), 62.0 (d, 2JCP¼6.9 Hz), 60.8 (d,
3JCP¼7.1 Hz), 50.4 (d, 1JCP¼142.1 Hz), 45.5, 20.2, 16.0 (d, 3JCP¼6.2 Hz),
15.8 (d, 3JCP¼6.2 Hz). Anal. Calcd for C21H30NO8P: C, 55.38; H, 6.64; N,
3.08. Found: C, 55.24; H, 6.41; N, 3.00.
6.67–6.78 (m, 3H, 3ꢁCHAr); 13C NMR (CDCl3):
d¼167.3 (d,
2JCP¼1.7 Hz), 149.0, 147.7, 146.5, 134.7 (d, JCP¼7.9 Hz), 119.5, 108.0,
106.4, 100.7, 82.7, 63.1 (d, 2JCP¼6.5 Hz), 61.9 (d, 2JCP¼6.7 Hz), 52.3 (d,
3JCP¼6.4 Hz), 50.4 (d, 1JCP¼139.9 Hz), 37.2 (d, 2JCP¼1.4 Hz), 27.4, 15.8
(d, 3JCP¼6.2 Hz),15.6 (d, 3JCP¼6.2 Hz). Anal. Calcd for C20H28NO8P: C,
54.42; H, 6.39; N, 3.17. Found: C, 54.27; H, 6.25; N, 3.09.
3
4.5. General procedure for the preparation of tert-butyl 4-
aryl-3-methylene-2-oxopyrrolidine-1-carboxylates 9a–d and
tert-butyl 3-aryl-2-methyl-4-methylene-5-oxopyrrolidine-1-
carboxylates 10a–d
4.4.5. (3R
*
,4S
*
,5S )-tert-Butyl 4-(4-bromophenyl)-3-(diethoxy-
*
phosphoryl)-5-methyl-2-oxopyrrolidine-1-carboxylate (8a)
Yield 1.38 g, 94%, white solid, mp 83–85 ꢀC; IR (CCl4): 1784, 1724,
1368, 1300, 1256, 1156, 1028; 31P NMR (CDCl3):
d
¼21.5; 1H NMR
To a stirred solution of the corresponding lactam 7 or 8
(2 mmol) in THF (15 mL), potassium tert-butoxide (269 mg,
3
(CDCl3):
d
¼1.25 (t, 3H, JHH¼7.1 Hz, CH3CH2OP), 1.32 (t, 3H,

6312
H. Krawczyk et al. / Tetrahedron 64 (2008) 6307–6314
4
2
2.4 mmol) was added and the resulting mixture was stirred at room
temperature for 30 min. Then paraformaldehyde (300 mg,
10 mmol) was added in one portion. After 1 h, the reaction mixture
was quenched with brine (15 mL), THF was removed under reduced
pressure, and the water layer was extracted with CH2Cl2 (2ꢁ15 mL).
The combined organic layers were dried over MgSO4 and concen-
trated in vacuo. The crude product was purified by column chro-
matography (eluent: CHCl3/acetone 98:2).
5.32 (dd, 1H, JHH¼2.3 Hz, JHH¼0.3 Hz, CHAHB]C), 6.30 (dd, 1H,
2
4JHH¼2.5 Hz, JHH¼0.3 Hz, CHAHB]C), 7.10–7.32 (m, 4H, 4ꢁCHAr);
13C NMR (CDCl3):
d
¼165.6,150.0,142.8,141.4,128.7 (2ꢁ),127.2 (2ꢁ),
127.1, 122.0, 82.8, 59.5, 49.8, 27.8, 20.9. Anal. Calcd for C17H20BrNO3:
C, 55.75; H, 5.50; N, 3.82. Found: C, 55.54; H, 5.36; N, 3.71.
4.5.6. (2R
*
,3S )-tert-Butyl 2-methyl-4-methylene-3-(4-methyl-
phenyl)-5-oxopyrrolidine-1-carboxylate (10b)
*
Yield 410 mg, 68%, pale-yellow oil; IR (CCl4): 1780, 1716, 1368,
3
4.5.1. tert-Butyl 4-(4-bromophenyl)-3-methylene-2-
oxopyrrolidine-1-carboxylate (9a)
1300, 1156; 1H NMR (CDCl3):
d
¼1.43 (d, 3H, JHH¼6.2 Hz, CH3CH),
1.55 (s, 9H, C(CH3)3), 2.34 (s, 3H, CH3Ar), 3.54 (ddd, 1H, 3JHH¼4.1 Hz,
3
Yield 359 mg, 51%, pale-yellow oil; IR (CCl4): 1780, 1716, 1480,
4JHH¼2.6, 2.3 Hz, CHAr), 4.07 (dq, 1H, JHH¼4.1, 6.2 Hz, CHN), 5.36
1392,1368,1320,1148; 1H NMR (CDCl3):
d
¼1.56 (s, 9H, C(CH3)3), 3.66
(dd, 1H, JHH¼2.3 Hz, JHH¼0.4 Hz, CHAHB]C), 6.34 (dd, 1H,
4
2
(dd, 3JHH¼6.5 Hz, 2JHH¼10.4 Hz, CHAHBN), 4.04 (dddd, 1H, 3JHH¼6.5,
4JHH¼2.6 Hz, JHH¼0.4 Hz, CHAHB]C), 7.05–7.26 (m, 4H, 4ꢁCHAr);
2
4
3
9.3 Hz, JHH¼2.7 Hz, 3.1 Hz, CHAr), 4.17 (dd, 1H, JHH¼9.3 Hz,
2JHH¼10.4 Hz, CHAHBN), 5.28 (d,1H, 4JHH¼2.7 Hz, CHAHB]C), 6.32 (d,
13C NMR (CDCl3):
d
¼165.8,150.1,143.0,138.4,136.8,129.4 (2ꢁ),127.8
(2ꢁ), 121.9, 82.8, 59.7, 49.6, 27.8, 20.9, 20.8. Anal. Calcd for
4
1H, JHH¼3.1 Hz, CHAHB]C), 7.21–7.41 (m, 4H, 4ꢁCHAr); 13C NMR
C18H23NO3: C, 71.73; H, 7.69; N, 4.65. Found: C, 71.89; H, 7.81; N, 4.75.
(CDCl3):
d
¼165.2, 149.8, 143.7, 140.5, 128.5 (2ꢁ), 127.5 (2ꢁ), 127.0,
120.9, 82.5, 51.2, 41.1, 27.6. Anal. Calcd for C16H18BrNO3: C, 54.56; H,
5.15; N, 3.98. Found: C, 54.72; H, 5.28; N, 4.08.
4.5.7. (2R
*
,3S )-tert-Butyl 3-(4-methoxyphenyl)-2-methyl-4-
methylene-5-oxopyrrolidine-1-carboxylate (10c)
*
Yield 508 mg, 80%, pale-yellow oil; IR (CCl4): 1776, 1736, 1512,
3
4.5.2. tert-Butyl 3-methylene-4-(4-methylphenyl)-2-oxo-
pyrrolidine-1-carboxylate (9b)
1300, 1252, 1156; 1H NMR (CDCl3):
d
¼1.43 (d, 3H, JHH¼6.2 Hz,
CH3CH), 1.55 (s, 9H, C(CH3)3), 3.52 (ddd, 1H, 3JHH¼4.4 Hz, 4JHH¼2.6,
3
Yield 425 mg, 74%, pale-yellow oil; IR (CCl4): 1780, 1716, 1508,
2.3 Hz, CHAr), 3.80 (s, 3H, CH3OAr), 4.04 (dq, 1H, JHH¼4.4, 6.2 Hz,
1248, 1148; 1H NMR (CDCl3):
d
2
¼1.55 (s, 9H, C(CH3)3), 2.34 (s, 3H,
CHN), 5.36 (d, 1H, JHH¼2.3, JHH¼0.4 Hz, CHAHB]C), 6.34 (dd, 1H,
2 3
4
2
3
CH3Ar), 3.62 (dd, JHH¼6.6 Hz, JHH¼10.5 Hz, CHAHBN), 4.00 (dddd,
4JHH¼2.6 Hz, JHH¼0.4 Hz, CHAHB]C), 6.88 (d, 2H, JHH¼8.8 Hz,
3
4
3
1H, JHH¼6.6 Hz, 9.4 Hz, JHH¼2.7 Hz, 3.1 Hz, CHAr), 4.14 (dd, 1H,
2ꢁCHAr), 7.10 (d, 2H, JHH¼8.8 Hz, 2ꢁCHAr); 13C NMR (CDCl3):
3JHH¼9.4 Hz, JHH¼10.5 Hz, CHAHBN), 5.27 (d, 1H, JHH¼2.7 Hz,
d
¼165.8, 158.6, 150.1, 143.1, 133.3, 128.4 (2ꢁ), 121.8, 114.1 (2ꢁ), 82.9,
2
4
4
CHAHB]C), 6.30 (d, 1H, JHH¼3.1 Hz, CHAHB]C), 7.11 (d, 2H,
59.8, 55.0, 49.0, 27.8, 20.8. Anal. Calcd for C18H23NO4: C, 68.12; H,
7.30; N, 4.41. Found: C, 68.01; H, 7.19; N, 4.30.
3JHH¼8.1 Hz, 2ꢁCHAr), 7.17 (d, 2H, JHH¼8.1 Hz, 2ꢁCHAr); 13C NMR
3
(CDCl3):
d
¼165.4, 149.9, 143.9, 137.5, 136.7, 129.2 (2ꢁ), 127.4 (2ꢁ),
120.8, 82.6, 51.4, 40.9, 27.6, 20.6. Anal. Calcd for C17H21NO3: C,
71.06; H, 7.37; N 4.87. Found: C, 71.22; H, 7.51; N, 4.99.
4.5.8. (2R
*
,3S )-tert-Butyl 2-methyl-4-methylene-3-(3,4-methyl-
*
enedioxyphenyl)-5-oxopyrrolidine-1-carboxylate (10d)
Yield 530 mg, 80%, white solid, mp 114–116 ꢀC; IR (CCl4): 1764,
4.5.3. tert-Butyl 4-(4-methoxyphenyl)-3-methylene-2-
oxopyrrolidine-1-carboxylate (9c)
1688, 1364, 1324, 1300, 1252, 1168; 1H NMR (CDCl3):
d
¼1.44 (d, 3H,
3JHH¼6.1 Hz, CH3CH), 1.57 (s, 9H, C(CH3)3), 3.49 (ddd, 1H,
Yield 528 mg, 87%, pale-yellow oil; IR (CCl4): 1780, 1716, 1512,
3JHH¼4.4 Hz, 4JHH¼2.6, 2.2 Hz, CHAr), 4.04 (dq, 1H, 3JHH¼4.4, 6.1 Hz,
1252, 1148; 1H NMR (CDCl3):
d
¼1.61 (s, 9H, C(CH3)3), 3.65 (dd,
CHN), 5.40 (dd, 1H, JHH¼2.2, JHH¼0.3 Hz, CHAHB]C), 5.98 (s, 2H,
4 2
4
2
2
3JHH¼6.8 Hz, JHH¼10.5 Hz, CHAHBN), 3.86 (s, 3H, CH3OAr), 4.04
CH2O2), 6.36 (dd, 1H, JHH¼2.6 Hz, JHH¼0.4 Hz, CHAHB]C), 6.67
4 3 4
3
4
(dddd, 1H, JHH¼6.8, 9.3 Hz, JHH¼2.8, 3.1 Hz, CHAr), 4.19 (dd, 1H,
(dd, 1H, JHH¼1.8 Hz, JHH¼8.4 Hz, CHAr), 6.77 (d, 1H, JHH¼1.8 Hz,
3
3JHH¼9.3 Hz, JHH¼10.5 Hz, CHAHBN), 5.32 (d, 1H, JHH¼2.8 Hz,
CHAr), 6.78 (d, 1H, JHH¼8.4 Hz, CHAr); 13C NMR (CDCl3):
¼165.5,
d
2
4
4
CHAHB]C), 6.35 (d, 1H, JHH¼3.1 Hz, CHAHB]C), 6.95 (d, 2H,
150.0, 147.9, 146.6, 142.8, 135.0, 122.0, 120.6, 108.1, 107.3, 100.9, 82.9,
59.6, 49.7, 27.8, 20.8. Anal. Calcd for C18H21NO5: C, 65.24; H, 6.39; N,
4.23. Found: C, 65.08; H, 6.25; N, 4.11.
3JHH¼8.7 Hz, 2ꢁCHAr), 7.20 (d, 2H, JHH¼8.7 Hz, 2ꢁCHAr); 13C NMR
3
(CDCl3):
d
¼165.5, 158.7, 150.0, 144.1, 132.3, 128.7 (2ꢁ), 120.9, 114.0
(2ꢁ), 82.7, 54.9, 51.6, 40.6, 27.7. Anal. Calcd for C17H21NO4: C, 67.31;
H, 6.98; N, 4.62. Found: C, 67.48; H, 7.11; N, 4.77.
4.6. General procedure for the preparation of 4-aryl-3-
methylenepyrrolidin-2-ones 11a–d and 4-aryl-5-methyl-3-
methylenepyrrolidin-2-ones 12a–d
4.5.4. tert-Butyl 3-methylene-4-(3,4-methylenedioxyphenyl)-2-
oxopyrrolidine-1-carboxylate (9d)
Yield 565 mg, 89%, white solid, mp 97–99 ꢀC; IR (CCl4): 1768,
To a solution of the corresponding lactam 9 or 10 (1 mmol) in
CH2Cl2 (10 mL), trifluoroacetic acid (5 mL) was added. The reaction
mixture was left at room temperature for 1 h. The solvent was
evaporated, the residue was dissolved in CH2Cl2 (15 mL), washed
with NaHCO3 (15 mL) and water (15 mL), and dried over MgSO4.
Evaporation of the solvent under reduced pressure afforded a crude
product, which was purified by column chromatography (eluent:
CHCl3/acetone 95:5).
1688,1504,1440, 1364,1312,1164,1036; 1H NMR (CDCl3):
d¼1.55 (s,
3
2
9H, C(CH3)3), 3.58 (dd, JHH¼6.8 Hz, JHH¼10.6 Hz, CHAHBN), 3.96
3
4
(dddd, 1H, JHH¼6.8, 9.3 Hz, JHH¼3.1, 2.8 Hz, CHAr), 4.13 (dd, 1H,
3JHH¼9.3 Hz, JHH¼10.6 Hz, CHAHBN), 5.31 (d, 1H, JHH¼2.8 Hz,
CHAHB]C), 5.97 (s, 2H, CH2O2), 6.32 (d,1H, 4JHH¼3.1 Hz, CHAHB]C),
6.67–6.71 (m, 2H, 2ꢁCHAr), 6.77–6.80 (m, 1H, CHAr); 13C NMR
2
4
(CDCl3):
d
¼165.4, 150.1, 147.9, 146.7, 143.8, 134.2, 121.2, 121.2, 108.2,
107.6, 101.0, 82.8, 51.5, 41.1, 27.8. Anal. Calcd for C17H19NO5: C,
64.34; H, 6.03; N, 4.41. Found: C, 64.51; H, 6.13; N, 4.55.
4.6.1. 4-(4-Bromophenyl)-3-methylenepyrrolidin-2-one (11a)
Yield 184 mg, 73%, white solid, mp 122–124 ꢀC; IR (CCl4): 1688,
4.5.5. (2R
*
,3S
*
)-tert-Butyl 3-(4-bromophenyl)-2-methyl-4-
1656, 1360, 1312, 1264; 1H NMR (CDCl3):
d
¼3.42 (dd, 1H,
2
3
methylene-5-oxopyrrolidine-1-carboxylate (10a)
3JHH¼9.8 Hz, JHH¼9.5 Hz, CHAHBN), 3.86 (dd, 1H, JHH¼5.8 Hz,
3
4
Yield 491 mg, 67%, white solid, mp 86–88 ꢀC; IR (CCl4): 1780,
2JHH¼9.5 Hz, CHAHBN), 4.18 (dddd, 1H, JHH¼9.8, 5.8 Hz, JHH¼3.1,
3
4
1736, 1296, 1152; 1H NMR (CDCl3):
d
¼1.38 (d, 3H, JHH¼6.2 Hz,
2.6 Hz, CHAr), 5.19 (d, 1H, JHH¼2.6 Hz, CHAHB]C), 6.14 (d, 1H,
3
CH3CH), 1.49 (s, 9H, C(CH3)3), 3.51 (ddd, 1H, JHH¼4.0 Hz,
4JHH¼3.1 Hz, CHAHB]C), 6.75 (s, 1H, NH), 7.22–7.40 (m, 4H,
4JHH¼2.5 Hz, 2.3 Hz, CHAr), 4.04 (dq, 1H, JHH¼4.0, 6.2 Hz, CHN),
4ꢁCHAr); 13C NMR (CDCl3):
¼171.0, 144.5, 141.9, 128.6 (2ꢁ), 127.6
d
3

H. Krawczyk et al. / Tetrahedron 64 (2008) 6307–6314
6313
3
4
(2ꢁ),126.9,117.2, 48.3, 44.5. Anal. Calcd for C11H10BrNO: C, 52.41; H,
3JHH¼6.1 Hz, CH3CH), 3.52 (ddd, 1H, JHH¼6.2 Hz, JHH¼2.7, 2.1 Hz,
3
4.00; N, 5.56. Found: C, 52.54; H, 3.84; N, 5.41.
CHAr), 3.63 (dq, 1H, JHH¼6.2, 6.1 Hz, CHN), 3.82 (s, 3H, CH3OAr),
4
5.10 (d, 1H, JHH¼2.1 Hz, CHAHB]C), 5.92 (s, 1H, NH), 6.09 (d, 1H,
4.6.2. 3-Methylene-4-(4-methylphenyl)pyrrolidin-2-one (11b)
4JHH¼2.7 Hz, CHAHB]C), 6.89 (d, 2H, 3JHH¼8.8 Hz, 2ꢁCHAr), 7.14 (d,
3
Yield 154 mg, 82%, white solid, mp 146–148 ꢀC; IR (CCl4): 1696,
2H, JHH¼8.8 Hz, 2ꢁCHAr); 13C NMR (CDCl3):
d
¼170.2, 158.6, 145.6,
1263, 1018; 1H NMR (CDCl3):
d
¼2.35 (s, 3H, CH3Ar), 3.39 (dd, 1H,
132.4, 129.2 (2ꢁ), 116.7, 114.0 (2ꢁ), 56.5, 55.0, 53.5, 20.6. Anal. Calcd
for C13H15NO2: C, 71.87; H, 6.96; N, 6.45. Found: C, 72.02; H, 7.10;
N, 6.61.
2
3
3JHH¼5.8 Hz, JHH¼9.7 Hz, CHAHBN), 3.83 (dd, 1H, JHH¼9.4 Hz,
2JHH¼9.7 Hz, CHAHBN), 4.17 (dddd, 1H, JHH¼9.4, 5.8 Hz, JHH¼3.1,
3
4
4
2.6 Hz, CHAr), 5.19 (d, 1H, JHH¼2.6 Hz, CHAHB]C), 6.13 (d, 1H,
4JHH¼3.1 Hz, CHAHB]C), 6.41 (s, 1H, NH), 7.10–7.18 (m, 4H, 4ꢁCHAr);
4.6.8. (4R
*
,5S )-5-Methyl-3-methylene-4-(3,4-methylene-
*
13C NMR (CDCl3):
117.5, 48.5, 44.2, 20.8. Anal. Calcd for C12H13NO: C, 76.98; H, 7.00; N,
7.48. Found: C, 77.13; H, 7.12; N, 7.61.
d
¼171.1, 144.6, 138.8, 136.6,129.4 (2ꢁ), 127.6 (2ꢁ),
dioxyphenyl)pyrrolidin-2-one (12d)
Yield 187 mg, 81%, white solid, mp 149–151 ꢀC; IR (CCl4): 1704,
1488, 1436, 1384, 1336, 1280, 1246; 1H NMR (CDCl3):
d
¼1.30 (d, 3H,
3
4
3JHH¼6.1 Hz, CH3CH), 3.51 (ddd, 1H, JHH¼5.9 Hz, JHH¼3.2, 2.3 Hz,
CHAr), 3.62 (dq, 1H, 3JHH¼6.1, 5.9 Hz, CHN), 5.14 (d, 1H, 4JHH¼2.3 Hz,
CHAHB]C), 5.97 (s, 2H, CH2O2), 6.11 (d, 1H, 4JHH¼3.2 Hz, CHAHB]C),
6.35 (s, 1H, NH), 6.69 (dd, 1H, 3JHH¼7.7 Hz, 4JHH¼1.8 Hz, CHAr), 6.77
(d, 1H, 4JHH¼1.8 Hz, CHAr), 6.78 (d, 1H, 3JHH¼7.7 Hz, CHAr); 13C NMR
4.6.3. 3-Methylene-4-(4-methoxyphenyl)pyrrolidin-2-one (11c)
Yield 104 mg, 51%, white solid, mp 191–193 ꢀC; IR (CCl4): 1697,
1510, 1296, 1244, 1175; 1H NMR (CDCl3):
d
¼3.36 (dd, 1H,
2
3JHH¼6.1 Hz, JHH¼9.7 Hz, CHAHBN), 3.81 (s, 3H, CH3OAr), 3.81 (dd,
3
2
3
1H, JHH¼9.3 Hz, JHH¼9.7 Hz, CHAHBN), 4.14 (dddd, 1H, JHH¼9.3,
6.1 Hz, 4JHH¼3.1, 2.7 Hz, CHAr), 5.18 (d, 1H, 4JHH¼2.7 Hz, CHAHB]C),
(CDCl3):
d
¼170.0, 147.8, 146.6, 145.3, 134.1, 121.6, 116.8, 108.1 (2ꢁ),
100.8, 56.4, 53.9, 20.6. Anal. Calcd for C13H13NO3: C, 67.52; H, 5.67;
N, 6.06. Found: C, 67.33; H, 5.51; N, 5.96.
4
6.09 (s, 1H, NH), 6.13 (d, 1H, JHH¼3.1 Hz, CHAHB]C), 6.87 (d, 2H,
3
3JHH¼8.8 Hz, 2ꢁCHAr), 7.16 (d, 2H, JHH¼8.8 Hz, 2ꢁCHAr); 13C NMR
(CDCl3):
d
¼170.7, 158.8, 144.3, 133.8, 128.9 (2ꢁ), 117.7, 114.2 (2ꢁ),
4.7. X-ray single crystal analysis for 8c
55.2, 48.5, 44.2. Anal. Calcd for C12H13NO2: C, 70.92; H, 6.45; N, 6.89.
Found: C, 70.73; H, 6.22; N, 6.66.
Formula:
C
21H32NO7P,
Mw¼441.45,
colorless
crystal
0.40ꢁ0.15ꢁ0.10 mm, a¼9.867(2), b¼10.363(2), c¼12.865(3) Å,
4.6.4. 3-Methylene-4-(3,4-methylenedioxyphenyl)pyrrolidin-2-
one (11d)
a¼111.50(3),
b
¼90.35(3),
g
¼102.00(3)ꢀ, V¼1192.3(4) Å3, Z¼2, crys-
tal system: triclinic, space group: Pꢃ1, rcalcd¼1.23 g cmꢃ3
, l(Mo
Yield 178 mg, 82%, white solid, mp 190–192 ꢀC; IR (CCl4): 1688,
Ka)¼0.71073 Å,
m
¼0.154 mmꢃ1, T¼293 K,
u scans,11,007 reflections
1648,1440,1320,1280,1248,1192; 1H NMR (CDCl3):
d
¼3.35 (ddd,1H,
collected (ꢂh, ꢂk, ꢂl), 2qmax¼50.0ꢀ, semi-empirical absorption
correction based on multiple scanned equivalent reflections31
(0.906<T<0.985), 4080 unique reflections (Rint¼0.022), 337 refined
parameters, refinement on F2 using all unique reflections, final
2
3
3JHH¼5.8, 0.7 Hz, JHH¼9.9 Hz, CHAHBN), 3.82 (ddd, 1H, JHH¼8.9,
2
3
1.0 Hz, JHH¼9.9 Hz, CHAHBN), 4.09 (dddd, 1H, JHH¼8.9, 5.8 Hz,
4JHH¼3.1, 2.1 Hz, CHAr), 5.20 (d, 1H, 4JHH¼2.1 Hz, CHAHB]C), 5.96 (s,
2H, CH2O2), 6.12 (d, 1H, 4JHH¼3.1 Hz, CHAHB]C), 6.69–6.79 (m, 3H,
R¼0.053 for 2735 observed reflections [Iꢄ2 (I)], Rall¼0.0773,
s
3ꢁCHAr), 7.37 (s, 1H, NH); 13C NMR (CD3OD):
¼172.3, 149.6, 148.3,
d
wRall(F2)¼0.166, max (min) residual electron density Drmax¼0.20
146.8,137.4,122.3,117.8,109.3,108.8,102.5, 49.5, 46.7. Anal. Calcd for
(
Drmin¼ꢃ0.37) e Åꢃ3, all hydrogen atoms refined as riding on their
C
12H11NO3: C, 66.35; H, 5.10; N, 6.45. Found:C, 66.49; H, 5.22;N, 6.62.
parent atoms. Disordered ethoxy groups at phosphorus were sat-
isfactory refined using a two site model with both site occupancies
representing each of the disordered atoms tied to sum to unity.
X-ray data were collected using the OXFORD DIFFRACTION KM4
XCALIBUR diffractometer equipped with the KM4CCD/SAPPHIRE
area detector. Computer programs used: data collection, data re-
duction, and absorption correction CrysAlis suite of programs,32
structure solution, refinement, and molecular graphics SHELXTL.33
Crystallographic data (excluding structural factors) for the
structure reported, herein, have been deposited at the Cambridge
Crystallographic Data Center as supplementary publication CCDC
677697. Copies of the data can be obtained free of charge on ap-
plication to The Director, CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK. Any request should be accompanied by a full literature citation.
4.6.5. (4R ,5S )-4-(4-Bromophenyl)-5-methyl-3-methylene-
*
*
pyrrolidin-2-one (12a)
Yield 210 mg, 79%, white solid, mp 112–114 ꢀC; IR (CCl4): 1696,
1664,1432,1336,1232; 1H NMR (CDCl3):
d
¼1.32 (d, 3H, 3JHH¼6.1 Hz,
3
4
CH3CH), 3.58 (ddd, 1H, JHH¼6.2 Hz, JHH¼3.2, 2.7 Hz, CHAr), 3.70
(dq, 1H, 3JHH¼6.1, 6.2 Hz, CHN), 5.12 (d, 1H, 4JHH¼2.7 Hz, CHAHB]C),
6.11 (d, 1H, 4JHH¼3.2 Hz, CHAHB]C), 6.64 (s, 1H, NH), 7.21–7.39 (m,
4H, 4ꢁCHAr); 13C NMR (CDCl3):
¼170.0, 145.3, 140.4, 128.5 (2ꢁ),
d
128.1 (2ꢁ), 126.9, 116.7, 56.3, 54.0, 20.7. Anal. Calcd for C12H12BrNO:
C, 54.16; H, 4.54; N, 5.26. Found: C, 54.00; H, 4.43; N, 5.13.
4.6.6. (4R
*
,5S )-5-Methyl-3-methylene-4-(4-methyl-
*
phenyl)pyrrolidin-2-one (12b)
Yield 125 mg, 62%, white solid, mp 138–140 ꢀC; IR (CCl4): 1698,
Acknowledgements
1514, 1438, 1391, 1333, 1261, 1231; 1H NMR (CDCl3):
d
¼1.30 (d, 3H,
3JHH¼6.1 Hz, CH3CH), 2.35 (s, 3H, CH3Ar), 3.55 (ddd,1H, 3JHH¼5.9 Hz,
4JHH¼3.5, 2.8 Hz, CHAr), 3.66 (dq, 1H, 3JHH¼6.1, 5.9 Hz, CHN), 5.11 (d,
This work was financed by the Ministry of Education and
Science (Project No. 3 T09A 075 28) and Institute of General and
Ecological Chemistry (J.W. and W.M.W.).
4
1H, JHH¼2.8 Hz, CHAHB]C), 5.91 (s, 1H, NH), 6.10 (d, 1H,
4JHH¼3.5 Hz, CHAHB]C), 7.10 (d, 2H, JHH¼8.4 Hz, 2ꢁCHAr), 7.17 (d,
3
2H, JHH¼8.4 Hz, 2ꢁCHAr); 13C NMR (CDCl3):
d
¼170.2, 145.5, 137.5,
3
References and notes
136.7, 129.3 (2ꢁ), 128.1 (2ꢁ), 116.8, 56.5, 53.8, 20.8, 20.8. Anal. Calcd
for C13H15NO: C, 77.58; H, 7.51; N, 6.96. Found: C, 77.73; H, 7.70; N,
7.11.
1. Belaud, C.; Roussakis, C.; Letourneux, Y.; Alami, N.; Villie´ras, J. Synth. Commun.
1985, 15, 1233.
2. Kornet, M. J. J. Pharm. Sci. 1979, 68, 350.
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