A short approach to chaetomellic anhydride A from 2,2-dichloropalmitic acid: Elucidation of the mechanism governing the functional rearrangement of the chlorinated pyrrolidin-2-one intermediate

Article abstract of DOI:10.1016/j.tet.2005.09.140

Chaetomellic anhydride A was efficiently attained in three steps, starting from 2,2-dichloropalmitic acid and 2-(3-chloro-2-propenylamino)pyridine. Atom transfer radical cyclisation selectively formed the cis-stereoisomer of the trichloropyrrolidin-2-one, which underwent a stereospecific functional rearrangement to form a substituted maleimide. The choice of 2-pyridyl, as 'cyclisation auxiliary' in the atom transfer radical cyclisation step, proved beneficial for hydrolysis of the maleimide to form the desired anhydride.

Full text of DOI:10.1016/j.tet.2005.09.140

Tetrahedron 62 (2006) 746–757
A short approach to chaetomellic anhydride A from
2,2-dichloropalmitic acid: elucidation of the mechanism governing
the functional rearrangement of the chlorinated
pyrrolidin-2-one intermediate
Franco Bellesia,a Chiara Danieli,a Laurent De Buyck,b Roberta Galeazzi,c Franco Ghelfi,a,
*
Adele Mucci,a Mario Orena,c Ugo M. Pagnoni,a Andrew F. Parsonsd and Fabrizio Roncagliaa
a
`
Dipartimento di Chimica, Universita degli Studi di Modena e Reggio Emilia, Via Campi 183, I-41100 Modena, Italy
bDepartment of Organic Chemistry, Faculty of Biosciences Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium
c
`
Dipartimento di Scienze dei Materiali e della Terra, Universita Politecnica delle Marche, Via Brecce Bianche, I-60131 Ancona, Italy
dDepartment of Chemistry, University of York, Heslington, York, YO10 5DD, UK
Received 20 June 2005; revised 26 September 2005; accepted 29 September 2005
Available online 7 November 2005
Abstract—Chaetomellic anhydride A was efficiently attained in three steps, starting from 2,2-dichloropalmitic acid and 2-(3-chloro-2-
propenylamino)pyridine. Atom transfer radical cyclisation selectively formed the cis-stereoisomer of the trichloropyrrolidin-2-one, which
underwent a stereospecific functional rearrangement to form a substituted maleimide. The choice of 2-pyridyl, as ‘cyclisation auxiliary’ in
the atom transfer radical cyclisation step, proved beneficial for hydrolysis of the maleimide to form the desired anhydride.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
R
HOOC
COOH
The screening of natural products to find new anticancer
agents for use in the chemotherapeutic intervention of
human tumors having mutated ras genes, has led to the
evaluation of various microbial fermentation extracts.1
From this intense screening work, carried out by a research
group at Merck, chaetomellic dicarboxylic acids, isolated
from the coelomycete Chaetomella Acutiseta, have been
shown to have promising activities. Of these compounds,
chaetomellic acid A (1a) (Scheme 1) proved to be the most
active substance, inhibiting recombinant human FPTase
with a IC50 value of 55 nM (Scheme 1).1,2
1a
R = CH2(CH2)12CH3
R
(pH>7)
R
-
OH
H+
OOC
COO
O
O
O
(pH<7)
3a
2a
Scheme 1.
towards the acceptor peptide Ras but is highly competitive
with respect to farnesyl pyrophosphate (FPP). This may be
explained by the structural similarity between dicarboxylate
anion 2a and FPP, since both possess a hydrophilic head
group bound to a hydrophobic tail (Fig. 1). The maleate unit
aligns well with the corresponding diphosphate moiety,
since the negatively charged oxygen atoms can achieve a
Chaetomellic dicarboxylic acids have a high propensity to
cyclize and 1a was, in fact, isolated as chaetomellic
anhydride A (3a). The cyclic form, however, is unstable
under mild basic conditions (pHZ7.5) and is readily
hydrolysed to the dicarboxylate anion 2a, which, appar-
ently, is the biologically active component (Scheme 1).1
FPTase activity of the diacid anion of 1 is noncompetitive
3
˚
spacing within 0.1 A, while the flexible nature of the
aliphatic chain permits it to fill the same space as the
hydrophobic end of FPP upon binding to the enzyme.1
Recently, in an effort to characterize the FPP binding site of
rubber transferase, and to identify if species-specific
differences exist for this enzyme, Vederas showed that 1
is able to inhibit, in vitro, rubber biosynthesis promoted by
rubber transferase from Hevea Brasiliensis.4 More recently
Keywords: Halocompound; Pyrrolidinone; Radical reaction;
Rearrangement.
*
Corresponding author. Fax: C39 059 373543;
e-mail: ghelfi.franco@unimore.it
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.09.140

F. Bellesia et al. / Tetrahedron 62 (2006) 746–757
747
elegant functional rearrangement (FR) of 8a to a maleimide
(9a) is employed,19 (v) the target molecule is prepared in
only four steps, (vi) the approach is efficient (an overall
yield of 55% from 6, and 46% from 4a) and (vii)
the synthesis involves simple experimental procedures.
Furthermore this route is versatile, as illustrated by the
preparation of structural analogues of 3a such as the
chaetomellic anhydride C and roccellic acid (a lichens
metabolite).20
O
P
O
P
O
O
O
O
O
O
farnesylpyrophosphate
O
O
O
Notwithstanding the long list of advantages of this
approach, there still remain a couple of aspects that need
to be improved and/or explained, if we want to increase the
appeal of the strategy for large scale production of 3a.
2a (chaetomellic acid A dianionic form)
Figure 1. Structural similarity between the dianionic form of chaetomellic
acid A (2a) and farnesyl pyrophosphate.
The first aspect that needs improvement concerns the
synthetic approach to 3a. In our previous work, the
conversion of the intermediate acetal 9a to chaetomellic
anhydride A (3a) is achieved by acid hydrolysis to 10a,
followed, according to Argade’s protocol,9 by a basic
hydrolysis, and finally, reaction under acid conditions gives
anhydride 3a. These series of operations are time-
consuming and the conditions for the basic hydrolysis
(KOH/10a, 21 mol/mol, and solvent/10a, 28 L/mol) are not
compatible with large-scale preparations.
the same author found that 1 was also able to reduce the
activity of the penicillin-binding protein 1b (PBP1b), albeit
with modest potency.5
Because of its potent inhibitory activity, chaetomellic acid
A has been the subject of considerable synthetic efforts. So
far, nine different routes have been devised for the
preparation of this interesting product.2,6–15 In general, the
synthesis of anhydride 3a has been targeted since this
compound is more easy to manipulate/isolate than diacid 1a.
The synthetic strategies investigated can be grouped
into two general categories: (i) alkylation of maleic
precursors6–11,15,16 and (ii) assembly of the pivotal
1,4-dicarbonyl group.2,12–14 In spite of the variety of
employed methods, all of the reported procedures suffer
from one or more of the following disadvantages: (i) low
yields, (ii) costly reagents, (iii) unstable precursors and/or
reactants, (iv) harmful solvents, (v) or unwieldy protocols.
As a result, these procedures are not well-suited for large
scale production, as evidenced by the high price of 1a,
which is sold by ICN or Calbio Chem at ca. 18,000 V/g.
The second aspect concerns the reaction mechanism for the
FR of 8a. The isolation of a moderate amount of (E)-11a,
the exo-dehydrohalogenated pyrrolidin-2-one by-produced
during the FR reaction of 8a to 9a/10a (Scheme 2), and the
evidence that this compound cannot be regarded as an
intermediate in the formation of 9a/10a cast some doubts on
the reaction mechanism we formerly proposed to rationalise
the FR.19 The FR of 4-methyl-pyrrolidin-2-ones A
chlorinated at the C(3) and C(6) positions (these are easily
prepared by ATRC of the parent N-(3-chloro-2-propenyl)-
a-perchloroamides) is a quite general reaction and takes
place when A is treated with a solution of alkaline
methoxide in methanol under mild conditions. In practice
two or three of the C–Cl groups at the C(3) and C(6)
positions of A are replaced by a double bond between
carbons C(3) and C(4), and one or two methoxy groups at
C(5) (Scheme 3). All transformations from A to B start with
a concerted hydro-halo-elimination (E2) and loss of C(4)–H
by either an endo- or an exo-path is possible. The preferred
pathway proceeds by the more stable anti-periplanar
Recently, our group has disclosed an original and robust
route to chaetomellic anhydride A (3a) (Scheme 2).17
Attractive features of the new strategy are: (i) an inexpen-
sive starting material, 2,2-dichloropalmitic (6) acid, is easily
prepared in two steps from the parent aliphatic alcohol (4a),
(ii) inexpensive reagents are used, (iii) a halogen atom
transfer radical cyclisation (ATRC) is used to efficiently
construct the trichlorinated 2-pyrrolidinone 8a,18 (iv) an
Cl
Cl
Bn
N
R
Cl
Cl Cl
R
Cl Cl
R
Cl Cl
R
b
c
d
OH
H
Cl
ATRC step
O
O
N
O
O
5a (84%)
6 (99%)
7a (89%)
8a (99%)
(cis/trans = 89/11)
Bn
a
FR step
R = C14H29
e
R
R
Cl
Cl
R
R
OH
f
OCH3
OCH3
R
4a
O
O
O
O
O
N
O
N
O
N
Bn
Bn
Bn
3a (70%)
(overall 46%)
(E)-11a
(9%)
10a (89%)
9a
Scheme 2. (a) Cl2, DMF–HCl, CHCl3, 70 8C, 3 h; (b) Br2, NaOH, CH2Cl2/H2O, 1.5 h; (c) (1) (COCl)2, CH2Cl2, DMF, 23 8C, 2 h, (2) N-benzyl-3-Cl-2-
propenylamine, Py, 23 8C, 1 h; (d) CuCl–TMEDA, CH3CN/CH2Cl2, argon, 60 8C, 20 h; (e) (1) Na0, CH3OH/ether, 25 8C, 20 h, (2) HC/H2O; (f) (1) KOH,
CH3OH/THF, reflux, 2 h, (2) HC/H2O.

748
F. Bellesia et al. / Tetrahedron 62 (2006) 746–757
6
2. Results and discussion
R
R
Cl
O
m
Cl
n
Σ
= 2 or 3
m+n
3
CH O
3
To reduce the number of steps required to convert the
intermediate acetal 9a into the target anhydride 3a, and
develop a method attractive for scale up, we investigated
two strategies. In the first instance, we sought to establish
acidic conditions that performed the transformation in a
straightforward manner, while we also looked at the use of
an alternative cyclisation auxiliary that made 9a and 10a
more susceptible to hydrolysis. Also, since the chlorinated
pyrrolidin-2-one 8a is isolated as a mixture of cis and trans
isomers, we sought to elucidate the origin of the side
product 11a and thereby understand the mechanism of the
FR. To do this it appeared necessary to isolate the cis and
trans isomers for a separate study of their behaviour towards
methoxide ion.
5
CH OH O
(OCH )
3 m+n-1
N
N
3
1
1
R
R
B
A
Scheme 3.
Cl
Cl
Cl
O
Cl
MeO
O
Me
O
O
N
N
N
C
D
G
E
Me
Bn
Bn
Bn
O
Cl
O
MeO
OMe
O
O
N
N
N
Foreseeable problems, including the difficulty in separating
cis-8a and trans-8a,17 steered us to use a molecule with a
smaller skeleton than 3a, as a model substrate. For this we
choose dimethyl maleic anhydride 3b, which is a very useful
building-block in organic synthesis.21 This substance, also
known as pyrocinchonic anhydride, represents the most
simple archetype for chaetomellic anhydride A (3a), the
long n-tetradecylic aliphatic chain on the carbon C(3) in 3a
being here replaced by a methyl group (Fig. 2).
H
F
Bn
Bn
Bn
Scheme 4.
conformation.19 The mechanism, we issued for the
illustrative case of the dichloro g-lactam C, is outlined in
Scheme 4. After initial formation of the exo-methylene
intermediate D, the double bond was expected to shift inside
the ring affording the 4-pyrrolin-2-one F, directly or via the
formation of D3 intermediate E. However, the isomerisation
of (E)-11a was not observed and so the mechanism needs to
be further investigated.
O
O
O
3a (chaetomellic anhydride A)
3b (pyrocinchonic anhydride)
Herein, we report that the effectiveness of the FR is linked to
the geometry of the starting 4-methyl-pyrrolidin-2-one,
since the exo C]C bond can only move into conjugation if
a hydrogen atom is present at C(3). As a consequence, the
higher is the percentage of the cis stereoisomer, which can
afford the pivotal 3-pyrrolin-2-one intermediate, the higher
the expected yield of the rearranged product. In this work,
we describe the use of 2-pyridyl group as a cyclisation
auxiliary in the ATRC step, which allowed the final
sequence of hydrolyses to be condensed to just a single
operation that is linked to the FR in a one-pot reaction. In
this way the efficiency of the overall process was
substantially improved.
O
O
O
Figure 2. Pyrocinchonic anhydride (3b) as a simple archetype for
chaetomellic anhydride A (3a).
Following the synthetic path developed for the synthesis of
3a (Scheme 2), 2,2-dichloropropanoyl chloride (12) was
treated with N-benzyl-3-chloro-2-propenylamine to afford
amide 7b in good yield (Scheme 5). Then 7b was efficiently
O
O
O
O
Cl Cl
Cl
3b (80%)
Cl
Cl
O
12
Cl
a
c
d
OCH3
OCH3
O
O
O
O
N
N
N
Bn
N
Cl Cl
Bn
Bn
Bn
9b (98%)
10b
cis-8b (76%)
b
Cl
Cl
Cl
Cl
Cl
Cl
O
O
Cl
7b (87%)
c
O
N
N
O
N
Bn
Bn
Bn
trans-8b (20%)
11b
13 (77%)
Scheme 5. (a) N-benzyl-3-Cl-2-propenylamine, Py, rt, 5 h; (b) CuCl–TMEDA, CH3CN, argon, rt, 20 h; (c) Na0, CH3OH, 25 8C, 20 h; (d) CH3SO3H/CH3COOH
(1/1), 140 8C, 20 h.

F. Bellesia et al. / Tetrahedron 62 (2006) 746–757
749
cyclised, using CuCl/N,N,N0,N0-tetramethylenediamine
(TMEDA) in acetonitrile (AN) at room temperature, to
provide the trichlorinated pyrrolidin-2-one 8b (96%) as a
79:21 mixture of cis-/trans- isomers.
In contrast to what was observed for 8a, we were pleased to
see that cis-8b and trans-8b were separable by flash
chromatography. To get an insight into the FR mechanism,
the two compounds were subjected to the FR using
methoxide in methanol, following the previously reported
protocol (Scheme 5).19 The major isomer cis-8b gave
almost a quantitative yield (98%) of N-benzyl-5,
5-dimethoxy-3,4-dimethyl-3-pyrrolin-2-one (9b).
As previously reported,22–26 the stereogenic centre at C-3 of
an 3-alkyl-3-chloro-4-chloroalkyl-g-lactams is configura-
tionally labile during the ATRC of the parent N-allyl
a-perchloroamide. This is due to a reversible radical
generation at the C(3) centre,† promoted by the redox
catalyst (Scheme 6).24,26 Consequently, the stereochemistry
of products is directed by thermodynamic factors and the
isomer that predominates has the largest appendages at C(3)
and C(4) on the opposite sides of the ring, that is, in this
example, the cis-8b isomer predominates (datum also
confirmed by computational calculations). Since C(3)
epimerization is a gradual process, a higher temperature
and a longer reaction time generally improve the selectivity
for the cis isomer. In fact when the ATRC of 7b was carried
out at 60 8C, rather than at room temperature, pyrrolidin-
2-one 8b was isolated in the same yield, but with a
significantly higher cis-/trans-ratio of 89:11 (compared
to 80:20).
On the contrary, when trans-8b was reacted with the
methoxide ion in methanol, the main product (77%) isolated
was (E)-N-benzyl-4-chloromethylen-3-methoxy-3-methyl-
2-pyrrolidinone (13), a compound with a similar structure
to (E)-11a, which was obtained as a byproduct from the FR
of 8a. Evidently, due to the relatively low steric crowding
around the C(3)–Cl group, the conceivable intermediate (E)-
11b underwent facile methoxy-de-halogenation. This
behaviour was confirmed by quenching the reaction of
trans-8b after 1 h; this gave (E)-11b, as the second main
product in the reaction mixture, after 13. A small amount
of 9b was also observed in the attempted FR of trans-8b, but
it was consistent with the small quantity of the cis-8b
contaminating the starting material. These results definitely
prove that the efficiency of the FR depends on the
diastereoisomeric ratio of the chlorinated pyrrolidin-2-
ones, and is consistent with the results obtained for the FR
of 8a17 (Scheme 2) or equivalent adducts.20
Cl
Cl
Cl
Cl
Cl
Cl
CuCl
O
O
N
N
In a previous work, we established that the FR starts with a
bimolecular hydro-halo-elimination.19 Hence, the more
easily the required anti-periplanar conformation is achieved
the more favourably the resulting E2 elimination will be.
Accordingly, cis-8b follows the endo-dehydrochlorination
Bn
cis-8b
Bn
trans-8b
Scheme 6.
Cl
OMe
O
N
Bn
16b
Cl
Cl
Cl
ii
Cl
Cl
Cl
Cl
H
Cl
MeO
H
ii
H
H
i
=
i
O
OMe
O
O
O
N
N
N
O
N
OMe
cis-8b
OMe
15b
Bn
Bn
Bn
Bn
17b
OMe
14b
Cl
Cl
H
MeO
i
ii
OMe
H
OMe
OMe
OMe
OMe
=
OMe
OMe
O
O
O
N
Ni
Bn
N
N
Bn
9b
Bn
Bn
ii
OMe
21b
19b
18b
OMe
OMe
20b
O
N
Bn
Scheme 7.
path to give the 3-pyrrolin-2-one 14b (Scheme 7), whereas
trans-8b is forced to dehydrohalogenate in the alternative
exo-direction to afford the 4-alkyliden-pyrrolidin-2-one
(E)-11b (Scheme 5).
† The configurational change through a nucleophilic attack was firmly
ruled out by the quantitative recovery of cis-8b after treatment with LiCl/
TMEDA or CuCl2/TMEDA under the same conditions of the ATRC
of 7b.

750
F. Bellesia et al. / Tetrahedron 62 (2006) 746–757
For compounds 14b and (E)-11b the C]C bond lies in a
different position. When the C]C bond is in conjugation
with the C]O bond, the electron-withdrawing effect of the
carbonyl group increases the acidity of vinylogous C(5)–H
hydrogen atom.27,28 This helps migration of the C]C bond
from the a,b-position (Scheme 7, adduct 14b) to the
b,g-position (Scheme 7, adduct 15b), a clear example of
tautomeric equilibrium where the conjugated form is
thermodynamically favoured.28,29 This property is well
known and has been extensively used to prepare silyl-
oxypyrroles from a,b-unsaturated g-lactams,27,30,31 and
also in the manipulation of the (CO)–C]C–CH moiety in
open chain compounds.32–37
2-pyrrolidinone (I), two substrates that react by an initial
exo-elimination, both rearrange in high yield to give
N-benzyl-4-methyl-3-pyrrolin-2-one (H) (Scheme 8).19 In
the light of our current observations, these two examples
appear to be exceptional, presumably because both have an
acidic a hydrogen at C(3), which allows the exo C]C bond to
move in to conjugation for the early intermediates D and L
(Scheme 8). In contrast, for adducts analogous to 11b, the lack
of C(3)–H bonds and the insufficient acidity of the C(5)–H
proton precludes the transposition.
Cl
Cl
Cl
Cl
The shift in the position of the C]C bond in 17b triggers
the subsequent substitution of one of the two exo chlorines
by a C]C exo/D3 base catalyzed transposition leading to
compound 18b (Scheme 7). Related reactions involving
consecutive prototropic and anionotropic changes have been
reported,38,39 including the transformation of a trialkyl-
g-chloroallylammonium salt into the corresponding
trialkyl-a-ethoxyallylammonium salt by reaction with
sodium ethoxide, described by Ingold and Rothstein back
in 1928.39 The conversion of 15b to 17b is likely to occur by
a stepwise mechanism involving the N-1 lone pair and the
participation of the acylimmonium cation intermediate 16b
(Scheme 7, path ii).37 Analogous steps are reasonably
implicated along the way from 18b to ac0etal 9b. The
alternative direct transformation by a SN2 substitution
(Scheme 7, path i)40,41 appears doubtful since the
nucleophilic substitution of allylic intermediate (E)-11b
proceeded without rearrangement (Scheme 5).
O
O
O
N
N
C
I
Bn
Bn
MeO
MeO
H
H
Cl
Cl
O
O
(61%)
O
(60%)
N
N
N
L
D
H
Bn
Bn
Bn
Scheme 8.
In summary, the configuration of the starting a,g-
halogenated 2-pyrrolidinones influences the FR. For an
effective FR the configuration of the precursor should
permit an endo-elimination. If, however, the reaction is
forced to proceed by exo-elimination then (for a successful
FR) the precursor must have a hydrogen atom at C(3).
Following our studies on the mechanism of the FR, we
tackled the problem of the one-pot hydrolysis of 9b to form
anhydride 3b. The process requires two sequential hydroly-
ses: the first hydrolysis forms maleimide 10b from acetal 9b
and the second forms anhydride 3b from 10b (Scheme 5). To
arrive at a one-pot process we needed a suitable acid that
promoted both hydrolyses and initial results using methane-
sulfonic acid (MSA) are collected in Table 1.
Good evidence for the stepwise mechanism was obtained by
analysing the reaction mixture after a short reaction time
(2 min). This allowed the detection and separation of the
proposed intermediate 18b. The isolation of 18b suggests
that the D3/D4 transposition of 18b to 19b is the slowest step
in the rearrangement.
The proposed shift of the exo C]C bond (to move inside the
ring) was erroneously formulated following experimental
evidence which showed that N-benzyl-3-chloro-4-chloro-
methyl-2-pyrrolidinone (C) and N-benzyl-4-dichloromethyl-
Hydrolysis of 10b to form 3b is possible using MSA in acetic
acid (Table 1, entries 4–9) but not in aqueous media,
Table 1. Solvolysis of the N-benzyl-5,5-dimethoxy-3,4-dimethyl-3-pyrrolin-2-one 9ba
Item
Promoter (mL)
Solvent (mL)
T (8C)
t (h)
Conversion (%)b
10b (%)b
3b (%)b
1
2
3
4
5
6
7
8
MSA (0.08)c
MSA (0. 45)
MSA (0. 45)
MSA (0.26)
MSA (0.26)
MSA (0.5)
MSA (0.5)
MSA (0.5)
MSA (0.65)
MSA (1.0)
H2O (1.2)
H2O (1.7)
H2O (1.7)
AcOH (1)
AcOH (1)
AcOH (0.5)
AcOH (0.5)
AcOH (0.5)
AcOH (0.65)
—
100
100
140
100
120
100
120
140
140
25
4
4
4
100
100
100
100
100
100
100
100
100
100
100
0
100
100
100
95
86
53
35
0
0
0
0
4
14
4
20
40
20
20
20
100
20
3
47
65
100 (79)d
9e
10
11
12
5
100
0f
95
0
Tracesf
0
H2SO4 (0.5)
NaOH (2.5)c
AcOH (0.5)
H2O (0.5)
120
120
0
a Substrate 1 mmol.
b GC values.
c Values in mmol.
d Determined on isolated material.
e Solvolysis performed directly on the crude product from the FR of cis-8b after solvent evaporation.
Extensive formation of black resinous material.
f

F. Bellesia et al. / Tetrahedron 62 (2006) 746–757
751
presumably because 10b is more soluble in acetic acid than in
water (Table 1, entries 1–3). The complete conversion of 10b
in to 3b required 0.5 mL of MSA per mmol of 10b, together
with heating at 140 8C for 20 h (Table 1, entry 8).
Unfortunately, when the crude FR product (obtained after
reaction solvent evaporation) from cis-8b was reacted under
these conditions, some maleimide 10b remained (Table 1,
entry 9). Also, reaction of 10b with MSA at room temperature,
or the use of H2SO4 in place of MSA, or the use of basic
conditions were ineffective (Table 1, entries 10–12).
reactions of a precursor with a 2-pyridyl auxiliary
(Scheme 9). N-(3-Chloro-2-propenyl)-N-(2-pyridyl)-2,
2-dichloropropanamide (22b) was easily prepared, in
excellent yield (89%), by a metathesis reaction between
12 and 2-(3-chloro-2-propenylamino)pyridine. An ATRC
reaction of 22b (under similar conditions to amide 7b)
afforded the halogenated pyrrolidin-2-one (23b) as a
mixture of cis-/trans- isomers (70:30) in an excellent yield
(88%). The FR of cis-23b/trans-23b was accomplished
using the same conditions as for 8b. As expected, along with
the desired acetal 24b, isolated in a respectable yield of
68%, we also recovered a moderate amount (21%) of the
exo-dehydrohalogenated pyrrolidin-2-one (E)-25.
As our studies on the solvolysis of N-benzylmaleimide 10b
were not completely satisfactory, we searched for an
auxiliary more suited to removal by hydrolysis. In this
respect, we were helped by the work of Baumann42 who
discovered an elegant way to prepare dimethylmaleic
In order to develop a one-pot hydrolysis reaction, we
investigated the reaction of crude product 24b (isolated by
Cl
Cl c,d
O
O
O
Cl
N
N
3b (57%)
Cl Cl
Cl Cl
a
b
Cl
N
Cl
O
O
N
Cl
O
O
c
12
22b (89%)
N
OMe
OMe
O
O
N
23b (88%)
(cis/trans = 70/30)
N
N
24b (68%)
25 (21%)
Scheme 9. (a) 2-(3-chloro-2-propenylamino)pyridine, Py, argon, 35 8C, 20 h; (b) CuCl–TMEDA, CH3CN, Argon, rt, 20 h; (c) Na0, CH3OH, 25 8C, 20 h;
(d) H2SO4 4 N, 110 8C, 1 h.
anhydride by dimerization of maleic anhydride using
2-aminopyridine. Interestingly, the last step in the synthesis
involved acid hydrolysis of N-(2-pyridyl)-3,4-dimethyl-
maleimide.42 This strategy was used by Argade for the
preparation of chaetomellic anhydride A from 2-bromo-
palmitoyl chloride—the final step in the synthesis involved
hydrolysis of a N-(2-pyridyl)maleimide derivative.13,14
solvent evaporation of the FR reaction mixture) with the acid
conditions reported by Baumann (H2SO4 4 N 1 mL/mmol of
substrate, heating at 110 8C) (Scheme 9). The reaction was
completed in just one hour and pyrocinchonic anhydride was
recovered in a satisfactory yield of 57%. If one takes into
account that only the cis-23b component can rearrange, the
yield of pyrocinchonic anhydride increases to 81%.
The apparent vulnerability of N-(2-pyridyl)maleimides to
acid conditions spurred us to investigate the ATRC and FR
When compared with the one-pot transformation of
N-benzyl lactam cis-8b to 3b (Scheme 5), the parallel
Cl
Cl
R
Cl
R
PG1
N
Cl Cl
R
c
b
Cl
O
O
O
N
N
O
7a (89%)
PG1
PG1
10a (89%)
a
a
8a (99%)
(cis/trans = 89/11)
Cl Cl
R
i) PG1 = Bn
OH
d
O
ii) PG2 = 2-Pyr
Cl
6
R
Cl
Cl
R
PG2
Cl Cl
R
(from 10a: 70%)
(overall from 8a 62%)
O
(overall 55%)
b
e
N
Cl
R = C14H29
O
O
N
O
3a
O
PG2
23a (93%)
(cis/trans=90/10)
22a (94%)
(from 23a: 78%)
(overall 68%)
Scheme 10. (a) (1) (COCl)2, CH2Cl2, DMF, 23 8C, 2 h, (2) N-benzyl-3-Cl-2-propenylamine (path i) or 2-(3-chloro-2-propenylamino)pyridine (path ii), Py,
23 8C, 1 h; (b) CuCl–TMEDA, CH3CN, argon, 60 8C, 20 h; (c) (1) Na0, CH3OH/ether, 25 8C, 20 h, (2) HC/H2O; (d) (1) KOH, CH3OH/THF, reflux, 2 h, (2)
H
C/H2O; (e) (1) Na0, CH3OH/ether, 25 8C, 20 h, (2) H2SO4 4 N, 110 8C, 2 h.

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F. Bellesia et al. / Tetrahedron 62 (2006) 746–757
one-pot conversion of the N-(2-pyridyl) lactam 23b to the
same anhydride (Scheme 9) has some advantages including:
(i) a lower reaction temperature, (ii) total conversion of
precursor and (iii) a simplified purification procedure
because byproduct 25 remains in the acidic aqueous phase.
found for both diastereomers, and the energy difference
among the two lowest ones resulted to be only 0.2 kcal/mol.
4. Conclusion
The good result using the new one-pot hydrolysis method
spurred us to apply this method to the synthesis of
chaetomellic anhydride A. Thus, the N-(3-chloro-2-prope-
nyl)-N-(2-pyridyl)-2,2-dichlorohexadecanamide 22a was
prepared and cyclised to give to 23a (as an inseparable
pair of cis-/trans- isomers in a ratio of 90:10) adhering to
standard protocols (Scheme 10, path ii). Both products were
delivered in high yields. It is noted that, owing to the polar
nature of the 2-pyridyl substituent, 22a was completely
soluble in acetonitrile, so the ATRC step did not require
dilution with a less polar cosolvent (e.g., CH2Cl2) as was
required for the N-benzyl amide 7a (Scheme 2).17 The
ensuing FR of 23a was accomplished using sodium in
methanol (at 25 8C), after which the solvent was removed
under vacuum and the residue dissolved in 4 N H2SO4. The
solution was then heated to 110 8C to give, after 2 h, the
target anhydride 3a in a respectable 78% yield. No effort
was spent to recover the side product derived from exo-
elimination. The overall yield of chaetomellic anhydride A
(3a) using this three step approach was 68% (Scheme 10,
path ii), which is significantly higher than the 55% yield
observed with the previously reported four step process
(Scheme 10, path i). The increased efficiency is due to the
increased effectiveness of the one-pot conversion of 23a to
3a (78%) compared to the stepwise conversion of 8a to 3a
(overall 62% yield).
Chaetomellic anhydride A has been efficiently obtained in
just three steps, starting from 2,2-dichloropalmitic acid and
2-(3-chloro-2-propenylamino)pyridine. The choice of
2-pyridyl, as ‘cyclisation auxiliary’45 in the ATRC step,
allowed the FR to be combined with the final hydrolysis step
in a straightforward one-pot reaction. We have also
succeeded in unravelling the FR mechanism. The FR,
which is promoted by bases in protic solvents, is observed
for a variety of polyhalogenated pyrrolidin-2-ones issued by
ATRC of N-allyl-a-perchloroamides.17,19,20 We have
discovered that for an effective FR the configuration of
the starting a,g-halogenated 2-pyrrolidinones is critical and
should be arranged in such a way that initial endo-
elimination is possible. However, even for those substrates
forced to undergo exo-eliminations, provided that at least
one hydrogen atom is present at C(3), the FR can proceed.
The procedure, here reported, can also be fruitfully used for
a short laboratory scale preparation of the versatile building-
block pyrocinchonic anhydride. Computational investi-
gations to confirm the proposed pathway and studies of
the exact role of the 2-pyridyl substituent on the hydrolysis
reaction are in progress and will be reported in due course.
5. Experimental
5.1. General
3. Computational investigation
Reagents and solvents were standard grade commercial
products, purchased from Aldrich, Acros, Fluka or RdH, and
used without further purification, except acetonitrile and
In order to investigate the major thermodynamic stability of
cis-8b with respect to trans-8b, a complete, extensive
unconstrained conformational analysis of both isomers was
performed by using AMBER* force field43 and the Monte
Carlo44 conformational search (MC/EM) varying all the
degrees of freedom including H2O as implicit solvent that
was chosen in order to simulate the polarity of the solution
media (methanol). All the conformers within the energy gap
of 6.0 kcal/mol were kept and subsequently only those
which lie below 3.6 kcal/mol were fully analysed. Within
this energy gap, 11 conformers were observed for
compound cis-8b, and 12 conformers for trans-8b. Then
the lowest energy conformation for both diastereomers was
optimized at ab initio level by using the density functional
method B3LYP/6-31G* and it resulted that cis-8b is
4.5 kcal/mol more stable than trans-8b. Thus, the reaction
path leading to the chaetomellic anhydride (Scheme 5) is the
most relevant one, the preferential formation of the major
isomer cis-8b being explained by its thermodynamic
stability.
˚
CH2Cl2 that were dried over three batches of 3 A sieves (5%
w/v, 12 h). The silica gel used for flash chromatography was
Silica Gel 60 Merck (0.040–0.063 mm). N-Benzyl-
3-chloro-2-propenylamine (as a 58/42 mixture of E/Z
isomers) was prepared by N-alkylation of benzylamine
with 1,3-dichloro-2-propene, following the procedure of
Shipman.46 2,2-Dichloropalmitic (6)17 acid and 2,2-dichloro-
propanoyl chloride (11)25 were prepared according given
1
procedures. H NMR, IR and MS spectra were recorded on
Bruker DPX 200 and Bruker Avance400, Perkin Elmer 1600
Series FTIR, and HP 5890 GC-HP 5989A MS instruments,
respectively. The structural assignment of compounds 8b, 13,
18b, 23a, 23b and 25 was determined by homonuclear
Nuclear Overhauser Enhancement and heteronuclear H,C
inverse-detection NMR correlation techniques. The direct
and long-range H,C correlations on 13, 18b and 25 allowed
us to unambiguously establish their regiochemistry, whereas
NOESY experiments enabled the configuration of the double
bond in 13 and 25, and the relative stereochemistry at the
C(3) and C(4) carbons in 8b, 23a and 23b, to be determined.
It is worth mentioning that a similar trend was observed
when the conformational analysis was carried out with the
corresponding cis- and trans-compounds having at C-3 a
C12 chain in place of the methyl, since the cis-isomer
resulted again more stable than the trans-one. However, in
this case a large number of low energy conformations were
5.2. Computational details
Molecular mechanics calculations were performed on SGI
IRIX 6.5 Octane2 workstations using the implementation of

F. Bellesia et al. / Tetrahedron 62 (2006) 746–757
753
Amber all-atom force field (AMBER*) within the frame-
work of Macromodel version 5.5.47 The solvent effect was
included by the implicit water GB/SA solvation model of
Still et al.48 The torsional space of each molecule was
randomly varied with the usage-directed Monte Carlo
conformational search of Chang-Guida-Still. For each
search, at least 1000 starting structures for each variable
torsion angle was generated and minimized until the
added to the stirred solution cooled in a ice-bath (15 min).
Next, the bath was removed and the reaction mixture left at
room temperature, while stirring. After 20 h, the mixture
was washed in sequence with HCl 2.5% w/v (2!15 mL)
and NaOH 2.5% w/v (20 mL). The organic phase was then
separated and concentrated. Flash-chromatography of the
crude product on silica gel, using petroleum ether (bp
40–60 8C)–diethyl ether (9.5/0.5) as eluent, afforded 2.67 g
of 7b (87%), as a mixture of E/Z stereoisomers; pale yellow
oil. [Found: C, 50.9; H, 4.6; N, 4.6. C13H14Cl3NO requires
C, 50.92; H, 4.60; N, 4.57]; 1H NMR (CDCl3, 200 MHz): d
2.40 (3H, s, Cl2CCH3), 3.7–5.1 (4H, br m, CH2NCH2),
5.7–6.3 (2H, br m, CH]CH), 7.2–7.4 (5H, br s, Ar(H)); IR
(film): 1660 (C]O) cmK1; m/z (EI): 305 (3%, MC), 270
(17), 230 (22), 91 (100).
˚
gradient was less than 0.05 kJ/(A mol). The cyclic moieties
containing the amide bonds were also included into the
search. Duplicate conformations and those with an energy in
excess of 6 kcal/mol above the global minimum were
discarded.
All DFT calculations were carried out using the standard
tools available in the Gaussian 98 package,49 with the DFT/
B3LYP functional (i.e., Becke’s three parameter hybrid
functional with the Lee-Yang-Parr correlation functional)50
and the 6-31G(d) basis set.
5.5. Cyclisation of N-benzyl-N-(3-chloro-2-propenyl)-
2,2-dichloropropanamide (7b)
CuCl (40 mg, 0.4 mmol) and the 2,2-dichloro-amide 7b
(1.23 g, 4 mmol) were weighted in a Schlenk tube fitted
with a perforable septum (blocked by a screw cap) and a
magnetic stirrer bar. Dry acetonitrile (4 mL) and TMEDA
(121 mL, 0.8 mmol) were then added under argon. The
mixture was stirred at room temperature and after 20 h
diluted with HClaq 5% w/v (5 mL) and extracted with
CH2Cl2 (3!6 mL). The combined organic layers were
concentrated and the crude product was purified by flash
chromatography on silica gel, eluting with a petroleum ether
(bp 40–60 8C)–diethyl ether gradient (from 10/0 to 5/5).
This gave the pyrrolidinones cis-8b (0.94 g, 76%), as a
white crystalline solid, and trans-8b (0.24 g, 20%), as a
yellow oil. The isomers could also be separated by
crystallization from diethyl ether.
5.3. Preparation of 2-(3-chloro-2-propenylamino)
pyridine
2-Aminopyridine (11.29 g, 120 mmol) was weighed in a
Schlenk tube fitted with a perforable septum (blocked by a
screw cap) and a stirring bar. Next, toluene (30 mL) and 1,3-
dichloropropene (mixture of E/Z isomers, 5.55 mL,
60 mmol) were added under argon. The solution, under
vigorous stirring, was heated at 100 8C. After 20 h, the
reaction mixture was diluted with H2O (30 mL) and
petroleum ether (bp 40–60 8C; 30 mL). The organic layer
was separated, whereas the aqueous phase was extracted
with a 1/1 solution of toluene/petroleum ether (20 mL). The
organic extracts were collected and concentrated under
vacuum. The crude product was recovered (6.59 g, 65%) as
a pale yellow liquid, which did not require further
purification; bp 119–121 8C (0.6 mmHg). [Found: C, 57.0;
H, 5.4; N, 16.7. C8H9ClN2 requires C, 56.98; H, 5.38; N,
5.5.1. cis-N-Benzyl-3-chloro-4-dichloromethyl-3-methyl-
2-pyrrolidinone (cis-8b). Mp 103–104 8C. [Found: C, 50.8;
H, 4.6; N, 4.5. C13H14Cl3NO requires C, 50.92; H, 4.60; N,
1
1
16.61]; H NMR (CDCl3, 200 MHz): d trans isomer 3.96
4.57]; H NMR (CDCl3, 400 MHz): d 1.97 (3H, s, C(3)
(2H, dt, JZ1.2, 5.9 Hz, NHCH2), 4.7 (1H, br s, NH); 6.05
(1H, dt, JZ13.8, 5.8 Hz, NHCH2CH), 6.22 (1H, dt, JZ
13.8, 1.3 Hz, CHCl), 6.38 (1H, dt, JZ8.4, 0.9 Hz, C(3)H),
6.60 (1H, ddd, JZ7.3, 5.0, 0.9 Hz, C(5)H), 7.42 (1H, ddd,
JZ8.4, 7.3, 2.0 Hz, C(4)H), 8.09 (1H, ddd, JZ5.0, 2.0,
0.9 Hz, C(6)H); cis isomer 4.13 (2H, dt, JZ1.7, 6.1 Hz,
NHCH2), 4.8 (1H, br s, NH); 5.94 (1H, dt, JZ7.5, 6.1 Hz,
NHCH2CH), 6.17 (1H, dt, JZ7.5, 1.7 Hz, CHCl), 6.40 (1H,
dt, JZ8.4, 0.9 Hz, C(3)H), 6.60 (1H, ddd, JZ7.3, 5.0,
0.9 Hz, C(5) H), 7.43 (1H, ddd, JZ8.4, 7.3, 2.0 Hz, C(4)H),
8.09 (1H, ddd, JZ5.0, 2.0, 0.9 Hz, C(6)H); m/z (EI): 168
(28%, MC), 133 (100), 119 (40), 116 (10), 107 (12), 79 (22),
78 (30).
CH3), 2.90 (1H, dt, JZ7.3, 9.3 Hz, C(4)H), 3.08 (1H, dd,
JZ10.2, 9.2 Hz, C(5)H), 3.38 (1H, dd, JZ10.2, 7.2 Hz,
C(5)H), 4.38 (1H, d, JZ14.7 Hz, N(1)CHAr), 4.66 (1H, d,
JZ14.7 Hz, N(1)CHAr), 5.98 (1H, d, JZ9.4 Hz, C(4)CH),
7.20–7.40 (5H, m, CHAr); 1H NMR (CD3OD, 400 MHz): d
1.92 (3H, s, C(3)CH3), 3.15 (2H, m, C(4)H, C(5)H), 3.49
(1H, m, C(5)H), 4.34 (1H, d, JZ14.8 Hz, N(1)CHAr), 4.71
(1H, d, JZ14.8 Hz, N(1)CHAr), 6.20 (1H, m, C(4)CH),
7.24–7.40 (5H, m, CHAr); 13C NMR (CD3OD, 400 MHz): d
26.30 (CH3), 47.80 (NCH2), 48.65 (NCH2), 55.47 (C(4)),
69.94 (C(3)), 73.06 (C(4)CH), 129.05 (Ar), 129.11 (Ar),
129.95 (Ar), 136.61 (Ar), 172.63 (C]O); IR (KBr): 1707
(C]O) cmK1; m/z (EI): 305 (3%, MC), 270 (100), 187 (17),
186 (33), 91 (100).
5.4. Preparation of N-benzyl-N-(3-chloro-2-propenyl)-
2,2-dichloropropanamide (7b)
5.5.2. trans-N-Benzyl-3-chloro-4-dichloromethyl-3-
methyl-2-pyrrolidinone (trans-8b). [Found: C, 50.8; H,
4.6; N, 4.5. C13H14Cl3NO requires C, 50.92; H, 4.60; N,
4.57]; 1H NMR (CDCl3, 400 MHz): d 1.82 (3H, s,
C(3)CH3), 3.30 (2H, m, C(4)H, C(5)H), 3.62 (1H, m,
C(5)H), 4.38 (1H, d, JZ14.7 Hz, N(1)CHAr), 4.68 (1H, d,
JZ14.7 Hz, N(1)CHAr), 5.89 (1H, d, JZ4.6 Hz, C(4)CH),
7.24–7.40 (5H, m, CHAr); 1H NMR (CD3OD, 400 MHz): d
1.77 (3H, s, CH3C(3)), 3.37 (2H, m, HC(4), HC(5)), 3.65
In a double-necked rounded bottom flask (100 mL), fitted
with a dropping funnel and a reflux condenser, closed on the
top with a CaCl2 tube, CH2Cl2 (15.0 mL), N-benzyl-3-
chloro-2-propenylamine (mixture of E/Z stereoisomers,
1.82 g, 10 mmol) and pyridine (1.0 mL, 12 mmol) were
introduced. A CH2Cl2 (5 mL) solution of 2,2-dichloropro-
panoyl chloride (12) (1.61 g, 10 mmol) was then carefully

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F. Bellesia et al. / Tetrahedron 62 (2006) 746–757
(1H, m, HC(5)), 4.47 (1H, d, JZ14.6 Hz, N(1)CHAr), 4.57
(1H, d, JZ14.6 Hz, N(1)CHAr), 6.33 (1H, d, JZ5.3 Hz,
C(4)CH), 7.27–7.40 (5H, m, CHAr); 13C NMR (CD3OD,
400 MHz): d 21.34 (CH3), 46.98 (NCH2), 48.02 (NCH2),
56.34 (C(4)), 69.16 (C(3)), 72.60 (C(4)CH), 129.10 (Ar),
129.41 (Ar), 129.90 (Ar), 136.52 (Ar), 172.90 (C]O); IR
(film): 1709 (C]O) cmK1; m/z (EI): 305 (3%, MC), 270
(100), 187 (17), 186 (33), 91 (100).
chloromethylen-3-methoxy-3-methyl-2-pyrrolidinone (13)
(0.41 g, 77%), as a colourless oil. [Found: C, 63.1; H, 6.1;
N, 5.3. C14H16ClNO2 requires C, 63.28; H, 6.07; N, 5.27];
1H NMR (CDCl3, 400 MHz): d 1.48 (3H, s, C(3)CH3), 3.17
(3H, s, OCH3), 3.82 (1H, dd, JZ15.3, 2.7 Hz, C(5)H2), 3.92
(1H, dd, JZ15.3, 2.7 Hz, C(5)H2), 4.53 (1H, d, JZ14.6 Hz,
NCH2Ar), 4.61 (1H, d, JZ14.6 Hz, NCH2Ar), 6.30 (1H, t,
JZ2.7 Hz, C]CHCl), 7.20–7.40 (5H, m, ArH); 13C NMR
(CDCl3, 400 MHz): d 24.80 (C(3)CH3), 46.51 (CH2Ar),
46.98 (C(5)), 52.38 (OCH3), 80.14 (C(3)), 116.48
(C]CHCl), 127.78 (CAr), 127.96 (CAr), 128.70 (CAr),
135.08 (CAr), 136.26 (C(4)), 171.95 (C]O); IR (film):
1707 (C]O) cmK1; m/z (EI): 265 (1%, MC), 235 (24), 230
(96), 229 (38), 214 (6), 174 (7), 132 (38), 97 (100), 91 (63).
5.6. Rearrangement of cis-N-benzyl-3-chloro-
4-dichloromethyl-3-methyl-2-pyrrolidinone (cis-8b)
In a Schlenk tube, fitted with a perforable septum blocked
by a screw cap, ethyl ether/CH3OH 2:1 (3 mL) and cis-8b
(0.61 g, 2 mmol) were added. The solution was thermo-
stated at 25 8C. Apart, in a second Schlenk tube, Na0
(0.184 g, 8 mmol) was carefully dissolved in CH3OH
(3 mL), and when the effervescence ceased, the alkaline
solution was thermostated at 25 8C, after which it was
poured into the first Schlenk tube. The reaction mixture was
stirred for 20 h. Then it was diluted with water (2 mL) and
extracted with CH2Cl2 (3!5 mL). The combined organic
layers were collected and concentrated. Flash-chromato-
graphy of the crude product on silica gel, using a petroleum
ether (bp 40–60 8C)/diethyl ether gradient (from 10/0 to
5/5) as eluent, afforded N-benzyl-5,5-dimethoxy-3,
4-dimethyl-3-pyrrolin-2-one (9b) (0.514 g, 98%), as a pale
yellow microcrystalline solid. Mp 63–64 8C. [Found: C,
68.7; H, 7.3; N, 5.4. C15H19NO3 requires C, 68.94; H, 7.33;
Following the previous procedure but carrying out the work
up after 1 h at 25 8C we succeeded in isolating a small
amount of (E)-N-benzyl-4-chloromethyl-3-methoxy-
3-methyl-2-pyrrolidinone (11b) (as the second main product
in the reaction mixture after 13), as a colourless oil. [Found:
C, 58.0; H, 4.9; N, 5.2. C13H13Cl2NO requires C, 57.80; H,
4.85; N, 5.18]; 1H NMR (CDCl3, 200 MHz): d 1.89 (3H, s,
C(3)CH3), 3.90 (1H, dd, JZ14.9, 2.5 Hz, C(5)H2), 4.00
(1H, dd, JZ14.9, 2.5 Hz, C(5)H2), 4.48 (1H, d, JZ14.7 Hz,
NCH2Ar), 4.69 (1H, d, JZ14.7 Hz, NCH2Ar), 6.54 (1H, t,
JZ2.5 Hz, C]CHCl), 7.23–7.42 (5H, m, ArH); IR (film)
1715 (C]O) cmK1; m/z (EI): 269 (10%, MC), 234 (100),
125 (17), 91 (83), 65 (23).
1
N, 5.36]; H NMR (CDCl3, 400 MHz): d 1.77 (3H, q, JZ
5.8. Hydrolysis of N-benzyl-5,5-dimethoxy-
3,4-dimethyl-3-pyrrolin-2-one (9b)
1.2 Hz, C(4)CH3), 1.90 (3H, q, JZ1.3 Hz, C(3)CH3), 2.78
(6H, s, OCH3), 4.37 (2H, s, NCH2Ar), 7.27–7.40 (5H, m,
CHAr), 13C NMR (CDCl3, 400 MHz): d 8.02 (C(3)CH3),
9.07 (C(4)CH3), 41.40 (CH2), 50.51 (OCH3), 112.73 (C(5)),
127.17 (C(40)Ar), 128.09 (C(30)Ar, C(50)Ar), 129.34
(C(20)Ar, C(60)Ar), 132.70 (C(3)), 137.39 (C(10)Ar),
144.06 (C(4)), 170.13 (C]O); IR (KBr): 1712 (C]O)
cmK1; m/z (EI): 262 (8%, MCC1), 261 (43), 231 (12), 230
(45), 214 (24), 202 (15), 156 (13), 141 (38), 91 (100).
In a Schlenk tube, were added acetal 9b (0.52 g, 1 mmol),
acetic acid (0.5 mL) and methanesulfonic acid (0.5 mL).
The mixture, under vigorous stirring, was heated to 140 8C
for 20 h, after which time it was diluted with H2O (4 mL)
and then extracted with CH2Cl2 (3!4 mL). The combined
organic layers were concentrated under vacuum. Flash
chromatography of the crude product on silica gel, using a
petroleum ether (bp 40–60 8C)–ethyl acetate gradient (from
10/0 to 8.5/1.5) as eluent, gave 3,4-dimethylmaleic
anhydride (3b) (0.10 g, 79%), as a pale brown microcristal-
line solid. Mp 92–94 8C. The MS spectrum is consistent
with that of an authentical sample purchased from Aldrich.
Following the previous procedure but carrying out the work
up after 2 min at 25 8C we succeeded in isolating the
N-benzyl-4-chloromethyl-3-methyl-5-methoxy-3-pyrrolin-
2-one (18b) (as the main product in the reaction mixture), as
a colourless oil. [Found: C, 63.1; H, 6.1; N, 5.3.
C14H16ClNO2 requires C, 63.28; H, 6.07; N, 5.27]; 1H
NMR (CDCl3, 400 MHz): d 2.01 (3H, t, JZ1.1 Hz,
C(3)CH3), 3.02 (3H, s, OCH3), 4.18 (1H, d, JZ14.8 Hz,
NCHAr), 4.19 (1H, dq, JZ12.0, 1.1 Hz, CHCl), 4.33 (1H, d,
JZ12.0 Hz, CHCl), 4.98 (1H, d, JZ14.8 Hz, NCHAr), 5.31
(1H, q, JZ1.1 Hz, HC(5)), 7.20–7.40 (5H, m, CHAr); 13C
NMR (400 MHz, CDCl3): 8.92 (CH3), 35.18 (CH2Cl), 43.62
(NCH2), 50.48 (OCH3), 86.0 (C(5)), 127.62 (Ar), 128.44
(Ar), 128.70 (Ar), 136.16 (C(3)), 136.81 (Ar), 143.55 (C(4))
169.58 (C]O); IR (film) 1695 (C]O) cmK1; m/z (EI): 265
(31%, MC), 250 (3), 235 (14), 234 (18), 233 (22), 230 (44),
200 (10), 170 (12), 91 (100).
5.9. Preparation of N-(3-chloro-2-propenyl)-N-
(2-pyridyl)-2,2-dichloropropanamide (22b)
In a double-necked round bottom flask (100 mL), fitted with
a dropping funnel and a reflux condenser, closed on the top
with a CaCl2 tube, CH2Cl2 (20 mL), 2-(3-chloro-2-
propenylamino)pyridine (mixture of E/Z stereoisomers,
4.22 g, 25 mmol) and pyridine (2.43 mL, 30 mmol) were
introduced. A CH2Cl2 (5 mL) solution of 2,2-dichloropro-
panoyl chloride (12) (4.84 g, 30 mmol) was then carefully
added to the stirred solution cooled in a ice-bath (15 min).
Next, the bath was removed and the reaction mixture left at
room temperature, under stirring. After 20 h, the mixture
was diluted with brine–H2O (10 mL/20 mL) and basified
with NaOH (pellets). Then diethyl ether (40 mL) was added.
The organic phase was separated while the aqueous layer
was further washed with diethyl ether–CH2Cl2 (1/1, 3!
20 mL). The combined organic extracts were finally
5.7. Rearrangement of trans-N-benzyl-3-chloro-
4-dichloromethyl-3-methyl-2-pyrrolidinone (trans-8b)
Following the procedure for the rearrangement of cis-8b,
trans-8b (0.61 g, 2 mmol) gave (E)-N-benzyl-4-

F. Bellesia et al. / Tetrahedron 62 (2006) 746–757
755
concentrated under reduced pressure. Flash chromatography
of the crude product on silica gel, using a petroleum ether
(bp 40–60 8C)–diethyl ether gradient (from 10/0 to 7/3) as
eluent, gave amide 22b (6.53 g, 89%, mixture of two E/Z
stereoisomers) as a pale yellow oil. [Found: C, 45.1; H, 3.7;
N, 9.4. C11H11Cl3N2O requires C, 45.00; H, 3.78; N, 9.54];
1H NMR (CDCl3, 200 MHz): d 2.35 (3H, s, trans CCl2CH3),
4.78 (2H, d, JZ5.8 Hz, trans C]CCH2N), 4.94 (2H, dd,
JZ6.1, 1.5 Hz, cis C]CCH2N), 5.91–6.14 (2H, m, cisC
trans HC]CH), 7.26 (1H, ddd, JZ7.3, 4.9, 1.1 Hz,
C(50)ArH), 7.41 (1H, dt, JZ8.4, 1.1 Hz, C(30)ArH), 7.76
(1H, ddd, JZ8.4, 7.3, 2.0 Hz, C(40)ArH), 8.54 (1H, ddd, JZ
(C(30)Ar), 120.51 (C(50)Ar), 137.98 (C(40)Ar), 147.77
(C(60)Ar), 150.83 (C(20)Ar), 169.72 (C]O); IR (KBr): 1717
(C]O) cmK1; m/z (EI): 292 (8%, MC), 257 (5), 209 (23), 173
(100), 145 (23).
5.11. Rearrangement of N-(2-pyridyl)-3-chloro-
4-dichloromethyl-3-methyl-2-pyrrolidinone (23b)
Following the procedure for the rearrangement of cis-8b,
23b (mixture 71/29 of cis/trans stereoisomers, 0.59 g,
2 mmol) gave the 3-pyrrolin-2-one 24b (0.34 g, 68%), as
a pale brown solid, and the lactam 25 (0.11 g, 21%), as a
yellow oil.
4.9, 2.0, 1.1 Hz, C(60)ArH); IR (film): 1670 (C]O) cmK1
;
m/z (EI): 292 (13%, MC), 257 (68), 167 (42), 131 (100), 78
(30), 75 (33).
5.11.1. N-(2-Pyridyl)-5,5-dimethoxy-3,4-dimethyl-3-
pyrrolin-2-one (24b). Mp 70-72 8C. [Found: C, 63.1; H,
6.5; N, 11.2. C13H16N2O3 requires C, 62.89; H, 6.50; N,
5.10. Cyclisation of N-(3-chloro-2-propenyl)-N-
(2-pyridyl)-2,2-dichloropropanamide (22b)
1
11.28]; H NMR (CDCl3, 400 MHz): d 1.87 (3H, q, JZ
CuCl (99 mg, 1 mmol) and the 2,2-dichloroamide 22b
(2.94 g, 10 mmol) were weighed in a Schlenk tube fitted
with a perforable septum (blocked by a screw cap) and a
magnetic stirrer bar. Dry acetonitrile (10 mL) and TMEDA
(302 mL, 2 mmol) were then added under argon. The
mixture was stirred at room temperature and after 20 h
diluted with NaOHaq (0.3% w/v, 20 mL) and extracted with
CH2Cl2 (3!10 mL). The combined organic layers were
concentrated and the crude product was purified by flash
chromatography on silica gel, eluting with petroleum ether
(bp 40–60 8C)–diethyl ether gradient (from 10/0 to 8/2).
This gave the pyrrolidinones cis-23b (1.82 g, 62%), as a
pale orange crystalline solid, and trans-23b (0.76 g, 26%),
as an orange solid.
1.2 Hz, C(4)CH3), 1.96 (3H, q, JZ1.2 Hz, C(3)CH3), 3.14
(6H, s, C(5)OCH3), 7.11 (1H, ddd, JZ7.3, 5.0, 1.2 Hz,
C(50)ArH), 7.64 (1H, dt, JZ8.5, 1.0 Hz, C(30)ArH), 7.71
(1H, ddd, JZ8.5, 7.3, 2.1 Hz, C(40)ArH), 8.54 (1H, ddd, JZ
5.0, 2.1, 1.2 Hz, C(60)ArH); 13C NMR (CDCl3, 400 MHz): d
8.19 (C(3)CH3), 9.25 (C(4)CH3), 51.09 (OCH3), 113.93
(C(5)), 117.05 (C(30)Ar), 120.57 (C(50)Ar), 132.37 (C(3)),
137.69 (C(40)Ar), 145.46 (C(4)), 148.90 (C(60)Ar), 149.57
(C(20)Ar), 169.16 (C]O); IR (KBr): 1713 (C]O) cmK1
;
m/z (EI): 248 (1%, MC), 233 (5), 217 (39), 203 (100),
135(12), 78 (23).
5.11.2. (E)-N-(2-Pyridyl)-4-chloromethylen-3-methoxy-
3-methyl-2-pyrrolidinone (25). [Found: C, 57.1; H, 5.2;
N, 11.0. C12H13ClN2O2 requires C, 57.04; H, 5.19; N,
11.09]; 1H NMR (CDCl3, 400 MHz): d 1.56 (3H, s,
C(3)CH3), 3.26 (3H, s, C(3)OCH3), 4.63 (1H, dd, JZ17.0,
2.8 Hz, C(5)H), 4.81 (1H, dd, JZ17.0, 2.6 Hz, C(5)H), 6.39
(1H, t, JZ2.7 Hz, C]CHCl), 7.12 (1H, ddd, JZ7.3, 5.0,
0.9 Hz, C(50)ArH), 7.75 (1H, ddd, JZ8.5, 7.3, 2.1 Hz,
C(40)ArH), 8.42 (1H, ddd, JZ5.0, 2.1, 0.9 Hz, C(60)ArH),
8.53 (1H, dt, JZ8.5, 1.0 Hz, C(30)ArH); 13C NMR (CDCl3,
400 MHz): d 25.37 (C(3)CH3), 47.72 (C(5)), 52.83 (OCH3),
81.71 (C(3)), 115.16 (C(30)Ar), 116.83 (C]CHCl), 120.45
(C(50)Ar), 135.53 (C(4)]CHCl), 137.96 (C(40)Ar), 147.73
(C(60)Ar), 150.75 (C(20)Ar), 172.35 (C]O); IR (film): 1723
(C]O) cmK1; m/z (EI): 252 (19%, MC), 222 (19), 217 (43),
216 (32), 189 (9), 185 (10), 173 (18), 157 (15), 132 (32), 97
(100), 78 (31).
5.10.1. cis-N-(2-Pyridyl)-3-chloro-4-dichloromethyl-3-
methyl-2-pyrrolidinone (cis-23b). Mp 112–114 8C.
[Found: C, 45.1; H, 3.8; N, 9.5. C11H11Cl3N2O requires C,
45.00; H, 3.78; N, 9.54]; 1H NMR (CDCl3, 400 MHz): d 2.02
(3H, s. C(3)CH3), 3.02 (1H, dt, JZ9.8, 7.4 Hz, C(4)H), 3.73
(1H, dd, JZ12.0, 9.9 Hz, C(5)H), 4.54 (1H, dd, JZ12.0,
7.4 Hz, C(5)H), 6.11 (1H, d, JZ9.7 Hz, C(4)CHCl2), 7.12
(1H, ddd, JZ7.3, 5.0,01.2 Hz, C(50)ArH), 7.74 (1H, ddd, JZ
8.5, 7.3, 2.1 Hz, C(4 )ArH), 8.37 (1H, dt, JZ8.5, 1.0 Hz,
C(30)ArH), 8.39 (1H, ddd, JZ5.0, 2.1, 0.9 Hz, C(60)ArH); 13C
NMR (CDCl3, 400 MHz): d 25.87 (C(3)CH3), 47.33 (C(5)),
53.93 (C(4)), 69.66 (C(3)), 71.36 (C(4)CHCl2), 115.09
(C(300)Ar), 120.65 (C(50)Ar), 138.05 (C(40)Ar), 147.77
(C(6 )Ar), 150.70 (C(20)Ar), 169.66 (C]O); IR (KBr): 1706
(C]O) cmK1; m/z (EI): 292 (8%, MC), 257 (5), 209 (23), 173
(100), 145 (23).
5.12. One-pot preparation of 3,4-dimethylmaleic
anhydride (3b)
5.10.2. trans-N-(2-Pyridyl)-3-chloro-4-dichloromethyl-
3-methyl-2-pyrrolidinone (trans-23b). Mp 104–105 8C.
[Found: C, 45.1; H, 3.8; N, 9.5. C11H11Cl3N2O requires C,
45.00; H, 3.78; N, 9.54]; 1H NMR (CDCl3, 400 MHz): d 1.89
(3H, s. C(3)CH3), 3.41 (1H, dt, JZ7.4, 4.3 Hz, C(4)H), 4.32
(1H, dd, JZ12.3, 4.1 Hz, C(5)H), 4.43 (1H, dd, JZ12.3,
7.4 Hz, C(5)H), 5.99 (1H, d, JZ4.4 Hz, C(4)CHCl2), 7.12
(1H, ddd, JZ7.3, 4.8,01.2 Hz, C(50)ArH), 7.74 (1H, ddd, JZ
8.5, 7.3, 2.1 Hz, C(4 )ArH), 8.39 (1H, dt, JZ8.5, 1.0 Hz,
C(30)ArH), 8.41 (1H, ddd, JZ4.8, 2.1, 0.9 Hz, C(60)ArH); 13C
NMR (CDCl3, 400 MHz): d 21.19 (C(3)CH3), 45.51 (C(5)),
54.00 (C(4)), 68.45 (C(3)), 70.82 (C(4)CHCl2), 114.97
Pyrrolidin-2-one 24b (a 71/29 mixture of cis/trans stereo-
isomers, 1.18 g, 4 mmol) was first rearranged following the
procedure described for the rearrangement of cis-8b. After
the 20 h period at 25 8C, the solvent was removed under
vacuum and the residue treated with H2SO4 4 N (4 mL). The
resulting mixture was then heated at 110 8C for 1 h, after
which time it was extracted with CH2Cl2 (3!3 mL). The
combined organic layers were concentrated under vacuum,
giving anhydride 3b (0.29 g, 57%).

756
F. Bellesia et al. / Tetrahedron 62 (2006) 746–757
5.13. Preparation of N-(3-chloro-2-propenyl)-N-(2-pyr-
idyl)-2,2-dichlorohexadecanamide (22a)
(CDCl3, 400 MHz): d 14.07 (CH3), 22.63 (CH3CH2), 25.52
(C(3)CH2CH2), 29.17, 29.30, 29.40, 29.44, 29.52, 29.59
((CH2)9), 31.86 (CH3CH2CH2), 37.14 (C(3)CH2), 47.00
(C(5)), 48.37 (C(4)), 71.60 (CHCl2), 73.26 (C(3)), 114.99
(C(30)Ar), 120.48 (C(50)Ar), 137.87 (C(40)Ar), 147.64
(C(60)Ar), 150.68 (C(20)Ar), 168.95 (C]O); 1H NMR
(CDCl3, 400 MHz): trans diastereoisomer (10%) d 0.89
(3H, t, JZ6.5 Hz, CH2CH2CH3), 1.10–1.60 (24H, br m,
C(3)CH2(CH2)12CH3), 2.40 (2H, m, C(3)CH2), 3.34 (1H, dt,
JZ4.2, 5.5 Hz, C(4)H), 4.37 (2H, d, JZ5.5 Hz, C(5)H2),
5.98 (1H, JZ4.2 Hz, CHCl2), 7.09 (1H, ddd, JZ7.4, 4.9,
1.0 Hz, C(50)ArH), 7.70 (1H, ddd, JZ8.4, 7.4, 1.9 Hz,
C(40)ArH), 8.37 (2H, m, C(30)ArH, C(60)ArH), 13C NMR
(CDCl3, 400 MHz): d 14.07 (CH3), 22.63 (CH3CH2), 24.42
(C(3)CH2CH2CH2), 29.17, 29.30, 29.40, 29.44, 29.52,
29.59 ((CH2)9), 31.66 (CH3CH2CH2), 32.95 (C(3)CH2),
45.37 (C(5)), 53.34 (C(4)), 70.51 (CHCl2), 72.66 (C(3)),
114.81 (C(30)Ar), 120.26 (C(50)Ar), 137.87 (C(40)Ar),
147.64 (C(60)Ar), 150.68 (C(20)Ar), 169.04 (C]O); IR
(film) 1726 (C]O) cmK1; m/z (EI): 475 (2%, MCHC), 439
(39), 369 (18), 355 (53), 280 (25), 278 (26), 195 (100).
2,2-Dichlorohexadecanoic acid (6) (6.51 g, 20 mmol) was
weighed in a Schlenk tube fitted with a perforable septum
(blocked by a screw cap) and a CaCl2 tube on the side arm.
Next, dry CH2Cl2 (10.5 mL) was added under argon. The
solution was thermostated at 23 8C, and while stirring, DMF
(33 mL) and (COCl)2 (2.64 mL, 40 mmol) were injected
using a syringe. The side arm stopcock was opened to vent
out any gases (CO, CO2 and HCl) produced during the
reaction. After 2 h, solvent and excess oxalyl chloride were
removed under reduced pressure. The crude acyl chloride
was diluted with dry CH2Cl2 (10 mL), then the solution,
thermostated at 23 8C, was treated with a solution of
pyridine (3.49 mL, 40 mmol) and 2-(3-chloro-2-propenyl-
amino)pyridine (mixture of E/Z stereoisomers, 7.60 g,
45 mmol) in CH2Cl2 (10 mL). The reaction mixture was
stirred for 2 h and then washed with NaOH 1 M (2!
20 mL). Next, the organic phase was recovered and
concentrated. Flash chromatography of the crude product
on silica gel, using a petroleum ether (bp 40–60 8C)–diethyl
ether gradient (from 10/0 to 9/1) as eluent, gave amide 22a
(8.95 g, 94%, mixture of two E/Z stereoisomers), as a
yellow oil. [Found: C, 60.7; H, 7.7; N, 5.9. C24H37Cl3N2O
5.15. One-pot preparation of 3-tetradecyl-4-methylma-
leic anhydride (chaetomellic anhydride A) (3a)
1
requires C, 60.57; H, 7.84; N, 5.89]; H NMR (CDCl3,
200 MHz) d 0.89 (3H, t, JZ6.5 Hz, CH2CH2CH3), 1.27
(22H, br s, (CH2)n), 1.62 (2H, qn, JZ7.1 Hz, CCl2CH2-
CH2), 2.49 (2H, m, CCl2CH2) 4.70 (1H, d, JZ5.8 Hz, trans
C]CCH2N), 4.87 (1H, dd, JZ6.2, 1.4 Hz, cis
C]CCH2N), 5.93–6.16 (2H, m, cisCtrans HC]CH),
7.25 (1H, ddd, JZ7.3,0 4.9, 1.1 Hz, C(50)ArH), 7.41 (1H,
dt, JZ8.4, 1.1 Hz, C(3 )ArH), 7.76 (1H, ddd, JZ8.4, 7.3,
2.0 Hz, C(40)ArH), 8.54 (1H, ddd, JZ4.9, 2.0, 1.1 Hz,
C(60)ArH); IR (film): 1669 (C]O) cmK1; m/z (EI): 475
(11%, MCC1), 439 (100), 403 (25), 257 (38), 195 (47), 167
(72), 131 (94), 75 (43).
In a Schlenk tube, fitted with a perforable septum blocked
by a screw cap, ethyl ether/CH3OH 1:1 (1.6 mL) and 23a
(0.48 g, 1 mmol) were added. The solution was thermo-
stated at 25 8C. In a second Schlenk tube, Na0 (92 mg,
4 mmol) was carefully dissolved in CH3OH (1.5 mL), and
when the effervescence ceased, the alkaline solution was
thermostated at 25 8C, after which it was poured into the first
Schlenk tube. The reaction mixture was stirred for 20 h.
Next, in the same Schlenk tube, was added H2SO4 (4 N,
0.25 mL), the solvent removed under vacuum and the
residue treated with H2SO4 (4 N, 0.75 mL) and water
(0.25 mL). The mixture was then heated at 110 8C for 2 h
(under a current of argon to remove CH3OH released from
hydrolysis of 23a), after which time it was diluted with H2O
(2 mL) and extracted with CH2Cl2 (3!3 mL) and the
combined organic layers concentrated under reduced
pressure. Flash chromatography of the crude product on
silica gel, using a petroleum ether (bp 40–60 8C)–ethyl
acetate gradient (from 10/0 to 9/1), gave 3a (0.24 g, 78%),1
as a pale yellow oil. [Found: 73.86; H, 10.52. C19H32O3
requires C, 73.98; H, 10.46]; 1H NMR (CDCl3, 200 MHz) d
0.88 (3H, t, JZ6.7 Hz, CH2CH2CH2CH3), 1.25 (22H, br s,
CH2(CH2)9CH2), 1.57 (2H, m, C(3)CH2CH2), 2.07 (3H, s,
C(4)CH3), 2.45 (2H, t, JZ7.6 Hz, C(3)CH2); IR (film):
1766 (C]O) cmK1; m/z (EI): 308 (5, MC), 290 (15), 280
(4), 263 (7), 235 (8), 150 (33), 126 (100), 43 (45).
5.14. Cyclisation of N-(3-chloro-2-propenyl)-N-
(2-pyridyl)-2,2-dichlorohexadecanamide (22a)
CuCl (99 mg, 1 mmol) and 22a (4.76 g, 10 mmol) were
weighed into a Schlenk tube fitted with a perforable septum
(blocked by a screw cap). Dry acetonitrile (10 mL) and
TMEDA (302 mL, 2 mmol) were then added, under argon.
The mixture was stirred at 60 8C and after 20 h the mixture
was diluted with NaOHaq 0.3% w/v (20 mL) and extracted
with CH2Cl2 (3!15 mL). The combined organic layers
were concentrated and the crude product was purified by
flash chromatography on silica gel, eluting with petroleum
ether (bp 40–60 8C)–ethyl acetate gradient (from 10/0 to
9.4/0.6). This gave the pyrrolidinone 23a (4.43 g, 93%), as
an 90/10 (1H NMR spectrum) mixture of inseparable cis-/
trans-diastereoisomers; pale yellow oil. [Found: C, 60.7; H,
7.9; N, 5.9. C24H37Cl3N2O requires C, 60.57; H, 7.84; N,
5.89]; 1H NMR (CDCl3, 400 MHz): cis diastereoisomer
(90%) d 0.89 (3H, t, JZ6.5 Hz, CH2CH2CH3), 1.10–1.60
(24H, br m, C(3)CH2(CH2)12CH3), 2.40 (2H, m, C(3)CH2),
3.23 (1H, dt, JZ7.5, 9.3 Hz, C(4)H), 3.73 (1H, dd, JZ9.4,
11.6 Hz, C(5)H), 4.50 (1H, dd, JZ7.5, 11.6 Hz, C(5)H),
6.10 (1H, d, JZ9.3 Hz, CHCl2), 7.09 (1H, ddd, JZ7.4, 4.9,
1.0 Hz, C(50)ArH), 7.70 (1H, ddd, JZ8.4, 7.4, 1.9 Hz,
C(40)ArH), 8.37 (2H, m, C(30)ArH, C(60)ArH), 13C NMR
Acknowledgements
`
We thank the Ministero della Universita e della Ricerca
Scientifica e Tecnologica (MURST) for financial assistance,
and the Fondazione Cassa di Risparmio di Modena for the
financial support given for the acquisition of the Bruker
Avance400 Spectrometer.

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