Preparation of the maleic anhydride nucleus from dichloro γ-lactams: Focus on the role of the N-substituent in the functional rearrangement and in the hydrolytic steps

Article abstract of DOI:10.1055/s-2008-1067273

The preparation of the 3,4-dialkyl-substituted maleic anhydride nucleus, through the functional rearrangement of dichloro γ-lactams, allowed the comparison of various N-substituents in the functional rearrangement step. The 2-pyridyl group proved to be the most appropriate N-substituent for the hydrolysis of the 5-methoxy-1,5-dihydro-2H-pyrrol-2-one intermediate into the 5-hydroxy adduct, and for the hydrolysis of the maleimide nucleus into the maleic anhydride. The oxidation of the 5-hydroxy-1,5-dihydro-2H-pyrrol-2-one into the corresponding maleimide was achieved with manganese(IV) oxide. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1067273

PAPER
3131
Preparation of the Maleic Anhydride Nucleus from Dichloro g-Lactams: Focus
on the Role of the N-Substituent in the Functional Rearrangement and in the
Hydrolytic Steps
P
reparationof
r
the Mal
a
n
N
ucleus
f
c
rom
D
ichlo
o
r
o
g
-Lactams Ghelfi,*a Mariella Pattarozzi,a Fabrizio Roncaglia,a Andrew F. Parsons,b Fulvia Felluga,c Ugo M. Pagnoni,a
Ennio Valentin,c Adele Mucci,a Franco Bellesiaa
a
Dipartimento di Chimica, Università degli Studi di Modena e Reggio Emilia, Via Campi 183, 41100 Modena, Italy
Fax +39(59)373543; E-mail: ghelfi.franco@unimore.it
Department of Chemistry, University of York, Heslington, York, YO10 5DD, UK
Dipartimento di Scienze Chimiche, Università di Trieste, via Licio Giorgieri 1, 34127 Trieste, Italy
b
c
Received 26 May 2008; revised 11 June 2008
preparation of higher homologues are not straightfor-
Abstract: The preparation of the 3,4-dialkyl-substituted maleic an-
hydride nucleus, through the functional rearrangement of dichloro
g-lactams, allowed the comparison of various N-substituents in the
functional rearrangement step. The 2-pyridyl group proved to be the
most appropriate N-substituent for the hydrolysis of the 5-methoxy-
1,5-dihydro-2H-pyrrol-2-one intermediate into the 5-hydroxy ad-
duct, and for the hydrolysis of the maleimide nucleus into the male-
ic anhydride. The oxidation of the 5-hydroxy-1,5-dihydro-2H-
pyrrol-2-one into the corresponding maleimide was achieved with
manganese(IV) oxide.
ward,5 and (iii) the only way to get the starting amine is by
amino-dehalogenation.
Interesting is the role played by the 2-pyridyl moiety,
which besides facilitating the solubility of A in water/H+,
may take part in the hydrolytic mechanism to form the
maleic anhydride, owing to the likely interaction, through
a hydrogen bridge, between the carbonyl group and the
protonated pyridyl nitrogen of the maleimide A
(Figure 1). Since the preparation of the analogous amines
3-(3-chloroprop-2-enylamino)pyridine and 4-(3-chloro-
prop-2-enylamino)pyridine by alkylation of the corre-
sponding aminopyridine with 1,3-dichloropropene failed,
we were unable to clarify the role played by the 2-pyridyl
moiety in the hydrolysis of A. Bowman, who first per-
formed the same hydrolysis step in his route to pyrochin-
conic anhydride, did not disclosed the mechanism of this
reaction.6
Key words: rearrangement, radical reactions, substituent effects,
halo compounds, g-lactams
Many natural products containing the maleic anhydride
ring show special biological activity including enzymatic
inhibition.1 Maleic anhydrides, in addition, are useful syn-
thons widely used in the construction of new organic skel-
etons.2 Several routes to this important cyclic skeleton
have been reported,1–3 but the development of new syn-
thetic paths for their preparation is still a useful and chal-
lenging task, which adds new arrows to the chemist’s
quiver.
R
Me
O
O
N
H
Recently, we exploited the functional rearrangement of 3-
alkyl-3-chloro-4-(dichloromethyl)-1-(2-pyridyl)pyrroli-
din-2-ones, completed by a one-pot hydrolytic step, to
construct disubstituted maleic anhydrides.4 This route,
however, suffers from a particularly inefficient use of 2-
aminopyridine for the preparation, by alkylation with 1,3-
dichloropropene, of the starting 2-(3-chloroprop-2-enyl-
amino)pyridine component (toluene, 100 °C, 20 h; 20–
30% yield). This monohalogenated amine was then acy-
lated with a 2,2-dichloroacyl chloride and the resulting
amide was converted, by atom-transfer radical cyclization
(ATRC), into the 3-alkyl-3-chloro-4-(dichloromethyl)-1-
(2-pyridyl)pyrrolidin-2-one intermediate.
N
+
A
Figure 1
With the scope to develop a more versatile procedure for
the preparation of disubstituted maleic anhydrides and
solve the aforementioned problems, we judged that the
use of secondary g-nonhalogenated allylamines, as radi-
cophilic building blocks, might be more advantageous
from a synthetic point of view, since a substantial number
of commercial starting materials are available and, in ad-
dition, their preparation can be easily accomplished with
trustworthy strategies, such as: (i) nucleophilic substitu-
tion of primary allylamines using compounds carrying
good nucleofuges, (ii) nucleophilic substitution reactions
between a primary allylamine and an allylic system con-
taining a good leaving group, and (iii) reductive amination
of carbonyl compounds.
The use of 1,3-dichloropropene limits the widespread ap-
plicability of the strategy because: (i) it is the only com-
mercially available g-chloroallyl chloride, (ii) the
SYNTHESIS 2008, No. 19, pp 3131–3141
x
x.
x
x
.
2
0
0
8
Advanced online publication: 05.09.2008
DOI: 10.1055/s-2008-1067273; Art ID: Z12108SS
© Georg Thieme Verlag Stuttgart · New York
This structural simplification has, however, an important
consequence on the synthetic path, since an oxidative step

3132
F. Ghelfi et al.
PAPER
is now needed for adjusting the oxidation level of the C5 To understand the influence of the 2-pyridyl group in the
site of the 5-methoxy-1,5-dihydro-2H-pyrrol-2-one 5, af- hydrolysis of A, we planned the preparation of a series of
forded by the functional rearrangement product of the di- maleimides, where the N-substituents differ in the number
halogenated pyrrolidin-2-one 4 (Scheme 1).
of nitrogen atoms and in their location. The preparation of
precursors 4a–d, as a first step toward the synthesis of the
pyrocinchonic imides 6a–d, was accomplished as out-
lined in Scheme 1. The starting allylamines 1a, 1b, and 1d
were efficiently prepared via nucleophilic aromatic sub-
stitution reactions between allylamine and either 2-chlo-
ropyridine, 4-chloropyridine, or 2-chloropyrimidine,
respectively (Scheme 2).8 Differently from that reported
in the literature, we carried out the reactions in the ab-
sence of solvent, making the procedure more attractive
from a practical and economic perspective. For the prepa-
ration of 2-[(prop-2-enylamino)methyl]pyridine (1c), in-
stead, we resorted to a nucleophilic substitution reaction
between 2-(aminomethyl)pyridine and allyl chloride; in
this way 1c was secured in an acceptable 42% yield.
Herein we report that pyrocinchonic anhydride, chosen as
archetype of the class and, by itself, a very useful building
block in organic synthesis,7 can be smoothly obtained
with the new strategy. In addition, the crucial role played
by the 2-pyridyl moiety bound to the starting amide, in the
two intermediate hydrolysis steps (Scheme 1) is dis-
cussed. The possibility to test a number of N-substituents
in the functional rearrangement step allowed the detection
of an interesting effect, albeit not exploitable in practical
terms.
Me
Me
Me
Me
O
O
[H2O]
O
OH
7
[H2O]
O
N
R
The amides 3 were effectively attained by reaction be-
tween allylamines 1a–d and 2,2-dichloropropanoyl chlo-
ride (2) (Scheme 3). Afterwards they were rearranged into
the corresponding dihalopyrrolidin-2-ones 4, applying
transition-metal-catalyzed atom-transfer radical cycliza-
tion (TMC-ATRC) (Scheme 3),9 an example of
isohypsic10 transformation.
[O]
Me
8
H+/H2O
?
?
Me
Me
Me
[O]
O
OMe
O
O
N
R
N
R
?
5
R
6
N
MeONa/
MeOH
RF
1
H
R
N
Cl Cl
Me
Cl Cl
Me Cl
Cl
R
N
Cl Cl
Me
O
ATRC
CuCl
b
2
Me Cl
a
O
Cl
Cl
O
N
R
H
N
O
3
4
3a (90%)
3b (71%)
3c (75%)
3d (100%)
R
O
N
R
4a (91%)
4b (67%)
4c (91%)
4d (84%)
1
N
N
N
N
R =
a
c
N
b
d
Scheme 3 Reagents and conditions: (a) MeCCl2COCl (2), pyridine,
CH2Cl2, r.t., 5 h; (b) CuCl–TMEDA, MeCN, argon, r.t., 24 h.
Scheme 1 Atom-transfer radical cyclization (ATRC) and functional
rearrangement (FR) in the synthesis of 5-methoxy-1,5-dihydro-2H-
pyrrol-2-ones and their hydrolysis.
The functional rearrangement of 4-methylpyrrolidin-2-
ones chlorinated at the C3 and C6 positions is a fairly gen-
eral reaction that takes place when the halogenated g-lac-
tam is treated with a solution of alkaline methoxide in
methanol. In practice, the C–Cl groups at the C3 and C6
positions are replaced by a double bond between carbons
C3 and C4, and one or two methoxy groups at C5 (the
functional rearrangement is also an isohypsic transforma-
tion).11 We discovered that for an effective functional re-
arrangement, the configuration of the starting a,g-
halogenated pyrrolidin-2-one is critical and should be ar-
ranged so that an initial endo elimination between the C3
and C4 positions is possible.4 This is so only for the more
stable cis-3-alkyl-3-chloro-4-(chloromethyl)pyrrolidin-2-
ones, which have a trans geometry between the C4–H and
the C3–Cl bonds. In contrast, the trans-pyrrolidinone iso-
mer undergoes an unproductive exo elimination.4
a
N
Cl
N
N
H
1a (72%)
1b (78%)
1d (95%)
1c (42%)
N
N
a
N
H
Cl
Cl
N
N
b
N
N
N
N
N
H
c
H
NH2
N
As experienced in previous studies,4 the C3 stereogenic
center of the 3-alkyl-3-chloro-4-(chloromethyl)pyrroli-
din-2-ones 4 appears configurationally unstable under the
reaction conditions of TMC-ATRC. Therefore, the stereo-
Scheme 2 Reagents and conditions: (a) allylamine, argon, 140 °C,
72 h; (b) allylamine, argon, r.t., 2 h; (c) 3-chloropropene, K2CO3,
THF, reflux, 18 h.
Synthesis 2008, No. 19, 3131–3141 © Thieme Stuttgart · New York

PAPER
Preparation of the Maleic Anhydride Nucleus from Dichloro g-Lactams
3133
chemistry of the halogenated g-lactams 4 is under thermo- by the residual amount of cis-4a isomer present in the
dynamic control and the isomer that predominates carries starting sample of trans-4a (Scheme 4).
the larger substituents at C3 and C4 on the opposite sides
of the ring. Since C3 epimerization is a gradual process,
When the functional rearrangement of 4a, as a 61:39 mix-
ture of cis/trans isomers, was carried out at 0 °C, we suc-
higher temperatures and longer reaction times generally
ceeded in obtaining the selective and complete conversion
improve the selectivity toward the more stable isomer [in
of the cis-isomer of 4a into 5a (yield 62%), while the
trans-isomer 4a was quantitatively recovered. This exper-
this case, the cis-3-alkyl-3-chloro-4-(chloromethyl)pyrro-
lidin-2-one]. Regardless of the above considerations, the
imental protocol offers two important practical advan-
cyclization of amides 3 was carried out at room tempera-
tages: first, trans-4a can be separated from 5a more easily
than from the cis-4a isomer, and second, once recovered,
trans-4a can be epimerized with copper(I) chloride–
ture so as to increase, as far as possible, the amount of the
trans-pyrrolidin-2-one 4, thereby giving a significant
amount of product derived from exo elimination, which
N,N,N¢,N¢-tetramethylethylenediamine into the cis-struc-
simplifies product characterization.
ture, thus improving the global effectiveness of the func-
At the beginning, we investigated the effect of the system tional rearrangement step.
ROH/RONa on the reaction pathway, using 4a as model
The functional rearrangement was then investigated using
compound (cis/trans 62:38). The four systems, which we
dichloro g-lactams 4b, 4c, and 4d and gave the expected
compared at room temperature under standard reaction
products (Scheme 5). Considering the straightforward
conditions,11 were, in order of increasing basicity: (i)
preparation of 4d, we examined, in greater detail, its func-
tional rearrangement in MeOH/MeONa (Table 1). The re-
sults collected in Table 1 resemble those obtained with 4a.
MeOH/MeONa, (ii) EtOH/EtONa, (iii) i-PrOH/i-PrONa,
and (iv) t-BuOH/t-BuONa. Under the most basic condi-
tions (EtOH/EtONa, i-PrOH/i-PrONa and t-BuOH/t-
Specifically, it is evident that the reaction of trans-4d with
BuONa) the exo-elimination product 9a did not form or it
sodium methoxide produced a small amount of the other-
wise forbidden product 5d (Table 1, entry 3). In addition,
as for 4a, it was also possible with 4d to stop the transfor-
degraded, whereas the yields of the 5-alkoxy-1,5-dihydro-
2H-pyrrol-2-ones (the functional rearrangement products)
gradually diminished [5-methoxy-1,5-dihydro-2H-pyr-
mation of the minor trans-isomer, by lowering the reac-
rol-2-one 5a (63%), 5-ethoxy-1,5-dihydro-2H-pyrrol-2-
tion temperature (Table 1, entry 4).
one (49%), 5-isopropoxy-1,5-dihydro-2H-pyrrol-2-one
(30%),
(0%)].
5-tert-butoxy-1,5-dihydro-2H-pyrrol-2-one
Cl Me
Me
Me
MeO Me
Cl
MeONa
+
O
N
R
O
OMe
MeOH–Et2O
25 °C, 22 h
O
N
N
R
Me
Me
Me
Cl
Cl
O
R
MeONa
5b (75%)
(cis/trans = 80:20)
4b
9b (10%)
O
OMe
N
N
MeOH–Et2O
25 °C, 22 h
Cl Me
Me
Me
MeO Me
Cl
N
N
MeONa
+
O
O
OMe
N
R
MeOH–Et2O
25 °C, 22 h
O
N
N
cis/trans 4a (100:0)
5a (96%)
R
R
Me
Cl
MeO
Me
(cis/trans = 74:26)
4c
5c (70%)
9c (15%)
Me
Me
Cl
Cl Me
Me
Me
Cl
MeO Me
MeONa
O
O
O
+
OMe
N
N
N
MeONa
MeOH–Et2O
25 °C, 22 h
O
N
R
O
OMe
MeOH–Et2O
25 °C, 22 h
+
N
R
O
N
N
N
N
R
(cis/trans = 65:35)
4d
5d (67%)
9d (7%)
9a (60%)
cis/trans 4a (2:98)
5a (11%)
Scheme 4
N
N
N
R =
c
As MeOH/MeONa gives the highest yield of the function-
al rearrangement product, we subjected the cis- and trans-
isomers of 4a to this reagent. As expected, cis-4a gave se-
lectively the 5-methoxy-3,4-dimethyl-1-(2-pyridyl)-1,5-
dihydro-2H-pyrrol-2-one (5a), whereas the corresponding
trans-isomer of 4a gave the adduct 9a, as the main prod-
uct, through an exo dehydrohalogenation, followed by the
nucleophilic replacement of the Cl atom at C3 by the
methoxide ion (Scheme 4). Astonishingly, trans-4a also
afforded some 5a, the yield of which cannot be explained
N
b
d
Scheme 5
The likely origin of the functional rearrangement product
obtained from the trans-4 diastereomers can be ascribed
to a partial epimerization to the cis-isomer. However, we
were unable to replace the chloro group at the C3 position
of trans-4d in methanol at 25 °C with Br– (from NaBr or
KBr) or I– (from NaI or KI). Moreover, no epimerization
Synthesis 2008, No. 19, 3131–3141 © Thieme Stuttgart · New York

3134
F. Ghelfi et al.
PAPER
H
N
was observed when chloride ion was introduced as tetra-
ethylammonium chloride. On these experimental grounds
we judged it more plausible that the methoxide ion was re-
sponsible for inversion of the configuration at the C3 po-
sition (then followed by rapid elimination of MeOH). This
view is supported by literature examples of substitutions
of tertiary alkyl halides a to amide groups by N- or O- nu-
cleophiles (the formation of 9 can be included in the se-
ries).12–14
SO2Me
N
Cl Cl
Me
a
b
MeO2S
3e (89%)
O
1e
Me Cl
Me
Me
Cl
c
O
O
OMe
N
N
SO2Me
SO2Me
Table 1 Functional Rearrangement of 4d (cis/trans 65:35)a,b
5e (76%)
4e (93%)
(cis/trans = 87:13)
Entry Temp (°C) Time (h) Conversionc (%) Yieldd (%)
Scheme 6 Reagents and conditions: (a) MeCCl2COCl (2), NaH,
Et2O, r.t., 1 h; (b) CuCl–PMDETA, toluene, argon, r.t., 18 h; (c) Na,
MeOH, toluene, –10 °C, 22 h.
5d
67
69
6
9d
7
1
25
10
22
24
24
24
100
100
100
74
2
12
57
0
After these failures, we speculated that the corresponding
5-hydroxy-1,5-dihydro-2H-pyrrol-2-ones 7 could be easi-
ly converted into the maleimides 6 (Scheme 1). Thus, we
attempted the hydrolysis of the 5-methoxy-1,5-dihydro-
pyrrol-2-ones 5 and the results are collected in Table 2.
The lactams 5a and 5c were effectively hydrolyzed at 140
and 100 °C, respectively (Table 2, entries 5 and 7), using
a solution of sulfuric acid in water. The best reaction con-
ditions for 5d gave, instead, relatively low yields (Table 2,
entry 8); hence 5-hydroxy-1,5-dihydro-2H-pyrrol-2-one
5d was set aside. In contrast, substrate 5b appeared com-
pletely unreactive at 140 °C (Table 2, entry 6). An attempt
to form 7a, from the functional rearrangement of 4a using
a biphasic system of toluene and 50% aqueous sodium hy-
droxide under phase-transfer catalysis (tetrabutylammo-
nium bromide) failed.
3e
4
10
–10
65
a 4d (4 mmol), MeOH (12 mL), MeONa (12 mmol).
b All the reactions were performed under argon.
c GC values.
d Determined on isolated material.
e Reaction performed on trans-4d alone.
Since the proclivity to nucleophilic substitution of the ha-
lide ion in the a-halo-(CO) compounds is gradually aug-
mented when increasingly electron-withdrawing groups
are bound to the carbonyl group,15 we considered it inter-
esting to study the functional rearrangement of pyrrolidin-
2-one 4e carrying a strongly electronegative substituent at
N1, such as the methylsulfonyl group (Scheme 6).
The successful hydrolysis of 5 into 7 is evidently linked to
the involvement of an intramolecular hydrogen bridge be-
tween the protonated basic nitrogen and the ethereal oxy-
gen, which makes viable the replacement of the methoxy
group under relatively mild reaction conditions. This op-
portunity is not possible for 5b. The greater hydrolytic
susceptibility of 5c, compared to 5a, is likely a conse-
quence of the reduced electron-withdrawing effect of the
2-pyridyl appendage, caused by the methylene tether. As
a result the methoxy oxygen of 5c is more basic, and con-
sequently more liable to acid catalysis, than the corre-
sponding oxygen of 5a.
The dichlorinated g-lactams 4e were synthesized by atom-
transfer radical cyclization of amide 3e, using as redox
catalyst the complex copper(I) chloride/N,N,N¢,N¢,N¢¢-
pentamethyldiethylenetriamine (PMDETA) (Scheme 6).
As expected, the amount of trans-4e (cis-4e/trans-4e
87:13) was lower than that observed in the preceding cas-
es. This is due to facile radical epimerization encouraged
by the electronic effect of the methylsulfonyl group.16 Un-
fortunately, the functional rearrangement of 4e gave in-
conclusive and unsatisfactory results. A first reaction, run
at 25 °C, was disappointing, affording 5e in only 23%
yield. A much higher yield of 5e (76%) was achieved at
–10 °C. Notwithstanding the improvement, it is apparent
that the selectivity in the transformation of 4e is worse
than that attained with 4a–d, and as a consequence the
study of the functional rearrangement of 4e was aban-
doned.
Before dealing with the conversion of 5-hydroxy-1,5-di-
hydro-2H-pyrrol-2-ones 7 into the corresponding maleim-
ides 6, we deemed it more helpful to study in advance the
hydrolysis of 6, prepared by another route.22 Since it was
ascertained that 6a can be effortlessly hydrolyzed with
aqueous 2 M sulfuric acid (1 equiv) at 110 °C,4,6 we tested,
under the same reaction conditions, the substrates 6b (to
understand the influence on hydrolysis, of the pyridylic
nitrogen location) and 6c (Scheme 7). The outcome was
unexpected, while the hydrolysis of 6b was successful,
maleimide 6c was recovered quantitatively (Scheme 7).
Given that 1,5-dihydro-2H-pyrrol-2-ones can be hydrox-
ylated with oxygen in the presence of a base,17,18 for the
oxidation of the C5–OMe moiety of 5a, we investigated
the functional rearrangement of 4a under oxygen and the
oxidation of 5a with potassium hydroxide/acetone/oxy-
gen, but unsuccessfully.19 The Baeyer–Villiger oxidation
of 5a with peracids20 or sulfuric acid/hydrogen peroxide21
was equally fruitless.
In contrast to the efficient hydrolysis of 5-methoxy-1,5-
dihydro-2H-pyrrol-2-ones 5, where an intramolecular
Synthesis 2008, No. 19, 3131–3141 © Thieme Stuttgart · New York

PAPER
Preparation of the Maleic Anhydride Nucleus from Dichloro g-Lactams
3135
Table 2 Hydrolysis of 5a
Entry
Substrate
5ad
5ad
5a
Volume H2SO4/H2O (mL)b Temp (°C)
Time (h)
Conversionc (%) Yieldc (%) of 7
1
2
3
4
5
6
7
8
0.5/0
80
100
120
140
140
140
100
120
4
5
7
3
3
3
3
3
0
0
0
0
0.5/0
0.3/0.2
100
100
100
0
96
96
83e
0
5a
0.3/0.2
5a
0.25/0.25
0.25/0.25
0.25/0.25
0.25/0.25
5b
5c
96
76e
52e
5d
91
a 5 (0.5 mmol).
b 2 M H2SO4.
c GC values.
d 5 (0.25 mmol).
e Yield of isolated product.
acid catalysis was required, the hydrolysis of 6 is promot- used as the solvent. In the end the hydrolysis of 6a with 2
ed by the increased electronegativity of the N-substituent, M sulfuric acid gave the expected pyrochinconic anhy-
after protonation of the pyridyl group, and by the possibil- dride 8 in high yield (93% yield).
ity that this increment can be directly transferred to the
maleimidic nitrogen. This makes the C=O function more
electrophilic and then more susceptible to attack by water
molecules (this was the case for substrates 6a and 6b,
whereas 6c is unreactive, since a methylene tether is be-
tween the pyridinium moiety and the maleimide nitrogen).
On the basis of these results it was evident that the choice
of the intermediate to be oxidized to the maleimide was
The route described herein from dichloro g-lactams to the
disubstituted maleic anhydride nucleus is more practical
than that from trichloro g-lactams, since both the prepara-
tions of the starting materials and of all the intermediates
were completed with simple, economic, and high yielding
procedures. The outcome of the functional rearrangement
of 4a may be further increased on carrying out the atom-
transfer radical cyclization of 3 under thermodynamic
control, so to get an even more favorable cis-4a/trans-4a
restricted to 7a.
After a number of unsuccessful attempts, we realized that ratio.
the oxidation of 5-hydroxy-1,5-dihydro-2H-pyrrol-2-one
This new method, in particular, was helpful in the recog-
nition of a positive effect, albeit in practice unexploitable,
of the N-substituent on the generation of 5 from the g-lac-
tams trans-4, which are the isomers endowed of an unfa-
7a into the corresponding maleimide 6a can be only
achieved using manganese(IV) oxide.23,24 This reagent is
particularly attractive from an industrial point of view ow-
ing to a number of helpful properties: low toxicity, low
vorable configuration for the functional rearrangement in
cost, easy handling, commercial availability, recyclabili-
MeONa/MeOH.4 The pivotal role played by the N-substit-
ty.25 Pleasingly, 7a was smoothly transformed by manga-
uent along the synthetic path, for the conversion of the 5-
nese(IV) oxide into maleimide 6a (Scheme 8), when
methoxy-1,5-dihydro-2H-pyrrol-2-ones into the corre-
toluene (83% yield) or dichloromethane (89% yield) was
sponding 5-hydroxy-1,5-dihydro-2H-pyrrol-2-ones and
for the effective hydrolysis of maleimides 6 into anhy-
Me
Me
Me
Me
Me
Me
dride 8 was also understood. Incidentally, the 5-hydroxy-
1,5-dihydro-2H-pyrrol-2-ones are interesting compounds
potentially usable as agrochemicals for crops protection,
e.g. 7a was patented by Ciba-Geigy AG.26
a
b
O
O
O
O
O
O
O
8
N
N
O
8
(95%)
6b
(96%)
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
b
a
b
X
a
O
O
O
O
O
OH
7a
N
O
N
O
O
O
O
O
8
O
8
(0%)
O
O
N
8 (93%)
N
N
N
6c
(94%)
6a
(89% in CH2Cl2)
(83% in toluene)
Scheme 7 Reagents and conditions: (a) 2-aminopyridine or 2-(ami-
Scheme 8 Reagents and conditions: (a) MnO2, solvent, r.t., 20 h; (b)
nomethyl)pyridine, xylene, reflux, 2 h; (b) 2 M H2SO4, 110 °C, 3 h.
2 M H2SO4, 110 °C, 3 h.
Synthesis 2008, No. 19, 3131–3141 © Thieme Stuttgart · New York

3136
F. Ghelfi et al.
PAPER
Reagents and solvents were standard grade commercial products,
purchased from Aldrich, Acros, Fluka, or RdH, and used without
further purification, except MeCN and CH2Cl2, which were dried
over three batches of 3 Å sieves (5% w/v, 12 h). The flash chroma-
tography used Silica Gel 60 Merck (0.040–0.063 mm); PE = petro-
leum ether (bp 40–60 °C). 2-{[(Prop-2-enyl)amino]methyl}py-
ridine (1c) was prepared by N-alkylation of 2-(aminomethyl)pyri-
dine with 3-chloropropene, following the procedure of Shipman.27
The maleimides 6b and 6c were obtained from commercial pyrocin-
chonic anhydride and 4-aminopyridine or 2-(aminomethyl)pyri-
dine, respectively, exploiting the procedure described by Padwa.22
N-(Prop-2-enyl)methanesulfonamide (3e)28 and 2,2-dichloropro-
panoyl chloride (2)4 were prepared according to given protocols.
2-(Prop-2-enylamino)pyrimidine (1d)
Following the typical procedure for 1a using 2-chloropyrimidine
(11.5 g, 100 mmol) and allylamine (15.0 mL, 200 mmol). The mix-
ture was cooled in a water bath at r.t., to control the exothermic re-
action and stirred vigorously at r.t. for 2 h. Workup as for 1a, but
using Et2O (3 × 20 mL), gave 1d (12.83 g, 95%) as a pale yellow
liquid; bp 89–90 °C/1.2 mbar.
IR (film): 3270 cm–1 (N–H).
1H NMR (200 MHz, CDCl3): d = 4.05 (tt, J = 1.6, 5.6 Hz, 2 H,
CH2), 5.11 (dq, J = 10.3, 1.6 Hz, 1 H, =CH2), 5.23 (dq, J = 17.2, 1.6
Hz, 1 H, =CH2), 5.88 (br s, 1 H, NH), 5.94 (ddt, J = 17.2, 10.3, 5.3
Hz, 1 H, CH=CH2), 6.49 (t, J = 4.8 Hz, 1 H, H5py), 8.24 (d, J = 4.8
Hz, 2 H, H4py, H6py).
1H NMR, IR, and MS spectra were recorded on Bruker DPX 200
and Bruker Avance 400, Perkin Elmer 1600 Series FTIR, and HP
5890 GC - HP 5989A MS instruments, respectively.
MS (EI, 70 eV): m/z (%) = 136 (8%) [M + 1]+, 135 (52) [M]+, 134
(44) [M – 1]+, 120 (100), 108 (27), 79 (21).
Anal. Calcd for C7H9N3: C, 62.20; H, 6.71; N, 31.09. Found: C,
62.3; H, 6.8; N, 31.1.
The structural assignment of compounds 4a–e, 5a–e, and 9a–e was
determined by heteronuclear H,C inverse-detection NMR correla-
tion techniques and for 4a–e also by homonuclear nuclear Over-
hauser enhancement. The direct and long-range H,C correlations
allowed us to establish unambiguously the regiochemistry of the
products, whereas NOESY experiments enabled the relative stereo-
chemistry at the C3 and C4 carbons in 4a–e to be determined. The
presence of an equilibrium (in soln) between 2 rotamers of com-
pound 3c was evidenced by NMR (hindered rotation around the
amide bond). An exchange spectroscopy experiment (EXSY) per-
mitted the reported assignments.
N-Allyl-2,2-dichloro-N-(2-pyridyl)propanamide (3a)
To a 100-mL, 2-necked round-bottomed flask fitted with a dropping
funnel and a reflux condenser, closed on the top with a CaCl2 tube,
was added CH2Cl2 (60 mL), 1a (16.55 g, 124 mmol), and pyridine
(13 mL, 155 mmol). The mixture was stirred and cooled in an ice
bath and a soln of 2,2-dichloropropanoyl chloride (2, 21.94 g, 136
mmol) in CH2Cl2 (30 mL) was then carefully added over 10 min.
The bath was removed and the mixture was stirred at r.t. for 20 h.
The mixture was made basic with 5% aq NaOH (110 mL) and ex-
tracted with CH2Cl2 (2 × 30 mL). The combined organic phases
were concentrated and the crude product was subjected to flash
chromatography (silica gel, PE–Et2O, gradient from 10:0 to 5:5) to
afford 3a (28.73 g, 90%) as a brownish oil.
2-(Prop-2-enylamino)pyridine (1a); Typical Procedure
To a Schlenk tube, fitted with a pierceable septum (blocked by a
screw cap) and a stirrer bar, was added under argon 2-chloropyri-
dine (9.5 mL, 100 mmol) and allylamine (15.0 mL, 200 mmol). The
soln was stirred vigorously and heated at 140 °C for 72 h. It was
then cooled to r.t., neutralized with 10% aq NaOH, and extracted
with Et2O (2 × 10 mL). The combined organic layers were evapo-
rated and the crude product thus obtained was purified by fractional
distillation to give 1a (9.65 g, 72%) as a pale yellow liquid; bp 104–
106 °C/5.33 mbar.
IR (film): 1665 cm–1 (C=O).
1H NMR (200 MHz, CDCl3): d = 2.30 (s, 3 H, CH3), 4.72 (td,
J = 6.0, 1.2, Hz, 2 H, CH2), 5.05 (dq, J = 10.2, 1.2 Hz, 1 H, =CH2),
5.08 (dq, J = 17.2, 1.2 Hz, 1 H, =CH2), 5.82 (ddt, J = 17.2, 10.2, 6.0
Hz, 1 H, CH=CH2), 7.18 (dd, J = 5.2, 7.0 Hz, 1 H, H5py), 7.37 (d,
J = 7.8 Hz, 1 H, H3py), 7.70 (td, J = 7.8, 1.3 Hz, 1 H, H4py), 8.49 (dd,
J = 5.2, 1.3 Hz, 1 H, H6py).
IR (film): 3264 cm–1 (N–H).
1H NMR (200 MHz, CDCl3): d = 3.89 (m, 2 H, CH2N), 5.02 (br s,
1 H, NH), 5.10 (m, 1 H, =CH2), 5.22 (m, 1 H, =CH2), 5.91 (m, 1 H,
CH=CH2), 6.34 (d, J = 8.4 Hz, 1 H, H3py), 6.52 (dd, J = 7.2, 5.1 Hz,
1 H, H5py), 7.35 (dd, J = 8.4, 7.2 Hz, 1 H, H4py), 8.05 (br d, J = 5.1
Hz, 1 H, H6py).
MS (EI, 70 eV): m/z (%) = 259 (3) [M + 1]+, 258 (10) [M]+, 257 (2)
[M – 1]+, 223 (15), 161 (92), 133 (100), 78 (20), 41 (38).
Anal. Calcd for C11H12Cl2N2O: C, 50.99; H, 4.67; N, 10.81. Found:
C, 51.0; H, 4.7; N, 10.8.
MS (EI, 70 eV): m/z (%) = 135 (6) [M + 1]+, 134 (39) [M]+, 133 (32)
N-Allyl-2,2-dichloro-N-(4-pyridyl)propanamide (3b)
[M – 1]+, 119 (100), 107 (38), 79 (25), 78 (36).
To a Schlenk tube, fitted with a pierceable septum (blocked by a
screw cap) and a stirrer bar, was added under argon 1b (3.35 g, 25
mmol), pyridine (2.25 mL, 30 mmol), and CH2Cl2 (20 mL). The
soln was stirred and cooled in an ice bath and a soln of 2,2-dichlo-
ropropanoyl chloride (2, 4.84 g, 30 mmol) in CH2Cl2 (20 mL) was
carefully added with a syringe. After 30 min the bath was removed
and the mixture was stirred at r.t. for 20 h at r.t.. The mixture was
then diluted with brine (20 mL), made basic with 5% aq NaOH (25
mL), and extracted with Et2O–CH2Cl2 (1:1, 3 × 20 mL). The com-
bined organic phases were concentrated and the crude product was
subjected to flash chromatography (silica gel, PE–Et2O, 5:5) to give
3b (4.64 g, 71%) as a white solid; mp 93–95 °C.
Anal. Calcd for C8H10N2: C, 71.61; H, 7.51; N, 20.87. Found: C,
71.5; H, 7.5; N, 21.0.
4-(Prop-2-enylamino)pyridine (1b)
Following the typical procedure for 1a using 4-chloropyridine·hy-
drochloride (15.0 g, 100 mmol) and allylamine (22.5 mL, 300
mmol) gave 1b (10.45 g, 78%) as a colorless liquid, which then be-
came a white solid; bp 140–142 °C/6.7 mbar; mp 66–68 °C.
IR (KBr): 3238 cm–1 (N–H).
1H NMR (200 MHz, CDCl3): d = 3.79 (m, 2 H, CH2), 4.67 (br s, 1
H, NH), 5.18 (m, 1 H, =CH2), 5.25 (m, 1 H, =CH2), 5.88 (m, 1 H,
CH=CH2), 6.42 (m, 2 H, H3py, H5py), 8.16 (m, 2 H, H2py, H6py).
IR (KBr): 1665 cm–1 (C=O).
1H NMR (200 MHz, CDCl3): d = 2.35 (s, 3 H, CH3), 4.57 (td,
J = 5.9, 1.3, Hz, 2 H, CH2), 5.10 (dq, J = 17.1, 1.3 Hz, 1 H, =CH2),
5.18 (dq, J = 10.1, 1.3 Hz, 1 H, =CH2), 5.87 (ddt, J = 17.1, 10.1, 5.9
Hz, 1 H, CH=CH2), 7.26 (m, 2 H, H3py, H5py), 8.57 (m, 2 H, H2py,
H6py).
MS (EI, 70 eV): m/z (%) = 135 (12) [M + 1]+, 134 (100) [M]+, 133
(83) [M – 1]+, 107 (98), 78 (45), 51 (43).
Anal. Calcd for C8H10N2: C, 71.61; H, 7.51; N, 20.87. Found: C,
71.6; H, 7.5; N, 20.9.
Synthesis 2008, No. 19, 3131–3141 © Thieme Stuttgart · New York

PAPER
Preparation of the Maleic Anhydride Nucleus from Dichloro g-Lactams
3137
MS (EI, 70 eV): m/z (%) = 259 (5) [M + 1]+, 258 (33) [M]+, 223
H2O was added to dissolve the formed salt and the mixture was ex-
(37), 187 (20), 161 (100), 133 (42), 78 (8), 41 (97).
tracted with CH2Cl2 (2 × 50 mL). The combined organic phases
were concentrated and the crude product was subjected to flash
chromatography (silica gel, PE–Et2O, gradient from 10:0 to 8:2) to
afford 3e (27.78 g, 89%) as a yellow oil.
Anal. Calcd for C11H12Cl2N2O: C, 50.99; H, 4.67; N, 10.81. Found:
C, 50.9; H, 4.7; N, 10.7.
N-Allyl-2,2-dichloro-N-[(2-pyridyl)methyl]propanamide (3c);
Typical Procedure
IR (film): 1696 cm–1 (C=O).
1H NMR (200 MHz, CDCl3): d = 2.33 (s, 3 H, CCl2CH3), 3.31 (s, 3
H, SCH3), 4.86 (dt, J = 5.8, 1.4 Hz, 2 H, CH2), 5.33 (dq, J = 10.3,
1.2 Hz, 1 H, =CH2), 5.19 (dq, J = 17.1, 1.2 Hz, 1 H, =CH2), 5.97
(ddt, J = 17.1, 10.3, 5.8 Hz, 1 H, CH=CH2).
MS (EI, 70 eV): m/z (%) = 259 (1) [M]+, 180 (14), 162 (16), 97 (17),
41 (100).
To a 100-mL 2-necked round-bottomed flask fitted with a dropping
funnel and a reflux condenser, closed on the top with a CaCl2 tube,
was added CH2Cl2 (50 mL), 1c (14.72 g, 100 mmol), and pyridine
(10 mL, 133 mmol). The mixture was stirred and cooled in an ice
bath and a soln of 2,2-dichloropropanoyl chloride (2, 16.14 g, 100
mmol) in CH2Cl2 (20 mL) was then carefully added over 10 min.
The bath was removed and the mixture was stirred at r.t. for 20 h.
The mixture was made basic with 5% aq NaOH (80 mL) and ex-
tracted with CH2Cl2 (2 × 30 mL). The combined organic phases
were concentrated and the crude product was subjected to flash
chromatography (silica gel, PE–Et2O, gradient from 10:0 to 7:3) to
afford 3c (20.47 g, 75%) as a pale yellow oil.
Anal. Calcd for C7H11Cl2NO3S: C, 32.32; H, 4.26; N, 5.38. Found:
C, 32.3; H, 4.3; N, 5.4.
3-Chloro-4-(chloromethyl)-3-methyl-1-(2-pyridyl)pyrrolidin-2-
one (4a); Typical Procedure
CuCl (1.09 g, 11.1 mmol) and 3a (28.73 g, 111 mmol) were
weighed in a Schlenk tube fitted with a pierceable septum (blocked
by a screw cap) and a magnetic stirrer bar. Anhyd MeCN (90 mL)
and TMEDA (3.3 mL, 22.2 mmol) were then added under argon.
The mixture was stirred at r.t. for 20 h and then diluted with H2O (30
mL) and CH2Cl2 (50 mL) and extracted with toluene (3 × 50 mL).
The combined organic layers were concentrated and the crude prod-
uct was purified by flash chromatography (silica gel, PE–Et2O, 7:3)
to give pyrrolidinones cis-4a (16.02 g, 56%) and trans-4a (10.24 g,
35%) both as white crystalline solids.
IR (film): 1656 cm–1 (C=O).
1H NMR (200 MHz, CDCl3): d = 2.35 (s, 3 H, CH3 major), 2.36 (s,
3 H, CH3 minor), 4.00 (d, J = 5.2 Hz, 2 H, CH2C= minor), 4.53 (d,
J = 5.7 Hz, 2 H, CH2C= major), 4.69 (s, 2 H, CH2py major), 5.12 (d,
J = 17.4 Hz, 1 H, =CH2 minor), 5.18 (d, J = 10.3 Hz, 1 H, =CH2 mi-
nor), 5.21 (s, 2 H, CH2py minor), 5.27 (d, J = 17.0 Hz, 1 H, =CH2
major), 5.29 (d, J = 9.5 Hz, 1 H, =CH2 major), 5.77 (ddt, J = 16.4,
10.1, 6.1 Hz, 1 H, CH=CH2 minor), 5.92 (ddt, J = 16.7, 10.6, 6.0
Hz, 1 H, CH=CH2 major), 7.17 (m, 2 H, H3py, H5py major), 7.21 (dd,
J = 7.8, 5.3 Hz, 1 H, H5py minor), 7.29 (d, J = 8.0 Hz, 1 H, H3py mi-
nor), 7.65 (t, J = 7.7 Hz, 1 H, H4py major), 7.69 (t, J = 7.7 Hz, 1 H,
H4py minor), 8.54 (d, J = 4.6 Hz, 1 H, H6py major), 8.58 (d, J = 4.7
Hz, 1 H, H6py minor).
cis-3-Chloro-4-(chloromethyl)-3-methyl-1-(2-pyridyl)pyrroli-
din-2-one (cis-4a)
Mp 72–75 °C.
IR (KBr): 1727 cm–1 (C=O).
1H NMR (400 MHz, CDCl3): d = 1.87 (s, 3 H, CH3), 2.67 (m, 1 H,
H4), 3.66 (dd, J = 11.4, 9.8 Hz, 1 H, H5), 3.78 (dd, J = 11.2, 8.7 Hz,
1 H, CH2Cl), 3.90 (dd, J = 11.2, 5.6 Hz, 1 H, CH2Cl), 4.50 (dd,
J = 11.4, 7.2 Hz, 1 H, H5), 7.08 (dd, J = 7.1, 5.3 Hz, 1 H, H5py), 7.71
(td, J = 7.9, 1.8 Hz, 1 H, H4py), 8.36 (m, 2 H, H3py, H6py).
13C NMR (400 MHz, CDCl3): d = 25.0 (CH3), 42.0 (CH2Cl), 46.6
(C4), 47.7 (C5), 70.5 (C3), 114.9 (C3py), 120.4 (C5py), 137.9 (C4py),
147.7 (C6py), 151.0 (C2py), 170.4 (C=O).
MS (EI, 70 eV): m/z (%) = 273 (1) [M + 1]+, 272 (1), [M]+, 201 (15),
175 (11), 147 (15), 93 (100).
Anal. Calcd for C12H14Cl2N2O: C, 52.76; H, 5.17; N, 10.26. Found:
C, 52.8; H, 5.1; N, 10.2.
N-Allyl-2,2-dichloro-N-(pyrimidin-2-yl)propanamide (3d)
Following the typical procedure for 3c using 1d (13.51 g, 100
mmol) gave, after flash chromatography of the crude product (silica
gel, CH2Cl2–MeOH, gradient from 10:0 to 9.5:0.5), 3d (26.32 g,
100%) as a pale orange solid; mp 34–36 °C.
MS (EI, 70 eV): m/z (%) = 258 (23) [M]+, 223 (28), 209 (17), 187
(67), 173 (100), 159 (27), 145 (32), 121 (42), 78 (38).
IR (KBr): 1673 cm–1 (C=O).
1H NMR (200 MHz, CDCl3): d = 2.43 (s, 3 H, CH3), 4.76 (dt,
J = 5.7, 1.4 Hz, 2 H, CH2), 5.09 (dq, J = 10.3, 1.4 Hz, 1 H, =CH2),
5.19 (dq, J = 17.1, 1.4 Hz, 1 H, =CH2), 5.91 (ddt, J = 17.1, 10.3, 5.7
Hz, 1 H, CH=CH2), 7.17 (t, J = 4.8 Hz, 1 H, H5py), 8.71 (d, J = 4.8
Hz, 2 H, H4py, H6py).
MS (EI, 70 eV): m/z (%) = 260 (1) [M + 1]+, 259 (8) [M]+, 162
(100), 134 (80), 108 (8), 79 (20), 41(65).
Anal. Calcd for C11H12Cl2N2O: C, 50.99; H, 4.67; N, 10.81. Found:
C, 51.1; H, 4.7; N, 10.8.
trans-3-Chloro-4-(chloromethyl)-3-methyl-1-(2-pyridyl)pyrro-
lidin-2-one (trans-4a)
Mp 90–93 °C.
IR (KBr): 1712 cm–1 (C=O).
1H NMR (400 MHz, CDCl3): d = 1.74 (s, 3 H, CH3), 3.06 (m, 1 H,
H4), 3.56 (dd, J = 11.2, 9.1 Hz, 1 H, CH2Cl), 3.82 (dd, J = 11.2, 4.5
Hz, 1 H, CH2Cl), 4.00 (dd, J = 11.7, 5.3 Hz, 1 H, H5), 4.38 (dd,
J = 11.7, 7.1 Hz, 1 H, H5), 7.10 (br t, J = 5.9 Hz, 1 H, H5py), 7.73
(td, J = 7.9, 1.3 Hz, 1 H, H4py), 8.38 (m, 2 H, H3py, H6py).
13C NMR (400 MHz, CDCl3): d = 21.5 (CH3), 42.3 (CH2Cl), 47.2
(C4), 47.5 (C5), 69.3 (C3), 115.0 (C3py), 120.4 (C5py), 137.9 (C4py),
147.7 (C6py), 151.0 (C2py), 170.6 (C=O).
Anal. Calcd for C10H11Cl2N3O: C, 46.17; H, 4.26; N, 16.15. Found:
C, 46.1; H, 4.2; N, 16.1.
N-Allyl-N-(2,2-dichloropropanoyl)methanesulfonamide (3e)
To a 100-mL, 3-necked round-bottomed flask fitted with a mechan-
ical stirrer and a reflux condenser, closed on the top with a CaCl2
tube, was added 1e (20.27 g, 150 mmol) and Et2O (200 mL). Then
NaH (60% dispersion in mineral oil, 6.0 g, 157 mmol) was carefully
added to the flask. When H2 evolution ceased, a soln of 2,2-dichlo-
ropropanoyl chloride (2, 19.36 g, 120 mmol) in Et2O (100 mL) was
slowly added through the dropping funnel. After the acyl halide ad-
dition, the mixture was stirred for 1 h and then diluted with toluene–
water (8 mL–2 mL) and acidified with 10% aq HCl. Then, sufficient
MS (EI, 70 eV): m/z (%) = 258 (23) [M]+, 223 (28), 209 (17), 187
(67), 173 (100), 159 (27), 145 (32), 121 (42), 78 (38).
Anal. Calcd for C11H12Cl2N2O: C, 50.99; H, 4.67; N, 10.81. Found:
C, 51.0; H, 4.6; N, 10.7.
Synthesis 2008, No. 19, 3131–3141 © Thieme Stuttgart · New York

3138
F. Ghelfi et al.
PAPER
3-Chloro-4-(chloromethyl)-3-methyl-1-(4-pyridyl)pyrrolidin-2-
one (4b)
Following the typical procedure 4a, 3b (2.60 g, 10 mmol) gave, af-
ter flash chromatography of the crude product (silica gel, PE–
MeOH, 95:5), 4b (1.73 g, 67%) as a white crystalline solid; cis/
trans 80:20 (1H NMR).
IR (KBr): 1735 cm–1 (C=O).
1H NMR (400 MHz, CDCl3): d (cis) = 1.88 (s, 3 H, CH3), 2.68 (m,
1 H, H4), 3.72 (dd, J = 11.1, 9.9 Hz, 1 H, H5), 3.79 (dd, J = 11.3,
8.9 Hz, 1 H, CH2Cl), 3.90 (dd, J = 11.3, 5.4 Hz, 1 H, CH2Cl), 4.38
(dd, J = 11.1, 7.1 Hz, 1 H, H5), 7.09 (t, J = 4.8 Hz, 1 H, H5py), 8.69
(d, J = 4.8 Hz, 2 H, H4py, H6py); d (trans) = 1.76 (s, 3 H, CH3), 3.04
(m, 1 H, H4), 3.53 (dd, J = 11.2, 9.4 Hz, 1 H, CH2Cl), 3.81 (dd,
J = 11.2, 4.4 Hz, 1 H, CH2Cl), 4.01 (dd, J = 11.6, 4.6 Hz, 1 H, H5),
4.37 (dd, J = 11.6, 6.7 Hz, 1 H, H5), 7.10 (t, J = 4.8 Hz, 1 H, H5py),
8.70 (d, J = 4.8 Hz, 2 H, H4py, H6py).
13C NMR (400 MHz, CDCl3): d (cis) = 24.7 (CH3), 41.8 (CH2Cl),
46.5 (C4), 48.4 (C5), 70.0 (C3), 117.3 (C5py), 157.2 (C2py) 158.2
(C4py, C6py), 169.3 (C=O); d (trans) = 21.4 (CH3), 42.2 (CH2Cl),
47.0 (C4), 48.0 (C5), 68.8 (C3), 117.3 (C5py), 157.2 (C2py) 158.2
(C4py, C6py), 169.5 (C=O).
IR (KBr): 1726 cm–1 (C=O).
1H NMR (400 MHz, CDCl3): d (cis) = 1.87 (s, 3 H, CH3), 2.74 (m,
1 H, H4), 3.63 (t, J = 9.8 Hz, 1 H, H5), 3.81 (dd, J = 11.3, 9.4 Hz, 1
H, CH2Cl), 3.91 (dd, J = 11.3, 5.1 Hz, 1 H, CH2Cl), 4.04 (dd,
J = 9.8, 7.1 Hz, 1 H, H5), 7.63 (d, J = 5.7 Hz, 2 H, H3py, H5py), 8.60
(br s, 2 H, H2py, H6py); d (trans) = 1.75 (s, 3 H, CH3), 3.11 (m, 1 H,
H4), 3.54 (dd, J = 11.3, 9.2 Hz, 1 H, CH2Cl), 3.74 (dd, J = 10.2, 4.4
Hz, 1 H, H5), 3.83 (dd, J = 11.3, 5.2 Hz, 1 H, CH2Cl), 4.18 (dd,
J = 10.2, 6.9 Hz, 1 H, H5), 7.63 (d, J = 5.7 Hz, 2 H, H3py, H5py),
8.60 (br s, 2 H, H2py, H6py).
13C NMR (400 MHz, CDCl3): d (cis) = 24.7 (CH3), 41.7 (CH2Cl),
46.8 (C4), 48.3 (C5), 69.3 (C3), 113.2 (C3py,5), 145.2 (C4py), 150.9
(C2py,6), 170.7 (C=O); d (trans) = 21.4 (CH3), 42.2 (CH2Cl), 47.2
(C4), 47.8 (C5), 68.0 (C3), 113.2 (C3py,5), 145.2 (C4py), 150.9
(C2py, C6py), 170.6 (C=O).
MS (EI, 70 eV): m/z (%) = 260 (5) [M + 1]+, 259 (39) [M]+, 224
(87), 210 (30), 188 (54), 174 (100), 160 (19), 122 (67).
Anal. Calcd for C10H11Cl2N3O: C, 46.17; H, 4.26; N, 16.15. Found:
C, 46.1; H, 4.2; N, 16.1.
3-Chloro-4-(chloromethyl)-1-mesyl-3-methylpyrrolidin-2-one
(4e)
MS (EI, 70 eV): m/z (%) = 258 (100) [M]+, 224 (53), 188 (53), 173
(33), 159 (40), 142 (83), 121 (70), 107 (88), 89 (78), 78 (78).
CuCl (0.10 g, 1 mmol) was weighed in a Schlenk tube fitted with a
pierceable septum (blocked by a screw cap) and a magnetic stirrer
bar. Toluene (8 mL) and PMDETA (0.208 mL, 1 mmol) were then
added under argon. The mixture was stirred at r.t. for ~0.5 h, after
which 3e (5.20 g, 20 mmol), solubilized in toluene (12 mL), was in-
troduced. The stirring was continued for a further 18 h. The mixture
was then diluted with H2O (30 mL) and CH2Cl2 (50 mL) and ex-
tracted with toluene (3 × 50 mL). The combined organic layers
were concentrated and the crude product was purified by flash chro-
matography (silica gel, CH2Cl2–Et2O, 9:1) to give 4e (4.84 g, 93%)
as a pale yellow powder; inseparable cis/trans-diastereomers 87:13
(1H NMR).
Anal. Calcd for C11H12Cl2N2O: C, 50.99; H, 4.67; N, 10.81. Found:
C, 51.0; H, 4.6; N, 10.8.
3-Chloro-4-(chloromethyl)-3-methyl-1-[(2-pyridyl)methyl]pyr-
rolidin-2-one (4c)
Following the typical procedure for 4a, 3c (2.73 g, 10 mmol) gave,
after flash chromatography of the crude product (silica gel, PE–
Et2O, gradient from 10:0 to 5:5), 4c (2.49 g, 91%) as a pale yellow
oil; cis/trans 74:26 (1H NMR).
IR (film): 1721 cm–1 (C=O).
1H NMR (400 MHz, CDCl3): d (cis) = 1.81 (s, 3 H, CH3), 2.60 (m,
1 H, H4), 3.18 (dd, J = 10.2, 9.1 Hz, 1 H, H5), 3.54 (dd, J = 10.2,
7.1 Hz, 1 H, H5), 3.66 (dd, J = 11.2, 9.1 Hz, 1 H, CH2Cl), 3.81 (dd,
J = 11.2, 5.5 Hz, 1 H, CH2Cl), 4.52 (d, J = 15.0 Hz, 1 H, NCH2),
4.72 (d, J = 15.0 Hz, 1 H, NCH2), 7.20 (ddd, J = 7.6, 4.8, 1.0 Hz, 1
H, H5py), 7.22 (br d, J = 7.8 Hz, 1 H, H3py), 7.65 (td, J = 7.8, 1.8 Hz,
1 H, H4py), 8.53 (ddd, J = 4.8, 1.8, 1.0 Hz, 1 H, H6py); d (trans) =
1.66 (s, 3 H, CH3), 2.94 (m, 1 H, H4), 3.29 (dd, J = 10.4, 4.8 Hz, 1
H, H5), 3.46 (dd, J = 11.0, 9.7 Hz, 1 H, CH2Cl), 3.69 (dd, J = 10.4,
7.0 Hz, 1 H, H5), 3.72 (dd, J = 11.0, 4.5 Hz, 1 H, CH2Cl), 4.59 (d,
J = 15.3 Hz, 1 H, NCH2), 4.64 (d, J = 15.3 Hz, 1 H, NCH2), 7.19 (m,
1 H, H5py), 7.24 (br d, J = 7.8 Hz, 1 H, H3py), 7.65 (td, J = 7.8, 1.8
Hz, 1 H, H4py), 8.52 (m, 1 H, H6py).
13C NMR (400 MHz, CDCl3): d (cis) = 25.0 (CH3), 42.0 (CH2Cl),
47.7 (C4), 48.4 (C5), 48.8 (NCH2), 68.8 (C3), 122.1 (C3py), 122.7
(C5py), 137.0 (C4py), 149.5 (C6py), 155.5 (C2py), 171.2 (C=O); d
(trans) = 21.4 (CH3), 42.3 (CH2Cl), 47.9 (C5), 48.5 (C4), 48.7
(NCH2), 67.8 (C3), 122.2 (C3py), 122.7 (C5py), 137.0 (C4py), 149.4
(C6py), 155.4 (C2py), 171.3 (C=O).
IR (KBr): 1742 cm–1 (C=O).
1H NMR (400 MHz, CDCl3): d (cis) = 1.77 (s, 3 H, CH3), 2.69 (m,
1 H, H4), 3.22 (s, 3 H, SCH3), 3.43 (dd, J = 10.1, 9.7 Hz, 1 H, H5),
3.66 (dd, J = 11.4, 8.5 Hz, 1 H, CH2Cl), 3.80 (dd, J = 11.4, 5.8 Hz,
1 H, CH2Cl), 4.07 (dd, J = 10.1, 7.1 Hz, 1 H, H5); d (trans) = 1.70
(s, 3 H, CH3), 2.98 (m, 1 H, H4), 3.23 (s, 3 H, SCH3), 3.57 (dd,
J = 11.7, 7.2 Hz, 1 H, CH2Cl), 3.74 (dd, J = 11.7, 4.2 Hz, 1 H,
CH2Cl), 3.75 (dd, J = 10.6, 3.5 Hz, 1 H, H5), 4.10 (dd, J = 10.6, 7.8
Hz, 1 H, H5).
13C NMR (400 MHz, CDCl3): d (cis) = 23.7 (CH3), 39.8 (SCH3),
40.8 (CH2Cl), 46.6 (C4), 47.0 (C5), 68.9 (C3), 169.9 (C=O); d
(trans) = 20.5 (CH3), 40.2 (SCH3), 42.3 (CH2Cl), 46.5 (C5), 46.7
(C4), 67.5 (C3), 170.0 (C=O).
MS (EI, 70 eV): m/z (%) = 260 (2) [M + 1]+, 259 (16) [M]+, 180 (5),
38 (37),102 (34), 89 (100), 56 (52).
Anal. Calcd for C7H11Cl2NO3S: C, 32.32; H, 4.26; N, 5.38. Found:
C, 32.4; H, 4.2; N, 5.4.
MS (EI, 70 eV): m/z (%) = 273 (1) [M]+, 236 (22), 201 (64), 187
(100), 119 (9), 93 (99).
5-Methoxy-3,4-dimethyl-1-(2-pyridyl)-1,5-dihydro-2H-pyrrol-
2-one (5a); Typical Procedure
To a Schlenk tube, fitted with a pierceable septum blocked by a
screw cap, was added Et2O–MeOH (1:1, 15 mL) and cis-4a (2.59 g,
10 mmol). The soln was thermostated at 25 °C. In a second Schlenk
tube, Na (0.69 g, 30 mmol) was carefully dissolved in MeOH (15
mL) and, when the effervescence ceased, the alkaline soln was ther-
mostated at 25 °C, after which it was poured into the first Schlenk
tube and the mixture was stirred for 22 h. Then it was diluted with
H2O (20 mL) and extracted with CH2Cl2 (3 × 10 mL). The com-
bined organic layers were collected and concentrated. The crude
product was subjected to flash chromatography (silica gel, PE–
Anal. Calcd for C12H14Cl2N2O: C, 52.76; H, 5.17; N, 10.26. Found:
C, 52.7; H, 5.1; N, 10.3.
3-Chloro-4-(chloromethyl)-3-methyl-1-(pyrimidin-2-yl)pyrro-
lidin-2-one (4d)
Following the typical procedure for 4a, 3d (2.60 g, 10 mmol) gave,
after flash chromatography of the crude product (silica gel, CH2Cl2–
MeOH, gradient from 100:0 to 97:3), 4d (2.19 g, 84%) as a pale
pink powder; cis/trans 65:35 (1H NMR).
Synthesis 2008, No. 19, 3131–3141 © Thieme Stuttgart · New York

PAPER
Preparation of the Maleic Anhydride Nucleus from Dichloro g-Lactams
3139
Et2O, gradient 10:0 to 5:5) to afford 5a (2.1 g, 96%) as a pale orange
IR (KBr): 1708 cm–1 (C=O).
oil.
1H NMR (400 MHz, CDCl3): d = 1.48 (s, 3 H, CH3), 3.21 (s, 3 H,
OCH3), 4.32–4.42 (m, 2 H, CH2), 5.44 (t, J = 2.0 Hz, 1 H, =CH2),
5.46 (t, J = 2.0 Hz, 1 H, =CH2), 7.75 (br s, 2 H, H3py, H5py), 8.70 (v
br s, 2 H, H2py, H6py).
13C NMR (400 MHz, CDCl3): d = 24.4 (CH3), 49.3 (C5), 52.5
(OCH3), 80.8 (C3), 111.8 ( =CH2), 113.3 (C3py, C5py), 139.4 (C4),
144.2 (C4py), 150.4 (C2py, C6py), 173.7 (C=O).
IR (film): 1712 cm–1 (C=O).
1H NMR (400 MHz, CDCl3): d = 1.86 (s, 3 H, C3-CH3), 1.99 (s, 3
H, C4-CH3), 3.09 (s, 3 H, OCH3), 6.22 (s, 1 H, H5), 7.00 (ddd,
J = 7.4, 4.9, 1.0 Hz, 1 H, H5py), 7.68 (ddd, J = 8.4, 7.4, 1.9 Hz, 1 H,
H4py), 8.12 (dt, J = 8.4, 1.0 Hz, 1 H, H3py), 8.38 (ddd, J = 4.9, 1.9,
1.0 Hz, 1 H, H6py).
13C NMR (400 MHz, CDCl3): d = 8.2 (C3-CH3), 11.5 (C4-CH3),
50.7 (OCH3), 87.4 (C5), 114.8 (C3py), 119.3 (C5py), 130.7 (C3),
137.7 (C4py), 147.7 (C4), 147.9 (C6py), 150.3 (C2py), 170.1 (C=O).
MS (EI, 70 eV): m/z (%) = 219 (1) [M + 1]+, 218 (4) [M]+, 203 (57),
188 (100), 175 (11), 159 (44), 78 (50).
Anal. Calcd for C12H14N2O2: C, 66.04; H, 6.47; N, 12.84. Found: C,
66.0; H, 6.5; N, 12.9.
MS (EI, 70 eV): m/z (%) = 218 (5) [M]+, 203 (60), 188 (100), 175
(10), 159 (42), 78 (35).
5-Methoxy-3,4-dimethyl-1-[(2-pyridyl)methyl)]pyrrolidin-2-
one (5c) and 3-Methoxy-3-methyl-4-methylene-1-[(2-py-
ridyl)methyl]pyrrolidin-2-one (9c)
Anal. Calcd for C12H14N2O2: C, 66.04; H, 6.47; N, 12.84. Found: C,
66.0; H, 6.4; N, 12.9.
Following the typical procedure for cis-4a, 4c (cis/trans, 74:26,
2.74 g, 10 mmol) gave, after flash chromatography of the crude
product (silica gel, Et2O–MeOH, gradient from 100:0 to 99:1), 5c
(1.62 g, 70%) as a yellow oil and 9c (0.35 g, 15%) as a yellow oil.
3-Methoxy-3-methyl-4-methylene-1-(2-pyridyl)pyrrolidin-2-
one (9a)
Following the typical procedure for cis-4a, trans-4a (1.05 g, 4
mmol) gave 9a (0.523 g, 60%) as a pale orange oil. 5a (0.096 g,
11%) was also recovered.
5-Methoxy-3,4-dimethyl-1-[(2-pyridyl)methyl)]pyrrolidin-2-
IR (film): 1720 cm–1 (C=O).
one (5c)
IR (film): 1706 cm–1 (C=O).
1H NMR (400 MHz, CDCl3): d = 1.49 (s, 3 H, CH3), 3.21 (s, 3 H,
OCH3), 4.57 (dt, J = 15.5, 2.4 Hz, 1 H, H5), 4.66 (dt, J = 15.5, 2.1
Hz, 1 H, H5), 5.36 (t, J = 2.4 Hz, 1 H, =CH2), 5.41 (t, J = 2.1 Hz, 1
H, =CH2), 7.05 (ddd, J = 7.1, 4.9, 0.9 Hz, 1 H, H5py), 7.69 (ddd, J =
8.5, 7.3, 1.9 Hz, 1 H, H4py), 8.34 (ddd, J = 4.9, 1.9, 0.9 Hz, 1 H,
H6py), 8.51 (dt, J = 8.2, 0.9 Hz, 1 H, H3py).
13C NMR (400 MHz, CDCl3): d = 24.8 (CH3), 49.1 (C5), 52.4
(OCH3), 81.4 (C3), 110.8 (=CH2), 115.1 (C3py), 120.0 (C5py), 137.7
(C4py), 140.4 (C4), 147.5 (C6py), 150.9 (C2py), 173.1 (C=O).
1H NMR (400 MHz, CDCl3): d = 1.83 (s, 3 H, C3-CH3), 1.86 (s, 3
H, C4-CH3), 2.95 (s, 3 H, OCH3), 4.30 (d, J = 15.6 Hz, 1 H, NCH2),
4.95 (d, J = 15.6 Hz, 1 H, NCH2), 5.16 (s, 1 H, H5), 7.12 (ddd,
J = 7.6, 4.8, 0.9 Hz, 1 H, H5py), 7.22 (dt, J = 7.8, 0.9 Hz, 1 H, H3py),
7.59 (td, J = 7.8, 1.8 Hz, 1 H, H4py), 8.50 (ddd, J = 4.9, 1.8, 0.9 Hz,
1 H, H6py).
13C NMR (400 MHz, CDCl3): d = 8.4 (C3-CH3), 11.3 (C4-CH3),
44.9 (NCH2), 49.5 (OCH3), 88.5 (C5), 122.2 (C5py), 122.2 (C3py),
131.5 (C3), 136.6 (C4py), 146.2 (C4), 149.3 (C6py), 157.1 (C2py),
171.2 (C=O).
MS (EI, 70 eV): m/z (%) = 219 (2) [M + 1]+, 218 (7) [M]+, 203
(100), 188 (27), 175 (45), 159 (10), 133 (18), 43 (70).
MS (EI, 70 eV): m/z (%) = 231 (1) [M – 1]+, 218 (17), 217 (100),
201 (14), 93 (25), 92 (45), 65 (10).
Anal. Calcd for C12H14N2O2: C, 66.04; H, 6.47; N, 12.84. Found: C,
66.1; H, 6.5; N, 12.8.
Anal. Calcd for C13H16N2O2: C, 67.22; H, 6.94; N, 12.06. Found: C,
67.2; H, 7.0; N, 12.0.
5-Methoxy-3,4-dimethyl-1-(4-pyridyl)-1,5-dihydro-2H-pyrrol-
2-one (5b) and 3-Methoxy-3-methyl-4-methylene-1-(4-py-
ridyl)pyrrolidin-2-one (9b)
Following the typical procedure for cis-4a, 4b (cis/trans 80:20, 1.30
g, 5 mmol), reaction time 20 h, gave, after flash chromatography of
the crude product (silica gel, Et2O–MeOH, 9:1), 5b (0.82 g, 75%)
as white crystals and 9b (0.11 g, 10%) as light yellow fine crystals.
3-Methoxy-3-methyl-4-methylene-1-[(2-pyridyl)methyl]pyrro-
lidin-2-one (9c)
IR (film): 1702 cm–1 (C=O).
1H NMR (400 MHz, CDCl3): d = 1.39 (s, 3 H, CH3), 3.12 (s, 3 H,
OCH3), 3.91 (t, J = 2.2 Hz, 2 H, H5), 4.60 (d, J = 15.1 Hz, 1 H,
NCH2-py), 4.64 (d, J = 15.1 Hz, 1 H, NCH2-py), 5.22 (t, J = 2.2 Hz,
1 H, =CH2), 5.29 (t, J = 2.2 Hz, 1 H, =CH2), 7.14 (ddd, J = 7.6, 4.9,
1.0 Hz, 1 H, H5py), 7.18 (dt, J = 7.6, 1.0 Hz, 1 H, H3py), 7.61 (td,
J = 7.6, 1.8 Hz, 1 H, H4py), 8.47 (ddd, J = 4.9, 1.9, 1.0 Hz, 1 H,
H6py).
5-Methoxy-3,4-dimethyl-1-(4-pyridyl)-1,5-dihydro-2H-pyrrol-
2-one (5b)
Mp 92–96 °C.
IR (KBr): 1718 cm–1 (C=O).
1H NMR (400 MHz, CDCl3): d = 1.87 (s, 3 H, C3-CH3), 1.97 (s, 3
H, C4-CH3), 2.90 (s, 3 H, OCH3), 5.68 (s, 1 H, H5), 7.87 (br s, 2 H,
H3py, H5py), 8.70 (v br s, 2 H, H2py, H6py).
13C NMR (400 MHz, CDCl3): d = 8.4 (C3-CH3), 11.4 (C4-CH3),
48.2 (OCH3), 87.9 (C5), 113.3 (C3py, C5py), 132.4 (C3), 144.2
(C4py), 146.9 (C4), 150.4 (C2py, C6py), 170.4 (C=O).
13C NMR (400 MHz, CDCl3): d = 24.5 (CH3), 48.2 (NCH2), 49.4
(C5), 52.2 (OCH3), 79.7 (C3), 110.6 (=CH2), 122.0 (C3py), 122.5
(C5py), 136.9 (C4py), 141.5 (C4), 149.3 (C6py), 155.7 (C2py), 173.1
(C=O).
MS (EI, 70 eV): m/z (%) = 232 (1) [M]+, 217 (7), 200 (26), 93 (100).
Anal. Calcd for C13H16N2O2: C, 67.22; H, 6.94; N, 12.06. Found: C,
67.3; H, 7.0; N, 12.1.
MS (EI, 70 eV): m/z (%) = 219 (10) [M + 1]+, 218 (60) [M]+, 203
(27), 187 (100), 159 (20), 105 (15), 78 (23).
5-Methoxy-3,4-dimethyl-1-(pyrimidin-2-yl)pyrrolidin-2-one
(5d) and 3-Methoxy-3-methyl-4-methylene-1-(pyrimidin-2-
yl)pyrrolidin-2-one (9d)
Anal. Calcd for C12H14N2O2: C, 66.04; H, 6.47; N, 12.84. Found: C,
66.0; H, 6.4; N, 12.8.
Following the typical procedure for cis-4a, but working under argon
(in this way the workup was easier), 4d (cis/trans 65:35, 1.04 g, 4
mmol) gave, after flash chromatography of the crude product (silica
3-Methoxy-3-methyl-4-methylene-1-(4-pyridyl)pyrrolidin-2-
one (9b)
Mp 125–128 °C.
Synthesis 2008, No. 19, 3131–3141 © Thieme Stuttgart · New York

3140
F. Ghelfi et al.
PAPER
gel, Et2O–MeOH, gradient from 100:0 to 99:1), 5d (0.587 g, 67%)
as a white solid and 9d (0.061 g, 7%) as yellow oil.
product (Et2O–PE) provided comparable results; white crystals; mp
92–94 °C.
IR (KBr): 3423 (OH), 1698 cm–1 (C=O).
5-Methoxy-3,4-dimethyl-1-(pyrimidin-2-yl)pyrrolidin-2-one
(5d)
Mp 77–79 °C.
IR (KBr): 1714 cm–1 (C=O).
1H NMR (400 MHz, CDCl3): d = 1.87 (s, 3 H, C3-CH3), 1.98 (s, 3
H, C4-CH3), 3.08 (s, 3 H, OCH3), 5.68 (br s, 1 H, H5), 7.02 (t,
J = 4.8 Hz, 1 H, H5py), 8.68 (d, J = 4.8 Hz, 2 H, H4py, H6py).
13C NMR (400 MHz, CDCl3): d = 8.3 (C3-CH3), 11.5 (C4-CH3),
50.2 (OCH3), 87.9 (C5), 116.5 (C5py), 131.4 (C3), 147.6 (C4), 156.2
(C2py), 158.2 (C4py, C6py), 168.8 (C=O).
1H NMR (400 MHz, CDCl3): d = 1.82 (s, 3 H, C3-CH3), 2.02 (s, 3
H, C4-CH3), 5.67 (br s, 1 H, OH), 5.94 (s, 1 H, H5), 6.95 (dd,
J = 7.3, 5.0 Hz, 1 H, H5py), 7.66 (td, J = 7.9, 1.9 Hz, 1 H, H4py), 8.21
(dd, J = 5.0, 1.9 Hz, 1 H, H6py), 8.32 (d, J = 8.5 Hz, 1 H, H3py).
13C NMR (400 MHz, CDCl3): d = 8.3 (C3-CH3), 11.5 (C4-CH3),
83.6 (C5), 113.1 (C3py), 118.7 (C5py), 130.1 (C3), 138.6 (C4py),
147.1 (C4), 149.3 (C6py), 151.6 (C2py), 169.7 (C=O).
MS (EI): m/z (%) = 204 (25) [M]+, 203 (40), 189 (100), 175 (20),
161 (22), 121 (30), 78 (40).
Anal. Calcd for C11H12N2O2: C, 64.69; H, 5.92; N, 13.72. Found: C,
64.7; H, 6.0; N, 13.8.
MS (EI, 70 eV): m/z (%) = 219 (1) [M]+, 204 (26), 189 (100), 188
(51), 160 (40), 79 (23).
Anal. Calcd for C11H13N3O2: C, 60.26; H, 5.98; N, 19.17. Found: C,
60.2; H, 6.0; N, 19.2.
5-Hydroxy-3,4-dimethyl-1-[(2-pyridyl)methyl]-1,5-dihydro-
2H-pyrrol-2-one (7c)
Following the typical procedure for 7a, but thermostating the mix-
ture at 100 °C, 5c (1.16 g, 5 mol) gave, after flash chromatography
of the crude product (silica gel, PE–Et2O, gradient from 2:8 to
0:100, followed by Et2O–MeOH, from 100:0 to 97.5:2.5), 7c (0.83
g, 76%) as a pale yellow oil.
3-Methoxy-3-methyl-4-methylene-1-(pyrimidin-2-yl)pyrroli-
din-2-one (9d)
IR (film): 1722 cm–1 (C=O).
1H NMR (400 MHz, CDCl3): d = 1.53 (s, 3 H, CH3), 3.26 (s, 3 H,
OCH3), 4.53 (dt, J = 15.3, 2.4 Hz, 1 H, H5), 4.66 (dt, J = 15.3, 2.0
Hz, 1 H, H5), 5.39 (t, J = 2.4 Hz, 1 H, =CH2), 5.41 (t, J = 2.0 Hz, 1
H, =CH2), 7.09 (t, J = 4.8 Hz, 1 H, H5py), 8.70 (d, J = 4.8 Hz, 2 H,
H4py, H6py).
13C NMR (400 MHz, CDCl3): d = 25.0 (CH3), 49.8 (C5), 52.5
(OCH3), 81.4 (C3), 110.8 ( =CH2), 117.0 (C5py), 140.2 (C4), 157.1
(C2py), 158.1 (C4py, C6py), 172.5 (C=O).
IR (film): 3423 (OH), 1685 cm–1 (C=O).
1H NMR (400 MHz, CDCl3): d = 1.76 (s, 3 H, C3-CH3), 1.98 (s, 3
H, C4-CH3), 4.55 (d, J = 15.9 Hz, 1 H, NCH2), 4.95 (d, J = 15.9 Hz,
1 H, NCH2), 5.22 (s, 1 H, H5), 7.08 (br s, 1 H, OH), 7.20 (dd,
J = 7.6, 4.8 Hz, 1 H, H5py), 7.37 (dd, J = 7.9, 0.9 Hz, 1 H, H3py),
7.66 (td, J = 7.8, 1.9 Hz, 1 H, H4py), 8.43 (ddd, J = 4.8, 1.8, 0.9 Hz,
1 H, H6py).
MS (EI, 70 eV): m/z (%) = 219 (2) [M]+, 204 (38), 189 (4), 176 (16),
134 (7), 98 (14), 97 (32), 43 (100).
13C NMR (400 MHz, CDCl3): d = 8.4 (C3-CH3), 11.4 (C4-CH3),
46.4 (NCH2), 85.1 (C5), 122.6 (C5py), 122.7 (C3py), 128.1 (C3),
137.7 (C4py), 148.4 (C6py), 150.2 (C4), 157.0 (C2py), 171.4 (C=O).
Anal. Calcd for C11H13N3O2: C, 60.26; H, 5.98; N, 19.17. Found: C,
60.2; H, 6.0; N, 19.1.
MS (EI, 70 eV): m/z (%) = 218 (7) [M]+, 217 (20), 203 (45), 107
(15), 93 (100), 92 (48).
1-Mesyl-5-methoxy-3,4-dimethyl-1,5-dihydro-2H-pyrrol-2-one
(5e)
Following the typical procedure for cis-4a, but replacing the Et2O
with toluene and thermostating the mixture at –10 °C, 4e (cis/trans
87:13, 1.04 g, 4 mmol) gave, after flash chromatography of the
crude product (silica gel, PE–Et2O, gradient from 1:1 to 2:8), 5e
(0.66 g, 76%) as a colorless thick oil.
Anal. Calcd for C12H14N2O2: C, 66.04; H, 6.47; N, 12.84. Found: C,
66.1; H, 6.4; N, 12.8.
5-Hydroxy-3,4-dimethyl-1-(pyrimidin-2-yl)-1,5-dihydro-2H-
pyrrol-2-one (7d)
Following the typical procedure for 7a, but thermostating the mix-
ture at 120 °C, 5d (1.10 g, 5 mmol) gave, after flash chromatogra-
phy of the crude product (silica gel, CH2Cl2–MeOH, gradient from
100:0 to 95:5), 7d (0.54 g, 52%) as a pale brownish solid; mp 150–
152 °C.
IR (KBr): 1733 cm–1 (C=O).
1H NMR (400 MHz, CDCl3): d = 1.82 (s, 3 H, C3-CH3), 1.97 (s, 3
H, C4-CH3), 3.29 (s, 3 H, SCH3), 3.38 (s, 3 H, OCH3), 5.68 (br s, 1
H, H5).
IR (KBr): 3218 (OH), 1719 cm–1 (C=O).
13C NMR (400 MHz, CDCl3): d = 8.1 (C3-CH3), 12.0 (C4-CH3),
41.9 (SCH3), 54.0 (OCH3), 89.9 (C5), 129.7 (C3), 151.4 (C4), 169.3
(C=O).
1H NMR (400 MHz, CDCl3): d = 1.87 (s, 3 H, C3-CH3), 2.06 (s, 3
H, C4-CH3), 5.18 (br s, 1 H, OH), 5.93 (s, 1 H, H5), 7.26 (t, J = 4.8
Hz, 1 H, H5py), 8.65 (d, J = 4.8 Hz, 2 H, H4py, H6py).
MS (EI, 70 eV): m/z (%) = 219 (2) [M]+, 189 (35), 188 (72), 110
(100).
13C NMR (400 MHz, CDCl3): d = 8.4 (C3-CH3), 11.6 (C4-CH3),
83.6 (C5), 116.0 (C5py), 130.7 (C3), 149.3 (C4), 156.9 (C2py), 158.3
(C4py, C6py), 168.4 (C=O).
Anal. Calcd for C8H13NO4S C, 43.82; H, 5.98; N, 6.39. Found: C,
43.9; H, 6.0; N, 6.4.
MS (EI, 70 eV): m/z (%) = 205 (33) [M]+, 204 (28), 190 (100), 176
(13), 162 (30), 122 (42), 79 (22).
5-Hydroxy-3,4-dimethyl-1-(2-pyridyl)-1,5-dihydro-2H-pyrrol-
2-one (7a); Typical Procedure
Anal. Calcd for C10H11N3O2: C, 58.53; H, 5.40; N, 20.48. Found: C,
58.6; H, 5.4; N, 20.4.
To a Schlenk tube was added 5a (2.18 g, 10 mmol), 2 M H2SO4 (5
mL), and H2O (5 mL). The mixture, under vigorous stirring, was
heated to 140 °C for 3 h, after which time it was neutralized with 1
M NaOH and extracted with CH2Cl2 (2 × 15 mL). The combined or-
ganic layers were concentrated under vacuum. Flash chromatogra-
phy of the crude product (silica gel, CH2Cl2–MeOH, gradient from
100:0 to 95:5) gave 7a (1.73 g, 83%); crystallization of the crude
N-(2-Pyridyl)-3,4-dimethylmaleimide (6a)
To a 250-mL round-bottom flask, 7a (2.04 g, 10 mmol), MnO2 (20
g), and CH2Cl2 (100 mL) were added in sequence. The mixture was
vigorously stirred at r.t. (GC monitoring). After 20 h the mixture
was filtered and the filtrate evaporated under reduced pressure. In
Synthesis 2008, No. 19, 3131–3141 © Thieme Stuttgart · New York

PAPER
Preparation of the Maleic Anhydride Nucleus from Dichloro g-Lactams
3141
this way maleimide 6a (1.80 g, 89%) was obtained as white crystals;
(11) Ghelfi, F.; Stevens, C.; Laureyn, I.; Van Meenen, E.; Rogge,
mp 116–118 °C.6
T. M.; De Buyck, L.; Nikitin, K. V.; Grandi, R.; Libertini,
M. C.; Pagnoni, U. M.; Schenetti, L. Tetrahedron 2003, 59,
1147.
Pyrocinchonic Anhydride (8)
To a Schlenk tube was added 6a (2.02 g, 10 mmol), 2 M H2SO4 (5
mL), and H2O (5 mL). The mixture, under vigorous stirring, was
heated to 110 °C for 3 h. After cooling, it was extracted with CH2Cl2
(2 × 15 mL). The combined organic layers were dried (Na2SO4).
Evaporation of the solvent gave 8 (1.17 g, 93%) as a white powder;
mp 92–94 °C.6
(12) Berdinskii, I. S.; Glushkov, V. A. Zh. Org. Khim. 1984, 20,
2149.
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(16) Motoyama, Y.; Hanada, S.; Shimamoto, K.; Nagashima, H.
Tetrahedron 2006, 62, 2779.
(17) Von Rohrscheidt, C.; Fritz, H. Justus Liebigs Ann. Chem.
1978, 680.
Acknowledgment
We thank the Ministero della Università e della Ricerca Scientifica
e Tecnologica (MURST) for financial assistance.
(18) Pal, M.; Swamy, N. K.; Hameed, P. S.; Padakanti, S.;
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Synthesis 2008, No. 19, 3131–3141 © Thieme Stuttgart · New York