Extending the scope of a known furan synthesis - A novel route to 1,2,4-trisubstituted pyrroles

Article abstract of DOI:10.1055/s-2002-22707

2-(Acylmethylene)propanediol diacetates, which cyclize readily under acidic conditions to give furans (76-84%) react with primary amines under palladium catalysis to give 1,2,4-trisubstituted pyrroles in moderate to good yields (39-53%). When glycine meth

Full text of DOI:10.1055/s-2002-22707

LETTER
619
Extending the Scope of a Known Furan Synthesis – A Novel Route to
1,2,4-Trisubstituted Pyrroles
A
N
ovel Route to 1,2, 4
a
-trisubstitu
r
ted Pyrr
k
a
Institut für Organische Chemie, Universität Göttingen, Tammannstrasse 2, 37077 Göttingen, Germany
b
Merck KgaA, Central Process Development, 64271 Darmstadt, Germany
Fax +49(551)399475; E-mail: Armin.deMeijere@chemie.uni-goettingen.de
Received 16 January 2002
Abstract: 2-(Acylmethylene)propanediol diacetates, which cyclize
readily under acidic conditions to give furans (76–84%) react with
primary amines under palladium catalysis to give 1,2,4-trisubstitut-
ed pyrroles in moderate to good yields (39–53%). When glycine
methyl ester is used as the amine, substituted methyl pyrrol-1-ylac-
etates (31–82%) are obtained.
Key words: heterocycles, Wittig olefination, palladium catalysis,
allylic substitution
Scheme 2 Horner–Wadsworth–Emmons olefination of 1,3-diace-
toxy-2-propanone (3) and subsequent cyclization to 2,4-disubstituted
furans. For details see Table 1.
Probably the best known access to furans and pyrroles is
by the Paal–Knorr synthesis.1 1,4-Dicarbonyl compounds
are cyclized under acid catalysis and with dehydration to
give furans; in the presence of primary amines or ammo-
nium salts, the corresponding pyrroles are formed. By a
similar mechanism, but under much milder conditions,
furans are also formed under acid catalysis from , -un-
saturated -hydroxyketones of type 1 (Scheme 1).2 Start-
ing from readily available dihydroxyacetone diacetate 3,3
we have extended a known access4 to functionally substi-
tuted furans 6 and developed an analogous, yet palladium-
catalyzed reaction leading to pyrroles.
Table 1 Horner–Wadsworth–Emmons Olefination of 1,3-Diace-
toxy-2-propanone (3) with -Ketophosphonates 4a–c and Subsequent
Cyclization of Products 5a–c to Furans 6a–c
R
Reaction Product Yield Reaction Product Yield
Time [h]
(%) Time [h]
(%)
Me
2.5
5a
5b
5c
76
83
62
1
1
6a
6b
6c
76
Et
18
79
4-F-C6H4
48
0.5
84
orophenyl-substituted furan 6c proceeded much faster
than the formation of the methyl- and ethyl-substituted
furans 6a,b.
Scheme 1 Furans from , -unsaturated -hydroxyketones
In a first attempt to further extend the scope of this reac-
tion to the synthesis of pyrroles, the simple addition of pri-
mary amines and ammonium salts to precursors 5a–c was
tested under acidic and basic conditions. But no trace of a
pyrrole could be detected in any case. Since pyrroles can
only be formed after nucleophilic substitution of at least
one of the allylic acetoxy groups in 5 by an amine, and
this kind of substitution is generally catalyzed by palla-
dium(0),6,7 compounds 5a,c were treated with two equiv-
alents of benzylamine and 5 mol% of tetrakis(tri-
phenylphosphine)palladium in refluxing tetrahydrofuran
to give the desired pyrroles 7a,c as orange oils in 53 and
39% yield, respectively (Scheme 3, Table 2).5
In this extension of the furan synthesis, , -unsaturated -
acetoxyketones 5a–c which were obtained by Horner–
Wadsworth–Emmons olefination of 1,3-diacetoxy-2-pro-
panone (3) with -ketophosphonates 4a–c in 62–83%
yield, were used as precursors (Scheme 2, Table 1).5
Upon treatment of the 3,3-bis(acetoxymethyl)-substituted
enones 5 with hydrochloric acid in methanol at 50 °C for
30–60 minutes, the corresponding 2-substituted 4-hy-
droxymethylfurans 6a–c were formed in 76–84% yield.5
This reaction involves the hydrolysis of the two acetoxy
moieties to give the bisallylic alcohol which, under the
acidic conditions, forms the furan. Formation of the 4-flu-
The low yields of isolated products must be partly due to
the low stability of the pyrroles 7a,c towards air and mois-
ture, as was indicated by the appearance of deeply colored
zones on the flash-chromatography column. The chroma-
Synlett 2002, No. 4, 29 03 2002. Article Identifier:
1437-2096,E;2002,0,04,0619,0621,ftx,en;G00802ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

620
M. Friedrich et al.
LETTER
While the reactions of 5a,b with glycine methyl ester pro-
ceeded cleanly at room temperature to give the pyrroles
10a,b in 80% and 82% yield, that of precursor 5c required
a temperature of 65 °C, and led to a more complex product
mixture, from which the pyrrole 10c could be isolated in
only 31% yield.5 At room temperature, again, only the
Michael adduct of methyl glycinate to 5 was formed.
Scheme 3 Synthesis of pyrroles 7a,c from enones 5a,c. For details
see Table 2.
Table 3 Reaction of Bisallylic Diacetates 5 with Methyl Glycinate
(9) to Pyrroles 10a–c
Enone
5a
R
Me
Conditions
25 °C, 2 d
25 °C, 2 d
65 °C, 15 h
Product
10a
Yield (%)
tography therefore had to be performed with a column as
short as possible, longer retention of the compounds 7a,c
on the column resulted in even lower yields.
80
82
31
5b
Et
10b
Table 2 Reaction of Precursors 5 with Benzylamine to Yield Pyr-
roles 7
5c
4-F-C6H4
10c
Starting
Material
R
Reaction
Time [h]
Product
Yield
(%)
The possibility to incorporate the amino function of an
amino acid ester into a pyrrole ring gives access to a class
of compounds known as pyrallic acids, which recently
have gained attention for their antibiotic properties.8
5a
5c
Me
10
3
7a
7c
53
39
4-F-C6H4
Acknowledgement
The attempted conversions of 5a,c with benzylamine to
7a,c did not succeed at ambient temperature. In the case
of 5a, no product was formed, while the treatment of 5c
with benzylamine at ambient temperature gave the Micha-
el adduct 8 as the only product in 53% yield (Scheme 4).
The same reaction took place in the absence of the palla-
dium catalyst. Since this Michael addition is reversible,
treatment of 8 with tetrakis(triphenylphosphine)palladi-
um at 65 °C also gave the pyrrole 7c.
This work was supported by Merck KGaA, Darmstadt and the
Fonds der Chemischen Industrie, Frankfurt. We are grateful to Dr.
B. Knieriem (Göttingen) for his careful proofreading of the final
manuscript.
References
(1) For reviews see: (a) Dean, F. M.; Sargent, M. V. In
Comprehensive Heterocyclic Chemistry, Part 3, Vol. 4; Bird,
C. W.; Cheeseman, G. W. H., Eds.; Pergamon Press: New
York, 1984, 531. (b) Bird, C. W.; Cheeseman, G. W. H. In
Comprehensive Heterocyclic Chemistry, Part 3, Vol. 4; Bird,
C. W.; Cheeseman, G. W. H., Eds.; Pergamon Press: Oxford,
1984, 89.
(2) (a) Baldwin, S. W.; Crimmins, M. T. J. Am. Chem. Soc.
1980, 102, 1198. (b) Anand, R. C.; Singh, V. Heterocycles
1993, 36, 1333. (c) Nokami, J.; Nishimura, A.; Sunami, M.;
Wakabayashi, S. Tetrahedron Lett. 1987, 28, 649.
Scheme 4 Michael addition of benzylamine to 5c
(3) Bentley, P. H.; McCrae, W. J. Org. Chem. 1970, 35, 2082.
(4) Díaz-Cortés, R.; Silva, A. L.; Maldonado, L. A. Tetrahedron
Lett. 1997, 38, 2207.
The reaction of the bisallylic diacetates 5a–c with glycine
methyl ester (9) in the presence of a palladium catalyst
gave the corresponding methyl 2-pyrrol-1-ylacetates
10a–c in 31–82% yield (Scheme 5, Table 3). In this case,
the best precatalyst system turned out to be bis(dibenz-
ylideneacetone)palladium with triphenylphosphine.
(5) All new compounds were fully characterized by
spectroscopic methods (IR, 1H and 13C NMR, MS); bulk
purity was established in most cases by satisfactory
elemental analysis data. Spectroscopic data of representative
examples are: 4-Hydroxymethyl-2-methylfuran (6a): IR
(KBr): 3357 (OH), 2923, 2878, 1740, 1557, 1449, 1385,
1272, 1234, 1123, 1021, 977, 918, 809, 737 cm–1. 1H NMR
(250 MHz, CDCl3): = 1.90 (s, 1 H, OH), 2.28 (s, 3 H, 2-
CH3), 4.51 (s, 2 H, CH2OH), 6.03 (br s, 1 H, 3-H), 7.26 (br
s, 1 H, 5-H). 13C NMR (62.9 MHz, CDCl3, DEPT):
= 13.36 (+, 2-CH3), 56.36 (–, CH2OH), 105.70 (+, C-3),
125.84 (Cquat, C-4), 137.87 (+, C-5), 152.87 (Cquat, C-2). MS
(EI, 70 eV): m/z (%) = 112(9) [M+], 88(10), 61(16), 45(15),
43(100). Calcd for C6H8O2: 112.0524; (correct HRMS). N-
Benzyl-4-acetoxymethyl-2-methylpyrrole (7a): IR (film):
3088, 3063, 3030, 2934, 1734 (CO), 1662, 1605, 1521,
1496, 1454, 1416, 1366, 1238, 1149, 1021, 943, 796, 734,
696 cm–1. 1H NMR (250 MHz, CDCl3): = 2.06 (s, 3 H),
Scheme 5 Synthesis of substituted pyrrol-1-ylacetates 14. For de-
tails see Table 3.
Synlett 2002, No. 4, 619–621 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
2.12 (s, 3 H), 4.93 (s, 2 H), 4.98 (s, 2 H), 5.99 (s, 1 H, 3-H),
A Novel Route to 1,2,4-Trisubstituted Pyrroles
621
3-H), 6.63 (br s, 1 H, 5-H). 13C NMR (62.9 MHz, CDCl3,
DEPT): = 11.63 (+, 2-CH3), 21.20 (+, COCH3), 48.03 (–,
N-CH2), 52.51 (+, CO2CH3), 60.21 (–, CH2OAc), 108.32 (+,
C-3), 117.80 (Cquat, C-4), 121.30 (+, C-5), 129.72 (Cquat, C-
2), 168.99 (Cquat), 171.25 (Cquat).
6.67 (br s, 1 H, 5-H), 7.01–7.04 (m, 2 H), 7.26–7.32 (m,
3 H). 13C NMR (62.9 MHz, CDCl3, DEPT): = 11.94 (+, 2-
CH3), 21.27 (+, COCH3), 50.36 (–), 60.42 (–), 108.04 (+, C-
3), 117.13 (Cquat, C-4), 121.06 (+, C-5), 126.47 (+), 127.42
(+), 128.71 (+), 129.57 (Cquat, C-2), 137.77 (Cquat), 171.25
(Cquat, COMe). MS (EI, 70 eV): m/z (%) = 243(70) [M+],
(6) For reviews see: (a) Tsuji, J.; Minami, I. Acc. Chem. Res.
1987, 20, 140. (b) Trost, B. M. Chemtracts: Org. Chem.
1988, 1, 415. (c) Trost, B. M.; Van Vranken, D. L. Chem.
Rev. 1996, 96, 395.
(7) Stolle, A.; Ollivier, J.; Piras, P. P.; Salaün, J.; de Meijere, A.
J. Am. Chem. Soc. 1992, 114, 4051.
+
201(25), 184(43) [M+ – OCOMe], 172(12), 91(100) [C7H7 ].
Methyl (4-Acetoxymethyl-2-methylpyrrol-1-yl)acetate
(10a): IR(film): 3443, 2952, 1732 (CO), 1666, 1525, 1436,
1419, 1368, 1347, 1232, 1158, 1141, 1023, 943, 798, 731,
694, 658 cm–1. 1H NMR (250 MHz, CDCl3): = 2.05 (s,
3 H, COCH3), 2.15 (s, 3 H, 2-CH3), 3.77 (s, 3 H, CO2CH3),
4.52 (s, 2 H, N-CH2), 4.94 (s, 2 H, CH2OAc), 5.97 (br s, 1 H,
(8) Brüning, M. Dissertation; Universität Göttingen: Germany,
1997.
Synlett 2002, No. 4, 619–621 ISSN 0936-5214 © Thieme Stuttgart · New York