Unusual access to 5-methoxy or 5,5-dimethoxy-4-methyl-3-pyrrolin-2-ones from chlorinated 4-methyl-pyrrolidin-2-ones

Article abstract of DOI:10.1016/S0040-4039(01)00792-4

The reaction of N-substituted 4-methyl-2-pyrrolidinones, carrying not less than two chlorine atoms on the C(3) and C(6) carbons afforded with alkaline methoxide in methanol, under mild conditions, the corresponding 5-methoxy or 5,5-dimethoxy-4-methyl-3-py

Full text of DOI:10.1016/S0040-4039(01)00792-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4573–4575
Unusual access to 5-methoxy or
5,5-dimethoxy-4-methyl-3-pyrrolin-2-ones from chlorinated
4-methyl-pyrrolidin-2-ones
Franco Bellesia,a Laurent De Buyck,b Maria V. Colucci,a Franco Ghelfi,a,* Inge Laureyn,b
Emanuela Libertini,a Adele Mucci,a Ugo M. Pagnoni,a Adriano Pinetti,a Tina M. Roggeb and
Christian V. Stevensb,*
aDipartimento di Chimica, Universita` degli Studi di Modena e Reggio Emilia, via Campi 183, 41100 Modena, Italy
bDepartment of Organic Chemistry, Faculty of Agricultural and Applied Biological Sciences, Ghent University,
Coupure Links 653, B-9000 Ghent, Belgium
Received 26 February 2001; accepted 11 May 2001
Abstract—The reaction of N-substituted 4-methyl-2-pyrrolidinones, carrying not less than two chlorine atoms on the C(3) and
C(6) carbons afforded with alkaline methoxide in methanol, under mild conditions, the corresponding 5-methoxy or 5,5-
dimethoxy-4-methyl-3-pyrrolin-2-ones in satisfactory yields. © 2001 Elsevier Science Ltd. All rights reserved.
The synthesis of isosteric aza-analogues of biologically
active lactones is gaining interest among organic
chemists.1,2 The replacement of the endocyclic oxygen
with a nitrogen atom leads to lactams of comparable
activity, but which are less toxic and/or less metaboli-
cally labile than their natural counterparts. Therefore,
these are more suitable for chemotherapeutic applica-
tions.2–4 Recently, we were involved in a project aiming
at the chemo-enzymatic synthesis of aza-analogues5 of
a-methylene paraconic acids.6–8 The synthetic strategy
to the paraconic acids target 3a started from the N-
benzyl-4-chloromethyl-3,3-dichloropyrrolidin-2-one 1a
(Scheme 1), a material readily available through halo-
gen atom transfer radical cyclisation, promoted by
CuCl(TMEDA)2, of the N-allyl-N-benzyl-2,2,2-
trichloroacetamide.9 The halogenated pyrrolidin-2-one
1a was selected, after retro-analysis, in view of the
straightforward introduction of the 3-alkylidene group
at C(3) from the 3,3-dihalo function via an intermediate
3-oxo function (Scheme 1).
Our first endeavour was routed to the alkoxy-dehalo-
genation of compound 1a, using lithium methoxide in
methanol. A range of conditions were evaluated. The
reaction gave generally a single, easy recoverable,
product. Astonishingly, after spectroscopic analysis
Cl
Cl
Cl
1a
O
N
CH3O-/CH3OH
CH3O-/CH3OH
Bzl
OCH3
OCH3
H3CO
O
COOH
O
OR
OCH3
OCH3
O
O
O
N
N
N
N
3a
2a
Bzl
4a
Bzl
Bzl
Bzl
Scheme 1.
Keywords: pyrrolidinones; pyrrolinones; lactams; eliminations.
* Corresponding authors. Fax: +39(059)373543 (F.G.); fax: +32(09)2646243 (C.V.S.); e-mail: ghelfi.franco@unimo.it; chris.stevens@rug.ac.be
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00792-4

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F. Bellesia et al. / Tetrahedron Letters 42 (2001) 4573–4575
1
(GC–MS, H NMR, 13C NMR, HMQC, HMBC) the
isolated material emerged as the N-benzyl-5,5-
dimethoxy-4-methyl-3-pyrrolin-2-one 4a rather than the
expected acetal 2a. The compound 4a was generated by
an unusual functional rearrangement of the polyhalo-
genated pyrrolidin-2-one 1a (Scheme 2), leading to the
normally difficult functionalisation at C(5).10 To our
knowledge, no reports on the functional rearrangement
in polychlorinated 2-pyrrolidinones have appeared in
the literature. A sporadic example of dehydrochlorina-
tion of trichloro-g-lactones by non nucleophilic bases
was, however, reported.11
drastically reduced or absent. Interestingly, under the
mildest conditions tested, small amounts of N-benzyl-3-
chloro-4-methyl-5-methoxy-3-pyrrolin-2-one
were
sometimes observed. Since this side-product was
smoothly converted into 4a, it can be considered as a
precursor of the N-benzyl-5,5-dimethoxy-4-methyl-3-
pyrrolin-2-one.
To check whether this unusual transformation had a
general character, we prepared the educts 1b–h, which
were then treated with alkaline methylate/methanol
under the optimum conditions (Table 1). All the com-
pounds tested displayed the same behaviour as 1a, i.e. a
dehydrohalogenation associated with the introduction
in position C(5) of as many methoxy groups as the
number of remaining halogens. It should be noted that
the final product (Table 1, items 1, 2, 11, 12 and 7, 8,
14, 15) is related to the total number of halide atoms
and not to their distribution. A more active system was
obtained by replacing the lithium ion with the sodium
ion, a less acidic counterion (Table 1, items 7, 11 and 8,
12). Interestingly, substrate 1e gave the highest yields;
this is probably due to the steric protection exerted by
the methyl substituent at C(3), which should prevent
the opening of the ‘lactam’ ring. Other alcoholate/alco-
hol combinations can replace the alkaline methylate/
methanol, however, it appears that on increasing the
size of the alcoholate, the yields decrease to some extent
(Table 1, item 6).
By a variation of the temperature, the reagent concen-
tration and the operational procedures, the best reac-
tion conditions for the model compound 1a were
established. Yields of 4a can be considered satisfactory
given the dense functionalisation of the ring. However,
the yields are not very high (62%) because of parasitic
polymerisation phenomena, probably due to the open-
ing of the lactam ring through alkaline alcoholate
attack on the 2-oxo group. We were not able to get rid
of this drawback by working at temperatures below
0°C, by using a stoichiometric amount of base or by
changing to less basic systems, such as Li2CO3/CH3OH.
The desired conversions, in fact, were in all these cases
6
R
R
Clm
O
4
Cln
3
2
5
R"O M
R"OH
All the transformations from 1 to 4 must begin with a
dehydrohalogenation, since, otherwise, the methoxy
group could not be located at the C(5) position. The
lack of reactivity under the usual conditions of N-ben-
zyl-4-chloromethyl-3,3-dichloro-4-methyl-pyrrolidin-2-
O
(OR")m+n-1
N
1
N
R'
4
1
R'
Scheme 2.
Table 1. Reaction of the polychloro 2-pyrrolidinones 1 with R%%O−/R%%OHa
No.
Educts
Products
R%%OM
t (h)
T (°C)
Conversion (%)b
Yield (%)c
R
R%
m
n
1
1a
1a
1a
1b
1c
1c
1d
1d
1e
1e
1f
–
–
–
–
–
–
H
H
CH3
CH3
H
H
–
Bzl
Bzl
Bzl
2
2
2
2
2
2
1
1
1
1
1
1
2
0
0
1
1
1
1
1
1
1
1
1
1
2
2
0
2
2
4a
4a
4a%
4b
4c
4c%
4d
4d
4e
4e
4b
4b
4d
4d
4d
CH3OLi
CH3OLi
EtOLi
2.5
2.5
1.5
3
15
15
16
2.33
24
24
1.5
2
0
25
0
97
100
100
100
100
100
93
100
100
91
100
100
100
100
100
62
56
56
45
66
40
61
60
57
78
47
64
6
2d
3e
4
N(CH3)2
CH2PO(OEt)2
CH2PO(OEt)2
CH3OLi
CH3ONa
i-PrONa
CH3OLi
CH3ONa
CH3OLi
CH3OLi
CH3OLi
CH3ONa
CH3OLi
CH3OLi
CH3ONa
25
25
25
25
25
25
25
80
25
25
80
80
5
6
7
Bzl
Bzl
Bzl
Bzl
Bzl
Bzl
Bzl
Bzl
Bzl
8d
9
10d
11
12
13
14
15
1f
1g
1h
1h
6
24
6
H
H
56
60
a 4 mmol of substrate, 16 ml of R%%OH and 4 equiv. of base were used.
b GC value.
c Determined on isolated material.
d Reaction performed in 16 ml of CH3OH/ether (1/1).
e Reaction performed in 8 ml of ethanol.

F. Bellesia et al. / Tetrahedron Letters 42 (2001) 4573–4575
4575
References
one, apart from some polymerisation, strongly supports
this hypothesis. For the moment, however, nothing can
be said about the regioselectivity of the starting elimi-
nation, if it is an endo-dehydrochlorination between
C(3) and C(4) positions or, alternatively, an exo-dehy-
drochlorination between the C(4) and C(6) carbons. In
any case, it is clear from the data of items 13 and 14
(Table 1) that satisfactory results can be achieved, only
if, at least, one chlorine atom is attached to C(6).
1. Garst, M. E.; Dolby, L. J.; Esfandiari, S.; Fedoruk, N. A.;
Chamberlain, N. C.; Avey, A. A. J. Org. Chem. 2000, 65,
7098–7104.
2. Borzilleri, R. M.; Zheng, X.; Schmidt, R. J.; Johnson, J.
A.; Kim, S.-H.; DiMarco, J. D.; Fairchild, C. R.;
Gougoutas, J. Z.; Lee, F. Y. F.; Long, B. H.; Vite, G. D.
J. Am. Chem. Soc. 2000, 122, 8890–8897.
3. Belaud, C.; Roussakis, C.; Letourneux, Y.; Alami, N. E.;
Villieras, J. Synth. Commun. 1985, 1233–1243.
4. Xie, X.; Lu, X. Tetrahedron Lett. 1999, 40, 8415–8418.
5. Felluga, F.; Prodan, M.; Valentin, E. Atti del XXV
Convegno Nazionale della Divisione di Chimica Organica,
Folgaria (TN), 1998, P 137.
6. Mandal, P. K.; Roy, S. C. Tetrahedron 1999, 55, 11395–
11398.
7. Forster, A.; Fitremann, J.; Renaud, P. Tetrahedron Lett.
1998, 39, 7097–7100.
8. Ghatak, A.; Sarkar, S.; Ghosh, S. Tetrahedron 1997, 53,
17335–17342.
In summary, we have described a satisfactory and
unusual preparation of N-substituted 5-methoxy or 5,5-
dimethoxy-4-methyl-3-pyrrolin-2-ones by reaction of
the corresponding 4-methyl-pyrrolidin-2-ones, poly-
chlorinated at C(3) and C(6), with alkaline methoxide
in methanol under mild conditions. The functional
rearrangement is fairly appealing since the 3-pyrrolin-2-
ones obtained can be envisaged as precursors for cyclic
N-acyliminium ions,12 which are in turn very useful
intermediates in organic synthesis.13 The availability of
polychloro 2-pyrrolidinones makes this route to cyclic
N-acyliminium ions alternative or competitive in com-
parison with the usual approach, which starts from
succinimide derivatives.14 Further studies directed
towards the rationalisation of the reaction mechanism,
and the application of the methodology in biologically
active compounds synthesis are currently under
investigation.
9. Ghelfi, F.; Bellesia, F.; Forti, L.; Ghirardini, G.; Grandi,
R.; Libertini, E.; Montemaggi, M. C.; Pagnoni, U. M.;
Pinetti, A.; De Buyck, L.; Parsons, A. F. Tetrahedron 1999,
55, 5839–5852.
10. Easton, C. J.; Pitt, M. J.; Ward, C. M. Tetrahedron 1995,
51, 12781–12790.
11. Takano, S.; Nishizawa, S.; Akiyama, M.; Ogasawara, K.
Heterocycles 1984, 22, 1779–1788.
12. De Koning, H.; Moolenaar, M. J.; Hiemstra, H.; Spekamp,
W. N. In Studies in Natural Products Chemistry; Atta-ur-
Rahman, Ed. Bioactive natural products (part A).;
Elsevier: Amsterdam, 1993; Vol. 13, pp. 473–518.
13. Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000, 56,
3817–3856.
Acknowledgements
We thank the Ministero della Universita` e della Ricerca
Scientifica e Tecnologica (MURST) and the F.W.O.-
Vlaanderen and BOF-RUG for financial assistance.
14. Iula, D. M.; Gawley, R. E. J. Org. Chem. 2000, 65,
6136–6201.
.