Synthesis of 3-alkyl-4-(chloromethyl)-1-RSO2-1 H-pyrrol-2(5 h)-ones, using a sequential ATRC/[1,2]-elimination, from 2,2-dichloro-N-(2- chloroallyl)-N-RSO2-amides

Article abstract of DOI:10.1055/s-0030-1258478

The preparation of 3-alkyl-4-(chloromethyl)-1-RSO1H-pyrrol-2(5H)-ones was efficiently accomplished through a [1,2]-elimination ofκ-lactams derived from the copper(I)-catalysed ATRC of 2,2-dichloro-N-(2-chloroallyl)-N-RSO ₂-amides. The two react

Full text of DOI:10.1055/s-0030-1258478

PAPER
1267
Synthesis of 3-Alkyl-4-(chloromethyl)-1-RSO2-1H-pyrrol-2(5H)-ones, Using a
Sequential ATRC/[1,2]-Elimination, from 2,2-Dichloro-N-(2-chloroallyl)-N-
RSO2-amides
S
ynthesis of 3-Alkyl-4
a
-(chloromethyl)-1-
t
RS
O
-
2 e
1
H
-pyrrol-
o
H
)-ones Bregoli,a Fulvia Felluga,b Vincenzo Frenna,c Franco Ghelfi,*a Ugo M. Pagnoni,a Andrew F. Parsons,d
Giovanni Petrillo,e Domenico Spinellif
a
Fax +39(59)373543; E-mail: franco.ghelfi@unimore.it
Dipartimento di Scienze Chimiche, Università degli Studi di Trieste, Via Licio Giorgieri 1, 34127 Trieste, Italy
Dipartimento di Chimica Organica ‘E.Paternò’, Università degli Studi di Palermo, Viale delle Scienze – Parco d’Orleans II,
b
c
90128 Palermo, Italy
Department of Chemistry, University of York, Heslington, York, YO10 5DD, UK
Dipartimento di Chimica e Chimica Industriale, Università degli Studi di Genova, Via Dodecaneso 31, 16146 Genova, Italy
Dipartimento di Chimica ‘G. Ciamician’, Alma Mater Studiorum, Via Selmi 2, 40126 Bologna, Italy
d
e
f
Received 17 December 2010; revised 31 January 2011
The recognized mechanism for the ATRC reaction con-
Abstract: The preparation of 3-alkyl-4-(chloromethyl)-1-RSO2-
sists of three elementary steps [Scheme 1 (a)].1 First the
Cu(I)X[Lm] metal complex reversibly abstracts a halogen
1H-pyrrol-2(5H)-ones was efficiently accomplished through a
[1,2]-elimination of g-lactams derived from the copper(I)-catalysed
ATRC of 2,2-dichloro-N-(2-chloroallyl)-N-RSO2-amides. The two
atom from the substrate A, generating a radical species
and increasing its oxidation state by one {Cu(II)X2[Lm]}.
The radical intermediate B, in the following step, adds to
the tethered C=C bond, yielding a new radical C. Finally,
this radical C is quenched by halogen transfer from the
copper(II) complex, affording the reaction product D. In
this way Cu(I)X[Lm], the active form of the catalyst, is re-
generated. The atom transfers to and from the metal com-
plex follow a concerted mechanism, via an inner-sphere
single-electron-transfer process.6
reactions can be integrated into a sequential one-pot process.
Key words: copper, cyclization, elimination, lactams, radical reac-
tion
The transition-metal-catalysed atom-transfer radical cy-
clization (TMC-ATRC) is a modern and powerful tech-
nique for the preparation of both N- and O-heterocycles.1
One particularly useful application is the synthesis of
polyhalogenated g-lactams from N-protected N-allyl-a-
haloamides.1,2a,3 Attractive aspects of the method are: (i)
high efficacy, (ii) easy execution and workup, (iii) high
productivity, (iv) catalytic nature, and (vi) preservation of
all the starting C–X functionalities on converting reactant
into product. Additionally, the preparation of interesting
natural or synthetic bioactive molecules, like chaetomellic
anhydrides A and C,4a–d roccellic acid,4d tyromicin A,4e
gabapentin,4f,g pilolactam,4h molecules with herbicidal ac-
tivity,4i and the alkaloids trachelanthamine, haemantidine,
and pretazzetine,4j has been achieved using a strategic
TMC-ATRC step in the synthetic route.
Cl
R1
N
R1
N
Cl Cl
R2
a)
R2
A
O
O
B
CuCl
CuCl2
R2 Cl
R2 Cl
Cl
O
N
R1
O
D
N
R1
C
Copper(I) halide complexes with polydentate nitrogen
ligands are by far the preferred catalysts,1a–f,2 being inex-
pensive and easy to prepare. Moreover they are versatile
since the redox features of the complex can be adjusted by
simply changing the ligand, whose number is large and
ever increasing, thanks to the advancements in the sister
technique of atom transfer radical polymerization.5 With
particularly reactive amides or when a nucleophilic sol-
vent, like acetonitrile or N,N-dimethylformamide, is used,
the ligand can be left out.2a
R2
R2 Cl
R2 Cl
b)
Cl
Cl
Cl
CuCl
CuCl
CuCl2
O
O
N
R1 B
CuCl2
O
N
R1
N
R1
trans-D
cis-D
Scheme 1 (a) Copper-catalyzed ATRC of N-allyl-a-polychloro-
amides to form g-lactams; (b) epimerization of the C3 centre of g-lac-
tams D
The substituent R1 on the nitrogen atom of amide A plays
a pivotal role in ensuring an efficient cyclization, since it,
by influencing rotation around the amide bond, allows A,
or the radical intermediate B, to adopt the appropriate con-
SYNTHESIS 2011, No. 8, pp 1267–1278
Advanced online publication: 16.03.2011
DOI: 10.1055/s-0030-1258478; Art ID: Z54710SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
1
1

1268
M. Bregoli et al.
PAPER
formation [Scheme 1 (a)].7 This occurs because the N–CO deed, to the best of our knowledge, the only viable process
rotational barrier is lowered as a result of a steric interac- is still that published by Slough and Rachita (Scheme 2),8c
tion, which can be also strengthened by an electronic ef- but it uses a heavy (MW = 958.8) and expensive rutheni-
fect. In fact, if the R1 group is electronegative, the um catalyst, and it operates in a toxic solvent (benzene),
resonance stabilization between the lone pair on nitrogen under diluted conditions (substrate concentration = 0.12
and the neighbouring C=O is decreased, resulting in an M).
amide bond having an enhanced single bond character. In
R2
addition, the electron-withdrawing substituent lowers the
LUMO energy of the Ca–Cl bond, facilitating chlorine
atom abstraction by the copper(I) complex.2a,7a,b Another
important facet of the TMC-ATRC reaction is the config-
urational instability of the C3 stereogenic centre in the g-
lactam product D, which, under the reaction conditions,
can be epimerized by the same ATRC catalyst [Scheme 1
(b)].2a,4b,8
EWG
δ+
R2
δ–
O
N
Nu
R1
EWG
R2
δ+
δ–
R2
O
O
N
R1
Y
Cl
δ+
Y
δ –
R2
O
N
R1
Cl
O
N
R1
Cl
E
E
Cl
δ–
N
R1
R2
Cl
Y
a
Y
δ+
– HCl
O
N
O
N
O
N
R1
Ts
Ts
cis
90%
Scheme 3 Some hypothetical uses of 4-(chloromethyl)-1H-pyrrol-
2(5H)-ones following reaction with nucleophilic, electrophilic, or
1,2- or 1,3-dipolar reagents (in bold is the mimicked trimethyleneme-
thane substructure)
Scheme 2 Reagents and conditions: (a) (Ph3P)3RuCl2 (5 mol%),
C6D6, argon, 100 °C, 72 h.
Although the preservation of all the halo functions in the
final product is a key feature of the reaction,1 the interest
in the preparation of polychlorinated pyrrolidin-2-ones,
using this technique, has essentially been confined to the
testing of new catalysts, whereas the exploitation of the
C–X functionalities in the cyclic products has been some-
what ignored. The few applications, reported in literature,
excluding hydrodehalogenations, have regarded: stepwise
or sequential radical processes,8b,9 functional rearrange-
ment into 5-methoxy-1H-pyrrol-2(5H)-ones or maleim-
ides,4a–4e,8a,10 preparation of bicyclo[3.2.0]hexan-2-ones,11
dehydrohalogenations,4j,8c,12 aromatization of bicyclic ad-
ducts,8b,9b and substitutions of the exo-Cl group with O-
nucleophiles.4j,13 Among these uses, the ruthenium-catal-
ysed dehydrochlorination of cis-3-chloro-4-(chlorometh-
yl)-1-tosylpyrrolidin-2-ones, reported by Slough and
Rachita,8c captured our attention (Scheme 2).
We have recently demonstrated a tandem approach, in-
volving an ATRC and a reductive [1,2]-elimination, both
mediated by the system CuCl[PMDETA]/ascorbic acid/
Na2CO3, to obtain E from N-(2-chloroallyl)-a-polychlo-
roamides.14 Unfortunately, the technique is devoid of any
general applicability, yielding acceptable results in only a
few cases.
For the sake of completeness, we have to mention two
other reports on the isolation of compounds of type E: the
preparation of a 4-(1-bromoethyl)-1H-pyrrol-2(5H)-one
by bromination, with N-bromosuccinimide, of an N-sub-
stituted 4-ethyl-1,3-dimethyl-5-tosyl-1H-pyrrol-2(5H)-
one (2 d, 70%),15a and the isolation of a 4-(chloromethyl)-
1H-pyrrol-2(5H)-one as byproduct in the ATRC of N-pro-
pargyl-N-tosyltrichloroacetamide.15b
In fact, 4-(chloromethyl)-1H-pyrrol-2(5H)-ones
E
Cl
Cl
(Scheme 3) are interesting molecules, which possess both
a g-exo electrophilic centre (the allylic chloro function)
and a quiescent g-endo nucleophilic site (the vinylogous
C5–H hydrogens are relatively acidic), both conjugated to
the a,b-unsaturated system. The synthetic potential of a
structure like this, which in a sense mimics a trimethyl-
enemethane arrangement, is enormous, as outlined by the
examples in Scheme 3. In addition, the D3-unsaturation is
a useful means to control the configuration of the substit-
uents, at C3 and C4, through stereoselective hydrogena-
tions.
SO2Me
N
Cl
Cl Cl
a
+
O
N
O
N
O
1a
SO2Me
SO2Me
2a (cis/trans = 8:92)
3a
44%
53%
Scheme 4 Reagents and conditions: (a) CuCl (10 mol%), DMF,
argon, 80 °C, 24 h.
During our recent studies on the ATRC of N-alkyl-N-al-
lyldichloroamides to g-lactams, catalyzed by ‘naked’ cop-
per(I) chloride (‘ligand-free-like’-ATRC), we observed
that, when N-mesyldichloroamide 1a and copper(I) chlo-
ride (10 mol%) were heated at 80 °C in N,N-dimethyl-
formamide (24 h), the g-lactam 2a was recovered along
Nevertheless, and quite astonishingly, the study of the re-
activity and of the synthetic potential of E has been com-
pletely neglected. Perhaps this is due to the absence of
appropriate methods for their large-scale preparation. In-
Synthesis 2011, No. 8, 1267–1278 © Thieme Stuttgart · New York

PAPER
Synthesis of 3-Alkyl-4-(chloromethyl)-1-RSO2-1H-pyrrol-2(5H)-ones
1269
Table 1 [1,2]-Elimination from 2a To Give 1H-Pyrrolidin-2-one 3a
Entry
Ratio cis/trans of 2aa Solvent (mL)
Et4NCl (mol%) Temp (°C)
Time (h)
40
Conv.b,c (%) Yieldb (%) of 3a
1
2
3
4
5
6
7
8e
58:42
57:43
57:43
66:34
55:45
87:13
87:13
87:13
DMF (3)
DMF (3)
DMF (4)
DMF (3)
DMF (3)
DMF (3)
NMP (3)
DMF (45)
0
5
80
80
86
88
84
40
84
10
20
0
80
24
87
86
80
23
90
90
100
100
100
100
24
100
100
100
100
94
0
24
93d
94d
94d
0
24
0
24
a Reactions were performed using 5 mmol of substrate.
b Determined by GC.
c Unreacted material, which was always trans-2a.
d Determined on isolated material.
e This reaction was performed using 73.5 mmol of substrate.
with the 4-(chloromethyl)-1H-pyrrol-2(5H)-one 3a interaction between the p-LUMO of the C=O and the elec-
(Scheme 4).2a To our surprise, the unsaturated g-lactam 3a tron density that builds up, in the transition state of the SN2
was the main product: clearly, an endo-[1,2]-elimination reaction, at the pentacoordinate C3 (this enhances the pro-
(E) follows the ATRC. Furthermore the usual large pref- clivity of the a-halogen in 2a to be displaced).18b Both fac-
erence for the cis-2a diastereomer was not observed as 2a tors, cooperating synergistically, facilitate the inversion
was isolated, almost exclusively, in the trans configura- of configuration at C3.
tion. These experimental facts indicate, beyond any doubt,
that 3a is derived from the anti-dehydrochlorination of
cis-2a.
Likely the increased reactivity of the a-chloro function,
brought about by the sulfonyl substituent, is also a requi-
site for the smooth dehydrohalogenation of 2a. The ab-
We deemed that this attractive ATRC/[1,2]-elimination sence of any 4-(chloromethyl)-1H-pyrrol-2(5H)-one in
tandem transformation could have potential application as the crude products obtained from the reaction of the N,N-
a new preparative method to form 4-(chloromethyl)-1H- diallyl- or N-allyl-N-benzyl-2,2-dichloropropanamides
pyrrol-2(5H)-ones. Our results are described herein.
using copper(I) chloride in N,N-dimethylformamide at
100 °C,2a firmly corroborates this assumption.
At first, we tried to answer a preliminary question: what is
the mechanism of the elimination step? The query was Gratified by this first test, we tried to force the elimination
clarified by heating 2a in N,N-dimethylformamide at 80 in 2a to completion. To this end, we thought it might be
°C (Table 1, entry 1). The efficient formation of 3a means beneficial to add a source of chloride ion to the reaction
that, contrary to the observations of Slough and Rachita, mixture (Table 1, entries 2–4). However, no improvement
the dehydrohalogenation, in our case, is not metal-cata- was apparent, even when the chloride-carrier amounted to
lysed. Instead it is a typical anti-[1,2]-elimination mediated 20 mol%. In contrast, a modest increase of the reaction
by N,N-dimethylformamide, which, therefore, plays the temperature to 100 °C was more rewarding: under these
role of both solvent and base in the reaction mixture.16
conditions, total conversion was indeed achieved (entries
5 and 6).
Incidentally, this first test shed light on how to enhance
the efficiency of the transformation. The fact that the yield The dehydrochlorination works efficiently also on a pre-
of 3a (84%) did not correspond to the percentage of the parative scale (entry 8) and N,N-dimethylformamide can
cis-isomer in the starting g-lactam 2a (58%) tells us two be replaced by N-methylpyrrolidin-2-one without encoun-
important things: (i) trans-2a epimerizes to cis-2a, and (ii) tering any problems (entry 7).
an ionic mechanism must be implicated, for the first time,
The elimination was carried out in a sealed Schlenk reac-
in the configuration reversal.17 Perhaps this involves an
tor and an increase in pressure was evident inside the re-
SN2 reaction of the a-C–Cl group of trans-2a with chlo-
ride ions, freed during the facile elimination from the cis
adduct (Scheme 5).
action tube. As we detected through the GC-MS of the
reaction tube headspace, the pressure build-up is caused
by the production of carbon monoxide. It originates
The unexpected epimerization can be fully understood if from the decomposition of N,N-dimethylformamide
we take into account: (i) the polar aprotic nature of N,N- (Scheme 5), a well-known phenomenon, whose rate in-
dimethylformamide, which exalts the chloride anion nu- creases at high temperatures and in the presence of acids
cleophilicity,18a and (ii) the powerful electron-withdraw- or bases.16a,19
ing effect of the sulfonyl group, which enforces the
Synthesis 2011, No. 8, 1267–1278 © Thieme Stuttgart · New York

1270
M. Bregoli et al.
PAPER
Cl
Cl
H
R3
Cl
R2
R3
Cl
R2
Cl
Cl
SO2R1
N
Cl Cl
R3
CuCl
DMF
O
O
N
N
O
N
O
N
cis-2a
SO2Me
SO2Me
3a
SO2R1
O
R2
SO2R1
1
2
3
N
H
N +
H
a
b
c
d
e
f
h
i
j
g
O
R1
R2
R3
Me
H
Me
H
CF3
H
Me
H
Me
H
Cl –
Me
H
4-tolyl
H
Me
Me
Me
Me
Ph
Me
Me
H
OH
Cl
Cl
C
O
H
H
H
Me
H
Et
Et
Et
i-Pr
n-Hex Cl
O
N
Cl –
N
+
SO2Me
trans-2a
Scheme 6 Copper(I) chloride catalyzed ATRC/[1,2]-elimination of
N-allyl-N-sulfonyl-a-polychloroamides
Scheme 5 Mechanism of the elimination/epimerization of 2a in
N,N-dimethylformamide
Owing to its thermal instability, substrate 1e was unsuited
to the ligand-free procedure at 100 °C. An ATRC cataly-
sed by a copper(I) chloride complex that can operate at a
lower temperature was, thus, needed. The powerful elec-
tron-withdrawing effect of the triflyl group ensures that 1e
has such a high activity, and an easy rotation around the
amide bond, that it successfully undergoes complete cy-
clization using CuCl[TMEDA]2 at even 0 °C (Table 2, en-
try 10).
To investigate the scope of the method, the starting N-al-
lyl-N-sulfonyl-2,2-dichloroamides 1b–g were synthe-
sized. These substrates were then cycloisomerized using
copper(I) chloride in acetonitrile, under ‘ligand-free-like’
conditions (Scheme 6 and Table 2).2a The desired g-lac-
tams 2 were secured in excellent yields and with a diaste-
reomeric cis/trans ratio of ca. 60:40. For comparison,
amides 1c and 1d were also cyclized, under standard con-
ditions, using the redox complex CuCl[TMEDA]2. As
predicted, the diastereomeric ratio ameliorated consistent-
ly (85:15); the product yields were unaffected (Table 2,
entries 3, 4 and 7, 8).2a
The g-lactams 2b–g (Scheme 6) were then subjected to
the elimination protocol established for 2a. The impact of
the R3 group at C3, on the reaction progress, was immedi-
ately apparent. When no substituent was present, as in 2b
(R3 = H), harsher conditions (120 °C) were required al-
though this resulted in an unselective reaction. Instead,
Table 2 Preparation of the g-Lactams 2 by Copper-Catalyzed ATRC
Entry
1
Substrate (mmol) Solvent (mL)
CuCl (mol%) Temp (°C)
Time (h)
23
Conv.a (%)
100
Yieldb (%) (ratioc cis/trans)
97 (57:43)
92 (27:73)
96 (67:33)
97 (86:14)
94 (86:14)
92 (85:15)
98 (61:39)e
95 (85:15)e
80 (84:16)e
93 (75:25)e
93 (75:25)
93 (93:7)
1a (5)
1b (5)
1c (15)
1c (5)
1c (5)
1c (5)
1d (5)
1d (5)
1e (5)
1e (5)
1f (5)
1g (5)
1j (5)
MeCN (2.5)
MeCN (2.5)
MeCN (7.5)
MeCN (4)
DMF (4)
10
100
120
100
35
2
10
24
99
3
10
24
100
4
10d
10d
5d
20
100
5
35
20
100
6
DMF (4)
35
20
100
7
MeCN (2.5)
MeCN (4)
MeCN (4)
MeCN (4)
MeCN (2.5)
MeCN (2.5)
MeCN (2.5)
10
100
35
22
100
8
10d
10d
10d
10
23
100
9
20
20
100
10
11
12
13
0
20
100
100
100
80
24
100
10
24
100
10
4
100
98
a Determined by GC.
b Determined on isolated material.
c Ratio cis/trans determined by 1H NMR.
d CuCl[TMEDA]2 was used.
e Ratio cis/trans determined by GC.
Synthesis 2011, No. 8, 1267–1278 © Thieme Stuttgart · New York

PAPER
Synthesis of 3-Alkyl-4-(chloromethyl)-1-RSO2-1H-pyrrol-2(5H)-ones
1271
when R3 was a larger sized group, such as in 2c (R3 = Et), derived from cis-2c (Scheme 7). This last point was defin-
a moderate regioselectivity problem arose. In addition to itively corroborated by the quantitative transformation of
the lactam 3c, derived from the expected endo dehydro- the single isomer cis-2e into 3e (entry 11). Under the same
chlorination, a small amount of the 3-ethylidene-g-lactam conditions 3e and 4e were recovered from the reaction of
4c (as a mixture of E/Z diastereomers) (Figure 1) was also trans-2e (entry 12). The ratio yield3e/yield4e ≈ 4 means the
afforded through a competing exo-elimination process epimerization is only slightly faster than the exo-elimina-
(Table 3, entry 2). It is likely that, for steric reasons, the tion (Scheme 7).
larger size of R3 (b-branching) slows down the epimeriza-
At this point the only remaining chance to substantially
tion of trans-2c sufficiently so that the alternative exo-
ameliorate the selectivity toward g-lactams 3 was to use,
dehydrohalogenation pathway becomes competitive
(Scheme 7).
as starting materials, dichloro-g-lactams 2 with a higher
cis/trans ratio (Table 3, entries 2, 7 and 8, 9). As men-
tioned earlier, this can be accomplished by carrying out
the ATRC in the presence of copper(I) chloride complex-
es using nitrogen ligands (Table 2, entry 3, 4 and 7, 8).
kepim
kE-endo/cis
Cl
Cl
Cl
Cl
Cl
Cl –
DMF
– HCl
Some years ago, during our studies on the functional rear-
rangement of polyhalogenated g-lactams,4a–c we noted
that, in sodium methoxide/methanol, molecules like
trans-7, although unable to undergo endo-elimination, un-
derwent dehydrohalogenation all the same, affording the
4-methylene-g-lactam 8 [Scheme 8 (a)].4b,c,10 Astonish-
ingly this exo-regioselectivity at the C4 position is at odds
with the exo-regioselectivity at C3, reported here, for the
similar molecule trans-2c [Scheme 8 (b)]. These findings
can be rationalized by considering that for trans-7, where
a ‘strong’ base is involved and the a-Cl is not particularly
activated, the elimination involved the more acidic C4–H
hydrogen (E2-E1cb like),20 while for trans-2c, where the
base is weak and the a-Cl is instead strongly activated,
elimination involved the more labile C3–Cl bond
(Scheme 8).
O
DMF
O
O
N
N
N
SO2Me
SO2Me
SO2Me
3c
trans-2c
cis-2c
DMF
– HCl
x
DMF
kE-exo/trans
–
HCl
Cl
4c
O
N
kE-endo/cis >> kepim > kE-exo/trans
SO2Me
Scheme 7 Full reaction scheme for the sequential ATRC/[1,2]-eli-
mination
c
d
e
h
i
R4
R1
R2
R3
R4
Me
H
Me
H
Cl
R2
Me 4-tolyl CF3
R3
H
H
H
H
H
H
In spite of the higher susceptibility towards the C4 exo-
elimination, substrates 2f and 2g, which have a secondary
exo C–Cl function, also gave the lactams 3. However, the
conversion of 2g was not as selective as usual, and the
yield of 3g was only fair (Table 3, entry 14). For 2f, the re-
action did not stop at the stage of 3f and, in part, a second
elimination occurred, delivering the conjugated dienone 5
(Table 3, entry 13 and Figure 1).
O
N
Me
H
SO2R1
Me
Me
Me
Me n-Pent
HO
4
Ph
O
O
N
N
SO2Me
SO2Me
6
5
DMF
Figure 1 Other products provided by the elimination step of g-lac-
tams 2
a)
H
Cl
H
H
O
Cl
Cl
H
DMF
H
We tried to suppress the side reaction by changing the re-
action conditions. Unfortunately, higher dilution (Table 3,
entry 3), harsher conditions (entry 4), the addition of a
chloride ion carrier (entry 5), or the use of more electrone-
gative sulfonyl groups (entries 8 and 10) had no effect on
the regioselectivity.
– HCl
O
N
N
SO2Me
trans-2c
SO2Me
DMF
3c
x
MeONa
b)
Cl
H
H
H
H
Cl
Cl
C5H11
C5H11
When stopping the dehydrohalogenation of 2c after only
4.5 hours (entry 6), we observed that the transformation of
the cis isomer was virtually complete, the unreacted mate-
rial was essentially trans, and 4c was formed in only 1%
yield. This result demonstrates that the endo-elimination
of cis-2c is by far the fastest process and that 4c cannot be
MeOH
– HCl
H
O
N
O
N
Bn
Bn
8
MeONa
trans-7
Scheme 8 Rationalization of the different exo-regioselectivity in
the elimination of analogous trans-3-chloro-4-(chloromethyl)-g-lac-
tams
Synthesis 2011, No. 8, 1267–1278 © Thieme Stuttgart · New York

1272
M. Bregoli et al.
PAPER
Table 3 Preparation of the a,b-Unsaturated g-Lactams 3
Entry
Substrate
(mmol)
Substrate
(dr)
Solvent
(mL)
CuCl
(%)
TMEDA Temp
Time
(h)
Conv.a Yield (%)
(%)
(°C)
100
100
100
120
100
100
100
100
100
100
100
100
100
100
80
(%)
100
100
99
3b
4b,c
Otherb
1
2
2a (3)
2c (5)
2c (5)
2c (5)
2c (5)
2c (5)
2c (3)
2d (3)
2d (3)
2e (3)
cis-2e (3)
trans-2e (1)
2f (5)
87:13
67:33
67:33
67:33
67:33
67:33
85:15
61:39
86:14
50:50
–
DMF (3)
0
0
0
24
24
24
18
24
4.5
24
24
24
24
23
23
24
24
6
93
75
75
76
76
66
84
74
89
85
91
76
46
53
87
92
78
94
80
86
83
48
0
0
–
DMF (3)
0
11 (60:40)
–
3
DMF (10)
DMF (3)
0
0
14 (82:18)
–
4
0
0
100
100
72b
10 (86:14)
–
5d
6
DMF (3)
0
0
14 (78:22)
–
DMF (3)
0
0
1
–
7
DMF (1.8)
DMF (1.8)
DMF (1.8)
DMF (1.8)
DMF (1.8)
DMF (1.8)
0
0
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
7 (68:32)
–
8
0
0
23 (81:19)
–
9
0
0
9 (80:20)
–
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
0
0
9 (87:13)
–
0
0
0
–
–
0
0
20 (82:18)
–
42:33:21:4 DMF (3)
0
0
0
46 (5)
2g (5)
2j (5)
62:31:7
DMF (3)
DMF (3)
DMF (4)
DMF (4)
NMP (4)
DMF (4)
DMF (4)
DMF (4)
DMF (4)
DMF (4)
DMF (4)
DMF (4)
0
0
0
–
–
–
–
–
–
–
–
–
–
–
–
0
0
–
–
1a (5)
1c (5)
1c (5)
1d (5)
1d (5)
1d (5)
1f (5)
10
10
10
10
5
0
100
100
100
100
24
24
24
24
0
–
0
6 (77:23)
–
0
0
–
0
15 (82:18)
–
e
e
10
10
0
–
–
9 (76:24)
–
f
f
5
–
–
11 (78:22)
–
10
10
10
10
100
100
100
100
24
24
24
24
0
43 (5)
1g (5)
1h (5)
1i (5)
0
0
49 (6)
0
77
76
14
–
–
0
10 (80:20)
a Determined by GC.
b Determined on isolated material.
c In parentheses is the E/Z ratio determined by 1H NMR.
d Et4NCl was added (20 mol%).
e TI = 35 °C (12 h) and TII = 100 °C (24 h).
f TI = 35 °C (5 min) to 100 °C in 25 min and TII = 100 °C (23.5 h).
Finally, we explored the integration of ATRC and [1,2]- (entry 23), rather than isolate 3g, the hydroxy analogue 6
elimination into a one-pot process. As both reactions can was recovered (this result was not examined further).
be carried out in the same solvent, this was very easy to
accomplish. In fact, it was just enough to heat at 100 °C a
mixture of the starting amide and copper(I) chloride in
N,N-dimethylformamide (or NMP), to obtain the 4-(chlo-
romethyl)-1H-pyrrol-2(5H)-ones 3, with the same effec-
tiveness observed with the step-by-step procedure
(Table 3, entries 16–25). Unexpectedly, with substrate 1g
The trichloroacetamide 1j was unsuited to the sequential
one-pot procedure. In fact, at 70–80 °C, the elimination
product 3j, likely owing to the presence of copper(I) chlo-
ride, came up against a number of side-transformations,
whereas at lower temperature (60 °C, 17 h) the dehydro-
halogenation was partial. Thus we opted for the stepwise
strategy and prepared in high yield, through the ligand-
Synthesis 2011, No. 8, 1267–1278 © Thieme Stuttgart · New York

PAPER
Synthesis of 3-Alkyl-4-(chloromethyl)-1-RSO2-1H-pyrrol-2(5H)-ones
1273
free ATRC of 1j, the trichlorolactam 2j (Table 2, entry cess. We urge parties who are interested in developing the
13). Owing to the double substitution with halogens at C3, chemistry of 4-(chloromethyl)-1H-pyrrol-2(5H)-ones to
the elimination step of 2j was facilitated, and the reaction contact us for a supply of these products.
could be effectively completed at 80 °C in only six hours,
giving the functionalised lactam 3j, which features one al-
Reagents and solvents were standard grade commercial products,
lylic and one vinylic chlorine (Table 3, entry 15). The low
reaction temperature, in this case, prevented the decompo-
sition of N,N-dimethylformamide hydrochloride and the
subsequent pressure build-up, inside the Schlenk tube.
and generally used without further purification. CuCl was a product
of purity grade puriss. p.a. ACS ≥ 97%. Flash chromatography was
performed using Silica Gel 60 Merck (0.040–0.063 mm); PE = pe-
troleum ether. 10% HCl was w/v.
The amides 1a–j were efficiently assembled by reaction of acyl
chlorides with sodium allyl(sulfonyl)amides, following or adapting
standard procedures.2a,8a,23 Only in the case of 1e, was the
acylation24 of the N-allyltrifluoromethanesulfonamide carried out in
the presence of pyridine [since 1e is prone to hydrolysis, the reac-
tion mixture was concentrated and directly purified as fast as possi-
ble by chromatography (PE–Et2O, 100:0 to 70:30); notwithstanding
the problem was only partially contained, and the product was re-
covered in only fair yield, 51%]. Commercial anhyd THF or
CH2Cl2, dried over three batches of 3 Å molecular sieves (5% w/v,
12 h), were used as solvents in these reactions.
Since the best outcome of the elimination step requires g-
lactams 2 with a higher content of cis diastereomer (see
above), we tried to reach such a goal, also in the sequential
process. To this aim we first established that the
CuCl[TMEDA]2 catalysed ATRCs in N,N-dimethylform-
amide or in acetonitrile were alike (Table 2, entries 4–6).
Then, the cycloisomerization in N,N-dimethylformamide,
catalysed by the copper(I) complex, was successfully
joined to the elimination step, having the forethought to
let the ATRC to go to completion at ‘low’ temperature
(Table 3, entry 19 and 20).
The starting N-allyl sulfonamides were easily obtained by sulfony-
lation, with commercial reagents, of allylamine, using or adapting
literature methods.25 Cinnamylamine and crotylamine were pre-
pared from the corresponding allyl chloride by the Delèpine meth-
od.26
Products 2a, 3a, and 2b are known compounds.2a,8a IR and MS spec-
tra were recorded, respectively, on Perkin Elmer 1600 Series FTIR,
or Avatar 320 FT/IR, and HP 5890 GC–HP 5989A MS (for EI 70
eV) or Bruker Esquire 4000 (for ESI) instruments. NMR spectra
were recorded on a Varian 500 MHz spectrometer. Signal attribu-
tions were based on gCOSY and gHSQC spectroscopy; only in the
case of 2j and 3j were signals assigned by analogy with related
products. The relative configurations of g-lactams 2 and 4 were de-
To bypass the regioselectivity problem we also tried the
ATRC of the N-(2-chloroallyl)-a-monohalopropanamides
9.21 The corresponding g-lactams 10, in fact, have an a-H
adjacent to the C=O function, which, reasonably, can be
easily epimerized under basic conditions, affording the
desired configuration for the endo-elimination step
(Scheme 9). Unfortunately, we were unable to achieve
any cyclization of 9, under a variety of reaction condi-
tions. Likely, as we observed in the case of the N-benzyl-
2,2-dichloro-N-(2-chloroallyl)acetamide,14 the alleged in-
tramolecular hydrogen bond, between the a-H and the vi- termined by NOESY experiments. Elemental analyses were per-
formed on the EA 1110 Carlo Erba.
nylic chlorine, forces the amide 9 to adopt a conformation
unsuitable for the cyclization, opening the door to side re-
actions.
3-Chloro-4-(chloromethyl)-3-methyl-1-(methylsulfonyl)pyrro-
lidin-2-one (2a); Typical Procedure 1
CuCl (0.050 mg, 0.5 mmol) and 2,2-dichloroamide 1a (1.301 g, 5
Cl
SO2Ph
N
mmol) were weighed in a Schlenk tube fitted with a pierceable sep-
tum (blocked by a screw cap) and a magnetic stirring bar. MeCN
(2.5 mL) was then added under argon. The mixture was stirred at
100 °C and after 23 h was diluted with H2O (30 mL), acidified with
10% HCl, and extracted with CH2Cl2 (4 × 5 mL). The combined or-
ganic layers were concentrated. Flash chromatography of the crude
(silica gel, PE–Et2O, 100:0 to 10:90) gave the pyrrolidinone 2a
(1.262 g, 97%) as a white powder; inseparable mixture of diastereo-
mers cis/trans 57:43 (1H NMR).
H
X
X
X
H
CuCl
x
DMF
O
O
N
N
O
Cl
SO2Ph
SO2Ph
9
10
11
X = Cl, Br
Scheme 9 ATRC/[1,2]-elimination of N-(2-chloroallyl)-a-mono-
halopropanamides
3-Chloro-4-(chloromethyl)-1-(methylsulfonyl)pyrrolidin-2-one
In this work we have shown that the 3-alkyl-4-(chloro- (2b)
Following typical procedure 1, 1b (1.231 g, 5 mmol) was treated
methyl)-1-RSO2-1H-pyrrol-2(5H)-ones can be efficiently
prepared through a [1,2]-elimination of g-lactams derived
from the copper-catalysed ATRC of 2,2-dichloro-N-(2-
chloroallyl)-N-RSO2-amides. The reactivity of these
products, although not fully assessed as yet, seems very
appealing. We also deem that the use of the carbon mon-
oxide, released by decomposition of N,N-dimethylform-
amide, in a consecutive carbonylative reaction of the
unsaturated lactams 3, might turn out to be synthetically
useful.22 Attractive features of the method are: simplicity,
inexpensive, high productivity, and the possibility to inte-
grate ATRC and elimination into a sequential one-pot pro-
with CuCl (0.050 mg, 0.5 mmol) in MeCN (2.5 mL) at 120 °C for
24 h. Flash chromatography of the crude product (silica gel, PE–
Et2O, 100:0 to 10:90) gave 2b (1.133 g, 92%) as a pale brownish
powder; inseparable mixture of diastereomers cis/trans 27:73 (1H
NMR).
3-Chloro-4-(chloromethyl)-3-ethyl-1-(methylsulfonyl)pyrroli-
din-2-one (2c)
Following typical procedure 1, 1c (4.113 g, 15 mmol) was treated
with CuCl (0.150 mg, 1.5 mmol) in MeCN (7.5 mL) at 100 °C for
24 h. Flash chromatography of the crude product (silica gel, PE–
Et2O, PE–Et2O, 80:20 to 20:80 gradient) gave 2c (3.948 g, 96%) as
Synthesis 2011, No. 8, 1267–1278 © Thieme Stuttgart · New York

1274
M. Bregoli et al.
PAPER
a pale yellow oil; inseparable mixture of diastereomers cis/trans
IR (film): 1748 cm–1 (C=O).
67:33 (1H NMR).
1H NMR (500 MHz, CDCl3): d = 1.08 (t, J = 7.5 Hz, 3 H, CH3CH2),
2.19, 2.28 (2 dq, J = 14.6, 7.5 Hz, 1 H each, 2 H, CH2CH3), 2.90 (m,
1 H, H4), 3.65 (t, J = 10.1 Hz, 1 H, H5), 3.68 (dd, J = 11.5, 9.0 Hz,
1 H, CHCl), 3.82 (dd, J = 11.5, 5.1 Hz, 1 H, CHCl), 4.22 (dd,
J = 10.1, 7.2 Hz, 1 H, H5).
13C NMR (125.68 MHz, CDCl3): d = 9.1, 29.4, 40.7, 42.8, 48.7,
71.9, 119.4, 167.8.
IR (film): 1743 cm–1 (C=O).
1H NMR (500 MHz, CDCl3): d (cis) = 1.06 (t, J = 7.4 Hz, 3 H,
CH3CH2), 2.22, 2.21 (dq, J = 7.4 Hz, 2 H, CH2CH3), 2.84 (m, 1 H,
H4), 3.27 (s, 3 H, CH3SO2), 3.49 (dd, J = 11.3, 10.0 Hz, 1 H, H5),
3.67 (dd, J = 11.4, 9.0 Hz, 1 H, CHCl), 3.80 (dd, J = 11.4, 5.2 Hz, 1
H, CHCl), 4.15 (dd, J = 10.0, 7.0 Hz, 1 H, H5); d (trans) = 1.18 (t,
J = 7.3 Hz, 3 H CH3CH2), 1.97, 2.15 (2 m, 2 H, CH2CH3), 2.97 (m,
1 H, H4), 3.28 (s, 3 H, CH3SO2), 3.52 (dd, J = 11.6, 11.4 Hz, 1 H,
CHCl), 3.73 (dd, J = 11.6, 3.8 Hz, 1 H, CHCl), 3.87 (dd, J = 10.6,
3.1 Hz, 1 H, H5), 4.11 (dd, J = 10.6, 6.4 Hz, 1 H, H5).
13C NMR (125.68 MHz, CDCl3): d (cis) = 9.3, 28.8, 39.9, 41.3,
43.0, 47.0, 72.8, 169.6; d (trans) = 8.3, 25.8, 40.3, 41.8, 46.1, 46.8,
72.2, 169.6.
MS (EI, 70 eV): m/z (%) = 245 (55) [(M + 1) – 29]+, 238 (6), 196
(100), 79 (31).
MS (EI, 70 eV): m/z (%) = 299 (38) [(M + 1) – 29]+, 250 (100), 69
(36).
Anal. Calcd for C8H10Cl2F3NO3S: C, 29.28; H, 3.07; N, 4.27; S,
9.77. Found: C, 29.31; H, 3.08; N, 4.28; S, 9.82.
Diastereomer trans-2e
Brownish oil; yield: 0.378 g (23%).
IR (film): 1745 cm–1 (C=O).
1H NMR (500 MHz, CDCl3): d = 1.21 (t, J = 7.8 Hz, 3 H, CH3CH2),
1.88, 2.20 (2 dq, J = 14.8, 7.8 Hz, 1 H each, 2 H, CH3CH2), 3.00 (m,
1 H, H4), 3.48 (dd, J = 12.0, 8.6 Hz, 1 H, CHCl), 3.73 (dd, J = 12.0,
3.9 Hz, 1 H, CHCl), 4.03 (dd, J = 11.0, 2.4 Hz, 1 H, H5), 4.26 (dd,
J = 11.0, 6.7 Hz, 1 H, H5).
13C NMR (125.68 MHz, CDCl3): d = 8.2, 25.7, 41.5, 45.8, 48.6,
71.3, 119.3, 167.8.
Anal. Calcd for C8H13Cl2NO3S: C, 35.05; H, 4.78; N, 5.11; S, 11.70.
Found: C, 34.92; H, 4.84; N, 5.11; S, 11.67.
3-Chloro-4-(chloromethyl)-3-ethyl-1-tosylpyrrolidin-2-one (2d)
Following typical procedure 1, 1d (1.751 g, 5 mmol) was treated
with CuCl (0.050 mg, 0.5 mmol) in MeCN (2.5 mL) at 100 °C for
22 h. Flash chromatography of the crude product (silica gel, PE–
Et2O, 80:20 to 20:80) gave 2d (1.716 g, 98%) as a white powder;
inseparable mixture of diastereomers cis/trans 61:39 (GC).
MS (EI, 70 eV): m/z (%) = 299 (29) [(M + 1) – 29]+, 250 (100), 69
(43).
IR (KBr): 1745 cm–1 (C=O).
Anal. Calcd for C8H10Cl2F3NO3S: C, 29.28; H, 3.07; N, 4.27; S,
9.77. Found: C, 29.19; H, 3.09; N, 4.29; S, 9.80.
1H NMR (500 MHz, CDCl3): d (cis) = 0.98 (t, J = 7.3 Hz, 3 H,
CH3CH2), 2.06, 2.12 (2 dq, J = 14.8, 7.3 Hz, 1 H each, CH2CH3),
2.44 (s, 3 H, CH3PhSO2), 2.77 (m, 1 H, H4), 3.44 (t, J = 10.0, 9.7
Hz, 1 H, H5), 3.59 (dd, J = 11.3, 9.1 Hz, 1 H, CHCl), 3.75 (dd,
J = 11.1, 5.2 Hz, 1 H, CHCl), 4.21 (dd, J = 10.0, 7.3 Hz, 1 H, H5),
7.35 (d, J = 8.2 Hz, 2 H, ArH), 7.90 (d, J = 8.4 Hz, 2 H, ArH);
d (trans) = 1.06 (t, J = 7.3 Hz, 3 H, CH3CH2), 1.68 (dq, J = 14.8, 7.3
Hz, 1 H, CH2CH3), 1.98 (dq, J = 14.8, 7.3 Hz, 1 H, CH2CH3), 2.44
(s, 3 H, CH3Ph), 2.85 (m, 1 H, H4), 3.32 (dd, J = 11.2, 9.8 Hz, 1 H,
CHCl), 3.64 (dd, J = 11.2, 4.0 Hz, 1 H, CHCl), 3.94 (dd, J = 10.6,
3.1 Hz, 1 H, H5), 4.09 (dd, J = 10.6, 6.3 Hz, 1 H, H5), 7.35 and 7.92
(2 d, J = 8.2 Hz, 2 H each, Ph).
3-Chloro-4-(1-chloroethyl)-3-methyl-1-(methylsulfonyl)pyrro-
lidin-2-one (2f)
Following typical procedure 1, 1f (1.371 g, 5 mmol) was treated
with CuCl (0.050 mg, 0.5 mmol) in MeCN (2.5 mL) at 100 °C for
24 h. Flash chromatography of the crude product (silica gel, PE–
Et2O, 100:0 to 20:80) gave 2f (1.278 g, 93%) as a pale-yellow oil;
inseparable mixture of diastereomers, cis/trans 75:25, (cisI + cisII)/
(transI + transII) (42 + 33):(21 + 4) (1H NMR).
IR (film): 1743 cm–1 (C=O).
1H NMR (500 MHz, CDCl3): d (cis I) = 1.71 (d, J = 6.7 Hz, 3 H,
CH3CH), 1.85 (s, 3 H, C3-CH3), 2.48 (dt, J = 10.5, 6.9 Hz, 1 H, H4),
3.28 (s, 3 H, CH3SO2), 3.53 (dd, J = 10.5, 9.5 Hz, 1 H, H5), 4.21
(dd, J = 10.5, 7.1 Hz, 1 H, H5), 4.27 (m, 1 H, CHCl); d (cis II) =
1.57 (d, J = 6.5 Hz, 3 H, CH3CH), 1.96 (s, 3 H, C3-CH3), 2.54 (dt,
J = 10.5, 6.9 Hz, 1 H, H4), 3.28 (s, 3 H, CH3SO2), 3.36 (dd,
J = 10.5, 9.5 Hz, 1 H, H5), 3.94 (dd, J = 10.5, 7.1 Hz, 1 H, H5), 4.33
(m, 1 H, CHCl); d (trans I) = 1.65 (d, J = 6.8 Hz, 3 H, CH3CH), 1.81
(s, 3 H, C3-CH3), 2.81 (dt, J = 10.5, 6.9 Hz, 1 H, H4), 3.28 (s, 3 H,
CH3SO2), 3.85 (dd, J = 10.5, 9.5 Hz, 1 H, H5), 4.14 (dd, J = 10.5,
7.1 Hz, 1 H, H5), 4.27 (m, 1 H, CHCl); d (trans II) = 1.48 (d, J = 6.5
Hz, 3 H, CH3CH), 1.78 (s, 3 H, C3-CH3), 3.01 (dt, J = 10.5, 6.9 Hz,
1 H, H4), 3.28 (s, 3 H, CH3SO2), 3.81 (dd, J = 10.5, 9.5 Hz, 1 H,
H5), 4.02 (dd, J = 10.5, 7.1 Hz, 1 H, H5), 4.21 (overlapped, 1 H,
CHCl).
13C NMR (125.68 MHz, CDCl3): d (cis) = 9.2, 21.6, 29.6, 41.3,
42.6, 47.5, 72.9, 127.9, 129.8, 133.7, 145.8, 168.3; d (trans) = 8.0,
21.6, 25.8, 42.6, 46.2, 47.3, 72.1, 128.0, 129.8, 134.0, 145.7, 168.3.
MS (EI, 70 eV): m/z (%) = 321 (3) [(M + 1) – 29]+, 285 (14), 272,
(6), 257 (5), 250 (7), 208 (14), 155 (35), 91 (100).
Anal. Calcd for C14H17Cl2NO3S: C, 48.01; H, 4.89; N, 4.00; S, 9.15.
Found: C, 48.24; H, 4.91; N, 4.02; S, 9.14.
3-Chloro-4-(chloromethyl)-3-ethyl-1-(trifluoromethylsulfo-
nyl)pyrrolidin-2-one (2e) in the Presence of a Nitrogen Ligand;
Typical Procedure 2
CuCl (50 mg, 0.5 mmol) and amide 1e (1.641 g, 5 mmol) were
weighed in a Schlenk tube fitted with a pierceable septum (blocked
by a screw cap) and a magnetic stirring bar. The tube was thermo-
statted at 0 °C. MeCN (4 mL) was added under argon and, then,
TMEDA (151 mL, 0.10 mmol) was injected through the septum with
a microsyringe. The mixture was stirred for 20 h. Afterwards it was
diluted with H2O (20 mL), acidified with 10% HCl and extracted
with CH2Cl2 (3 × 10 mL). Flash chromatography of the crude prod-
uct (silica gel, PE–Et2O, 100:0 to 30:70) gave the g-lactams cis-2e
and trans-2e).
13C NMR (125.68 MHz, CDCl3): d (cis I) = 23.9, 25.3, 39.9, 47.7,
51.9, 56.6, 68.0, 170.3; d (cis II) = 22.9, 25.0, 39.8, 45.8, 51.9, 53.8,
69.9, 170.5; d (trans I) = 20.4, 23.5, 40.5, 44.4, 51.3, 55.5, 67.8,
170.4; d (trans II) = 20.9, 23.9, 40.3, 44.4, 51.7, 54.3, 67.2, 170.45.
MS (ESI): m/z = 274.1 [M + H]+.
Anal. Calcd for C8H13Cl2NO3S: C, 35.05; H, 4.78; N, 5.11; S, 11.70.
Found: C, 35.22; H, 4.80; N, 5.08; S, 11.69.
Diastereomer cis-2e
Brownish oil; yield: 1.152 g (70%).
Synthesis 2011, No. 8, 1267–1278 © Thieme Stuttgart · New York

PAPER
Synthesis of 3-Alkyl-4-(chloromethyl)-1-RSO2-1H-pyrrol-2(5H)-ones
1275
3-Chloro-4-[chloro(phenyl)methyl]-3-methyl-1-(methylsulfo-
nyl)pyrrolidin-2-one (2g)
pierceable septum (blocked by a screw cap) and a magnetic stirring
bar. DMF (4 mL) was then added under argon. The mixture was
stirred at 100 °C and after 24 h was diluted with H2O (30 mL), acid-
ified with 10% w/v HCl, and extracted with CH2Cl2 (4 × 5 mL). The
combined organic layers were concentrated. Flash chromatography
of the crude (silica gel, PE–Et2O, 90:10 to 20:80) gave the pyrroli-
dinone 3a (1.029 g, 92%) as a white powder.
Following typical procedure 1, 1g (1.681 g, 5 mmol) was treated
with CuCl (0.050 mg, 0.5 mmol) in MeCN (2.5 mL) at 100 °C for
24 h. Flash chromatography of the crude product (silica gel, PE–
Et2O, 100:0 to 0:100) gave 2g (1.563 g, 93%) as a pale-yellow oil;
inseparable mixture of diastereomers, cis/trans 93:7, (cisI + cisII)/
(trans) (65 + 28):7 (1H NMR).
4-(Chloromethyl)-3-ethyl-1-(methylsulfonyl)-1H-pyrrol-2(5H)-
one (3c)
IR (film): 1744 cm–1 (C=O).
1H NMR (500 MHz, CDCl3): d (cis I) = 0.96 (s, 3 H, C3-CH3), 2.99
(m, 1 H, H4), 3.30 (s, 3 H, CH3SO2), 3.68 (dd, J = 10.3, 10.0 Hz, 1
H, H5), 4.38 (dd, J = 10.3, 6.7 Hz, 1 H, H5), 5.16 (d, J = 10.2 Hz, 1
H, CHCl), 7.41 (m, 5 H, Ph); d (cis II) = 2.00 (s, 3 H, C3-CH3), 2.99
(m, 1 H, H4), 3.12 (t, J = 10.0 Hz, 1 H, H5), 3.23 (s, 3 H, CH3SO2),
3.27 (m, 1 H, H5), 5.13 (d, J = 9.8 Hz, 1 H, CHCl), 7.41 (m, 5 H,
Ph); d (trans) = 1.90 (s, 3 H, C3-CH3), 3.26 (m, 1 H, H4), 3.32 (s, 3
H, CH3SO2), 3.88 (dd, J = 4.2, 11.1 Hz, 1 H, H5), 4.07 (dd, J = 7.3,
11.1 Hz, 1 H, H5), 5.20 (d, J = 4.9 Hz, 1 H, CHCl), 7.41 (m, 5 H,
Ph).
Following typical procedure 4, 1c (1.371 g, 5 mmol) was treated
with CuCl (0.050 g, 0.5 mmol) in DMF (4 mL) at 100 °C for 24 h.
Flash chromatography of the crude product (silica gel, PE–Et2O,
100:0 to 0:100) gave an inseparable mixture of 3c and a-alkylidene-
g-lactams 4c (constitutional isomers) [1.003 g, 84%; 3c/4c = 93:7;
E/Z = 73:23 (1H NMR)] as a white powder. A clean sample of 3c
was obtained by crystallization (Et2O–PE).
White needles; mp 75–77 °C.
IR (KBr): 1715 (C=O), 1756 cm–1 (C=C).
13C NMR (125.68 MHz, CDCl3): d (cis I) = 23.5, 40.0, 47.8, 52.1,
61.4, 69.0, 128.0, 129.1, 129.8, 138.4, 170.2; d (cis II) = 25.1, 39.9,
46.2, 51.7, 59.9, 69.9, 127.4, 129.5, 129.8 137.7, 170.4; d (trans) =
21.0, 40.6, 44.6, 51.8, 61.0, 70.1, 127.3, 129.3, 129.7, 137.5, 170.4.
1H NMR (500 MHz, CDCl3): d = 1.10 (t, J = 7.6 Hz, 3 H, CH3CH2),
2.33 (q, J = 7.6 Hz, 2 H, CH2CH3), 3.30 (s, 3 H, CH3SO2), 4.35 (s,
2 H, CH2Cl), 4.40 (s, 2 H, H5).
13C NMR (125.68 MHz, CDCl3): d = 12.7, 17.0, 36.6, 40.8, 50.0,
137.0, 148.0, 169.1.
MS (ESI): m/z = 336.1 [M + H]+.
Anal. Calcd for C13H15Cl2NO3S: C, 46.44; H, 4.50; N, 4.17; S, 9.54.
Found: C, 46.65; H, 4.51; N, 4.16; S, 9.58.
MS (EI, 70 eV): m/z (%) = 237 (45) [M]+, 202 (41), 188 (8), 158
(100), 124 (49), 79 (50).
Anal. Calcd for C8H12ClNO3S: C, 40.42; H, 5.09; N, 5.89; S, 13.49.
Found: C, 40.32; H, 5.1; N, 5.90; S, 13.43.
3,3-Dichloro-4-(chloromethyl)-1-(methylsulfonyl)pyrrolidin-2-
one (2j)
Following typical procedure 1, 1j (1.403 g, 5 mmol) was treated
with CuCl (0.050 mg, 0.5 mmol) in MeCN (2.5 mL) at 80 °C for 4
h. Flash chromatography of the crude product (silica gel, PE–Et2O,
100:0 to 20:80) gave 2j (1.380 g, 98%) as a white powder; mp 88–
90 °C.
(E)- and (Z)-4-(Chloromethyl)-3-ethylidene-1-(methylsulfo-
nyl)pyrrolidin-2-one (4c)
1H NMR (500 MHz, CDCl3): d (E) = 1.93 (dd, J = 7.4, 1.0 Hz, 3 H,
CH3CH), 3.28 (s, 3 H, CH3SO2), 3.43 (br m, 1 H, H4), 3.53 (dd,
J = 11.1, 8.2 Hz, 1 H, CHCl), 3.63 (dd, J = 11.1, 4.0 Hz, 1 H,
CHCl), 3.89 (m, 2 H, H5), 6.90 (dq, J = 7.4, 1.8 Hz, 1 H, =CHCH3);
d (Z) = 2.22 (dd, J = 7.6, 1.8 Hz, 3 H, CH3CH), 3.23 (br m, 1 H, H4),
3.29 (s, 3 H, CH3SO2), 3.55 (dd, J = 11.4, 7.5 Hz, 1 H, CHCl), 3.63
(overlapped, 1 H, CHCl), 3.73 (dd, J = 10.4, 3.7 Hz, 1 H, H5), 3.89
(overlapped, 1 H, H5), 6.35 (dq, J = 7.6, 1.8 Hz, 1 H, =CHCH3).
IR (KBr): 1764 cm–1 (C=O).
1H NMR (500 MHz, CDCl3): d = 3.19 (m, 1 H, H4), 3.33 (s, 3 H,
CH3SO2), 3.60 (dd, J = 10.5, 9.1 Hz, 1 H, H5), 3.76 (dd, J = 11.9,
9.6 Hz, 1 H, CHCl), 3.97 (dd, J = 11.9, 4.6 Hz, 1 H, CHCl), 4.19
(dd, 10.5, 7.8 Hz, 1 H, H5).
13C NMR (125.68 MHz, CDCl3): d = 40.1, 40.4, 46.8, 50.7, 82.5,
164.5.
13C NMR (125.68 MHz, CDCl3): d (E) = 15.0, 36.0, 40.4, 45.8,
47.2, 131.2, 138.1, 166.2; d (Z) = 14.0, 38.7, 40.5, 46.9, 47.3, 129.6,
142.0, 166.6.
MS (EI, 70 eV): m/z (%) (E) = 237 (17) [M]+, 202 (18); 188 (21),
158 (21), 130 (60), 110 (40), 95 (100), 79 (15).
MS (EI, 70 eV): m/z (%) = 279 (2) [M]+, 158 (13), 122 (22), 109
(100), 79 (15).
Anal. Calcd for C6H8Cl3NO3S: C, 25.69; H, 2.87; N, 4.89; S, 11.43.
Found: C, 25.71; H, 2.89; N, 5.00; S, 11.38.
4-(Chloromethyl)-3-ethyl-1-tosyl-1H-pyrrol-2(5H)-one (3d)
Following typical procedure 4, 1d (1.751 g, 5 mmol) was treated
with CuCl (0.050 g, 0.5 mmol) in DMF (4 mL) at 100 °C for 24 h.
Chromatography of the crude product (silica gel, CH2Cl2–PE–Et2O,
50:50:0 to 50:0:50) gave a mixture of 3d and a-alkylidene-g-lac-
tams 4d (constitutional isomers) [1.491 g, 95%; 3d/4d 82:18,
E/Z 80:20 (1H NMR)] as a white powder. A clean sample of 3d was
obtained by crystallization (Et2O).
4-(Chloromethyl)-3-methyl-1-(methylsulfonyl)-1H-pyrrol-
2(5H)-one (3a) by Elimination; Typical Procedure 3
[WARNING!! High pressure develops inside the reaction tube due
to release of CO]. g-Lactam 2a (1.301 g, 5 mmol) was weighed in a
Schlenk tube fitted with a pierceable septum (blocked by a screw
cap) and a magnetic stirring bar. DMF (3 mL) was then added. The
mixture was stirred at 100 °C and after 24 h was diluted with H2O
(30 mL), acidified with 10% HCl, and extracted with CH2Cl2 (4 × 5
mL). The combined organic layers were concentrated. Flash chro-
matography of the crude (silica gel, PE–Et2O, 90:10 to 20:80) gave
the pyrrolidinone 3a (1.040 g, 93%) as a white powder.
White powder; mp 143–145 °C.
IR (KBr): 1714 (C=O), 1665 cm–1 (C=C).
1H NMR (500 MHz, CDCl3): d = 1.03 (t, J = 7.6 Hz, 3 H, CH3CH2),
2.25 (q, J = 7.4 Hz, 2 H, CH2CH3), 2.43 (s, 3 H, CH3PhSO2), 4.33
(s, 2 H, CH2Cl), 4.44 (s, 2 H, H5), 7.35 (d, J = 8.2 Hz, 2 H, ArH),
7.96 (d, J = 8.2 Hz, 2 H, ArH).
4-(Chloromethyl)-3-methyl-1-(methylsulfonyl)-1H-pyrrol-
2(5H)-one (3a) by a Sequential Process; Typical Procedure 4
[WARNING!! High pressure develops inside the reaction tube due
to release of CO]. CuCl (0.050 g, 0.5 mmol) and 2,2-dichloroamide
1a (1.301 g, 5 mmol) were weighed in a Schlenk tube fitted with a
13C NMR (125.68 MHz, CDCl3): d = 12.4, 16.9, 21.4, 37.0, 50.5,
128.0, 129.8, 135.2, 137.3, 145.3, 147.6, 168.3.
Synthesis 2011, No. 8, 1267–1278 © Thieme Stuttgart · New York

1276
M. Bregoli et al.
PAPER
4-(1-Chloroethyl)-3-methyl-1-(methylsulfonyl)-1H-pyrrol-
MS (EI, 70 eV): m/z (%) = 313 (1) [M]+, 278 (3), 264 (1), 249 (36),
234 (19), 214 (67), 91 (100).
2(5H)-one (3f)
Following typical procedure 4, 1f (1.441 g, 5 mmol) was reacted
with CuCl (0.050 g, 0.5 mmol) in DMF (4 mL) at 100 °C for 24 h.
Flash chromatography of the crude product (silica gel, PE–Et2O,
100:0 to 20:80) gave an inseparable mixture of 3f and 5 [1.010 g;
3f/5 1:1 (1H NMR), yield: 46%/46%] as a pale-yellow oil.
Anal. Calcd for C14H16ClNO3S: C, 53.59; H, 5.14; N, 4.46; S, 10.22.
Found: C, 53.67; H, 5.11; N, 4.45; S, 10.28.
(E)- and (Z)-4-(Chloromethyl)-3-ethylidene-1-tosylpyrrolidin-
2-one (4d)
1H NMR (500 MHz, CDCl3): d (E) = 1.85 (dd, J = 7.4, 1.1 Hz, 3 H,
CH3CH), 2.43 (s, 3 H, CH3PhSO2), 3.34 (br m, 1 H, H4), 3.41 (dd,
J = 11.1, 9.6 Hz, 1 H, CHCl), 3.56 (dd, J = 11.1, 3.8 Hz, 1 H,
CHCl), 3.88 (dd, J = 10.5, 7.5 Hz, 1 H, H5), 4.04 (dd, J = 10.5, 1.7
Hz, 1 H, H5), 6.78 (dq, J = 7.5, 1.8 Hz, 1 H, =CHCH3), 7.35 (d,
J = 8.2 Hz, 2 H, ArH), 7.93 (d, J = 8.2 Hz, 2 H, ArH); d (Z) = 2.13
(dd, J = 7.4, 1.8 Hz, 3 H, CH3CH), 2.43 (s, 3 H, CH3PhSO2), 3.15
(br m, 1 H, H4), 3.45 (dd, J = 11.2, 8.5 Hz, 1 H, CHCl), 3.62 (over-
lapped, 1 H, CHCl), 3.83 (dd, J = 10.3, 3.4 Hz, 1 H, H5), 4.07 (dd,
J = 10.2, 6.9 Hz, 1 H, H5), 6.23 (dq, J = 7.6, 1.8 Hz, 1 H, =CHCH3),
7.35 (d, J = 8.2 Hz, 2 H, ArH), 7.96 (d, J = 8.2 Hz, 2 H, ArH).
3f
1H NMR (500 MHz, CDCl3): d = 1.71 (d, J = 6.9 Hz, 3 H,
CH3CHCl), 1.88 (t, 5J = 2.0 Hz, 3 H, CH3C=), 3.33 (s, 3 H,
CH3SO2), 4.38 (part A of an ABX3, 2J = 16.6 Hz, 5J = 2.0 Hz, 1 H,
H5), 4.52 (part B of an ABX3, 2J = 16.6 Hz, 5J = 2.0 Hz, 1 H, H5),
5.06 (q, J = 6.9 Hz, 1 H, CHCl).
13C NMR (125.68 MHz, CDCl3): d = 8.7, 23.6, 41.0, 48.0, 49.7,
129.5, 152.9, 169.7.
MS (ESI): m/z = 238.1 [M + H]+.
13C NMR (125.68 MHz, CDCl3): d (E) = 14.7, 36.1, 45.3, 47.6,
128.1, 129.7, 131.3, 137.6, 165.2; d (Z) = 13.7, 38.6, 41.2, 46.9,
132.6, 141.4, 169.0.
MS (EI, 70 eV): m/z (%) (E) = 264 (1) [M – 49]+, 249 (80), 234 (37),
200 (42), 95 (84), 91 (100).
3-Methyl-1-(methylsulfonyl)-4-vinyl-1H-pyrrol-2(5H)-one (5)
1H NMR (500 MHz, CDCl3): d = 1.90 (t, J = 1.7 Hz, 3 H, CH3C=),
3.31 (s, 3 H, CH3SO2), 4.56 (s, 2 H, H5), 5.53 (d, J = 11.0 Hz, 1 H,
CH2=CH), 5.59 (d, J = 17.7 Hz, 1 H, CH2=CH), 6.72 (dd, J = 17.7,
11.0 Hz, 1 H, CH=CH2).
13C NMR (125.68 MHz, CDCl3): d = 8.6, 40.9, 48.9, 126.1, 129.4,
130.0, 148.1, 170.6.
4-(Chloromethyl)-3-ethyl-1-(trifluoromethylsulfonyl)-1H-pyr-
rol-2(5H)-one (3e)
Following typical procedure 3, 2e (1.641 g, 5 mmol, cis/trans
50:50) was heated in DMF (4 mL) at 100 °C for 24 h. Flash chro-
matography of the crude product (silica gel, PE–Et2O, 100:00 to
20:80) gave 3e and 4e.
MS (ESI): m/z = 202.3 [M + H]+.
4-[Hydroxy(phenyl)methyl]-3-methyl-1-(methylsulfonyl)-1H-
pyrrol-2(5H)-one (6)
Following typical procedure 4, 1g (1.681 g, 5 mmol) was reacted
with CuCl (0.050 g, 0.5 mmol) in DMF (4 mL) at 100 °C for 24 h.
Flash chromatography of the crude product (silica gel, PE–Et2O,
100:0 to 0:100) gave 6 (0.689 g, 49%) as a white powder; mp >200
°C (dec.).
White flakes; yield: 1.237 g (85%); mp 83–85 °C.
IR (KBr): 1752 cm–1 (C=O).
1H NMR (500 MHz, CDCl3): d = 1.14 (t, J = 7.3 Hz, 3 H, CH2CH3),
2.39 (q, J = 7.3 Hz, 2 H, CH2CH3), 4.39 (s, 2 H, H5), 4.51 (s, 2 H,
CH2Cl).
13C NMR (125.68 MHz, CDCl3): d = 12.5, 17.3, 36.5, 51.5, 136.4,
149.6, 166.7.
MS (EI, 70 eV): m/z (%) = 291 (15) [M]+, 256 (22), 222 (11), 158
(100).
IR (Nujol): 3399 (OH), 1716 cm–1 (C=O).
1H NMR (500 MHz, CDCl3): d = 1.60 (br s, 1 H, OH), 1.88 (s, 3 H,
C3-CH3), 3.16 (s, 3 H, CH3SO2), 4.19 (pseudo q J = 17.0 Hz, 2 H,
H5), 4.69 (s, 1 H, CHOH), 7.23 (t, 2 H, Ph), 7.34 (d, 1 H, Ph), 7.39
(d, 2 H, Ph).
13C NMR (125.68 MHz, CDCl3): d = 9.1, 40.8, 46.9, 48.5, 127.2,
128.8, 129.8, 129.9, 137.1, 153.2, 169.7.
Anal. Calcd for C8H9ClF3NO3S: C, 32.94; H, 3.11; N, 4.80; S,
10.99. Found: C, 32.97; H, 3.05; N, 4.80; S, 11.04.
MS (EI, 70 eV): m/z (%) = 265 (19) [(M + 1) – 17]+, 187 (30), 91
(100).
(E)- and (Z)-4-(Chloromethyl)-3-ethylidene-1-(trifluoromethyl-
sulfonyl)pyrrolidin-2-one (4e)
Anal. Calcd for C13H15NO4S: C, 55.50; H, 5.37; N, 4.98; S, 11.40.
Found: C, 55.30; H, 5.42; N, 4.96; S, 11.46.
Colourless oil that gets brownish; yield: 0.137 g (9%); E/Z 87:13
(1H NMR).
4-[Chloro(phenyl)methyl]-3-methyl-1-(methylsulfonyl)-1H-
pyrrol-2(5H)-one (3g)
Following typical procedure 3, 2g (1.681 g, 5 mmol) was heated in
DMF (4 mL) at 100 °C for 24 h. Flash chromatography of the crude
product (silica gel, PE–Et2O, 100:0 to 0:100) gave 3g (0.789 g,
53%) as a brownish oil.
IR (film): 1758 (C=O), 1670 cm–1 (C=C).
1H NMR (500 MHz, CDCl3): d (E) = 2.00 (dd, J = 7.4, 1.0 Hz, 3 H,
CH3CH=), 3.49 (br m, 1 H, H4), 3.53 (dd, J = 10.5, 8.7 Hz, 1 H,
CHCl), 3.65 (dd, J = 10.5, 3.4 Hz, 1 H, CHCl), 3.99 (dd, J = 10.4,
7.3 Hz, 1 H, H5), 4.07 (dd, J = 10.4, 1.5 Hz, 1 H, H5), 7.09 (dq,
J = 7.4, 1.0 Hz, 1 H, CHCH3); d (Z) = 2.28 (dd, J = 7.4, 1.7 Hz, 3 H,
=CHCH3), 3.30 (m, 1 H, H4), 3.56 (dd, J = 10.9, 7.5 Hz, 1 H,
CHCl), 3.65 (overlapped, 1 H, CHCl), 3.88 (dd, J = 10.5, 3.5 Hz, 1
H, H5), 4.03 (overlapped, 1 H, H5), 6.52 (dq, J = 7.4, 1.0 Hz, 1 H,
=CHCH3).
IR (liquid): 1720 cm–1 (C=O).
1H NMR (500 MHz, CDCl3): d = 1.93 (s, 3 H, C3-CH3), 3.32 (s, 3
H, CH3SO2), 4.17 and 4.55 (2 dq, J = 18.4, 1.8 Hz, 1 H each, H5),
6.02 (s, 1 H, CHCl), 7.41 (s, 5 H, Ph).
13C NMR (125.68 MHz, CDCl3): d (E) = 15.4, 36.2, 45.1, 48.9,
119.6, 129.6, 141.6, 164.3; d (Z) = 13.9, 39.0, 46.4, 48.7, 119.6,
132.6, 145.9, 164.3.
13C NMR (125.68 MHz, CDCl3): d = 8.9, 41.0, 48.7, 56.0, 126.8,
129.2, 130.1, 136.7, 151.8, 169.6.
MS (EI, 70 eV): m/z (%) = 299 (8) [M]+, 264 (100), 221 (19), 143
(82), 129 (75), 125 (73).
MS (EI, 70 eV): m/z (%) (E) = 291 (14) [M]+, 256 (13), 242 (100),
222 (33), 95 (95); m/z (%) (Z) = 291 (10) [M]+, 256 (4), 242 (100).
Anal. Calcd for C13H14ClNO3S: C, 52.09; H, 4.71; N, 4.67; S, 10.70.
Found: C, 51.99; H, 4.72; N, 4.70; S, 10.75.
Synthesis 2011, No. 8, 1267–1278 © Thieme Stuttgart · New York

PAPER
Synthesis of 3-Alkyl-4-(chloromethyl)-1-RSO2-1H-pyrrol-2(5H)-ones
1277
4-(Chloromethyl)-3-isopropyl-1-(methylsulfonyl)-1H-pyrrol-
2(5H)-one (3h)
(br t, 3 H, CH3CH2), 1.29 [m, 4 H, (CH2)2], 1.49 (m, 2 H, CH2), 2.74,
(br q, J = 7.8 Hz, 2 H, CH2CH=), 3.30 (s and m, 4 H, CH3SO2 , H4),
3.56 (dd, J = 11.2, 8.0 Hz, 1 H, CHCl), 3.64 (overlapped, 1 H,
CHCl), 3.74 (dd, J = 10.4, 3.4 Hz, 1 H, H5), 3.93 (overlapped, 1 H,
H5), 6.26 (t, J = 7.6, 1.4 Hz, 1 H, CHC=C).
13C NMR (125.68 MHz, CDCl3): d (E) = 13.9, 22.4, 28.2, 29.3,
31.4, 36.2, 40.4, 46.1, 47.2, 130, 143.4, 166.3; d (Z) = 13.4, 27.4,
28.7, 32.5, 38.6, 40.3, 46.9, 47.3, 128.5, 139.0, 160.1.
Following typical procedure 4, 1h (1.323 g, 5 mmol) was reacted
with CuCl (0.050 g, 0.5 mmol) in DMF (4 mL) at 100 °C for 24 h.
Flash chromatography of the crude product (silica gel, PE–Et2O,
100:0 to 0:100) gave an inseparable mixture of 3h and a-alkylidene-
g-lactam 4h (constitutional isomers) [1.142 g, 91%; 3h/4h 85:15
(1H NMR)] as a white powder. A clean sample of 3h was obtained
by crystallization (Et2O–i-Pr2O).
MS (EI, 70 eV): (E) m/z (%) = 244 (100) [M – 49]+, 224 (76); 211
(43), 162 (71), 79 (36).
White needles; mp 106–108 °C.
IR (KBr): 1717 (C=O), 1659 cm–1 (C=C).
4-(Chloromethyl)-3-chloro-1-(methylsulfonyl)-1H-pyrrol-
2(5H)-one (3j)
Following typical procedure 3, 2j (1.403 g, 5 mmol) was heated in
DMF (4 mL) at 80 °C for 6 h. Flash chromatography of the crude
product (silica gel, PE–Et2O, 100:0 to 0:100) gave 3j (1.067 g, 87%)
as a white solid; mp 67–69 °C.
IR (KBr): 1722 cm–1 (C=O).
1H NMR (500 MHz, CDCl3): d = 3.27 (s, 3 H, CH3SO2), 3.40 (s, 2
H, CH2Cl), 3.47 (s, 2 H, H5).
13C NMR (125.68 MHz, CDCl3): d = 36.1, 40.6, 49.8, 124.9, 148.7,
163.2.
MS (EI, 70 eV): m/z (%) = 243 (26) [M]+, 208 (37), 194 (100), 164
(41), 130 (74), 116 (92), 79 (48).
1H NMR (500 MHz, CDCl3): d = 1.26 [d, J = 7.0 Hz, 6 H,
(CH3)2CH], 2.89 [sept, J = 7.0 Hz, 1 H, CH(CH3)2], 3.32 (s, 3 H,
CH3SO2), 4.36 (s, 2 H, CH2Cl), 4.39 (s, 2 H, H5).
13C NMR (125.68 MHz, CDCl3): d = 19.9, 25.4, 36.6, 40.6, 49.5,
139.7, 147.3, 168.4.
MS (EI, 70 eV): m/z (%) = 251 (61) [M]+, 236 (9), 222 (21), 216
(39), 188 (16), 172 (90), 158 (22), 130 (100), 79 (47).
Anal. Calcd for C9H14ClNO3S: C, 42.94; H, 5.61; N, 5.56; S, 12.74.
Found: C, 43.08; H, 5.57; N, 5.59; S, 12.80.
4-(Chloromethyl)-3-isopropylidene-1-(methylsulfonyl)pyrroli-
din-2-one (4h)
1H NMR (500 MHz, CDCl3): d = 1.96 (s, 3 H, CH3 cis to CH2Cl),
2.25 (s, 3 H, CH3 trans to CH2Cl), 3.28 (s, 3 H, CH3SO2), 3.33 (m,
1 H, H4), 3.47 (dd, J = 11.2, 9.0 Hz, 1 H, CHCl), 3.57 (dd, J = 11.2,
3.5 Hz, 1 H, CHCl), 3.79 (dd, J = 11.4, 7.4 Hz, 1 H, H5), 3.91 (dd,
J = 11.4, 1.1 Hz, 1 H, H5).
Anal. Calcd for C6H7Cl2NO3S: C, 29.52; H, 2.89; N, 5.74; S, 13.14.
Found: C, 29.43; H, 2.97; N, 5.69; S, 13.22.
13C NMR (125.68 MHz, CDCl3): d = 19.9, 23.7, 37.9, 40.1, 45.8,
Acknowledgment
46.0, 123.4, 154.0, 166.4.
We thank the Ministero della Istruzione, dell’Università e della
Ricerca (MIUR) for financial assistance (20085E2LXC-003,
20085E2LXC-001, 20085E2LXC-004).
MS (EI, 70 eV): m/z (%) = 251 (17) [M]+, 216 (12), 202 (79), 124
(35), 79 (24).
4-(Chloromethyl)-3-hexyl-1-(methylsulfonyl)-1H-pyrrol-
2(5H)-one (3i)
References
Following typical procedure 4, 1i (1.651 g, 5 mmol) was reacted
with CuCl (0.050 g, 0.5 mmol) in DMF (4 mL) at 100 °C for 24 h.
Flash chromatography of the crude product (silica gel, PE–Et2O,
80:20 to 20:80) gave an inseparable mixture of 3i and a-alkylidene-
g-lactams 4i (constitutional isomers) [1.267 g, 86%; 3i/4i 88:12,
E/Z 80:20, (1H NMR)] as yellowish flakes. A clean sample of 3i was
obtained by crystallization (Et2O–PE).
(1) (a) Rowlands, G. J. Tetrahedron 2010, 66, 1593.
(b) Eckenhoff, W. T.; Pintauer, T. Catal. Rev. 2010, 52, 1.
(c) Clark, A. J. Chem. Soc. Rev. 2002, 31, 1. (d) Kobrakov,
K. I.; Ivanov, A. V. Chem. Heterocycl. Compd. (Engl.
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N. J. Org. Chem. 2010, 75, 7408. (f) Udding, J. H.; Tuijp,
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White powder; mp 49–51 °C.
IR (KBr): 1715 (C=O), 1660 cm–1 (C=C).
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109, 3817. (h) Severin, K. Curr. Org. Chem. 2006, 10, 217.
(i) Nagashima, H.; Itoh, K. J. Synth. Org. Chem., Jpn. 1995,
53, 298.
1H NMR (500 MHz, CDCl3): d = 0.88 (br t, 3 H, CH3CH2), 1.29 [m,
6 H, (CH2)3], 1.49 (m, 2 H, CH2), 2.31 (t, J = 7.7 Hz, 2 H, CH2C=),
3.33 (s, 3 H, CH3SO2), 4.35 (s, 2 H, CH2Cl), 4.43 (s, 2 H, H5).
13C NMR (125.68 MHz, CDCl3): d = 14.0, 22.4, 23.7, 28.0, 29.1,
31.4, 36.9, 40.9, 50.1, 135.9, 148.5, 169.3.
(2) (a) Pattarozzi, M.; Roncaglia, F.; Giangiordano, V.; Davoli,
P.; Prati, F.; Ghelfi, F. Synthesis 2010, 694. (b) Rowlands,
G. J. Tetrahedron 2009, 65, 8603.
(3) (a) Motoyama, Y.; Kamo, K.; Yuasa, A.; Nagashima, H.
Chem. Commun. 2010, 46, 2256. (b) McGonacle, F. I.;
Brown, L.; Cooke, A.; Sutherland, A. Org. Biomol. Chem.
2010, 8, 3418. (c) Clark, A. J.; Wilson, P. Tetrahedron Lett.
2008, 49, 4848. (d) Bull, J. A.; Hutchings, M. G.; Luján, C.;
Quayle, P. Tetrahedron Lett. 2008, 49, 1356. (e) Thommes,
K.; Içli, B.; Scopelliti, R.; Severin, K. Chem. Eur. J. 2007,
13, 6899. (f) Clark, A. J.; Geden, J. V.; Thom, S. J. Org.
Chem. 2006, 71, 1471.
(4) (a) Ghelfi, F.; Pattarozzi, M.; Roncaglia, F.; Giangiordano,
V.; Parsons, A. F. Synth. Commun. 2010, 40, 1040.
(b) Bellesia, F.; Danieli, C.; De Buyck, L.; Galeazzi, R.;
Ghelfi, F.; Mucci, A.; Orena, M.; Pagnoni, U. M.; Parsons,
MS (EI, 70 eV): m/z (%) = 293 (7) [M]+, 258 (30), 250 (10), 244
(50), 188 (100), 79 (13).
Anal. Calcd for C12H20ClNO3S: C, 49.05; H, 6.86; N, 4.77; S, 10.91.
Found: C, 49.38; H, 6.79; N, 4.81; S, 10.87.
(E)- and (Z)-4-(Chloromethyl)-3-hexylidene-1-(methylsulfo-
nyl)pyrrolidin-2-one (4i)
1H NMR (500 MHz, CDCl3): d (E) = 0.88 (br t, 3 H, CH3CH2), 1.29
[m, 4 H, (CH2)2], 1.49 (m, 2 H, CH2), 2.25 (dq, J = 8.6, 1.8 Hz, 2 H,
CH2CH=), 3.30 (s, 3 H, CH3SO2), 3.41 (br m, 1 H, H4), 3.52 (dd,
J = 11.2, 6.5 Hz, 1 H, CHCl), 3.62 (dd, J = 11.2, 3.9 Hz, 1 H,
CHCl), 3.89 (dd, J = 10.6, 7.8 Hz, 1 H, H5), 3.94 (dd, J = 10.6, 1.8
Hz, 1 H, H5), 6.86 (dt, J = 8.6, 1.2 Hz, 1 H, CHC=C); d (Z) = 0.88
Synthesis 2011, No. 8, 1267–1278 © Thieme Stuttgart · New York

1278
M. Bregoli et al.
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Synthesis 2011, No. 8, 1267–1278 © Thieme Stuttgart · New York