A novel pyrrole synthesis: One-pot preparation of ethyl 5-methylpyrrole-2-carboxylate

Full text of DOI:10.1021/jo961322h

9
068
J . Org. Chem. 1996, 61, 9068-9069
A Novel P yr r ole Syn th esis: On e-P ot
Sch em e 1
P r ep a r a tion of Eth yl
-Meth ylp yr r ole-2-ca r boxyla te
5
Timothy P. Curran* and Meghan T. Keaney
Department of Chemistry, College of the Holy Cross,
Worcester, Massachusetts 01610-2395
Received J uly 12, 1996
The preparation of ethyl 5-methylpyrrole-2-carboxylate
(
1), a starting material for the synthesis of porphyrin
1
analogs, can be achieved using a number of literature
procedures.2 The various syntheses generally follow well-
known routes to pyrroles (like the Fischer-Fink synthe-
sis) and require several steps, either for the preparation
of the starting materials or for the actual reaction
sequence. This paper reports a one-pot synthesis of 1
from the reaction of commercially available starting
materials. An interesting feature of the reaction is its
mechanism, which we postulate involves formation and
reaction of a butatriene intermediate.
Sch em e 2
The discovery of this synthesis came about during
studies aimed at preparing bis-amino acid 2 following a
3
literature synthesis where the first step calls for reaction
of 2 equiv of diethyl acetamidomalonate (3) and 1 equiv
of 1,4-dichloro-2-butyne (4) with 2 equiv of NaOEt in
refluxing EtOH to yield 5 (see Scheme 1). In the process
of repeating the literature work the reaction was inad-
vertantly run using 10 equiv of NaOEt; under these
conditions the major product obtained following chro-
matographic purification bore no resemblance spectro-
scopically to the expected product 5; rather, the major
product was identified by spectroscopic and combustion
analysis as the pyrrole 1.
Subsequent studies of this reaction have shown that 1
equiv each of 3 and 4 along with an excess of NaOEt is
sufficient to obtain 1. Both 3 and 4 are needed for
formation of 1, indicating that 1 is derived from the
combination of 3 and 4. Also, heat is required for
formation of 1; when the reaction is run at room tem-
perature none of the pyrrole 1 is formed. Although the
yield of pure 1 has been modest (between 30-45%), the
ready availability of the starting materials and the ease
with which the reaction can be run make this an
attractive route for synthesizing 1.
butatriene intermediate 7.4 In the next step, 7 undergoes
base-promoted nucleophilic attack by the amide carbonyl
oxygen on the central double bond of the butatriene to
yield the oxazepine intermediate 8. Butatrienes are
known to be unstable and to undergo addition reactions
An obvious question regarding this reaction is the
mechanism that generates 1. Outlined in Scheme 2 is
one possible mechanism for the formation of 1 from 3 and
4
based on literature precedents. Initial alkylation of the
5
sodium salt of 3 with 4 generates propargyl chloride 6,
with a variety of substances at the central double bond.
which then undergoes a 1,4-elimination to generate the
In addition, Williams and Kwast recently discovered a
new synthesis of bicyclic piperazine-2,5-diones, and they
postulated that the key reaction in the synthesis involved
(
1) Chang, C. K. J . Org. Chem. 1981, 46, 4610.
(2) (a) Fischer, H.; Beller, H.; Stern, A. Chem. Ber. 1928, 61B, 1074.
6
formation and enolate addition to a butatriene.
(
b) Terry, W. G.; J ackson, A. H.; Kenner, G. W.; Kornis, G. J . Chem.
Soc. 1965, 4389. (c) Falk, H.; Hofer, O.; Lehner, H. Monatsh. Chem.
973, 104, 925. (d) Elder, T.; Gregory, L. C.; Orozco, A.; Pflug, J . L.;
1
(4) Schubert, W. M.; Liddicoet, T. H.; Lanka, W. A. J . Am. Chem.
Soc. 1954, 76, 1929.
(5) Fischer, H. Cumulenes. In The Chemistry of Alkenes; Patai, S.,
Ed.; Interscience: London, 1964; Chapter 13, p 1100.
Wiens, P. S.; Wilkinson, T. J . Synth. Commun. 1989, 19, 763. (e) Lash,
T. D.; Hoehner, M. C. J . Heterocycl. Chem. 1991, 28, 1671.
(3) Schlogl, K. Monatsh. Chem. 1958, 89, 377.
S0022-3263(96)01322-9 CCC: $12.00 © 1996 American Chemical Society

Notes
Decarboxylation of 8 yields the isomeric 1,3-oxazepine
monoester 9. Species like 9 are known to undergo base-
promoted fragmentation to yield ketones (like 10) that
J . Org. Chem., Vol. 61, No. 25, 1996 9069
portions of EtOAc. The EtOAc layers were combined and
washed: three times with 25 mL portions of saturated NaHCO ,
3
three times with 25 mL portions of 1 M HCl, and one time with
a 25 mL portion of brine. The organic layer was treated with
4
decolorizing carbon and anhydrous MgSO and then evaporated
then undergo further reaction to yield pyrrolidines (like
7
1
1). In the last step 11 undergoes elimination and then
to yield a light yellow oil. On exposure to high vacuum for 16 h
the oil crystallized to yield 137 mg (49%, mp 94-98 °C) of 1 as
a light orange solid. Flash chromatography (2:1 hexane/ether)
yielded 107 mg (38%) of pure 1 as light yellow crystals: mp 98-
hydrolysis on workup to yield 1.
This novel pyrrole synthesis and the findings of Wil-
6
liams and Kwast indicate that investigations of the
2b
2e
1
2e,8
1
(
4
00 °C (lit. mp 100 °C,2a 97-99 °C, 92-95 °C ); H NMR
formation and reaction of butatriene intermediates, an
area that has not received much attention to date, could
yield rapid, new, and/or improved routes to a variety of
organic compounds.
300 MHz, CDCl
3
) δ 9.1 (1H, br s), 6.80 (1H, m), 5.91 (1H, m),
1
3
.30 (2H, q, J ) 7 Hz), 2.30 (3H, s), 1.35 (3H, t, J ) 7 Hz);
C
2e,9
3
NMR (75 MHz, CDCl ) δ 161.8, 135.4, 121.3, 116.3 109.0, 60.2,
1
4.6, 13.2; TLC, R
NO : C, 62.75; H, 7.19; N, 9.15. Found: C, 62.75; H, 7.24; N,
.00.
f 8 11
0.3 (2:1 hexane/ether). Anal. Calcd for C H -
2
9
Exp er im en ta l Section
Eth yl 5-Meth ylp yr r ole-2-ca r boxyla te, 1. To 9.0 mL of 1
M NaOEt/EtOH (9 mmol) was added 0.395 g (1.82 mmol) of
diethyl acetamidomalonate (3) and the resulting solution brought
to reflux, and 190 µL (1.94 mmol) of 1,4-dichloro-2-butyne (4)
was added. After 1 h an additional 190 µL (1.94 mmol) of 1,4-
dichloro-2-butyne (4) and 0.70 mL (1.8 mmol) of 21 wt % NaOEt
in EtOH were added. Reflux was continued for an additional 1
h, after which the EtOH was evaporated. The remaining brown
residue was partitioned between 50 mL of EtOAc and 50 mL of
water. The aqueous layer was extracted twice with 50 mL
Ack n ow led gm en t. This research was supported by
an award from Research Corporation (CC3786). The
NMR spectrometer used in the experiments was pur-
chased with a grant from the National Science Founda-
tion (NSF-ILI USE-8852774).
J O961322H
(8) Roomi, M. W.; Dugas, H. Can. J . Chem. 1970, 48, 2303.
(
9) (a) Abraham, R. J .; Lapper, R. D.; Smith, K. M.; Unsworth, J . F.
(
(
6) Williams, R. M.; Kwast, A. J . Org. Chem. 1988, 53, 5787.
7) Pedersen, C. L.; Buchardt, O. Acta Chem. Scand. 1973, 27, 271.
J . Chem. Soc., Perkin Trans. 2 1974, 1004. (b) Cushley, R. J .; Sykes,
R. J .; Shaw, C.-K.; Wasserman, H. W. Can. J . Chem. 1975, 53, 148.