A general synthesis of substituted formylpyrroles from ketones and 4-formyloxazole

Article abstract of DOI:10.1021/ol070340q

A novel two-step synthesis of substituted 2-formylpyrroles Is described. Aldol adducts of ketones and 4-formyloxazole undergo a dehydration/ oxazote hydrolysis/cyclization cascade on sequential treatment with MsCl/Et₃N and aqueous NaOH to yield

Full text of DOI:10.1021/ol070340q

ORGANIC
LETTERS
2007
Vol. 9, No. 10
1875-1878
A General Synthesis of Substituted
Formylpyrroles from Ketones and
4-Formyloxazole
Jonathan T. Reeves,* Jinhua J. Song, Zhulin Tan, Heewon Lee,
Nathan K. Yee, and Chris H. Senanayake
Department of Chemical DeVelopment, Boehringer Ingelheim Pharmaceuticals, Inc.,
900 Old Ridgebury Road, P.O. Box 368, Ridgefield, Connecticut 06877-0368
jreeVes@rdg.boehringer-ingelheim.com
Received February 9, 2007
ABSTRACT
A novel two-step synthesis of substituted 2-formylpyrroles is described. Aldol adducts of ketones and 4-formyloxazole undergo a dehydration/
oxazole hydrolysis/cyclization cascade on sequential treatment with MsCl/Et3N and aqueous NaOH to yield 5-substituted and 4,5-disubstituted
2-formylpyrroles. The methodology was extended to an N-benzyl thiazolium salt.
Substituted 2-formylpyrroles are useful intermediates in the
preparation of heterocyclic scaffolds such as 6-azaindoles,1
pyrrolo[1,2-a]pyrazines,2 and pyrrolizin-3-ones.3 Recently we
required a practical synthesis of 5-substituted and 4,5-
disubstituted 2-formylpyrroles. Herein we describe a simple
two-step protocol for annulation of the 2-formylpyrrole
moiety onto a variety of ketones.
be cleaved readily under the reaction conditions to give B
(or an equivalent tautomer). Cyclization of the free amino
group onto the pendant ketone (following isomerization to
the appropriate olefin geometry) would afford 2-formyl-
pyrrole C after dehydration and tautomerization.
To test the feasibility of the reaction, â-(4-oxazolyl)enone
3 was prepared (Scheme 1). Partial reduction of commercially
In pioneering work on the synthesis and reactivity of
oxazoles, Cornforth and co-workers reported that various
2-substituted 4-formyloxazoles underwent alkaline hydrolysis
to give N-acylated aminomalondialdehydes.4,5 We reasoned
that a Vinylogous extension of Cornforth’s reaction may be
applicable to the synthesis of 2-formylpyrroles (Figure 1).
Initial hydrolytic attack at C2 of the oxazole ring of enone
A would lead to an N-formyl intermediate, and unlike
Cornforth’s N-acylated substrates, the N-formyl group should
(1) Dekhane, M.; Potier, P.; Dodd, R. H. Tetrahedron 1993, 49, 8139-
8146.
(2) Herz, W.; Tocker, S. J. Am. Chem. Soc. 1955, 77, 6355-6357.
(3) Campbell, S. E.; Comer, M. C.; Derbyshire, P. A.; Despinoy, X. L.
M.; McNab, H.; Morrison, R.; Sommerville, C. C.; Thornley, C. J. Chem.
Soc., Perkin Trans. 1 1997, 2195-2202.
(4) Cornforth, J. W.; Fawaz, E.; Goldsworthy, L. J.; Robinson, R. J.
Chem. Soc. 1949, 1549-1553.
(5) For reviews on the chemistry of oxazoles, see: (a) Turchi, I. J.;
Dewar, M. J. S. Chem. ReV. 1975, 75, 389-437. (b) Wiley, R. H. Chem.
ReV. 1945, 37, 401-442.
Figure 1. Cornforth’s acylaminomalondialdehyde synthesis and
our proposed vinylogous extension for pyrrole formation.
10.1021/ol070340q CCC: $37.00
© 2007 American Chemical Society
Published on Web 03/14/2007

Scheme 1. Synthesis of 4-Formyloxazole (2) and Hydrolytic
Conversion of â-(4-Oxazolyl)enone 3 to Formylpyrrole 4
Table 1. Two-Step Synthesis of Substituted 2-Formylpyrroles
from Ketones and 4-Formyloxazole (2)
available ethyl 4-oxazolecarboxylate (1) with DIBALH gave
4-formyloxazole (2) in 64% yield after recrystallization.6
Horner-Wadsworth-Emmons olefination of 2 with diethyl
(2-oxo-2-phenylethyl)phosphonate gave 3 in 79% yield as a
single E olefin isomer.7 Gratifyingly, heating 3 in aqueous
2 N NaOH/THF at 70 °C for 14 h produced the desired
formylpyrrole 4 in 82% yield.8
Although Horner-Wadsworth-Emmons olefination of 2
represents a convenient route to â-(4-oxazolyl)enones, the
number of commercially available â-ketophosphonates (or
analogous Wittig reagents) is limited. These reagents may
be prepared from commercial materials in one or two steps,
but we sought a more direct route.9 Aldol reaction of ketones
with 2 would give â-hydroxy-â-(4-oxazolyl)ketones, which
on dehydration would provide â-(4-oxazolyl)enones.10 This
aldol/dehydration strategy proved to be viable, and the
dehydration and oxazole hydrolysis steps could conveniently
be performed in the same pot. Thus, reaction of the lithium
enolate of acetophenone 5 (1.1 equiv of LDA, THF, -70
°C, 30 min) with 2 gave aldol 6 in 84% yield (Scheme 2).11
Scheme 2. One-Pot Conversion of Aldol 6 to Formylpyrrole 4
a Isolated yield. b Diastereomeric ratio determined from 1H NMR of crude
product. c 2.2 equiv of LDA used in aldol reaction. d Hydrolysis time of
48 h. e LHMDS (1.1 equiv) used instead of LDA. f The mixture of
diastereomers was purified by chromatography on SiO2 and used as such
in the next step. g The major diastereomer was crystallized from the crude
product mixture and used as such in the next step.
After some optimization, it was found that treatment of 6
with MsCl (1.5 equiv) and Et3N (3.0 equiv) in THF at 0 °C
for 1 h followed by addition of aqueous 2 N NaOH and
heating at 70 °C for 16 h gave 4 in 70% yield. It was
necessary only to achieve complete mesylation of the aldol
(6) For a previous synthesis of 4-formyloxazole, see: Hodges, J. C.; Patt,
W. C.; Connolly, C. J. J. Org. Chem. 1991, 56, 449-452.
(7) Maryanoff, B. E.; Reitz, A. B. Chem. ReV. 1989, 89, 863-927.
(8) For a previous synthesis of 4, see: Padwa, A.; Smolanoff, J.; Tremper,
A. J. Am. Chem. Soc. 1975, 97, 4682-4691.
prior to addition of aqueous NaOH. The subsequent elimina-
tion to give the â-(4-oxazolyl)enones is fast (typically <0.5
h) after addition of aqueous NaOH, whereas with Et3N in
THF this elimination required >24 h at room temperature
to reach completion.12
Having developed optimized conditions for a two-step
synthesis of the required substituted 2-formylpyrroles from
ketones and 2, we explored the substrate scope of the process
(Table 1). Aldol reaction of methyl ketones (entries 1-3)
with 2 and subsequent dehydration/pyrrole formation gave
(9) (a) Lee, K.; Wiemer, D. F. J. Org. Chem. 1991, 56, 5556-5560. (b)
Kim, D. Y.; Kong, M. S.; Kim, T. H. Synth. Commun. 1996, 26, 2487-
2496.
(10) A synthesis of N-Boc-2-benzyl-4,5-disubstituted pyrroles by aldol
reaction of cyclic ketones with N-Boc-L-phenylalaninal and subsequent acid-
catalyzed cyclization has been reported: Konieczny, M. T.; Cushman, M.
Tetrahedron Lett. 1992, 33, 6939-6940.
(11) (a) Stork, G.; Kraus, G. A.; Garcia, G. A. J. Org. Chem. 1974, 39,
3459-3460. (b) Heathcock, C. H.; Buse, C. T.; Kleschick, W. A.; Pirrung,
M. C.; Sohn. J. E.; Lampe, J. J. Org. Chem. 1980, 45, 1066-1081.
1876
Org. Lett., Vol. 9, No. 10, 2007

5-substituted 2-formylpyrroles, while the reaction of higher
ketones (entries 4-9) gave 4,5-disubstituted 2-formyl-
pyrroles. In the latter cases the intermediate aldol adducts
were formed as a mixture of two diastereomers. In some
cases (entries 5, 7, and 8) the major diastereomer crystallized
from the crude product mixture and was used as a single
diastereomer in the subsequent pyrrole-forming reaction. The
yield of aldol adduct in these entries is therefore the isolated
yield of major diastereomer. For entries 4, 6, and 9, the
mixture of diastereomers was purified by chromatography
and used as such in the pyrrole-forming reaction. Control
experiments indicated no significant difference in reaction
rate or purity profile for diastereomeric aldol adducts. The
protocol allowed incorporation of alkyl, aryl, and alkenyl
functionality on the 2-formylpyrrole core. Halogenated
substrates could be prepared (entries 3 and 4), and offer
possibilities for further functionalization via cross-coupling
reactions.13 An N-unprotected indole could be incorporated
(entry 2). In this case the aldol reaction was performed via
the dianion of 3-acetylindole.14 Hydrolysis of the resultant
aldol 9 was unusually slow (48 h at 70 °C), possibly due to
resonance contributions from the partially deprotonated
indole nitrogen to the ketone carbonyl attenuating the
inductive electron withdrawl from the oxazole ring. The use
of cyclic ketones generated bicyclic and tricyclic formyl-
pyrroles (entries 6-9) in good yields.
Extension of the methodology to a â-(4-thiazolyl)enone
was explored. These substrates, if they followed the same
reaction pathway as the corresponding oxazole systems,
could give 2-thioformylpyrroles. In contrast to other thio-
aldehydes, 2-thioformylpyrroles are known to be fairly stable
as a result of electron donation of the pyrrole ring into the
CdS double bond, and their formation using this chemistry
appeared feasible.15 Olefination of commercially available
4-formylthiazole 25 gave the requisite enone 26 as a single
(E)-alkene isomer (Scheme 3). Prolonged exposure of 26 to
aqueous NaOH at temperatures up to 120 °C, however, gave
primarily recovered starting material and no thioformyl-
pyrrole or formylpyrrole products.16 It is known that N-alkyl
thiazolium salts such as thiamine are readily attacked by
hydroxide at C2 to give N-formyl enethiolates.17 We sus-
pected that activation of our system as an N-alkyl thiazolium
salt could lead, after hydrolysis of the N-formyl group, to
the corresponding N-alkyl 2-thioformylpyrrole. N-Benzyl-
ation of 26 proceeded slowly but smoothly to give thiazolium
Scheme 3. Synthesis and Hydrolysis of Thiazolium Salt 27
salt 27 in 71% yield (Scheme 3). Treatment of 27 with excess
aqueous NaOH at temperatures up to 120 °C gave small
amounts (<5%) of N-benzyl 2-formylpyrrole 28 along with
a complex mixture of unidentified products. We suspected
that the intermediate enethiolate A may be unstable under
the reaction conditions. S-Methylation of A would give an
intermediate sulfide B, which could undergo hydroxide
addition/methylthiolate elimination to give intermediate C,
which in turn should lead to N-benzyl pyrrole 28 after
hydrolysis of the N-formyl group in analogy with the
oxazole-based substrates. Exposure of 27 to 3 equiv of NaOH
and 1 equiv of MeI at room temperature quickly gave the
S-methylated intermediate B as detected by LC-MS analy-
sis.18 Subsequent addition of excess 6 N NaOH and heating
at 70 °C for 0.5 h completely converted B to an intermediate
corresponding to C by LC-MS analysis, formed as a 2:1
mixture of isomers. Further heating at 120 °C for 17 h
effected cleavage of the N-formyl group and cyclization to
give N-benzyl pyrrole 28 in 64% yield.
In conclusion, we have described a unique two-step
methodology for the synthesis of 5-monosubstituted and 4,5-
disubstituted 2-formylpyrroles. The use of readily available
starting materials and reagents and the operationally simple
reaction conditions make this an attractive route for as-
sembling structurally diverse 2-formylpyrroles. Although this
report makes use of the aldol reaction of lithium enolates
with 4-formyloxazole (2) for incorporation of the oxazole
moiety, in principle numerous alternative aldol reaction
conditions may be employed. In addition, the direct olefin-
ation of 2 with ketone-derived olefination reagents represents
an alternative strategy for accessing the hydrolysis precur-
sors.19 Although application of the methodology to direct
(12) Attempts to effect direct conversion of 6 to 4 by treatment with
aqueous base led primarily to retro-aldol reaction and only traces of 4.
(13) Handbook of Organopalladium Chemistry for Organic Synthesis;
Negishi, E., Ed.; John Wiley & Sons: New York, 2002; Vols. 1 and 2.
(14) Byers, J. H.; Zhang, Y. Heterocycles 2002, 57, 1293-1297.
(15) (a) Woodward, R. B.; Ayer, W. A.; Beaton, J. M.; Bickelhaupt, F.;
Bonnett, R.; Buchschacher, P.; Closs, G. L.; Dutler, H.; Hannah, J.; Hauck,
F. F.; Ito, S.; Langemann, A.; Le Goff, E.; Leimgruber, W.; Lwowski, W.;
Sauer, J.; Valenta, Z.; Volz, H. J. Am. Chem. Soc. 1960, 82, 3800-3802.
(b) Wilton-Ely, J. D. E. T.; Pogorzelec, P. J.; Honarkhah, S. J.; Reid, D.
H.; Tocher, D. A. Organometallics 2005, 24, 2862-2874.
(16) Hydrolysis of thioaldehydes to aldehydes: Muraoka, M.; Yamamoto,
T.; Enomoto, K.; Takeshima, T. J. Chem. Soc., Perkin Trans. 1 1989, 1241-
1252.
(18) For an example of N-alkyl thiazolium hydrolysis/intramolecular
S-alkylation, see: Federsel, H.-J.; Glasare, G.; Ho¨gstro¨m, C.; Weistal, J.;
Zinko, B.; O¨ dman, C. J. Org. Chem. 1995, 60, 2597-2606.
(19) Korotchenko, V. N.; Nenajdenko, V. G.; Balenkova, E. S.; Shastin,
A. V. Russ. Chem. ReV. 2004, 73, 957-989.
(17) (a) El Hage Chahine, J.-M.; DuBois, J.-E. J. Am. Chem. Soc. 1983,
105, 2335-2340. (b) Bordwell, F. G.; Satish, A. V. J. Am. Chem. Soc.
1991, 113, 985-990.
Org. Lett., Vol. 9, No. 10, 2007
1877

hydrolysis of thiazole or N-benzyl thiazolium substrates failed
to give the desired thioformylpyrrole, S-methylation of an
intermediate enethiolate allowed the synthesis of an N-benzyl
2-formylpyrrole. This methodology should prove useful for
the synthesis of pharmaceutical intermediates and natural
products.
Supporting Information Available: Experimental pro-
cedures, characterization data, and copies of 1H and 13C NMR
spectra for 2-4, 6-24, and 26-28. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL070340Q
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