Functional rearrangement of polychlorinated pyrrolidin-2-ones to 5-imino-lactams promoted by n-propylamine

Article abstract of DOI:10.1016/j.tet.2004.09.073

The reaction of 4-methyl-pyrrolidin-2-ones, chlorinated at the C(3) and C(6) positions, with n-propylamine constitutes a new method for the preparation of 5-propylimino-pyrrolidin-2-ones or 3-pyrrolin-2-ones in generally good yields. The transformation involves a series of eliminations, substitutions and double bond shifts. This constitutes a remarkable example of a functional rearrangement. Graphical Abstract.

Full text of DOI:10.1016/j.tet.2004.09.073

Tetrahedron 60 (2004) 11493–11501
Functional rearrangement of polychlorinated pyrrolidin-2-ones
to 5-imino-lactams promoted by n-propylamine
a
a
b
Chiara Danieli,a Franco Ghelfi,a, Adele Mucci, Ugo M. Pagnoni, Andrew F. Parsons,
*
Mariella Pattarozzia, and Luisa Schenetti
*
a
a
`
Dipartimento di Chimica, Universita degli Studi di Modena e Reggio Emilia, via Campi 183, 41100 Modena, Italy
bDepartment of Chemistry, University of York, Heslington, York YO10 5DD, UK
Received 25 June 2004; revised 6 September 2004; accepted 17 September 2004
Available online 7 October 2004
Abstract—The reaction of 4-methyl-pyrrolidin-2-ones, chlorinated at the C(3) and C(6) positions, with n-propylamine constitutes a new
method for the preparation of 5-propylimino-pyrrolidin-2-ones or 3-pyrrolin-2-ones in generally good yields. The transformation involves a
series of eliminations, substitutions and double bond shifts. This constitutes a remarkable example of a functional rearrangement.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
particular promise, in this context, is the nitrogenation of
g-lactams that carry a C(5)-halogen atom by reaction with
N-nucleophiles. This approach was originally investigated
by Foucaud30,31 and has recently been re-evaluated by
Nikitin and Andryukhova.32 Interestingly, the Russian
researchers obtained 5-amino-1,5-dihydro-2H-pyrrol-2-
ones in only two steps from the 5-methoxy analogues.
This involved conversion of the 5-methoxy analogues into
the corresponding 5-chloro intermediates (Scheme 1).33
Pyrrolidin-2-ones (g-lactams) and 3-pyrrolin-2-ones incor-
porating a nitrogen substituent at the C(5) carbon are
important structural motifs, which are found in numerous
biologically active compounds. This includes herbicides
and plant growth regulators,1–10 nootropic agents,11
cognition enhancing pharmaceuticals,12 antidepressants13,14
and azamitosane systems.15,16 Moreover, some g-lactams
have found application in the assembly of polymers with
semiconducting properties.17
In spite of the current interest in these types of compounds,
only a few preparative routes have been described in the
literature. The most common method exploits the cycliza-
tion of succinic or maleic acid derivatives, typically succinic
or maleic monoamides,18–20 b-cyanoamides,21 succinic
diamides or amidines,22,23 succinonitriles,24,25 3-cyano-
propanoates26 and, for analogy, 4-oxobutanoate esters.11
Other interesting approaches to these compounds involve a
three-component reaction using a-aminoalkenes, isonitriles
and isocyanates,27 and the rearrangement of N-acyl-N0-
enylhydrazines.28 Alternatively, the nitrogen appendage can
be introduced at the C(5) position through the manipulation
of preexisting functional groups, as in the case of
alkylimino-de-oxo-bisubstitution of succinic or maleic
imides,13,15 and autoxidation of pyrrole systems.29 Of
Scheme 1.
During our recent studies on the synthesis and reactivity of
4-methyl-pyrrolidin-2-ones (A) chlorinated at the C(3) and
C(6) positions, we disclosed that when treated with a
solution of alkaline methoxide (in methanol under mild
conditions), these compounds were converted into the
corresponding N-substituted 5-methoxy or 5,5-dimethoxy-
4-methyl-3-pyrrolin-2-ones (B) (Scheme 2).34 The trans-
formation involves a series of eliminations/substitutions that
give rise to a remarkable functional rearrangement (FR) in
which the oxidation state of the starting molecule is
preserved and the functionalities repositioned. In practice,
two or three of the C–Cl groups at the C(3) and C(6)
positions of A are replaced by a double bond at C(3)–C(4)
and, respectively, one or two methoxy groups at C(5). The
Keywords: Radical reactions; Pyrrolidinones; Rearrangements;
N-Nucleophiles.
* Corresponding authors. Fax: C39 059 373543;
e-mail: ghelfi.franco@unimore.it
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.09.073

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C. Danieli et al. / Tetrahedron 60 (2004) 11493–11501
study the functional rearrangement of polychlorinated
pyrrolidin-2-ones.
Herein we report, for the first time, our findings on the
reaction of various chlorinated g-lactams with n-propyl-
amine (PA). The choice of PA was made on the basis of the
low boiling point (48 8C) of this amine. It can easily be
evaporated from reaction mixtures and so can play a
combined role as reagent and solvent. As a consequence of
the FR using PA, the 5-imino functional group was, in each
case considered, introduced on the g-lactam ring in
generally good yield.
Scheme 2.
starting polyhalogenated pyrrolidin-2-ones A can be easily
prepared, as a mixture of cis- and trans-isomers, by the atom
transfer radical cyclization (ATRC) of N-allyl a-perchloro
amides C (Scheme 3).35 This reaction is typically mediated
by redox catalysts, such as the complex between CuCl and
N,N,N0,N0-tetramethylethylenediamine (TMEDA).36,37 The
C(3) stereocentre of the lactams is configurationally
unstable under the reaction conditions and the thermo-
dynamically more stable diastereoisomer predominates.
This diastereoisomer has the larger substituents at the
C(3) and C(4) positions on the opposite faces of the ring.35
2. Results and discussion
Our preliminary studies on the viability of the FR involved
reaction of N-benzyl-3-chloro-4-chloromethyl-pyrrolidin-2-
one (1a) with PA at different temperatures and concen-
trations (Table 1). Unexpectedly, in all cases, N-propyl-4-
methyl-5-propylimino-pyrrolidin-2-one (2) was recovered
as the main product (Scheme 4). This result contrasts with
the reaction of 1a with sodium methoxide in methanol,
which led to 5-methoxy-4-methyl-3-pyrrolin-2-one.34 For
reaction with PA, the double bond of the FR product is
located between C(5) and the exocyclic nitrogen and not, as
foreseen, between the C(3) and C(4) positions.
The discrepancy may be explained by the higher valency of
nitrogen compared to oxygen which, when an NHPr group
residues at C(5), should permit the double bond to move
from C(3)–C(4) to form an imine bond at C(5). We believe
that FR of 1a with PA should then provide the predicted
N-benzyl-4-methyl-5-propylamino-3-pyrrolin-2-one (20a),
but as a transient product, which immediately undergoes
double bond isomerisation. Indeed, when 1a was reacted
with (CH3CH2)2NH (DEA), a secondary amine, N-benzyl-
4-methyl-5-diethylamino-3-pyrrolin-2-one (3) was obtained
Scheme 3.
The effectiveness and generality of the FR of polychlori-
nated pyrrolidin-2-ones with alkaline alcoholates prompted
us to investigate if alternative nucleophilic/basic systems
could be equally effective. Of particular interest was the
Table 1. Reaction of 1a with PAa
Entry
PA (mL)
T (8C)
Conv. (%)b
2 (%)c
1
2
3
4
5
2.5
2.5
2.5
2.5
5
60
80
120
140
140
100
100
100
100
100
28
40
47
48
54
a 1 mmol of substrate was used; reaction time 24 h.
b GC values.
c Yield determined on isolated material.
incorporation of nitrogen nucleophiles in the functional
rearrangement as this could allow the direct introduction of
a nitrogen atom at the unfunctionalized C(5) position. This
would avoid the need to start from C(5)-oxygen substituted
g-lactams.13,15,30–32 Previous studies of alcohols with
polychlorinated pyrrolidinones showed the importance of
the alcohol structure (on increasing the size of the alkyl
group in the alcohol from methyl to ethyl, yields decrease to
some extent) and reaction conditions in the FR (e.g., no FR
occurred when methanol was combined with a weak base,
like carbonate).34 Based on this work, amines appeared to be
the most appropriate nitrogen nucleophiles with which to
Scheme 4.

C. Danieli et al. / Tetrahedron 60 (2004) 11493–11501
11495
as the main product (Scheme 5). In this case, as the
exocyclic nitrogen in the intermediate pyrrolin-2-one is
unable to form a double bond at C(5), so the unsaturation
has to remain inside the ring. Further evidence that the FR of
1a with PA involves intermediate 20a comes from the
related, and recently observed, rearrangement of 5-hydroxy-
2(5H)-furanone to succinic anhydride under basic con-
ditions (Scheme 6).38 In this reaction, double bond
isomerisation was observed to form an intermediate
dicarboxylate.
pyrrolidin-2-ones bearing an N-propyl chain. In this way,
any exchange of the N-substituent with PA would not
generate a new product. This tactic allowed us to investigate
the FR under mild reaction conditions. Indeed, the FR of
pyrrolidin-2-one 1b with PA (Scheme 4) was observed at
temperatures as low as 40 8C (Table 2). Moreover, when
using 2 mL of PA to 1 mmol of 1b, the 5-imino pyrrolidin-
2-one 2 was isolated in a respectable 57% yield (Table 2,
entry 7).
Gratified by these preliminary results and with a view to
assessing the scope of the method, the four chlorinated
pyrrolidin-2-ones 4–7 were prepared in high yield through
the HATRC of the respective N-allyl amides with CuCl/
TMEDA.
The FR of pyrrolidin-2-one 4 at 40 8C with 2 mL of
n-propylamine per mmol of substrate, gave the 5-imino
pyrrolidin-2-one 9 as the main product together with a small
amount of the expected g-lactam 8 (Scheme 7; Table 3,
entry 5). It is likely that lactam 9 is formed by a highly
regioselective Michael-type addition of PA onto the C]C
bond of 8. When the temperature of the reaction was raised,
and the mixture heated at 80 8C, only the Michael-type
adduct was isolated (Table 3, entry 6). In order to avoid the
Michael-type addition, the reaction was carried out at lower
temperatures. Pleasingly, following reaction of 4 with PA at
K13 8C for 4 h, only the 3-pyrrolin-2-one 8 was isolated in
a respectable yield of 63% (Table 3, entry 1).
Scheme 5.
Scheme 6.
Another remarkable feature of this reaction is replacement
of the N-benzyl group in 1a with a propyl appendage in
product 2. Evidently, during the course of the reaction, most
likely following formation of the 5-imino lactam 200a,
substitution of the benzylamine moiety with n-propylamine
takes place (Scheme 4).39,40 As a consequence, two different
primary amines come to share the same reaction mixture.
This resulted in the formation of a variety of byproducts that
contained the benzylic group (as indicated by GC-MS),
unless forcing conditions, such as high temperature (140 8C)
and relatively large volumes of n-propylamine (5 mL/
mmol) were employed.
When substrate 5 was heated with PA (2 mL/mmol of
substrate) for 16 h at 40 8C, some starting material remained
and a variety of products were formed. From the crude
reaction mixture we isolated the FR adduct 10, in low yield
(6%), and N-propyl-3-methyl-4-(propylamino)methyl-3-
pyrrolin-2-one (11) as the main product (Scheme 8;
Table 3, entry 7). On increasing the reaction temperature
to 80–100 8C, it was possible to obtain complete conversion
of starting material and to improve the yield of 10 to 29%
(Table 3, entry 8 and 9), whereas the yield of 11 remained
As a consequence of the facile substitution of the N-benzyl
group in 1a, we decided to study the FR of polychlorinated
Table 2. Reaction of 1b with PAa
Entry
PA (mL)
t (h)
T (8C)
Conv. (%)b
2 (%)c
1
2
3
4
5
6
7
1
1
1
1
1
1
2
24
24
16
24
24
24
24
20
40
40
60
80
100
40
73
100
97
100
100
100
99
28
48
45
42
38
43
57
a 1 mmol of 1b was used.
b GC values.
c Yield determined on isolated material.
well above 50%. The unwanted product 11 could derive
from one, or more, of the three possible paths outlined in
Scheme 9, wherein an amino-de-halogenation step is
variously combined with a dehydrohalogenation step.
As far as the g-lactam 6 is concerned, the FR with
n-propylamine (2 mL/mmol of substrate) at 40 8C was
disappointing. The rearranged product, N-propyl-3,4-
dimethyl-5-propylimino-3-pyrrolin-2-one (12), was isolated
Scheme 7.

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C. Danieli et al. / Tetrahedron 60 (2004) 11493–11501
Table 3. Reaction of pyrrolidin-2-ones 4–7 with PAa
Entry
Substrate
t (h)
T (8C)
Conv. (%)b
Products (%)c
8 (63); 9 (0)
8 (63); 9 (6)
8 (61); 9 (15)
8 (53); 9 (41)
8 (7); 9 (59)
9 (56)
10 (6); 11 (64)
10 (28); 11 (68)
10 (29); 11 (59)
12 (5)
12 (9)
12 (22)
1d
2
3
4
5
6
7
8
4
4
4
4
4
4
5
5
5
6
6
6
6
6
7
7
7
7
7
7
7
4
K13
K13
0
20
40
60
40
80
100
40
60
80
100
120
K13
K13
K13
0
100
100
100
100
100
100
85
100
100
100
100
100
100
100
100
100
100
100
100
100
100
16
16
16
16
16
16
16
16
16
16
16
16
16
0.5
1
9
10
11
12
13
14
15e
16e
17
18
19
20
21
12 (25)
12 (15)
13 (68); 14 (0)
13 (63); 14 (0)
13 (13); 14 (0)
13 (7); 14 (0)
13 (0); 14 (23)
13 (0); 14 (37)
13 (0); 14 (44)
16
16
16
16
16
40
60
80
a Substrate (1 mmol), PA (2 mL).
b GC values.
c Yield determined on isolated material.
d The substrate was thermostated at K13 8C before addition of PA.
e The substrate was thermostated at K13 8C before addition of PA and 1 mL of diethyl ether was added to prevent its solidification.
in only 5% yield (Scheme 10; Table 3, entry 10). In this
case, heating the reaction mixture to 100 8C was also
beneficial and the yield of 12 increased to 25% (Table 3,
entry 13).
Finally, treatment of the polychlorinated pyrrolidin-2-one 7
with PA (at 40 8C) surprisingly afforded the degradation
product 14 as the main component of the reaction crude
(23%). No trace of the rearranged lactam 13 was detected
(Scheme 11; Table 3, entry 19). As observed for the
previous rearrangements, temperature proved to be a critical
reaction parameter. In fact, on mixing the reagents at
K13 8C for no more than 0.5 h (Scheme 11; Table 3, entry
15), the FR proceeded efficiently, providing the rearranged
lactam 13 in good yield (68%). Temperatures higher than
40 8C caused, on the contrary, a progressive increase in the
amount of imine 14. Interestingly, from the MS analysis of
the crude reaction mixtures containing N-propyl-5-propyl-
imino-pyrrolidin-2-one (14) it was possible to detect a peak,
which can be assigned to N,N0-dipropylformamidine (15).
This was confirmed after comparison of the spectrum with
an authentic sample of 15, synthesized by a literature
procedure.41 The simultaneous formation of amidine 15
together with lactam 14 sheds some light on the mechanism
of degradation of substrate 7. The degradation is likely to
start by substitution of the two exo-Cl atoms in 7 by two
PA units. Then, from the resulting N,N-acetal, a base
catalyzed fragmentation should afford amidine 15 and the
intermediate N-propyl-3-chloro-3-pyrrolin-2-one, which in
Scheme 8.
Scheme 9.
Scheme 11.
Scheme 10.

C. Danieli et al. / Tetrahedron 60 (2004) 11493–11501
11497
a few further steps could be transformed into 14
(Scheme 12).
with benzylamine (3 equiv) and NaI in THF at reflux.42
Given that these are similar reaction conditions to the ones
described for the FR, it is surprising that different products
are formed. Consequently, the reaction with the N-benzyl-3-
chloro-4-chloromethyl-pyrrolidin-2-one was repeated and,
as expected from the results of the present work, the
structure of the reaction product was, without doubt, defined
as N-benzyl-5-benzylimino-4-methyl-pyrrolidin-2-ones.
This means that our former product characterization was
erroneous and that the same functional rearrangement is
operative.
3. Structural characterizations of the (E)- and
(Z)-5-iminolactams 2, 8–10, 12–14
For all the 5-iminolactams, the (E) configuration largely or
exclusively prevails. For adducts 2, 9, 10 and 14 only the
(E)-isomer was isolated, while for products 8, 12 and 13,
11–15% of the minor (Z)-isomer (in equilibrium with the
(E)-counterpart) was observed.
The stereochemistry of the 5-propylimino group was
derived from 1H NMR two-dimensional nuclear Overhauser
enhancement experiments in the phase sensitive mode
(NOESY-TPPI),43 that were run after a complete assign-
ment of the 1H and 13C NMR spectra, through inverse
detection techniques (HMQC).44 This was used in order to
unambiguously assign all proton and carbon signals, in
particular, those of the different propyl chains. NOESY-
TPPI experiments permit the detection of protons close to
one another in space and, at the same time, to evidence
exchange processes which are slow enough on the NMR
timescale.45 The two situations can be distinguished from
the sign of the relevant cross-peaks with respect to that of
diagonal peaks: cross-peaks denoting proximity of two
protons have opposite sign, whereas cross-peaks deriving
from exchange phenomena have the same sign with respect
to the diagonal ones (which are set as negative). From
NOESY-TPPI spectra it was readily seen that the signals of
methylene protons bonded to the imino moiety share
positive cross-peaks with the signals of groups at the C(4)
position in derivatives 2, 9, 10 and 14, and this indicates an
(E)-type configuration. In the case of compounds 8, 12 and
Scheme 12.
The results from all these experiments clearly show that
similarities can be drawn between the FR of polychlorinated
pyrrolidin-2-ones using PA or CH3OH/CH3ONa. Therefore,
it is reasonable to assume that the same type of mechanism
is occurring in both transformations. In agreement with our
previous proposal34 and taking 1b as a model pyrrolidin-2-
one, we believe that the reaction starts with a base-promoted
dehydrohalogention. This is an exo or endo elimination
according to the ease with which the required anti-
periplanar conformation is attained. The double bond then
shifts from the C(4)–C(5) position to afford an intermediate
D4-pyrrolin-2-one. This can react further to afford, via a
solvolysis step, a stable N-acyliminium cation that, after
condensation with PA, is converted into the final product 2
(Scheme 13).
1
13, H NMR spectra showed the presence of two sets of
signals, and negative correlations were found between the
corresponding signals of the two forms in NOESY-TPPI
spectra, evidencing that an exchange process between two
isomeric species is present.42 Moreover, positive cross-
peaks were found, for the major isomer only, among the
signals of the iminopropyl appendage and those of the
groups at the C(4) position, indicating that the (E)-type
configuration also prevails in these products. It is interesting
to note that the tendency to have a small amount of the
(Z)-isomer of the iminopropyl group (in equilibrium with
the prevailing (E)-isomer) is only observed for the
g-lactams with a C(4)sp2 carbon. The (Z)-isomer is not
observed for those compounds with a C(4)sp3 carbon, even
when two substituents are present, for example, as in the
case of the pyrrolidin-2-one 9. The preponderance of the
(E)-isomers, then, is attributed to the higher thermodynamic
stability of these frameworks.
Scheme 13.
A few years ago we reported that N-substituted-3-benzyl-
imino-pyrrolidin-2-ones could be prepared by heating
N-substituted-3-chloro-4-chloromethyl-pyrrolidin-2-ones

11498
C. Danieli et al. / Tetrahedron 60 (2004) 11493–11501
4. Conclusion
were added under argon. The mixture was stirred at 80 8C
and after 24 h diluted with HCl (5% w/v, 20 mL) and
extracted with CH2Cl2 (3!10 mL). The combined organic
layers were dried with toluene (10 mL) through azeotropic
distillation. Flash-chromatography of the crude product on
silica, eluting with a petroleum ether (bp 40/60 8C)/diethyl
ether gradient, afforded the pyrrolidin-2-one 1b (3.40 g,
81%) as an unseparable mixture of cis/trans diastereo-
isomers (27/73); orange oil; [found: C, 45.59; H, 6.31; N,
6.76. C8H13Cl2NO requires C, 45.73; H, 6.24; N, 6.67]; IR
The reaction of 4-methyl-pyrrolidin-2-ones chlorinated at
the C(3) and C(6) positions with PA establishes a new
method for the preparation, generally in good yield, of
5-propylimino pyrrolidin-2-ones or 3-pyrrolin-2-ones. This
FR is similar to that observed when the same substrates are
treated with CH3OH/CH3ONa. In order to obviate the
problem of substitution of the N-substituent on the g-lactam
ring, the FR with PA requires the use of polychlorinated
pyrrolidin-2-ones bearing an N-propyl group. In this way,
notwithstanding that the exchange still occurs, it cannot be
noticed owing to the degeneracy of the phenomenon. This
structural prerequisite, however, restricts the versatility of
the method. Current studies are investigating the application
of the methodology to the synthesis of roccellic acid46 and
the results will be reported in due course.
(liquid film) 1707 (C]O) cmK1 1H NMR (200 MHz,
;
CDCl3): trans diastereoisomer (73%) d 0.91 (3H, t, JZ
7.4 Hz, CH2CH2CH3), 1.57 (2H, m, CH2CH2CH3), 2.65–
3.05 (1H, m, C(4)H), 3.05–3.91 (6H, m, CH2NCH2-
C(4)HCH2), 4.33 (1H, d, JZ7.6 Hz, C(3)H); cis diastereo-
isomer (27%) d 0.91 (3H, t, JZ7.4 Hz, CH2CH2CH3), 1.57
(2H, m, CH2CH2CH3), 2.65–3.05 (1H, m, C(4)H), 3.05–
3.91 (6H, m, CH2NCH2C(4)HCH2), 4.44 (1H, d, JZ7.6 Hz,
C(3)H); MS (EI, 70 eV) m/z: 209 (17, MC), 194 (35), 180
(100), 174 (52), 152 (22), 42 (17).
5. Experimental
5.1. General
5.2.2. N-Propyl-3,3-dichloro-4-chloromethyl-pyrrolidin-
2-one (4). According to the general procedure, cyclization
of N-allyl-N-propyl-trichloroacetamide (4.90 g, 20 mmol)
at 25 8C for 20 h gave the pyrrolidin-2-one 4 (4.35 g, 89%)
as yellow oil; [found: C, 39.41; H, 5.01; N, 5.86.
C8H12Cl3NO requires C, 39.29; H, 4.95; N, 5.73]; IR
1H NMR and 13C NMR spectra were recorded in CDCl3
solutions with a Bruker Avance 400 Spectrometer and a
Bruker DPX 200 spectrometer, and the chemical shifts are
reported in ppm relative to tetramethylsilane as external
standard. Conditions for HMQC spectra were: evolution
delayZ50 ms, spectral widthZ10 ppm with 2048 complex
points in f2; 256 t1 values and 64 scans for t1 value. A
squared sine function (SSBZ2) in f2 and f1 was applied
before Fourier transformation. Conditions for NOESY
phase-sensitive spectra by time-proportional phase incre-
mentation (TPPI) were: mixing time of 600 ms, spectral
width 8.16 ppm with 2048 complex points in f2; 128 t1
values and 64 scans for t1 value. A squared sine function
(SSBZ2) in f2 and gaussian multiplication (LBZK1,
GBZ0.01) in f1 were applied before Fourier transform-
ation. IR spectra were obtained with a 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
Acros, Aldrich or Fluka, and used without further
purification. Acetonitrile (for the radical cyclizations) was
(liquid film) 1729 (C]O) cmK1 1H NMR (200 MHz,
;
CDCl3): d 0.92 (3H, t, JZ7.4 Hz, CH2CH2CH3), 1.61 (2H,
m, CH2CH2CH3), 2.87–4.17 (7H, m, CH2NCH2C(4)HCH2);
MS (EI, 70 eV) m/z: 243 (13, MC), 228 (47), 214 (100), 208
(55), 180 (28), 42 (47).
5.2.3. N-Propyl-3-chloro-4-chloromethyl-3-methyl-
pyrrolidin-2-one (5). According to the general procedure,
cyclization of N-allyl-N-propyl-2,2-dichloropropanamide
(4.48 g, 20 mmol) at 25 8C for 20 h gave the pyrrolidin-2-
one 5 (4.30 g, 96%) as an unseparable mixture of cis/trans
diastereoisomers (56/44); orange oil; [found: C, 48.34; H,
6.68; N, 6.12. C9H15Cl2NO requires C, 48.23; H, 6.75; N,
6.25]; IR (liquid film) 1706 (C]O) cmK1 1H NMR
;
(200 MHz, CDCl3): cis diastereoisomer (56%) d 0.91 (3H, t,
JZ7.4 Hz, CH2CH2CH3), 1.58 (2H, m, CH2CH2CH3), 1.76
(3H, s, C(3)CH3), 2.36–2.68 (1H, m, C(4)H), 3.04–4.00
(6H, m, CH2NCH2C(4)HCH2); trans diastereoisomer (44%)
d 0.91 (3H, t, JZ7.4 Hz, CH2CH2CH3), 1.58 (2H, m,
CH2CH2CH3), 1.63 (3H, s, C(3)CH3), 2.80–3.04 (1H, m,
C(4)H), 3.04–4.00 (6H, m, CH2NCH2C(4)HCH2); MS (EI,
70 eV) m/z: 223 (17, MC), 208 (25), 194 (100), 188 (48),
160 (18), 42 (22).
˚
dried over three batches of 3 A sieves (5% w/v, 12 h). The
silica gel used for flash chromatography was 60 Merck
(0.040–0.063 mm). N-propyl-2-propenylamine and N-pro-
pyl-3-chloro-2-propenylamine were prepared for N-alkyl-
ation of n-propylamine with allyl bromide or 1,3-
dichloropropene. The N-allyl-N-propyl a-perchloro amide
precursors of polychlorinated pyrrolidin-2-ones 1b and 4–7
were obtained by amino-de-chlorination of the appropriate
acyl chlorides.35 N-Benzyl-3-chloro-4-chloromethyl-pyrro-
lidin-2-one (1a) was prepared according to the literature.47
5.2.4. N-Propyl-3-chloro-4-dichloromethyl-3-methyl-
pyrrolidin-2-one (6). According to the general procedure,
cyclization of N-(3-chloroallyl)-N-propyl-2,2-dichloro-
propanamide (5.17 g, 20 mmol) at 25 8C for 20 h gave the
pyrrolidin-2-one 6 (4.71 g, 91%) as an unseparable mixture
of cis/trans diastereoisomers (75/25); light yellow oil;
[found: C, 41.84; H, 5.39; N, 5.36. C9H14Cl3NO requires
C, 41.81; H, 5.46; N, 5.42]; IR (liquid film) 1711 (C]O)
5.2. Preparation of polychlorinated pyrrolidin-2-ones
5.2.1. Typical procedure for the preparation of poly-
chlorinated pyrrolidin-2-ones: N-propyl-3-chloro-4-
chloromethyl-pyrrolidin-2-one (1b). CuCl (0.20 g,
2 mmol) and the N-allyl-N-propyl-dichloroacetamide
(4.20 g, 20 mmol) were weighted in a Schlenk tube, then
dry acetonitrile (10 mL) and TMEDA (0.6 mL, 4 mmol)
1
cmK1; H NMR (200 MHz, CDCl3): cis diastereoisomer
(75%) d 0.92 (3H, t, JZ7.4 Hz, CH2CH2CH3), 1.59 (2H, m,
CH2CH2CH3), 1.91 (3H, s, C(3)CH3), 2.89 (1H, td, JZ7.4,
9.5 Hz, C(4)H), 3.03–3.56 (4H, m, C(5)H2NCH2CH2), 6.04

C. Danieli et al. / Tetrahedron 60 (2004) 11493–11501
11499
(1H, d, JZ9.5 Hz, C(4)CH); trans diastereoisomer (25%) d
0.94 (3H, t, JZ7.4 Hz, CH2CH2CH3), 1.59 (2H, m,
CH2CH2CH3), 1.78 (3H, s, C(3)CH3), 3.03–3.56 (4H, m,
CH2NC(5)HC(4)H), 3.77 (1H, dd, JZ7.6, 11.4 Hz, C(5)H),
5.93 (1H, d, JZ4.5 Hz, C(4)CH); MS (EI, 70 eV) m/z: 257
(15, MC), 242 (33), 228 (100), 222 (52), 194 (23), 42 (25).
14.91 (C(4)CH3), 15.04 (N(CH2CH3)2), 43.0 (br,
N(CH2CH3)2), 43.27 (CH2Ar), 79.15 (C(5)N), 123.36
(C(3)), 127.07 (Ar), 127.75 (Ar), 128.44 (Ar), 138.18 (Ar),
158.55 (C(4)), 170.29 (C]O); MS (EI, 70 eV) m/z: 258 (5,
MC), 186 (67), 91 (100).
5.3.3. Preparation of N-propyl-4-methyl-5-propylimino-
3-pyrrolin-2-one (8). According to the general procedure,
the rearrangement of 4 (0.24 g, 1 mmol) with n-propyl-
amine (2 mL) at K13 8C for 4 h gave 8 (0.12 g, 63%) as an
unseparable mixture of E/Z diastereoisomers (85/15);
yellow oil; [found: C, 68.10; H, 9.41; N, 14.47.
C11H18N2O requires C, 68.01; H, 9.34; N, 14.42]; IR (liquid
5.2.5. N-Propyl-3,3-dichloro-4-dichloromethyl-pyrro-
lidin-2-one (7). According to the general procedure,
cyclization of N-(3-chlorallyl)-N-propyl-trichloroacetamide
(5.58 g, 20 mmol) at 25 8C for 20 h gave the pyrrolidin-2-
one 7 (5.08 g, 91%) as pale yellow oil; [found: C, 34.53; H,
4.04; N, 5.09. C8H11Cl4NO requires C, 34.44; H, 3.97; N,
5.02]; IR (liquid film) 1733 (C]O) cmK1 1H NMR
;
1
film) 1654 cmK1 (C]N), 1724 cmK1 (C]N); H NMR
(200 MHz, CDCl3): d 0.94 (3H, t, JZ7.4 Hz, CH2CH2CH3),
1.62 (2H, m, CH2CH2CH3), 3.22–3.51 (4H, m, CH2-
NC(5)HC(4)H), 3.64 (1H, dd, JZ6.8, 9.6 Hz, C(5)H),
6.09 (1H, d, JZ7.9 Hz, C(4)CH); MS (EI, 70 eV) m/z: 277
(10, MC), 264 (58), 250 (100), 242 (48), 214 (27), 159 (20),
130 (47), 109 (20), 42 (30).
(400 MHz, CDCl3): (E)-diastereoisomer (85%) d 0.84 (3H,
t, JZ7.5 Hz, N(1)CH2CH2CH3), 0.96 (3H, t, JZ7.4 Hz,
C]NCH2CH2CH3), 1.55 (2H, m, N(1)CH2CH2), 1.67 (2H,
m, C]NCH2CH2), 2.26 (3H, d, JZ1.6 Hz, C(4)CH3), 3.50
(2H, t, JZ7.3 Hz, N(1)CH2), 3.71 (2H, t, JZ6.8 Hz,
C]NCH2), 6.13 (1H, q, JZ1.6 Hz, C(3)H); (Z)-diastereo-
isomer (15%) d 0.87 (3H, t, JZ7.4 Hz, N(1)CH2CH2CH3),
0.98 (3H, t, JZ7.2 Hz, C]NCH2CH2CH3), 1.55 (2H, m,
N(1)CH2CH2), 1.67 (2H, m, C]NCH2CH2), 2.01 (3H, d,
JZ1.5 Hz, C(4)CH3), 3.66 (2H, t, JZ7.6 Hz, N(1)CH2),
3.67 (2H, t, JZ6.8 Hz, C]NCH2), 6.06 (1H, q, JZ1.5 Hz,
C(3)H); 13C NMR (100 MHz, CDCl3): (E)-diastereoisomer
(85%) d 11.27 (N(1)CH2CH2CH3), 11.72 (C]NCH2CH2-
CH3), 17.43 (C(4)CH3), 21.77 (N(1)CH2CH2), 25.31
(C]NCH2CH2), 39.61 (N(1)CH2), 51.08 (C]NCH2),
129.09 (C(3)), 140.63 (C(4)), 152.76 (C(5)), 169.96
(C(2)); (Z)-diastereoisomer (15%) d 10.97 (N(1)CH2CH2-
CH3), 11.72 (C]NCH2CH2CH3), 11.99 (C(4)CH3), 23.76
(N(1)CH2CH2), 25.20 (C]NCH2CH2), 42.79 (N(1)CH2),
50.27 (C]NCH2), 122.78 (C(3)), 150.40 (C(4)), 150.72
(C(5)), 172.54 (C(2)); MS (EI, 70 eV) m/z: 194 (100, MC),
179 (28), 165 (58), 151 (58), 137 (37), 123 (35), 111 (22), 94
(67), 41 (22).
5.3. Functional rearrangement of polychlorinated
pyrrolidin-2-ones
5.3.1. Preparation of (E)-N-propyl-4-methyl-5-propyl-
imino-pyrrolidin-2-one (2). The polychlorinated pyrro-
lidin-2-one 1a (0.26 g, 1 mmol) was weighted in a Schlenk
tube, then n-propylamine (5 mL) was added under argon.
The mixture was stirred at 140 8C for 24 h, then evaporated
under vacuum to remove n-propylamine, and finally diluted
with H2O (4 mL) and extracted with CH2Cl2 (2!5 mL).
Flash-chromatography of the crude product on silica,
eluting with a petroleum ether (bp 40/60 8C)/diethyl ether
gradient, afforded 2 (106 mg, 54%) as an orange yellow oil;
[found: C, 67.40; H, 10.21; N, 14.19. C11H20N2O requires
C, 67.31; H, 10.27; N, 14.27]; IR (liquid film) 1660 cmK1
(C]N), 1737 cmK1 (C]O); 1H NMR (400 MHz, CDCl3):
d 0.87 (3H, t, JZ7.4 Hz, N(1)CH2CH2CH3), 0.94 (3H, t,
JZ7.4 Hz, C]NCH2CH2CH3), 1.21 (3H, d, JZ7.2 Hz,
C(4)CH3), 1.58 (2H, m, C]NCH2CH2), 1.61 (2H, m,
N(1)CH2CH2), 2.15 (1H, dd, JZ1.9, 17.5 Hz, C(3)H), 2.76
(1H, dd, JZ8.8, 17.5 Hz, C(3)H), 3.09 (1H, m, C(4)H), 3.28
(1H, m, C]NCH), 3.35 (1H, m, C]NCH), 3.50 (2H, m,
N(1)CH2); 13C NMR (100 MHz, CDCl3): d 11.27
(N(1)CH2CH2CH3), 11.84 (C]NCH2CH2CH3), 19.28
(C(4)CH3), 20.46 (N(1)CH2CH2), 24.87 (C]NCH2CH2),
29.01 (C(4)), 37.88 (C(3)), 40.47 (N(1)CH2), 50.97
(C]NCH2), 161.80 (C(5)), 175.64 (C(2)); MS (EI, 70 eV)
m/z: 196 (100, MC), 181 (40), 167 (68), 153 (40), 139 (83),
126 (57), 113 (25), 97 (20), 41 (22).
5.3.4. Preparation of (E)-N-propyl-4-methyl-4-propyl-
amino-5-propylimino-pyrrolidin-2-one (9). According to
the general procedure, the rearrangement of 4 (0.24 g,
1 mmol) with n-propylamine (2 mL) at 40 8C for 16 h gave
9 (0.15 g, 59%) as a yellowish oil; [found: C, 66.45; H,
10.76; N, 16.48. C14H27N3O requires C, 66.36; H, 10.74; N,
16.58]; IR (liquid film) 1668 cmK1 (C]N), 1733 cmK1
1
(C]O); H NMR (400 MHz, CDCl3): d 0.84 (3H, t, JZ
7.5 Hz, N(1)CH2CH2CH3), 0.89 (3H, t, JZ7.4 Hz, NHCH2-
CH2CH3), 0.93 (3H, t, JZ7.4 Hz, C]NCH2CH2CH3),
1.40–1.50 (2H, m, NHCH2CH2), 1.46 (3H, s, C(4)CH3),
1.55 (2H, m, N(1)CH2CH2), 1.58 (2H, m, C]NCH2CH2),
2.26 (1H, dt, JZ7.1, 10.5 Hz, NHCH), 2.34 (1H, d, JZ
18.0 Hz, C(3)H2), 2.43 (1H, dt, JZ7.1, 10.5 Hz, NHCH),
2.74 (1H, d, JZ18.0 Hz, C(3)H2), 3.48 (2H, t, JZ7.3 Hz,
N(1)CH2), 3.59 (2H, t, JZ6.8 Hz, C]NCH2); 13C NMR
(100 MHz, CDCl3): d 11.30 (N(1)CH2CH2CH3), 11.75
(NHCH2CH2CH3), 11.82 (C]NCH2CH2CH3), 20.44
5.3.2. Preparation of N-benzyl-5-diethylamino-4-methyl-
3-pyrrolin-2-one (3). According to the general procedure,
the rearrangement of 1a (0.26 g, 1 mmol) with diethylamine
(2.5 mL) at 100 8C for 24 h gave 3 (0.10 g, 40%) as a
yellowish oil; [found: C, 74.34; H, 8.62; N, 10.77.
C16H22N2O requires C, 74.38; H, 8.58; N, 10.84]; IR (liquid
film) 1696 cmK1; 1H NMR (400 MHz, CDCl3): d 0.97 (6H,
t, JZ7.1 Hz, N(CH2CH3)2), 1.93 (3H, d, JZ1.4 Hz,
C(4)CH3), 2.60 (4H, broad m, N(CH2CH3)2), 4.02 (1H, d,
JZ15.1 Hz, N(1)CHAr), 4.53 (1H, s, C(5)H), 5.07 (1H, d,
JZ15.1 Hz, N(1)CHAr), 5.88 (1H, q, JZ1.4 Hz, C(3)H),
7.19–7.30 (5H, m, Ar(H)); 13C NMR (100 MHz, CDCl3): d
(N(1)CH2CH2),
23.54
(NHCH2CH2),
25.22
(C]NCH2CH2), 26.60 (C(4)CH3), 40.38 (N(1)CH2),
42.77 (C(3)), 45.34 (NHCH2), 48.58 (C]NCH2), 59.77
(C(4)), 157.68 (C(5)), 173.69 (C(2)); MS (EI, 70 eV) m/z:
253 (1, MC), 238 (3), 224 (8), 194 (100), 179 (22), 126 (45),
84 (23), 42 (15).

11500
C. Danieli et al. / Tetrahedron 60 (2004) 11493–11501
5.3.5. Preparation of (E)-N-propyl-3,4-dimethyl-5-
propylimino-pyrrolidin-2-one (10). According to the
general procedure, the rearrangement of 5 (0.22 g,
1 mmol) with n-propylamine (2 mL) at 100 8C for 16 h
gave 10 (61 mg, 29%) as an unseparable mixture of cis/trans
diastereoisomers (23/77); yellow oil; [found: C, 68.64; H,
10.59; N, 13.33. C12H22N2O requires C, 68.53; H, 10.54; N,
13.32]; IR (liquid film) 1671 cmK1 (C]N), 1736 cmK1
(C]O); 1H NMR (400 MHz, CDCl3): trans diastereo-
isomer (77%) d 0.84 (3H, t, JZ7.5 Hz, N(1)CH2CH2CH3),
0.90 (3H, t, JZ7.4 Hz, C]NCH2CH2CH3), 1.18 (3H, d,
JZ7.2 Hz, C(4)CH3), 1.19 (3H, d, JZ7.4 Hz, C(3)CH3),
1.56 (2H, m, N(1)CH2CH2), 1.58 (2H, m, C]NCH2CH2),
2.22 (1H, m, JZ1.9, 7.4 Hz, C(3)H), 2.61 (1H, m, JZ1.9,
7.2 Hz, C(4)H), 3.20–3.53 (4H, m, CH2NC]NCH2); cis
diastereoisomer (23%) d 0.83 (3H, t, JZ7.4 Hz, N(1)CH2-
CH2CH3), 0.91 (3H, t, JZ7.4 Hz, C]NCH2CH2CH3), 1.02
(3H, d, JZ7.3 Hz, C(4)CH3), 1.15 (3H, d, JZ7.4 Hz,
C(3)CH3), 1.55 (2H, m, N(1)CH2CH2), 1.57 (2H, m,
C]NCH2CH2), 2.71 (1H, m, JZ7.8 Hz, C(3)H), 3.12
(1H, m, JZ7.7 Hz, C(4)H), 3.20–3.53 (4H, m, CH2-
NC]NCH2); 13C NMR (100 MHz, CDCl3): trans dia-
stereoisomer (77%) d 11.18 (N(1)CH2CH2CH3), 11.77
(C]NCH2CH2CH3), 17.57 (C(3)CH3), 18.57 (C(4)CH3),
20.43 (N(1)CH2CH2), 24.85 (C]NCH2CH2), 37.67 (C(4)),
40.32 (N(1)CH2), 44.50 (C(3)), 50.96 (C]NCH2), 161.03
(C(5)), 179.06 (C(2)); cis diastereoisomer (23%) d 9.44
(C(3)CH3), 11.23 (N(1)CH2CH2CH3), 11.82 (C]NCH2-
CH2CH3), 13.27 (C(4)CH3), 20.47 (N(1)CH2CH2), 24.83
(C]NCH2CH2), 33.11 (C(4)), 38.89 (C(3)), 40.36
(N(1)CH2), 51.05 (C]NCH2), 161.63 (C(5)), 178.35
(C(2)); MS (EI, 70 eV) m/z: 210 (65, MC), 195 (43), 181
(45), 167 (35), 153 (100), 140 (52), 111 (32), 55 (20), 41
(18).
t, JZ7.4 Hz, N(1)CH2CH2CH3), 0.97 (3H, t, JZ7.4 Hz,
C]NCH2CH2CH3), 1.55 (2H, m, N(1)CH2CH2), 1.68 (2H,
m, C]NCH2CH2), 1.89 (3H, q, JZ1.1 Hz, C(3)CH3), 2.16
(3H, q, JZ1.1 Hz, C(4)CH3), 3.52 (2H, t, JZ7.2 Hz,
N(1)CH2), 3.72 (2H, t, JZ6.8 Hz, C]NCH2); (Z)-dia-
stereoisomer (15%) d 0.88 (3H, t, JZ7.4 Hz, N(1)CH2CH2-
CH3), 0.98 (3H, t, JZ7.3 Hz, C]NCH2CH2CH3), 1.57
(2H, m, N(1)CH2CH2), 1.70 (2H, m, C]NCH2CH2), 1.87
(3H, m, C(3)CH3), 1.93 (3H, q, JZ1.1 Hz, C(4)CH3), 3.66
(2H, m, C]NCH2), 3.67 (2H, m, N(1)CH2); 13C NMR
(100 MHz, CDCl3): (E)-diastereoisomer (85%) d 8.18
(C(3)CH3), 11.33 (N(1)CH2CH2CH3), 11.76 (C]NCH2-
CH2CH3), 14.40 (C(4)CH3), 21.87 (N(1)CH2CH2), 25.45
(C]NCH2CH2), 39.70 (N(1)CH2), 51.05 (C]NCH2),
132.53 (C(3)), 136.65 (C(4)), 152.93 (C(5)), 171.01
(C(2)); (Z)-diastereoisomer (15%) d 8.70 (C(3)CH3), 9.51
(C(4)CH3), 11.33 (N(1)CH2CH2CH3), 11.76 (C]NCH2-
CH2CH3), 22.66 (N(1)CH2CH2), 25.35 (C]NCH2CH2),
43.11 (N(1)CH2), 50.25 (C]NCH2), 130.55 (C(3)), 139.42
(C(4)), 151.02 (C(5)), 170.81 (C(2)); MS (EI, 70 eV) m/z:
208 (100, MC), 193 (43), 179 (73), 165 (53), 151 (83), 138
(48), 123 (22), 108 (48).
5.3.8. Preparation of N-propyl-3-chloro-4-methyl-5-pro-
pylimino-3-pyrrolin-2-one (13). According to the general
procedure, the rearrangement of 7 (0.28 g, 1 mmol) with
n-propylamine (2 mL) at K13 8C for 0.5 h gave 13 (0.15 g,
68%) as an unseparable mixture of E/Z diastereoisomers
(89/11); orange oil; [found: C, 57.64; H, 7.56; N, 12.17.
C11H17ClN2O requires C, 57.77; H, 7.49; N, 12.25]; IR
1
(liquid film) 1657 cmK1 (C]N), 1734 cmK1 (C]O); H
NMR (400 MHz, CDCl3): (E)-diastereoisomer (89%) d 0.84
(3H, t, JZ7.4 Hz, N(1)CH2CH2CH3), 0.96 (3H, t, JZ
7.4 Hz, C]NCH2CH2CH3), 1.56 (2H, m, N(1)CH2CH2),
1.68 (2H, m, C]NCH2CH2), 2.27 (3H, s, C(4)CH3), 3.56
(2H, t, JZ7.2 Hz, N(1)CH2), 3.72 (2H, t, JZ6.8 Hz,
C]NCH2); (Z)-diastereoisomer (11%) d 0.88 (3H, t, JZ
7.4 Hz, N(1)CH2CH2CH3), 0.97 (3H, t, JZ7.3 Hz,
C]NCH2CH2CH3), 1.56 (2H, m, N(1)CH2CH2), 1.68
(2H, m, C]NCH2CH2), 2.01 (3H, s, C(4)CH3), 3.67 (2H,
t, JZ6.8 Hz, C]NCH2), 3.70 (2H, t, JZ7.7 Hz, N(1)CH2);
13C NMR (100 MHz, CDCl3): (E)-diastereoisomer (89%) d
11.18 (N(1)CH2CH2CH3), 11.66 (C]NCH2CH2CH3),
14.40 (C(4)CH3), 21.72 (N(1)CH2CH2), 25.15
(C]NCH2CH2), 40.22 (N(1)CH2), 51.31 (C]NCH2),
132.55 (C(3)), 134.22 (C(4)), 149.71 (C(5)), 164.20
(C(2)); (Z)-diastereoisomer (11%) d 9.89 (C(4)CH3),
10.89 (N(1)CH2CH2CH3), 11.66 (C]NCH2CH2CH3),
23.56 (N(1)CH2CH2), 25.09 (C]NCH2CH2), 43.81
(N(1)CH2), 50.58 (C]NCH2), 127.0 (C(3)), 143.5 (C(4)),
147.5 (C(5)), 164.20 (C(2)); MS (EI, 70 eV) m/z: 228 (100,
MC), 213 (20), 199 (77), 185 (47), 171 (35), 158 (42), 151
(72), 145 (27), 128 (53).
5.3.6. Preparation of N-propyl-3-methyl-4-(propyl-
amino)methyl-3-pyrrolin-2-one (11). According to the
general procedure, the rearrangement of 5 (0.22 g, 1 mmol)
with n-propylamine (2 mL) at 80 8C for 16 h gave 11
(0.14 g, 68%) as a pale yellow oil; [found: C, 68.51; H,
10.58; N, 13.40. C12H22N2O requires C, 68.53; H, 10.54; N,
1
13.32]; IR (liquid film) 1681 cmK1; H NMR (400 MHz,
CDCl3): d 0.80 (3H, t, JZ7.5 Hz, N(1)CH2CH2CH3), 0.81
(3H, t, JZ7.5 Hz, NHCH2CH2CH3), 1.40 (2H, m, NHCH2-
CH2), 1.48 (2H, m, N(1)CH2CH2), 1.73 (3H, s, C(3)CH3),
2.45 (2H, m, NHCH2), 3.29 (2H, t, JZ7.3 Hz, N(1)CH2),
3.47 (2H, s, C(4)CH2), 3.77 (2H, d, JZ1.4 Hz, C(5)H2); 13
C
NMR (100 MHz, CDCl3): d 8.79 (C(3)CH3), 11.18
(N(1)CH2CH2CH3), 11.58 (NHCH2CH2CH3), 21.78
(N(1)CH2CH2), 22.96 (NHCH2CH2), 43.72 (N(1)CH2),
46.08 (C(3)CH2), 51.58 (NHCH2), 52.01 (C(5)), 130.08
(C(3)), 147.63 (C(4)), 172.18 (C(2)); MS (EI, 70 eV) m/z:
210 (1, MC), 181 (4), 151 (100).
5.3.7. Preparation of N-propyl-3,4-dimethyl-5-propyl-
imino-3-pyrrolin-2-one (12). According to the general
procedure, the rearrangement of 6 (0.26 g, 1 mmol) with
n-propylamine (2 mL) at 100 8C for 16 h gave 12 (52 mg,
25%) as an unseparable mixture of E/Z diastereoisomers
(85/15); yellow oil; [found: C, 69.08; H, 9.71; N, 13.40.
C12H20N2O requires C, 69.19; H, 9.68; N, 13.45]; IR (liquid
5.3.9. Preparation of (E)-N-propyl-5-propylimino-
pyrrolidin-2-one (14). According to the general procedure,
the rearrangement of 7 (0.28 g, 1 mmol) with n-propyl-
amine (2 mL) at 80 8C for 16 h gave 14 (80 mg, 44%) as an
orange-yellow oil; [found: C, 65.78; H, 9.88; N, 15.41.
C10H18N2O requires C, 65.90; H, 9.95; N, 15.37]; IR (liquid
1
film) 1671 cmK1 (C]N), 1739 cmK1 (C]O); H NMR
1
film) 1656 cmK1 (C]N), 1718 cmK1 (C]O); H NMR
(400 MHz, CDCl3): d 0.88 (3H, t, JZ7.4 Hz, N(1)CH2-
CH2CH3), 0.92 (3H, t, JZ7.4 Hz, C]NCH2CH2CH3), 1.59
(400 MHz, CDCl3): (E)-diastereoisomer (85%) d 0.85 (3H,

C. Danieli et al. / Tetrahedron 60 (2004) 11493–11501
11501
´
´
¨
¨¨
18. Tahtinen, P.; Silanpaa, R.; Stajer, G.; Szabo, A. E.; Pihlaja, K.
J. Chem. Soc., Perkin Trans. 2 1997, 597–606.
19. Katritzky, A. R.; Xu, Y.-J.; He, H.-Y.; Steel, P. J. J. Chem.
Soc., Perkin Trans. 1 2001, 1767–1770.
(2H, m, N(1)CH2CH2), 1.60 (2H, m, C]NCH2CH2), 2.53–
2.57 (2H, m, C(3)H2), 2.60–2.65 (2H, m, C(4)H2), 3.22 (2H,
t, JZ6.9 Hz, C]NCH2), 3.52 (2H, t, JZ7.4 Hz, N(1)CH2);
13C NMR (100 MHz, CDCl3): d 11.29 (N(1)CH2CH2CH3),
11.83 (C]NCH2CH2CH3), 20.45 (N(1)CH2CH2), 21.80
(C(4)), 24.27 (C]NCH2CH2), 28.29 (C(3)), 40.79
(N(1)CH2), 51.47 (C]NCH2), 158.73 (C(5)), 176.47
(C(2)); MS (EI, 70 eV) m/z: 182 (78, MC), 167 (48), 153
(100), 139 (73), 125 (92), 112 (62), 99 (30), 83 (47), 68 (45),
54 (63), 41 (83).
20. Capraro, H.-G.; Winkler, T.; Martin, P. Helv. Chim. Acta 1983,
66, 362–378.
21. Nisole, C.; Uriac, P.; Toupet, L.; Huet, J. Tetrahedron 1993,
49, 889–900.
22. Mazurkiewicz, R. Pol. J. Chem. 1988, 62, 115–125.
23. Dougherty, T. J. J. Am. Chem. Soc. 1961, 83, 4849–4853.
24. Morel, G. C. R. Acad. Sci. (Paris) 1964, 259, 1146–1149.
25. Foucaud, A. Bull. Soc. Chim. 1964, 123–127.
26. Schuster, L. Ger. Offen. DE 3,928,982; Chem. Abstr. 1991,
114, 247131.
Acknowledgements
`
We thank the Ministero della Universita e della Ricerca
27. Ley, K.; Eholzer, U.; Nast, R. Angew. Chem., Int. Ed. Engl.
1965, 4, 519–520.
Scientifica e Tecnologica (MURST) for financial assistance,
and the Fondazione Cassa di Risparmio di Modena for the
financial support given for the acquisition of the Bruker
Avance400 Spectrometer.
28. Yasuyuki, E.; Koichi, S. Heterocycles 1992, 33, 91–95.
29. Marchand, E.; Morel, G.; Sinbandhit, S. Eur. J. Org. Chem.
1999, 1729–1738.
30. Foucaud, A.; Plusquellec, P. Bull. Soc. Chim. 1968, 12,
3813–3816.
31. Foucaud, A.; Plusquellec, P. Bull. Soc. Chim. 1968, 7,
3029–3032.
References and notes
32. Nikitin, K. V.; Andryukhova, N. P. Can. J. Chem. 2000, 78,
1285–1288.
1. Kume, T.; Goto, T.; Kamochi, A.; Yanagi, A.; Yagi, S.;
Myauchi, H. Eur. Pat. Appl. EP 286,816; Chem. Abstr. 1989,
110, 135246v.
33. Nikitin, K. V.; Andryukhova, N. P. Synthesis 2001, 89–92.
34. Ghelfi, F.; Stevens, C. V.; Laureyn, I.; Van Meenen, E.;
Rogge, T. M.; De Buyck, L.; Nikitin, K. V.; Grandi, R.;
Libertini, E.; Pagnoni, U. M.; Schenetti, L. Tetrahedron 2003,
59, 1147–1157.
2. Jensen-Korte, U.; Schallner, O.; Santel, H. J.; Schmidt, R. R.;
Strang, H. Eur. Pat. Appl. EP 334,133; Chem. Abstr. 1989,
112, 178966.
35. Ghelfi, F.; Bellesia, F.; Forti, L.; Ghirardini, G.; Grandi, R.;
Libertini, E.; Montemaggi, M. C.; Pagnoni, U. M.; Pinetti, A.;
De Buyck, L.; Parsons, A. F. Tetrahedron 1999, 55,
5839–5852.
3. Kohasaka, H.; Takase, M. Eur. Pat. Appl. EP 218,048; Chem.
Abstr. 1987, 107, 154334.
4. Kamimura, M.; Sakamoto, M.; Yoshikawa, N. Jpn. Kokai
Tokkyo Koho JP 62289581; Chem. Abstr. 1987, 109, 93006.
5. Kamimura, M.; Sakamoto, M.; Yoshikawa, N. Jpn. Kokai
Tokkyo Koho JP 62292783; Chem. Abstr. 1987, 110, 135239.
6. Ashkar, S. A. USP 4,093,441; Chem. Abstr. 1979, 90, 49647p.
7. Ashkar, S. A. USP 4,067,718; Chem. Abstr. 1978, 88, 165485s.
8. Los, M. Ger. Offen. DE 2,700,269; Chem. Abstr. 1978, 89,
146905h.
36. Clark, A. J. Chem. Soc. Rev. 2002, 31, 1–11.
37. Cagnoli, R.; Ghelfi, F.; Pagnoni, U. M.; Parsons, A. F.;
Schenetti, L. Tetrahedron 2003, 59, 9951–9960.
38. Poskonin, V. V.; Badovkaya, L. A. Chem. Heterocycl. Comp.
2003, 39, 594–597.
39. Barret, G.; Foucaud, A. Bull. Soc. Chim. 1968, 11, 4594–4599.
40. Elvidge, J. A.; Linstead, R. P. J. Chem. Soc. 1954, 442–448.
41. Taylor, E. C.; Ehrhart, W. A. J. Org. Chem. 1963, 28,
1108–1112.
9. Ashkar, S. A. USP 4,090,860; Chem. Abstr. 1978, 89,
192503y.
10. Los, M. USP 4,041,045; Chem. Abstr. 1977, 87, 168034j.
11. Pinza, M.; Riccaboni, M. T.; Cerri, A.; Farina, C. Eur. Pat.
Appl. EP 335,483; Chem. Abstr. 1990, 112, 158246a.
12. Pinza, M.; Farina, C.; Cerri, A.; Pfeiffer, U.; Riccaboni, M. T.;
Banfi, S.; Biagetti, R.; Pozzi, O.; Magnani, M.; Dorigotti, L.
J. Med. Chem. 1993, 36, 4214–4220.
42. Ghelfi, F.; Ghirardini, G.; Libertini, E.; Forti, L.; Pagnoni,
U. M. Tetrahedron Lett. 1999, 40, 8595–8597.
43. Neuhaus, D.; Williamson, M. The Nuclear Overhauser Effect
in Structural and Conformational Analysis; VCH: New York,
1989; p 253 ff.
44. Bax, A.; Griffey, R. H.; Hawkins, B. L. J. Magn. Reson. 1983,
55, 301–315.
13. Eguchi, S.; Takeuchi, H. J. Chem. Soc., Chem. Commun. 1989,
602–603.
45. Neuhaus, D.; Williamson, M. The Nuclear Overhauser Effect
in Structural and Conformational Analysis; VCH: New York,
1989; p 141 ff.
14. Sulkowski, T. S. USP 3,763,178; Chem. Abstr. 1974, 80,
3547w.
15. Balasubramaniyan, V.; Balasubramaniyan, P.; Patil, S. V.
Indian J. Chem. 1990, 29B, 124–127.
´
´
46. Brebion, F.; Delouvrie, B.; Najera, F.; Fensterbank, L.;
Malacria, M.; Vaissermann, J. Angew. Chem., Int. Ed. 2003,
42, 5342–5345.
16. Caccamese, S.; Principato, G.; Chimirri, A.; Grasso, S.
Tetrahedron: Asymmetry 1996, 9, 2577–2584.
17. Woehrle, D. Makromol. Chem. 1972, 160, 99–110. Chem.
Abstr. 1972, 78, 16521.
47. Benedetti, M.; Forti, L.; Ghelfi, F.; Pagnoni, U. M.; Ronzoni,
R. Tetrahedron 1997, 53, 14031–14042.