Synthesis of 5-methoxylated 3-pyrrolin-2-ones via the rearrangement of chlorinated pyrrolidin-2-ones

Article abstract of DOI:10.1016/S0040-4020(03)00044-9

The reaction of N-substituted 4-methyl-2-pyrrolidinones or 4-diethoxyphosphoryl analogues, carrying at least two chlorine atoms between the C(3) and C(6) carbons, with alkaline methoxide in methanol afforded the corresponding 5-methoxylated 3-pyrrolin-2-ones, useful adducts for the preparation of agrochemicals or medicinal compounds.

Full text of DOI:10.1016/S0040-4020(03)00044-9

Tetrahedron 59 (2003) 1147–1157
Synthesis of 5-methoxylated 3-pyrrolin-2-ones via the
rearrangement of chlorinated pyrrolidin-2-ones
b
b
b
b
Franco Ghelfi,a Christian V. Stevens, Inge Laureyn, Ellen Van Meenen, Tina M. Rogge,
,
,
*
*
Laurent De Buyck,b Kirill V. Nikitin,c Romano Grandi,a Emanuela Libertini,a
Ugo M. Pagnonia and Luisa Schenettia
a
`
Dipartimento di Chimica, Universita degli Studi di, Modena e Reggio Emilia, Via Campi 183, 41100 Modena, Italy
bDepartment of Organic Chemistry, Faculty of Agricultural and Applied Biological Sciences, Ghent University, Coupure Links 653,
B-9000 Ghent, Belgium
cDepartment of Chemistry, University College Dublin, Belfield, Dublin 4, Ireland
Received 7 October 2002; revised 9 December 2002; accepted 2 January 2003
Abstract—The reaction of N-substituted 4-methyl-2-pyrrolidinones or 4-diethoxyphosphoryl analogues, carrying at least two chlorine
atoms between the C(3) and C(6) carbons, with alkaline methoxide in methanol afforded the corresponding 5-methoxylated 3-pyrrolin-2-
ones, useful adducts for the preparation of agrochemicals or medicinal compounds. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
lin-2-ones gave complete control of Amarantus lividus and
Chenopodium album while leaving the preemergent corn
unaffected.4
Research and development in the field of crop protection is
no longer distinguishable, in terms of scientific rigour and
demand of high quality results, from the one driving the
pharmaceutical industry.1 The need to safeguard con-
sumers’ health, and to protect natural equilibria, imposes
nowadays the development of more specific and environ-
mentally friendly active compounds. This challenge has
been accepted by the agrochemical industry and now stands
for one of its primary objectives.1
Since a,b-unsaturated-g-lactams are important synthetic
intermediates8–10 and their structural unit is frequently
found in natural products (many of them displaying
pharmacological activity),11–15 the development of general
methods for the preparation of these heterocycles is still an
issue of increasing interest.8,9,12,15–21 As far as compounds
with herbicidal characteristics are concerned, a synthetic
route which has the opportunity to introduce substituents on
the C-5 carbon of the lactam ring is advantageous. The most
convenient way at the moment (Scheme 1) starts from the
reduction of maleimides (A).4–6 The 5-hydroxy-3-pyrrolin-
2-ones (B), thus obtained, being precursors of cyclic
N-acyliminium ions,22 afford a viable way to insert a wide
range of functionalities at the C(5) position (Scheme 1).23
Among the new chemical structures, the 3-pyrrolin-2-one
(a,b-unsaturated-g-lactam or 1,5-dihydro-2H-pyrrol-2-one)
compounds2–6 (Fig. 1) exhibit remarkable bio-activity,
showing high herbicidal power against annual weeds at
extremely low doses.7 For example 0.25 Kg/ha of the N-(5-
t-butyl-1,3,4-thiadiazol-2-yl)-3,4-dimethyl-5-oxo-3-pyrro-
The OH function, however, is not a good nucleofuge and
requires the presence of a Bronsted or Lewis acid for
weakening the C–O bond.22,23 Recently, it was demon-
strated that the scope of the substitution protocol at C(5)
could be improved with Cl as the leaving group. The
replacement of the halo function in 5-chloro-pyrrolin-2-
ones D can in fact be smoothly accomplished with a wide
variety of C-, N- and O-nucleophiles (Scheme 2).24,25 The
preparation of D typically involves substitution of the
5-hydroxy group of the 1,5-dihydro-2H-pyrrol-2-one B
using thionyl chloride (Scheme 2). However, the two-step
procedure, first methoxylation of B, followed by chloro-de-
methoxylation with PCl5 (Scheme 2), proved preferable
Figure 1.
Keywords: pyrrolidinones; pyrrolinones; lactams; eliminations.
*
Corresponding authors. Tel.: þ39-059-2055049; fax: þ39-059-373543;
ghelfi.franco@unimo.it; chris.stevens@rug.ac.be
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00044-9

1148
F. Ghelfi et al. / Tetrahedron 59 (2003) 1147–1157
Scheme 1.
Scheme 2.
since it avoids the formation of hydrogen chloride which
complicates some further transformations.25
limited, the phosphonated lactams proved valuable sub-
stances to study this class of compounds in more detail.
An alternative route to the a,b-unsaturated-g-lactams C,
circumventing the need to start from substituted maleic
anhydrides, has been serendipitously found experimenting
with chlorinated pyrrolidin-2-ones, formed by halogen
atom transfer radical cyclization (HATRC) of N-allyl
a-perchloroamides, as substrates for the production of
paraconic acids.26 The novel approach to the 5-methoxy-3-
pyrrolin-2-ones through a remarkable functional rearrange-
ment of chlorinated lactams is described in this article
(Scheme 3).26 The reaction appears to be quite general:
similar chlorinated 1-diethoxyphosphorylmethyl and even
4-diethoxyphosphoryl lactams undergo the rearrange-
ment.27 The phosphonated lactams were evaluated in view
of the importance of many acyclic phosphonic acids as
agrochemicals, e.g. glyphosate and bialaphos. Since the
research on azaheterocyclic phosphonates is much more
2. Results and discussion
The halogen atom transfer radical cyclization of N-allyl
a-perchloroamides 1 (HATRC) is a valuable technique for
the preparation of pyrrolidin-2-ones 3 (Scheme 3).28–30 One
of the more appealing features of this rearrangement is the
preservation of all the carbon–halogen functions on the
final skeleton. To date, the synthetic utility of chlorinated
lactams has been largely overlooked.31–33 Only the hydro-
de-halogenation, resulting in a functionality decrease of the
molecules, has been widely employed.30,32–37
Aiming at the chemo-enzymatic synthesis of aza-
analogues38 of a-methylene paraconic acids, we planned a
synthetic strategy to the target structure 7 from N-benzyl-4-
Scheme 3.

F. Ghelfi et al. / Tetrahedron 59 (2003) 1147–1157
1149
Scheme 4.
chloromethyl-3,3-dichloropyrrolidin-2-one 3a, relying on
the introduction of the methylidene group at the C(3)Cl2
carbon after its conversion in a 3-oxo group via the
intermediate 3,3-dimethoxy function (Scheme 4).
of the base appeared to strongly affect the performance of
the rearrangement. The highest efficiency was observed at
08C, when 4 mmole of alkaline methanolate (excess) and
4 mL of MeOH, for each mmole of substrate, were used
(Table 1, entry 3). The yields never exceeded 62% due to
polymerization.41 A test on the stability of 5a at 258C
(4 mmol, LiH 12 mmole, MeOH 16 mL) in fact resulted,
after 4 h, in a 3-pyrrolin-2-one degradation of about 20%
(25% after 24 h). The polymerization reaction was observed
either by working below 08C (Table 1, entries 4–6), or by
using a stoichiometric amount of base (Table 1, entry 7).
Even changing to less basic systems, such as LiOH or
Li2CO3/MeOH (Table 1, entries 8, 9) the undesiderable
pathway could not be prevented. On the contrary, the
conversions were drastically reduced or no advantages were
found, e.g. the reaction with LiOH. Dilution of methanol
with ethyl ether, modifications of the reaction protocol
(LiOMe or 3a slowly added (2 h) to the reaction mixture
with a syringe pump) provided no better results (Table 1,
entries 10–12). The yields of 5a, in any case, can be
considered satisfactory in view of the functionalisation of
the lactam ring. Interestingly, under the mildest conditions
tested, small amounts of N-benzyl-3-chloro-4-methyl-5-
methoxy-3-pyrrolin-2-one 6 (Scheme 4) were observed.
Since 6 was smoothly converted into 5a, it should be
considered as an intermediate on the route to N-benzyl-5,5-
dimethoxy-4-methyl-3-pyrrolin-2-one.
The alkoxy-de-halogenation of 3a, using an excess of
lithium methoxide in methanol at room temperature, was
evaluated at first. To our satisfaction the reaction gave a
single, easy recoverable, product. However the isolated
material emerged not to be the expected acetal but
N-benzyl-5,5-dimethoxy-4-methyl-3-pyrrolin-2-one 5a
(Scheme 4). The compound 5a clearly originates from a
functional rearrangement of the polyhalogenated pyrrolidin-
2-one 3a, which relocates the C(3) acetal function at the
C(5) carbon. A similar dehydrochlorination of 3,3-dichloro-
4-chloromethyl-g-lactones by a non-nucleophilic base
(DBU) has been reported.39 The potential usefulness of
this rearrangement became apparent considering the
difficulties for the direct functionalization of the lactam
C(5)H2, for which only relatively inefficient oxidations are
mentioned in the literature.40
The reaction variables for the model compound 3a were at
first carefully adjusted in order to get the optimal conditions
(Table 1). Reagent concentration, temperature and amount
Table 1. Reaction of 3a with LiOMe
No.
LiH/MeOH
(mmol)/(mL)
T
(8C)
t
(h)
Conv.a
(%)
Yieldb,c 5a
(%)
Secondly the scope and generality of the rearrangement was
examined. The educts 3b–n, were prepared and then treated
with alkaline methanolate/methanol under the best con-
ditions (Table 2). To our satisfaction all the compounds
tested displayed the same behaviour as 3a, i.e. a dehydro-
halogenation associated with the introduction in position
C(5) of as many methoxy groups as the remaining halogens,
consistently with the number of the C(5) hydrogens.
Moreover for a given carbon skeleton, the final product
relates to the total number of halide atoms carried on the
C(3) and C(6) carbons and not to their distribution between
the same positions (Table 2, entries 1, 8, 9, and 11–15).
Remarkably, substrate 3e gave the highest yields; the
methyl substituent at C(3) prevents in fact, likely for steric
reasons, the degradation of the lactam ring (polymerization)
otherwise observable in all the other cases.
1
2
3
4
5
6
7
8
16/8
16/16
16/32
16/8
16/8
16/8
0
0
0
28
223
245
0
0
0
25
25
25
1.33
2.5
2
2
1
2
1.5
2
1
2.5
2
100
97
94
40
29
0
92
96
0
55
62
38 (11)
20 (8)
3 (14)
0
43 (16)
54 (4)
0
56
56 (11)
62
12/8
16d/8
12e/8
16/16f
16/16f
16/16f
9
10
11g
12h
100
97
100
2
4 mmole of 3a were used.
GC value.
a
b
Determined on isolated material.
c
In parentheses the N-benzyl-3-Cl-4-methyl-5-methoxy-3-pyrrolin-2-one
6.
LiH was replaced by LiOH.
d
e
f
Replacing the lithium ion with the sodium ion (a less acidic
counterion) a more active system was obtained and
therefore, reaction times and temperatures could be
shortened or lowered (Table 2, entries 2, 11, 14 and 3, 12,
LiH was replaced by Li2CO3.
Reaction performed in 16 mL of MeOH/ether (1/1).
LiOMe added to the reaction mixture with a syringe pump (2 h).
Addition of 3a to the reaction mixture with a syringe pump (2 h).
g
h

1150
F. Ghelfi et al. / Tetrahedron 59 (2003) 1147–1157
Table 2. Reaction of the polychloro 2-pyrrolidinones 3 with R3OM/R3OH (see Scheme 3)
No.
m
n
Educts
R
R1
R2
Products
R1
R3OM
t (h)
T (8C)
Conv.a (%)
Yieldb (%)
R2
1
3a
3a
3a
3b
3c
3c
3d
3e
3e
3f
3g
3g
3h
3i
3i
3l
2
2
2
2
2
2
2
1
1
1
1
1
2
0
0
1
1
1
2
2
2
2
1
1
1
1
1
1
1
1
1
1
2
2
0
2
2
2
1
1
1
1
1
1
Bzl
Bzl
Bzl
–
–
–
–
–
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
H
H
H
H
5a
5a0
5a0
5b
5c
5c0
5d
5e
5e
5f
5a
5a
5e
5e
5e
5g
5h
5i
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
Cl
Cl
H
H
H
H
H
–
–
–
–
–
–
–
H
H
H
–
MeOLi
EtOLi
EtONa
2.5
1.5
2
0
0
0
97
95
62
56
58
45
66
40
10
61
60
78
47
64
6
56
60
66
2c
3
100
100
100
100
100
93
4
5
6
7
8
9
10
11
12
13
14
15
16d
17
18
19
20
21
22
N(CH3)2
CH2PO(OEt)2
CH2PO(OEt)2
CH(Ph)PO(OEt)2
MeOLi
MeONa
i-PrONa
MeONa
MeOLi
MeONa
MeOLi
MeOLi
MeONa
MeOLi
MeOLi
MeONa
MeONa
MeONa
MeONa
MeONa
MeONa
MeONa
MeONa
3
25
25
25
25
25
25
25
80
25
25
80
80
25
0
15
15
15
16
2.33
24
1.5
2
6
24
6
2
3
–
–
Bzl
Bzl
Bzl
Bzl
Bzl
Bzl
Bzl
Bzl
Bzl
Bzl
Bzl
t-but
Bzl
i-Pr
c-Hex
H
H
Me
H
H
–
H
H
Cl
Cl
H
–
100
91
100
100
100
100
100
100
100
100
100
100
100
90
–
H
H
H
H
Me
Me
–
–
–
–
3m
3n
4a
4b
4c
4d
60
54 (4)e
65
18f
20f
16f
24
6
1
3.5
1
25
65
65
65
65
5l
–
–
–
5a
5m
5n
4 mmol of substrate, 16 mmole of R3OM and 16 mL of R3OH were used.
a
GC value.
Determined on isolated material.
Reaction performed in 8 mL of ethanol.
20 mmole of NaOMe were used.
In parentheses the N-benzyl-4-methyl-5-methylene-3-pyrrolin-2-one 13.
The yield drops considerably during purification.
b
c
d
e
f
15). Other alcoholate/alcohol combinations were also
evaluated and compared to the alkaline methanolate/
methanol couple. While the EtONa/EtOH produced a result
indistinguishable from that with MeONa/MeOH (Table 2,
entries 1, 2), it was clear that on increasing further the size
of the alcoholate, the yields decreased to some extent
(Table 2, entries 5, 6).
old and unexpected reaction, seldom taken into account, but
perceptible during trichloroacetylation of low reactive
amines with TCAC/TEA.45 Finally, the HATRC of 2
proved as satisfactory (yields 44–71%) as with the
analogous precursors 1 (yields 40–66%), which does not
bear the phosphono group on the vinyl moiety.
2.1. Reaction mechanism
In contrast to the 1-diethylphosphorylmethyl-2-pyrrolidi-
nones 3c,d, where the phosphonate moiety can be seen as an
inert group behaving like a standard alkyl appendage, in the
lactams 4a–d the phosphonate function appeared labile and,
under the appropriate reaction conditions, the same
functional rearrangement was observed as with 3 (Table 2,
entries 19–22). The synthesis of 4 proved not to be
straightforward. The starting diethyl 1-bromomethylvinyl-
phosphonate was synthesised from tetraethyl methylene-
bisphosphonate after reaction with formaldehyde and
phosphorus tribromide;42 this appears the method of choice
to get multigram quantities, other reported procedures are
less convenient.43,44
All the transformations from 3 to 5 start with a hydro-halo-
elimination, since, otherwise, the alkoxy group could not be
located at the C(5) position. The lack of reactivity under the
optimum conditions of N-benzyl-4-chloromethyl-3,3-
dichloro-4-methyl-pyrrolidin-2-one 8 (Fig. 2), apart from
some polymerization, strongly supports this hypothesis. The
starting elimination can split into two paths: an endo-
dehydrochlorination at the C(3) and C(4) positions or,
alternatively, an exo-dehydrochlorination at the C(4) and
C(6) carbons. Since the rearrangement is related to the base
strength, infact 3a with Li2CO3/CH3OH showed quite
unreactive (Table 1, entry 9), a bimolecular process is
clearly involved.46 The easier the required periplanar
conformation is achieved the more favored the correspond-
ing elimination should be. Molecular mechanics calcu-
lations are able to provide some insights for the alternative
Ensuing acylation of the diethyl 1-aminomethylvinyl-
phosphonates (prepared by reaction of diethyl 1-bromo-
methylvinylphosphonate and the proper amine; slow
addition of the phosphonate) with trichloroacetyl chloride
(TCAC)/triethylamine (TEA) ought to lead smoothly to the
precursors 2. However, because of the low nucleophilicity
of the amino group, long reaction times were needed and
this resulted in variable amounts of 4-diethylaminobut-3-
ene-2-one. This side product is formed through an ionic
pathway from trichloroacetyl chloride and triethylamine, an
Figure 2.

F. Ghelfi et al. / Tetrahedron 59 (2003) 1147–1157
1151
Table 3. DE (kcal/mole) of the periplanar conformations required for the
elimination of 3a and 3e (Calculations were performed using MM2.)
show that the course of the dehydrochlorination is governed
by the number of chloro atoms bound at the C(3): two Cl’s
(3a) should drive towards an endo elimination, whereas one
(3e) should lead to an endo or exo process depending on the
relative substitution geometry between the C(3) and C(4)
positions. For 3e, in particular, owing to the configurational
instability of the carbon C(3) under basic conditions, the exo
path should be favoured. The result of the hydro-de-
halogenation of chlorinated lactones E and F (Scheme 5)
with DBU, investigated by Takano,39 strengthens this
arguments.
Conformations
3a
3ea
cis
trans
endob syn
endob anti
exoc syn
4.42
1.13
4.57
3.48
–
2.60
–
4.69
0.43
1.89
4.66
3.57
exoc anti
a
The cis and trans stereoisomers under basic conditions easily
interconvert.
C(4)HC(3)Cl.
C(4)HC(6)Cl.
b
c
The formation of the intermediate 6 and the products 5g and
5h, being all 3-Cl-3-pyrrolin-2-ones, implies that once the
first chloro atom is removed, the remaining Cl atoms at C(6)
are much more mobile than any Cl bound at the C(3).
Likely, this behaviour could have a connection with the
different performances observed from 3e and 3i, on one
hand, and 3h on the other hand (Table 2, entries 8, 13, 14),
which in any case reveal that for a satisfactory functional
rearrangement, at least one exo chlorine atom has to be
carried by the C(6) carbon.
A tentative mechanism for 3e is outlined in Scheme 6. After
the initial formation of the exo-methylene intermediate 9,
the double bond shifts inside the ring affording the D3 (10)
or the D4 (11) pyrrolin-2-ones. The two species are in
equilibrium,47 but 11 can react further and through an easy
solvolysis delivers the stable cation 12, which, collapsing
with a methoxide anion, affords the ending product 5e.
Analogous steps are reasonably involved in the rearrange-
ment of all the other chlorinated pyrrolidin-2-ones.
Scheme 5.
Interestingly on monitoring the rearrangement of 3n, we
observed that at low conversions 13 was the main product,
this then smoothly added a molecule of MeOH (Scheme 7)
behaving as an enamine reagent (endo attack) and not as a
Michael acceptor (exo attack).
For the lactams bearing a 4-diethylphosphonate group
(4a–d), the rearrangement should start instead with a Grob-
type elimination:48 i.e. attack of the alkoxide on the
phosphonate group (Scheme 8), followed by an anti
elimination of the chloride on the C(3) carbon. The diethyl
methyl phosphate observed among the reaction products
strongly stresses this rationale. From that point on, the
reaction mechanism is identical to the one of the alkyl
pyrrolidin-2-ones including the switch of the functionality
from the C(3) to the C(5) position.
Scheme 6.
Scheme 7.
2.2. Structural characterizations of 5
paths. The computed potential energies of the anti-
periplanar and syn-periplanar conformations relative to
the dihedral arrangements C(4)HC(3)Cl and C(4)HC(6)Cl
of 3a and 3e have been collected in Table 3. These data
The correct regiochemistry of N-benzylpyrrolidin-2-ones 5a
and 5e–i was derived from H,C inverse-detection NMR
Scheme 8.

1152
F. Ghelfi et al. / Tetrahedron 59 (2003) 1147–1157
tive in comparison with the usual approach, which starts
from succinimide derivatives.51 Although the yields still
need to be improved in the series of the phosphonate
analogues, the reaction mechanism proves to be quite
general, and is even accompanied by a Grob elimination if
the lactam ring is carrying a phosphonate moiety on C(4).
Further studies directed towards the application of the
methodology in biologically active compound synthesis are
currently under investigation.
Figure 3.
techniques. Both heteronuclear multiple-quantum
(HMQC)49 and multiple-bond (HMBC)50 experiments
were employed to find the H,C pairs directly bonded, and
the ones separated by two or three bonds, respectively. In
both cases experimental conditions were optimized on the
basis of the expected coupling constant values. For all
derivatives the long-range H,C correlations involving
benzylic protons play a crucial role in the reconstruction
of the molecular structure. In fact, benzylic protons show
four correlations (Fig. 3) in HMBC spectra, three with
carbons at chemical shift values typical of Csp2 signals
(CvO, C-10 and C-20,60), and one with a carbon (C-5) which
correlates also with the methoxy protons. This picture
enable the originally expected structure, G in Fig. 3, to be
ruled out in favour of structure H. The correlations
involving the remaining protons agree with H type
regiochemistry and permit to unambiguously locate all the
ring substituents. For instance, the methyl on C-3 is readily
distinguished from the methyl on C-4 in derivative 5f, (once
their casual chemical shift equivalence has been removed
adding C6D6 to the CDCl3 solution) because the former
correlates with the carbonyl carbon at 171.0 ppm, whereas
the latter correlates with the carbon at 87.7 ppm, which in
turn correlates also with the methoxy and the benzylic
protons. Finally, it is worth noting that, in derivatives 5a and
5e–i, the N-benzylic group shifts for 20.2 to 20.5 ppm the
methoxy proton signals (with respect to the typical spectral
position of methyl ether or acetal at 3.2–3.3 ppm) as a
consequence of the magnetic anisotropy effect exerted by
the phenyl ring. This shielding effect is absent in derivative
5b, where methoxy signal is found in its usual position.
4. Experimental
4.1. General
1H NMR spectra were recorded in CDCl3 solutions with a
Bruker 400AMX WB and a Jeol EX 270 spectrometer, and
the chemical shifts reported are in ppm relative to
tetramethylsilane as external standard. Conditions for
HMQC49 spectra were: evolution delay¼3.57 ms, spectral
width¼7 ppm with 2048 complex points in f2; 256 t1 values
and 32 scans for t1 value. A squared sine function (SSB¼2)
in f2 and f1 was applied before Fourier transformation.
Similar conditions were used for HMBC50 experiments
except: delay for low-pass filter¼3.57 ms, evolution
n
delay¼50 ms (optimization of J(H,C)¼10 Hz responses)
and 64 scans for t1 value. IR spectra were obtained with
Perkin–Elmer 1600 Series FTIR. Mass spectra were
acquired with a combined HP 5890 GC/HP 5989A MS
Engine. Reagents and solvents were standard grade
commercial products, purchased from Aldrich or Fluka,
and used without further purification. All the chlorinated
pyrrolidin-2-ones 3 were prepared through HATRC,
promoted by CuCl-TMEDA, of N-allyl-a-perchloroamides
1,30,52 except 3h, which was assembled by cyclization of the
N-allyl-N-benzyl-trichloroacetamide with But3SnH/
AIBN,53 and 3i, which was instead obtained from 3g
through selective hydro-de-chlorination of the most labile
3-chloro function with Zn/HOAc.30 The diethyl N-allyl-
aminomethylphosphonate54 and the diethyl 1-bromo-
methylvinylphosphonate42 were secured according to
literature.
As an additional proof for the identification of the
rearranged products, 5l, the adduct from the functional
rearrangement of 4a, was hydrolized using hydrochloric
acid, and the maleimide, thus generated, was fully identified
by comparison with original material.
4.1.1. Preparation of N-diethoxyphosphorylmethyl-3,3-
dichloro-4-chloromethyl-pyrrolidin-2-one (3c). CuCl
(0.8 g, 8 mmol) and N-allyl-N-diethoxyphosphorylmethyl
trichloroacetamide (4.23 g, 12.0 mmol) were weighted in a
50 mL flask; then deoxygenated acetonitrile (25 mL) was
added, under argon. The mixture was refluxed for 2 h,
diluted with water (20 mL) and extracted with CH2Cl2
(2£25 mL). The combined organic layers were dried over
MgSO4, concentrated and chromatographed, eluting with
chloroform/acetonitrile gradient, to give 3c (3.45 g, 82%),
as a yellowish oil; [Found: C, 34.2; H, 4.8; N, 3.8.
C10H17Cl3NO4 requires C, 34.07; H, 4.86; N, 3.97]; nmax
(NaCl) 1730, 1240 cm21; dH (270 MHz CDCl3) 4.20–4.13
(4H, m, P(OCH2Me)2), 4.02–3.60 (5H, m, NCH2, CH2Cl,
NCHaHbP), 3.49 (1H, dd, JAB¼8.1 Hz, JHP¼10.1 Hz,
NCHaHbP), 3.17–3.11 (1H, m, CHCH2Cl), 1.41–1.31
(6H, m, P(OCH2CH3)2); dC (270 MHz CDCl3) 165.89,
82.89, 63.02 (JPC¼6.4 Hz), 62.92 (JPC¼6.1 Hz), 51.88,
48.97, 40.88, 39.62 (JPC¼156.3 Hz), 16.46 (JPC¼2.5 Hz),
16.37 (JPC¼2.5 Hz); m/z (EI): 351 (2 Mþ), 317 (17), 315
3. Conclusion
In summary, a satisfactory and unusual preparation of
N-substituted 5-methoxy or 5,5-dimethoxy-4-methyl-3-
pyrrolin-2-ones has been described by reaction of the
corresponding 4-methyl-pyrrolidin-2-ones, polychlorinated
at C(3) and C(6), with alkaline methoxide in methanol under
mild conditions. The functional rearrangement is fairly
appealing since the 3-pyrrolin-2-ones obtained can be
envisaged as precursors for cyclic N-acyliminium ions,
which are in turn very useful intermediates in organic
synthesis22,23 and in the preparation of agrochemicals.24,25
The availability of polychloro 2-pyrrolidinones makes this
route to cyclic N-acyliminium ions alternative or competi-

F. Ghelfi et al. / Tetrahedron 59 (2003) 1147–1157
1153
(25), 279 (41), 251 (36), 223 (32), 216 (15), 214 (19), 178
(14), 130 (20), 125 (14), 42 (100).
procedure53 N-allyl-N-benzyl-trichloroacetamide (1.17 g,
4.0 mmol) was cycled with But3SnH/AIBN and gave 3h
(0.62 g, 60%) as a white powder, mp 68–728C; [Found: C,
56.0; H, 5.3; N, 5.6. C12H13Cl2NO requires C, 55.83; H,
5.08; N, 5.43]; nmax (Nujol) 1713 cm21; dH (400 MHz
CDCl3) 7.44–7.24 (5H, m, Ph), 4.61 (1H, d, J¼14.7 Hz,
CHaHbPh), 4.49 (1H, d, J¼14.7 Hz, CHaHbPh), 3.25 (1H,
dd, J¼9.5, 6.8 Hz, NCHaHb), 2.94 (1H, dd, J¼9.5, 8.4 Hz,
NCHaHb), 2.69–2.86 (1H, m, CH), 1.15 (3H, d, J¼6.5 Hz,
Me); m/z (EI): 222 (67), 91 (100).
4.1.2. N-(Phenyl-diethoxylphosphorylmethyl)-3,3-
dichloro-4-chloromethyl-pyrrolidin-2-one (3d). Accord-
ing to the previous procedure, but using xylene and 15 h of
reflux, the N-allyl-N-diethoxyphosphorylmethyl trichloro-
acetamide (1.00 g, 2.3 mmol) gave 3d (0.37 g, 37%) as a
brownish oil (two isomers A and B, not separable);
[Found: C, 44.8; H, 4.9; N, 3.2. C16H21Cl3NO4P
requires C, 44.83; H, 4.94; N, 3.27]; nmax (liquid
film) 1732, 1260 cm21; dH (270 MHz CDCl3) 7.64–7.38
(5H, m, Ph), 5.67 (1H, d, JHP¼21.1 Hz, CHP, B), 5.65 (1H,
d, JHP¼20.8 Hz, CHP, A), 4.26–3.89 and 3.77–3.52 (8H,
m, P(OCH2Me)2, CH2Cl, CH2N), 2.98–2.85 (1H, m,
CHCH2Cl), 1.36 (3H, t, J¼7.1 Hz, OCH2Me, B), 1.35
(3H, t, J¼7.1 Hz, OCH2Me, A), 1.15 (3H, t, J¼7.1 Hz,
OCH2Me, B), 1.14 (3H, t, J¼7.1 Hz, OCH2Me, A);
dP (270 MHz CDCl3) 18.53, 18.19; m/z (ES): 427 (100
MHþ).
4.1.6. Preparation of N-benzyl-4-dichloromethyl-pyrro-
lidin-2-one (3i). According to the literature procedure29 3g
(1.17 g, 4.0 mmol) with Zn (2.34 g) in HOAc (16 mL) gave
3i (0.61 g, 59%) as colourless oil; [Found: C, 55.9; H, 4.9;
N, 5.2. C12H13Cl2NO requires C, 55.83; H, 5.08; N, 5.43];
nmax (film) 1688 cm21; dH (400 MHz CDCl3) 7.42–7.24
(5H, m, Ph), 5.76 (1H, d, J¼5.5 Hz, CHCl2), 4.53 (1H, d,
J¼14.7 Hz, CHaHbPh), 4.39 (1H, d, J¼14.7 Hz, CHaHbPh),
3.47 (1H, dd, J¼10.3, 8.6 Hz, COCHaHb), 3.30 (1H, dd,
J¼10.3, 6.0 Hz, COCHaHb), 3.20–3.02 (1H, m, CH), 2.74
(1H, dd, J¼17.3, 9.1 Hz, NCHaHb), 2.62 (1H, dd, J¼17.3,
7.4 Hz, NCHaHb); m/z (EI): 257 (77 Mþ), 256 (16), 222
(14), 91 (100).
4.1.3. Preparation of N-benzyl-3,3-dichloro-4-dichloro-
methyl-pyrrolidin-2-one (3l). CuCl (0.04 g, 0.4 mmol)
and N-benzyl-N-(3-chloro-2-propenyl) trichloroacetamide
(1.31 g, 4.0 mmol) were weighted in a Schlenk tube; then
acetonitrile (8 mL) and TMEDA (0.092 g, 0.8 mmol) were
added, under argon. The mixture was stirred at 608C, and
after 20 h diluted with 2.5% HCl (20 mL) and extracted with
CH2Cl2 (2£10 mL). The combined organic layers were
dried over MgSO4, concentrated and chromatographed,
eluting with a petroleum ether (bp 40–608C)/diethyl
ether/methanol gradient, to give 3l (1.15 g, 88%), as pale
brown solid, mp 93–948C; [Found: C, 44.0; H, 3.5; N, 4.4.
C12H11Cl4NO requires C, 44.07; H, 3.39; N, 4.28]; nmax
(KBr) 1710 cm21; dH (400 MHz CDCl3) d 7.46–7.25 (5H,
m, Ph), 6.05 (1H, d, J¼8.2 Hz, CHCl2), 4.64 (1H, d,
J¼14.6 Hz, CHaHbPh), 4.52 (1H, d, J¼14.6 Hz, CHaHbPh),
3.58–3.40 (2H, m, NCHaHbCH), 3.18 (1H, dd, J¼9.3,
6.6 Hz, NCHaHb); m/z (EI): 325 (1 Mþ), 290 (58), 254 (2),
206 (6), 91 (100).
4.2. Preparation of 4-phosphonated lactams
In a 25 mL flask, nitrogen gas was passed (20 min)
through xylene (15 mL), followed by the addition of N-t-
butyl-N-2-diethoxyphosphoryl-allyl trichloroacetamide
(0.43 g, 1.1 mmol) and CuCl (1.5 equiv.). After refluxing
the reaction mixture for 3–15 h (31P NMR monitoring),
it was cooled to room temperature, poured into an
aqueous solution and extracted with toluene (2£15 mL).
The combined organic layers were dried over MgSO4,
filtered and evaporated under reduced pressure. The
crude product 4a was purified by flash chromatography
(50% petroleum ether/ethyl acetate) (0.29 g, 67%).
4.2.1. N-t-Butyl-3,3-dichloro-4-chloromethyl-4-diethoxy-
phosphorylpyrrolidin-2-one (4a). Yellowish solid, mp
59–638C; [Found: C, 39.8; H, 5.8; N, 3.7. C13H23Cl3NO4P
requires C, 39.56; H, 5.87; N, 3.55]; nmax (KBr) 1735,
1249 cm21; dH (270 MHz CDCl3) 4.24–4.19 (6H, m,
4.1.4. N-Benzyl-3-chloro-4-chloromethyl-5-methyl-pyr-
rolidin-2-one (3m). According to the previous procedure
the N-benzyl-N-(2-methyl-prop-2-enyl) dichloroacetamide
(1.09 g, 4.0 mmol) gave 3m (0.92 g, 84%) as pale yellow
powder, mixture of four diastereomers (1/1/0.5/0.2);
[Found: C, 57.4; H, 5.4; N, 5.0. C13H15Cl2NO requires C,
57.37; H, 5.55; N, 5.15]; nmax (KBr) 1715 cm21; dH first
main isomer (400 MHz CDCl3) 7.41–7.25 (5H, m, Ph), 5.08
(1H, d, J¼14.9 Hz, CHaHbPh), 4.32 (1H, d, J¼9.7 Hz,
CHCl), 4.04 (1H, d, J¼14.9 Hz, CHaHbPh), 3.88–3.70 (2H,
m, CHaHbCl and CHMe), 3.60 (1H, dd, J¼11.0, 10.0 Hz,
CHaHbCl), 2.85–2.69 (1H, m, CH), 1.19 (3H, d, J¼6.7 Hz,
P(OCH2Me)2, NCH2), 4.10 (1H, dd, JHP¼16.8 Hz, JAB
¼
10.8 Hz, CHaHbCl), 3.50 (1H, dd, JHP¼16.8 Hz, JAB
¼
10.8 Hz, CHaHbCl), 1.43 (9H, s, CMe3), 1.44–1.34 (6H, m,
P(OCH2Me)2); dP (270 MHz CDCl3) 20.69; m/z (EI): 393 (1
Mþ), 206 (10), 164 (13), 138 (78), 111 (23), 108 (10), 86
(35), 84 (56), 82 (10), 81 (15), 57 (55), 51 (32), 49 (100), 47
(18), 41 (26).
4.2.2. N-Benzyl-3,3-dichloro-4-chloromethyl-4-diethoxy-
phosphorylpyrrolidin-2-one (4b). According to the
general procedure the N-alkyl-N-(2-diethoxyphosphoryl)-
allyl trichloroacetamide (1.28 g, 3 mmol) gave 4b (0.86 g,
73%, purity 70%) as brown oil; nmax (KBr) 1736,
1244 cm21; dH (270 MHz CDCl3) 7.35–7.28 (5H, m, Ph),
4.53 (2H, s, NCH2Ph), 4.21–4.12 (6H, m, P(OCH2Me)2,
NCH2), 3.86 (1H, dd, JHP¼12.5 Hz, JAB¼10.8 Hz, CHaHb-
Cl), 3.31 (1H, dd, JHP¼17.0 Hz, JAB¼10.8 Hz, CHaHbCl),
1.32 (3H, t, J¼7.6 Hz, OCH2Me), 1.29 (3H, t, J¼7.3 Hz,
OCH2Me); dP (270 MHz CDCl3) 20.24; m/z (EI): 391 (55
1
Me); dH second main isomer (400 MHz CDCl3): H NMR
(CDCl3): d 7.41–7.22 (5H, m, Ph), 5.01 (1H, d, J¼15.1 Hz,
CHaHbPh), 4.51 (1H, d, J¼7.8 Hz, CHCl), 4.15 (1H, d,
J¼15.1 Hz, CHaHbPh), 3.89–3.63 (2H, m, CHaHbCl), 360–
3.43 (1H, m, CHMe), 2.50–2.39 (1H, m, CH), 1.32 (3H, d,
J¼6.3 Hz, Me); m/z (EI): 271 (11 Mþ), 236 (100), 186 (17),
106 (12), 91 (61).
4.1.5. Preparation of N-benzyl-3,3-dichloro-4-methyl-
pyrrolidin-2-one (3h). According to the literature

1154
F. Ghelfi et al. / Tetrahedron 59 (2003) 1147–1157
Mþ2HCl), 390 (52), 389 (77), 356 (23), 355 (71), 256
(100), 255 (26), 254 (100), 220 (20), 91 (55).
C14H17NO3 requires C, 78.10; H, 7.96; N, 6.51]; nmax
(liquid film) 1710 cm21; dH (400 MHz CDCl3) 7.50–7.21
(5H, m, Ph), 6.02 (1H, q, J¼1.7 Hz, COCH), 4.35 (2H, s,
CH2Ph), 2.81 (6H, s, C(OMe)2), 1.86 (3H, d, J¼1.7 Hz,
Me); dC (400 MHz CDCl3) 168.84, 153.32, 137.45, 129.49,
128.26, 127.37, 125.54, 113.49, 50.78, 41.43, 11.47; m/z
(EI): 248 (11 MHþ), 247 (64), 232 (29), 216 (23), 142 (20),
127 (76), 106 (32), 91 (100).
4.2.3. N-i-Propyl-3,3-dichloro-4-chloromethyl-4-
diethoxyphosphorylpyrrolidin-2-one (4c). According to
the general procedure, but heating during 6 h, the N-alkyl-
N-(2-diethoxyphosphoryl)-allyl trichloroacetamide (0.5 g,
1.3 mmol) gave 4c (0.22 g, 44%) as yellowish solid, mp
56–608C; [Found: C, 38.0; H, 5.6; N, 3.7. C12H21Cl3NO4P
requires C, 37.87; H, 5.56; N, 3.68]; nmax (KBr) 1679,
1258 cm21; dH (270 MHz CDCl3) 4.35 (1H, sept, J¼6.8 Hz,
NCHMe2), 4.26–4.20 (6H, m, P(OCH2Me)2, NCH2), 3.99
(1H, dd, JHP¼23.4 Hz, JAB¼10.7 Hz, CHaHbCl), 3.34 (1H,
dd, JHP¼17.2 Hz, JAB¼10.7 Hz, CHaHbCl), 1.43–1.33 (6H,
m, P(OCH2Me)2), 1.16 (3H, d, J¼6.8 Hz, CHMe), 1.13 (3H,
d, J¼6.8 Hz, CHMe); dP (270 MHz CDCl3) 20.52; m/z (EI):
380 (1 MHþ), 235 (36), 193 (42), 173 (35), 168 (43), 150
(44), 139 (43), 138 (46), 122 (51), 109 (93), 91 (100), 82
(59), 81 (58), 72 (40), 65 (45), 55 (71), 43 (80).
4.3.2. N-Benzyl-3-chloro-4-methyl-5-methoxy-3-pyrro-
lin-2-one (6). According to the general procedure (entry 2
of Table 1 for the reaction conditions) 3a (1.170 g, 4 mmol)
gave a separable mixture of 5a (0.401 g, 43%) and 6
(0.141 g, 14%). Pale brown oil; [Found: C, 61.9; H, 5.7; N,
5.5. C13H14ClNO2 requires C, 62.03; H, 5.61; N, 5.56]; nmax
(liquid film) 1718 cm21; dH (400 MHz CDCl3) 7.43–7.24
(5H, m, Ph), 5.08 (1H, s, NCH), 5.01 (1H, d, J¼14.7 Hz,
NCHaHb), 4.12 (1H, d, J¼14.7 Hz, NCHaHb), 3.01 (3H, s,
–OMe), 1.99 (3H, s, Me); dC (400 MHz CDCl3) 164.70,
146.40, 136.46, 128.28, 128.18, 127.78, 127.02, 86.76,
49.56, 43.89, 11.45; m/z (EI): 251 (42 Mþ), 236 (5), 220
(18), 158 (5), 146 (28), 131 (11), 118 (8), 91 (100).
4.2.4. N-c-Hexyl-3,3-dichloro-4-chloromethyl-4-
diethoxyphosphorylpyrrolidin-2-one (4d). According to
the general procedure the N-alkyl-N-(2-diethoxy-
phosphoryl)-allyl trichloroacetamide (1.51 g, 3.6 mmol)
gave 4d (1.01 g, 67%) as brown solid, mp 91–93.58C;
[Found: C, 43.1; H, 6.1; N, 3.2. C15H25Cl3NO4P requires C,
42.83; H, 5.99; N, 3.33]; nmax (KBr) 1737, 1260 cm21; dH
(270 MHz CDCl3) 4.27–4.18 (5H, m, P(OCH2Me)2, NCHa-
Hb), 4.11 (1H, d, J¼11.9 Hz, NCHaHb), 4.00 (1H, dd,
JHP¼12.0 Hz, JAB¼11.0 Hz, CHaHbCl), 3.92–3.94 (1H, m,
NCH), 3.42 (1H, dd, JHP¼16.8 Hz, JAB¼11.0 Hz, CHaHb-
Cl), 2.00–1.70 (5H, m, C–Hex), 1.37 (3H, t, J¼7.0 Hz,
OCH2Me), 1.36 (3H, t, J¼7.0 Hz, OCH2Me), 1.44–1.13
(5H, m, C–Hex); dP (270 MHz CDCl3) 20.46; m/z (EI): 383
(12 Mþ2HCl), 349 (31), 348 (83), 284 (36), 282 (36), 249
(70), 247 (44), 246 (100), 212 (31), 166 (52), 138 (78), 111
(39).
4.3.3. N-Benzyl-4-methyl-5,5-diethoxy-3-pyrrolin-2-one
(5a0). According to the general procedure 3a (1.170 g,
4 mmol) gave 5a0 (0.618 g, 56%) as colourless oil; [Found:
C, 71.0; H, 6.5; N, 5.1. C16H21NO3 requires C, 70.83; H,
6.32; N, 5.16]; nmax (liquid film) 1709 cm21; dH (400 MHz
CDCl3) 7.28–7.18 (5H, m, Ph), 5.9 (1H, q, J¼1.6 Hz,
COCH), 4.88 (1H, d, J¼14.8 Hz, NCHaHb), 4.09 (1H, d,
J¼14.8 Hz, NCHaHb), 3.04–3.29 (4H, m, C(OCH2Me)2),
1.92 (3H, d, J¼1.6 Hz, Me), 1.10 (6H, t, J¼7.0 Hz,
C(OCH2Me)2); m/z (EI): 276 (5 MHþ), 275 (28), 246
(38), 230 (15), 141 (68), 124 (100), 91 (67).
4.3.4. N-Dimethylamino-4-methyl-5,5-dimethoxy-3-pyr-
rolin-2-one (5b). According to the general procedure 3b
(0.982 g, 4 mmol) gave 5b (0.360 g, 45%) as colourless oil;
[Found: C, 57.9; H, 8.6; N, 7.4. C9H16N2O3 requires C,
58.05; H, 8.66; N, 7.52]; nmax (liquid film) 1724 cm21; dH
(400 MHz CDCl3) 5.86 (1H, q, J¼1.72 Hz, COCH), 3.35
(6H, s, C(OMe)2), 2.96 (6H, s, NMe2), 1.86 (3H, d,
J¼1.72 Hz, Me); m/z (EI): 200 (68 Mþ), 185 (23), 169 (22),
158 (33), 127 (100), 94 (22), 59 (30), 44 (30).
4.3. Typical procedure: functional rearrangement of 3a
to 5a
In a Schlenk, fitted with a perforable septum blocked by a
screw cap, CH3OH (14 mL) and LiH (0.128 g, 16 mmol)
were added.† When the effervescence ceased, the alkaline
solution was thermostated at 08C and a solution of 3,3-
dichloro-4-chloromethyl-pyrrolidin-2-one 3a (1.170 g,
4 mmol) in CH3OH (14 mL) was syringed. The reaction
was stirred for 2.5 h (complete conversion monitored by GC
analysis), afterwards was diluted with water (20 mL) and
extracted with CH2Cl2 (2£15 mL). The combined organic
layers were dried over MgSO4 and concentrated. Column
chromatography of the crude product on silica gel, using a
petroleum ether (bp 40–608C)/diethyl ether gradient, gave
0.578 g of the 3-pyrrolin-2-one 5a (62%) as colourless oil.
On using the solution CH3OH/diethyl ether (1/1), as
reaction solvent, the reaction mixture was as an alternative
diluted with brine (10 mL) and extracted with ether
(2£15 mL).
4.3.5. N-Diethylphosphorylmethyl-4-methyl-5,5-
dimethoxy-3-pyrrolin-2-one (5c). According to the
general procedure 3c (0.398 g, 1.13 mmol) gave 5c
(0.229 g, 66%) as brownish oil; [Found: C, 46.9; H, 7.4;
N, 4.7. C12H22NO6P requires C, 46.91; H, 7.22; N, 4.56];
n
max (NaCl) 1720 cm21; dH (270 MHz CDCl3) 6.06 (1H, q,
J¼1.6 Hz, COCH), 4.25–4.14 (4H, m, P(OCH2Me)2), 3.59
(2H, d, JHP¼11.6 Hz, NCH2P), 3.14 (6H, s, C(OMe)2), 1.94
(3H, d, J¼1.6 Hz, Me), 1.35 (6H, t, J¼6.9 Hz,
P(OCH2Me)2); dC (270 MHz CDCl3) 168.66, 154.25,
125.56, 112.92, 62.42 (JCP¼6.1 Hz), 51.28, 33.49
(JCP¼163.6 Hz), 16.38 (JCP¼6.1 Hz), 11.87; m/z (EI): 307
(2 Mþ), 277 (21), 276 (25), 262 (28), 188 (9), 171 (10), 170
(100), 140 (46), 127 (11), 124 (30), 110 (15), 95 (11), 86
(25), 84 (40), 59 (18), 56 (14).
4.3.1. N-Benzyl-4-methyl-5,5-dimethoxy-3-pyrrolin-2-
one (5a). Colourless oil; [Found: C, 78.1; H, 7.8; N, 6.5.
4.3.6. N-Diethylphosphorylmethyl-4-methyl-5,5-diiso-
propoxy-3-pyrrolin-2-one (5c0). According to the general
†
When the base was NaOMe, the same equivalents of Na replaced LiH.

F. Ghelfi et al. / Tetrahedron 59 (2003) 1147–1157
1155
procedure 3c (0.201 g, 0.57 mmol) gave 5c0 (0.083 g, 40%)
C, 59.68; H, 5.72; N, 4.97]; nmax (liquid film) 1719 cm21
;
as pale yellow oil; [Found: C, 52.8; H, 8.4; N, 4.0.
C16H30NO6P requires C, 52.88; H, 8.32; N, 3.85]; nmax
(NaCl) 1720 cm21; dH (270 MHz CDCl3) 5.87 (1H, q,
J¼1.6 Hz, COCH), 4.22–4.14 (4H, m, P(OCH2Me)2),
3.95–3.91 (2H, m, C(OCHMe2)2), 3.56 (2H, d,
JHP¼12.2 Hz, NCH2P), 2.03 (3H, d, J¼1.3 Hz, Me), 1.33
(6H, t, J¼7.1 P(OCH2Me)2 Hz,), 1.19 (3H, d, J¼5.9 Hz,
OCHMeaMeb), 1.17 (3H, d, J¼6.3 Hz, OCHMeaMeb); dC
(270 MHz CDCl3) 168.75, 157.48, 123.14, 111.28, 67.37,
62.35 (JCP¼7.3 Hz), 35.78 (JCP¼163.6 Hz), 23.90, 16.43
(JCP¼6.1 Hz), 13.33; m/z (EI): 363 (1 Mþ), 262 (12), 155
(18), 126 (10), 124 (18), 113 (22), 98 (100), 82 (17), 56 (21),
45 (17), 43 (20), 42 (16), 41 (36).
dH (400 MHz CDCl3) 7.50–7.25 (5H, m, Ph), 4.40 (2H, s,
NCH2), 2.84 (6H, s, C(OMe)2), 1.89 (3H, s, Me). dC
(400 MHz CDCl3) 163.66, 145.00, 136.62, 129.33, 128.17,
127.78, 127.44, 111.74, 50.80, 41.86, 9.41; m/z (EI): 265 (38
Mþ), 234 (32), 160 (39), 91 (100).
4.3.11. N-Benzyl-3-chloro-4,5-dimethyl-5-methoxy-3-
pyrrolin-2-one (5h). According to the general procedure
3m (1.226 g, 4 mmol) gave 5h (0.690 g, 60%) as colourless
oil; [Found: C, 63.1; H, 6.2; N, 5.5. C14H16ClNO2 requires
C, 63.28; H, 6.07; N, 5.27]; nmax (liquid film) 1721 cm21
;
dH (400 MHz CDCl3) 7.36–7.20 (5H, m, Ph), 4.69 (1H, d,
J¼15.3 Hz, NCHaHb), 4.30 (1H, d, J¼15.3 Hz, NCHaHb),
2.72 (3H, s, OMe), 1.91 (3H, s, Me), 1.30 (3H, s, NCMe); dC
(400 MHz CDCl3) 164.76, 149.59, 137.70, 128.44, 128.31,
127.38, 126.03, 93.17, 50.06, 42.45, 22.54, 10.12; m/z (EI):
281 (45 Mþ), 250 (23), 234 (13), 176 (15), 161 (36), 113
(20), 91 (100).
4.3.7. N-(1-Phenyl-diethylphosphorylmethyl)-4-methyl-
5,5-dimethoxy-3-pyrrolin-2-one (5d). According to the
general procedure 3d (0.214 g, 0.5 mmol) gave 5d (0.019 g,
10%) as brown oil; [Found: C, 56.3; H, 6.9; N, 3.7.
C18H26NO6P requires C, 56.39; H, 6.84; N, 3.65]; nmax
(NaCl) 1721, 1254 cm21; dH (270 MHz CDCl3) 7.79–7.27
(5H, m, Ph), 6.05 (1H, q, J¼1.3 Hz, COCH), 4.66 (1H, d,
JHP¼26.1 Hz, CHP), 4.40–4.27 (2H, m, OCH2Me), 4.17–
3.89 (2H, m, OCH2Me), 3.38 (3H, s, OMe), 2.44 (3H, s,
OMe), 1.88 (3H, d, J¼1.7 Hz, Me), 1.29 (3H, t, J¼7.0 Hz,
OCH2Me), 1.23 (3H, t, J¼7.0 Hz, OCH2Me); dC (270 MHz
CDCl3) 168.21, 153.38, 136.40, 129.94, 129.85, 128.17,
127.88, 125.86, 113.86 (JCP¼6.1 Hz), 64.00 (JCP¼6.1 Hz),
61.83 (JCP¼7.3 Hz), 52.23 (JCP¼155.0 Hz), 51.70, 51.01,
16.36 (JCP¼6.1 Hz), 16.22 (JCP¼6.1 Hz), 11.86; m/z (EI):
352 (100), 227 (57).
4.3.12. N-Benzyl-4,5-dimethyl-5-methoxy-3-pyrrolin-2-
one (5i). According to the general procedure 3n (1.088 g,
4 mmol) gave 5i (0.499 g, 54%) as colourless oil; [Found:
C, 72.9; H, 7.3; N, 5.9. C14H17NO2 requires C, 72.70; H,
7.41; N, 6.06]; nmax (liquid film) 1711 cm21; dH (400 MHz
CDCl3) 7.35–7.16 (5H, m, Ph), 5.94 (1H, q, J¼1.6 Hz,
COCH), 4.66 (1H, d, J¼15.4 Hz, NCHaHb), 4.21 (1H, d,
J¼15.4 Hz, NCHaHb), 2.72 (3H, s, OMe), 1.87 (3H, d,
J¼1.6 Hz, Me), 1.24 (3H, s, NCMe); dC (400 MHz CDCl3)
169.91, 158.14, 138.39, 128.34, 128.07, 127.08, 123.61,
94.46, 49.80, 41.71, 12.08; m/z (EI): 231 (45 Mþ), 200 (27),
126 (100), 111 (36), 91 (96). From the crude product,
0.114 g of N-benzyl-4-methyl-5-methylen-3-pyrrolin-2-one
(13) (0.032, 4%) was also recovered as pale yellow oil;
[Found: C, 73.9; H, 5.9; N, 6.4. C13H13NO requires C,
73.99; H, 5.77; N, 6.16]; nmax (liquid film) 1694 cm21; dH
(400 MHz CDCl3) 7.32–7.18 (5H, m, Ph), 6.00–5.98 (1H,
m, COCH), 4.79 (1H, dd, J¼2.2, 0.6 Hz, vCHaHb), 4.79
(2H, s, NCH2), 4.71 (1H, dd, J¼1.7, 2.2 Hz, vCHaHb), 2.11
(3H, d, J¼1.5 Hz, vCMe); dC (400 MHz CDCl3) 170.06,
147.29, 146.69, 137.24, 128.59, 127.24, 126.95, 121.28,
93.64, 42.77, 12.03; m/z (EI): 199 (100 Mþ), 198 (51), 184
(13), 170 (26), 91 (63).
4.3.8. N-Benzyl-4-methyl-5-methoxy-3-pyrrolin-2-one
(5e). According to the general procedure 3e (1.032 g,
4 mmol) gave 5e (0.529 g, 61%) as colourless oil; [Found:
C, 71.8; H, 6.8; N, 6.7. C13H15NO2 requires C, 71.87; H,
6.96; N, 6.45]; nmax (liquid film) 1707 cm21; dH (400 MHz
CDCl3) 7.37–7.23 (5H, m, Ph), 5.96 (1H, dq, J¼1.7,
0.7 Hz, COCH), 5.02 (1H, br s, NCH), 4.95 (1H, d,
J¼14.8 Hz, NCHaHb), 4.04 (d, J¼14.8 Hz, 1H, NCHaHb),
2.98 (3H, s, OMe), 1.95 (3H, dd, J¼1.7, 0.6 Hz, Me); dC
(400 MHz CDCl3) 169.97, 155.02 137.19, 128.64, 128.42,
127.49, 124.91, 88.62, 49.24, 43.03, 13.60; m/z (EI): 217 (66
Mþ), 202 (4), 186 (18), 156 (26), 112 (100), 106 (21), 91
(92).
4.3.13. N-t-Butyl-4-methyl-5,5-dimethoxy-3-pyrrolin-2-
one (5l). Following the same general procedure outlined
for the substrates 3, 4a (1.627 g, 4.13 mmol) gave 5l
(0.572 g, 65%) as brownish oil; [Found: C, 61.8; H, 9.0; N,
6.7. C11H19NO3 requires C, 61.95; H, 8.98; N, 6.57]; nmax
(KBr) 1698 cm21; dH (270 MHz CDCl3) 5.87 (1H, q,
J¼2.0 Hz, COCH), 3.16 (6H, s, C(OMe)2), 1.82 (3H, d,
J¼1.7 Hz, Me), 1.52 (9H, s, CMe3); dC (270 MHz CDCl3)
169.67, 152.07, 125.89, 116.06, 54.59, 50.99, 27.73, 11.07;
m/z (EI): 213 (10 Mþ), 199 (37), 198 (100), 170 (26), 168
(28), 166 (72), 126 (70), 121 (56), 119 (56), 94 (51), 88 (54),
86 (67), 84 (74), 82 (42), 73 (27), 70 (27), 51 (31), 49 (44),
47 (40).
4.3.9. N-Benzyl-3,4-dimethyl-5-methoxy-3-pyrrolin-2-
one (5f). According to the general procedure 3f (1.088 g,
4 mmol) gave 5f (0.721 g, 78%) as colourless oil; [Found:
C, 72.8; H, 7.6; N, 6.0. C14H17NO2 requires C, 72.70; H,
7.41; N, 6.06]; nmax (liquid film) 1701 cm21; dH (400 MHz
50% CDCl3/C6D6) 7.20–7.00 (5H, m, Ph), 4.82 (1H, d,
J¼14.7 Hz, PhCHaHb), 4.68 (1H, br s, NCH), 3.88 (1H, d,
J¼14.7 Hz, PhCHaHb), 2.63 (3H, s, OMe), 1.65 (3H, dq,
J¼1.2, 1.2 Hz, Me), 1.45 (3H, dq, J¼1.2, 0.7 Hz, Me); dC
(400 MHz CDCl3) 171.00, 145.72, 137.38, 131.63, 128.58,
128.47, 127.40, 87.68, 49.01, 43.23, 11.25, 8.49; m/z (EI):
231 (34 Mþ), 216 (8), 200 (26), 91 (100).
4.3.14. N-i-Propyl-4-methyl-5,5-dimethoxy-3-pyrrolin-2-
one (5m). Following the same general procedure outlined
for the substrates 3, 4c (0.5 g, 1.3 mmol) gave 5m (52 mg,
20%) as yellowish oil; [Found: C, 60.0; H, 8.7; N, 6.9.
C10H17NO3 requires C, 60.28; H, 8.60; N, 7.03.]; nmax (KBr)
4.3.10. N-Benzyl-3-chloro-4-methyl-5,5-dimethoxy-3-
pyrrolin-2-one (5g). According to the general procedure
3l (1.308 g, 4 mmol) gave 5g (0.743 g, 66%) as pale yellow
oil; [Found: C, 59.7; H, 5.9; N, 4.9. C14H16ClNO3 requires

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F. Ghelfi et al. / Tetrahedron 59 (2003) 1147–1157
1707 cm21; dH (270 MHz CDCl3) 5.92 (1H, q, J¼2.0 Hz,
COCH), 3.71 (1H, sept, J¼6.9 Hz, CHMe2), 3.15 (6H, s,
C(OMe)2), 1.88 (3H, d, J¼2.0 Hz, Me), 1.41 (6H, d,
J¼6.9 Hz, CHMe2); dC (270 MHz CDCl3) 11.63, 20.18,
42.77, 51.34, 114.16, 126.45, 152.15, 168.71; m/z (EI): 200
(11, MHþ), 185 (100), 169 (37), 153 (69), 127 (62), 94 (45).
15. James, G. D.; Mills, S. D.; Pattenden, G. J. Chem. Soc., Perkin
Trans. 1 1993, 2581–2584.
16. Dieter, R. K.; Lu, K. J. Org. Chem. 2002, 67, 847–855.
17. Kang, S.-K.; Kim, K.-J.; Yu, C.-M.; Hwang, J.-W.; Do, Y.-K.
Org. Lett. 2001, 3, 2851–2853.
18. Ru¨ck-Braun, K.; Amrhein, P. Eur. J. Org. Chem. 2000,
3961–3969.
4.3.15. N-c-Hexyl-4-methyl-5,5-dimethoxy-3-pyrrolin-2-
one (5n). Following the same general procedure outlined for
the substrates 3, 4d (0.7 g, 1.6 mmol) gave 5m (61 mg,
16%) as brown oil; [Found: C, 65.4; H, 8.9; N, 5.8.
C13H21NO3 requires C, 65.25; H, 8.84; N, 5.85]; nmax (KBr)
1706 cm21; dH (270 MHz CDCl3) 5.29 (1H, br s, COCH),
3.37–3.28 (1H, m, NCH), 3.14 (6H, s, C(OMe)2), 2.19–
1.11 (10H, m, CHex), 1.87 (3H, d, J¼1.3 Hz, Me); dC
(270 MHz CDCl3) 168.66, 151.97, 126.49, 114.30, 51.43,
51.11, 29.92, 26.31, 25.32, 11.66; m/z (EI): 239 (45 Mþ),
224 (36), 196 (35), 193 (64), 150 (43), 127 (100), 126 (93),
113 (53), 112 (57), 94 (55), 81 (30), 67 (33), 57 (80).
´
19. Beltaıef, I.; Besbes, R.; Amor, F. B.; Amri, H.; Villieras, M.;
¨
´
Villieras, J. Tetrahedron 1999, 55, 3949–3958.
´
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21. For a collection of representative procedures to 3-pyrrolin-2-
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22. Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000, 56,
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25. Nikitin, K. V.; Andryukhova, N. P. Synthesis 2001, 89–92.
26. Part of this work has been published as a preliminary
communication: Bellesia, F.; De Buyck, L.; Colucci, M. V.;
Ghelfi, F.; Laureyn, I.; Libertini, E.; Mucci, A.; Pagnoni,
U. M.; Pinetti, A.; Rogge, T. M.; Stevens, C. V. Tetrahedron
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Acknowledgements
`
We thank the Ministero della Universita e della Ricerca
Scientifica e Tecnologica (MURST) and and the ‘F.W.O.-
Vlaanderen’ and I.W.T. for financial assistance.
27. Laureyn, I.; Stevens, C. V.; Ghelfi, F.; Rogge, T.; Van
Meenen, E.; Van der Ha, O. BOSS-9 (Belgian Organic
Synthesis Symposium), Namur, July 8–12, TH086 2002.
28. Clark, A. J. Chem. Soc. Rev. 2002, 31, 1–11.
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