Synthesis of 2,4-Disubstituted pyrroles by rearrangements of 2-furanyl carbamates

Article abstract of DOI:10.1021/ol900059e

2,4-Disubstituted pyrroles were synthesized by an oxidative rearrangement of a furanyl carbamate followed by sequential reaction of the resulting 5-methoxypyrrol-2(5H)-one with different alkyl lithiates. The final step of the procedure involves heating th

Full text of DOI:10.1021/ol900059e

ORGANIC
LETTERS
2009
Vol. 11, No. 6
1233-1235
Synthesis of 2,4-Disubstituted Pyrroles
by Rearrangements of 2-Furanyl
Carbamates
Sezgin Kiren, Xuechuan Hong, Carolyn A. Leverett, and Albert Padwa*
Department of Chemistry, Emory UniVersity, Atlanta, Georgia, 30322
chemap@emory.edu
Received January 12, 2009
ABSTRACT
2,4-Disubstituted pyrroles were synthesized by an oxidative rearrangement of a furanyl carbamate followed by sequential reaction of the
resulting 5-methoxypyrrol-2(5H)-one with different alkyl lithiates. The final step of the procedure involves heating the ring opened 1-methoxy-
5-oxopentylcarbamate with a primary amine.
The biological activity of substituted pyrroles has made them
a focus of medicinal chemistry over the years.1 Pyrroles occur
Scheme 1
in numerous pharmacologically active natural and unnatural
products.2 Additionally, functionalized pyrroles represent
building blocks of natural tetrapyrrole pigments, such as
porphorobilinogen or bilirubin, and of various other natural
products and their analogues.3 For more than a century, many
diverse methods have been developed to prepare pyrroles
with various ring substitution patterns,4 including the classical
Hantzsch, Knorr and Paal-Knorr procedures.5 We describe
and C4-positions using alkyl lithiates and aromatization can
be accomplished under nonaqueous conditions.
here, the details of a new method for preparing 2,4-
disubstituted pyrroles starting from a furanyl carbamate (i.e.,
1) (Scheme 1). The advantage of this methodology is that
various substituents can be selectively introduced at the C2
Some years ago, we reported a useful protocol for the
preparation of hydroxylated piperidine alkaloids6 by making
use of the aza-Achmatowicz oxidation.7 This earlier work
prompted us to explore the related oxidative rearrangement
of furanyl carbamate 1 into 5-methoxypyrrol-2(5H)-one (2).
5-Alkoxypyrrol-2(5H)-ones (4) exhibit a wide range of
interesting pharmacological properties,8 have been used as
key intermediates in the synthesis of various alkaloids,9 and
(1) (a) Balme, G. Angew Chem., Int. Ed. 2004, 43, 6238. Pyrroles: (b)
Jones, R. A., Ed. The Chemistry of Heterocyclic Compounds; Wiley: New
York, 1996; Vol 48, Part 1.
(2) Falk, H. The Chemistry of Linear Oligopyrroles and Bile Pigments;
Springer: Wien, 1989; p 355.
(3) Sunberg, R. J. In ComprehensiVe Heterocyclic Chemistry; Bird,
C. W., Cheesemen, G. W. H., Eds.; Pergamon Press: Oxford, 1984; Vol. 4,
p 331.
(6) (a) Harris, J. M.; Padwa, A. J. Org. Chem. 2003, 68, 4371. (b)
Leverett, C. A.; Cassidy, M. P.; Padwa, A. J. Org. Chem. 2006, 71, 8591.
(7) Ciufolini, M. A.; Hermann, C. Y. W.; Dong, Q.; Shimizu, T.;
Swaminathan, S.; Xi, N. Synlett. 1998, 105.
(4) Gribble, G. W. In ComprehensiVe Heterocyclic Chemistry II;
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Elsevier: Oxford,
1996; Vol 2, p 207.
(8) (a) Wooldridge, T. A.; Lightner, D. A. J. Heterocycl. Chem. 1977,
14, 1283. (b) Vitillo, B.; Buniva, G.; Bernareggi, A.; Assandri, A.; Perazzi,
A.; Fuccella, L. M.; Palumbo, R. Int. Clin. Parmacol. Ther. Toxicol. 1984,
22, 273.
(5) (a) Schmuck, C.; Rupprecht, D. Synthesis 2007, 3095. (b) Ferreira,
V. F.; deSouza, M. C. B. V.; Cunha, A. C.; Pereira, L. O. R.; Ferreira,
M. L. C. Org. Prep. Proced. Int. 2001, 33, 413.
10.1021/ol900059e CCC: $40.75
Published on Web 02/20/2009
2009 American Chemical Society

are also suitable precursors for the preparation of unusual
γ-amino acids such as statine and its analogues.10 The
chemistry of this unique pyrrolidinone ring has been explored
by a number of research groups.11 Because of its multifunc-
tional core, this heterocyclic system can take part in several
stereoselective transformations such as conjugate addition,12
cycloadditions,13 acyliminium ion chemistry,14 and allylic
substitutions15 (Scheme 2).
furanyl carbamate (1) to give 5-methoxypyrrol-2(5H)-one
(2), (ii) conjugate addition of a cuprate reagent to the C4
position of the heterocyclic ring, (iii) further reaction of the
resulting 2-methoxy-5-oxopyrrolidine 11 with an alkyl
lithium to furnish a ring-opened alkyl 1-methoxy-5-oxopen-
tylcarbamate 12 and (iv) cyclization with a primary amine
under microwave conditions to afford the pyrrole derivative.
The 5-methoxypyrrol-2(5H)-one required for this methodol-
ogy was readily prepared by the addition of I2 to a solution
of the furanyl carbamate 1 in aqueous acetone which
contained a 2 mol excess of NaHCO3. More than likely the
reaction proceeds Via intermediates 8 and 9 as indicated in
Scheme 3. The initially formed 2-hydroxy-5-oxo-2,5-dihy-
Scheme 2
Scheme 3
Besides some specialized methodologies,16 the majority
of synthetic approaches used for the preparation of 5-alkoxy-
pyrrol-2(5H)-ones are based on the cyclization of R,ꢀ-
unsaturated keto amides,17 amination reactions of the cor-
responding γ-lactones,18 Grignard addition to maleimide
derivatives,19 and the photosensitized oxygenation of pyr-
roles,20 diazepines21 and 2-furyl carbamates.22
dro-1H-pyrrole 10 was smoothly converted into the corre-
sponding methoxy derivative 2 by treatment with methyl
iodide and silver (I) oxide in CH2Cl2 at 25 °C. The yield of
the resulting 5-methoxypyrrol-2(5H)-one from the furanyl
carbamate is quite good (ca 85%) and the final product is
easily isolated by column chromatography on silica gel.
The conjugate addition of various cuprates to the R,ꢀ-
unsaturated lactam system of 2 proceeded in 60-92% yield
with high stereoselectivity. The 1H NMR spectra of the crude
product only showed the presence of a single trans-addition
We now describe a four-step synthesis of 2,4-disubstituted
pyrroles (3) involving (i) an oxidative rearrangement of a
(9) (a) Klaver, W. J.; Hiemstra, H.; Speckamp, W. N. J. Am. Chem.
Soc. 1989, 111, 2588. (b) Newcombe, N. J.; Ya, F.; Vijin, R. J.; Hiemstra,
H.; Speckamp, W. N. J. Chem. Soc., Chem. Commun. 1994, 767. (c)
Speckamp, W. N.; Newcombe, N. J.; Hiemstra, H.; Ya, F.; Vijin, R. J.;
Koot, W. J. Pure Appl. Chem. 1994, 66, 2163. (d) Casiraghi, G.; Spanu,
P.; Rassu, G.; Pinna, L.; Ulgheri, F. J. Org. Chem. 1994, 59, 2906. (e)
Griffart-Brunet, D.; Langois, N. Tetrahedron Lett. 1994, 35, 119.
(10) (a) Jouin, P.; Castro, B. J. Chem. Soc., Perkin Trans. 1 1987, 1177.
(b) Ma, D.; Ma, J.; Ding, W.; Dai, L. Tetrahedron Asymmetry 1996, 7,
2365.
1
product in all cases. The assignment was based on the H
NMR vicinal coupling constant of H5. In a trans-lactam this
coupling is 0-1 Hz, whereas a cis-lactam has a coupling of
5-6 Hz.23 The products obtained from the cuprate additions
(11) (a) Romo, D.; Meyers, A. I. Tetrahedron 1991, 47, 9503. (b)
Meyers, A. I.; Snyder, L. J. Org. Chem. 1992, 57, 3814. (c) Farina, F.;
Martin, M. V.; Paredes, M. C. Synthesis 1973, 167. (d) Ma, S.; Xie, H.
Org. Lett. 2000, 2, 3801.
(18) (a) Shiraki, R.; Sumino, A.; Tadano, K. I.; Ogawa, S. J. Org. Chem.
1996, 61, 2845. (b) Farina, F.; Martin, M. V.; Paredes, M. C. Heterocycles
1984, 22, 1733. (c) Gill, G. B.; James, G. D.; Oates, K. V.; Pattenden, G.
J. Chem. Soc., Perkin Trans. 1 1993, 2567. (d) Kotera, M.; Roupioz, Y.;
Defrancq, E.; Bourdat, A. G.; Garcia, J.; Coulombeau, C.; Lhomme, J.
Chem.-Eur. J. 2000, 6, 4163.
(12) (a) Jimenez, M. D.; Ortega, R.; Tito, A.; Farina, F. Heterocycles
1988, 27, 173. (b) Koot, W. J.; Hiemstra, H.; Speckamp, W. N. Tetrahedron
Asymmetry 1993, 4, 1941.
(13) (a) Koot, W. J.; Hiemstra, H.; Speckamp, W. N. J. Org. Chem.
1992, 57, 1059. (b) Cooper, D. M.; Grigg, R.; Hargreaves, S.; Kennewell,
P.; Redpath, J. Tetrahedron 1995, 51, 7791.
(19) Bartfeld, H. D.; Flitsch, W. Chem. Ber. 1973, 106, 1423.
(20) Lightner, D. A.; Bisacchi, G. S.; Norris, R. D. J. Am. Chem. Soc.
1976, 98, 802.
(14) Koot, W. J.; Hiemstra, H.; Speckamp, W. N. Tetrahedron Lett.
1992, 33, 7969.
(15) Cuiper, A. D.; Kellogg, R. M.; Feringa, B. L. Chem. Commun.
1998, 655.
(21) (a) Kurita, J.; Kojima, H.; Tsuchiya, T. Chem. Parm. Bull. 1986,
34, 4871. (b) Kurita, J.; Kojima, H.; Tsuchiya, T. Heterocycles 1984, 22,
721.
(16) (a) McKennis, H.; Bowman, E. R.; Quin, L. D.; Denney, R. C.
J. Chem. Soc., Perkin Trans. 1 1973, 2046. (b) Veronese, A. C.; Callegari,
R.; Basato, M.; Valle, G. J. Chem. Soc., Perkin Trans. 1 1994, 1779. (c)
Arzoumanian, H.; Jean, M.; Nuel, D.; Garcia, J. L.; Rosas, N. Organome-
tallics 1997, 16, 2726.
(22) Kakushijin, K.; Suzuki, R.; Kawaguchi, N.; Tsuboi, Y.; Furakawa,
H. Chem. Pharm. Bull. 1986, 34, 2049.
(23) Koot, W. J.; Van Ginkel, R.; Kranenburg, M.; Hiemstra, H.;
Louwrier, S.; Moolenaar, M. J.; Speckamp, W. N. Tetrahedron Lett. 1991,
32, 401.
(17) Lightner, D. A.; Low, L. K. J. Heterocycl. Chem. 1972, 9, 167.
1234
Org. Lett., Vol. 11, No. 6, 2009

were then used in the next step which consisted of treating
the 2-methoxy-3-alkyl substituted 5-oxopyrrolidinone 11 with
an alkyl lithium reagent to give the ring opened 1-methoxy-
5-oxopentylcarbamate 12. The results for the conjugate
addition-alkyl lithiation reaction of differently substituted
systems in THF at -78 °C are summarized in Table 1. From
pyrrole 3j. However, when 12a is heated in toluene in the
presence of a CSA/quinoline catalyst, only the Boc-pyrrole
3k was formed in 76% yield.
Interestingly, when the reaction was carried out in a one-
pot fashion using 5-oxopyrrolidinone 11c and vinyl lithium
followed by heating with benzyl amine, the only product
that could be isolated corresponded to N-benzyl-4-n-butyl-
2-methyl-1H-pyrrole (3f). This surprising result can be
explained by the series of reactions outlined in Scheme 5.
Table 1. Conjugate Addition-Alkyl Lithiation Reaction of
5-Methoxypyrrol-2(5H)-one (2)
Scheme 5
entry
R1
yield of 11
R2
allyl
CH3
Ph
yield of 12
a
b
c
d
e
f
t-Bu
Ph
n-C4H9
n-C4H9
CH3
80%
75%
92%
-
80%
-
72%
70%
94%
85%
86%
80%
65%
CH3
2-thienyl
n-C4H9
C2H5
CH3
n-C6H13
g
60%
the table it can be seen that the reaction is quite general: R2
) various alkyl, phenyl or 2-thienyl groups with yields
ranging from 65% to 94%.
The 2,4-disubstituted pyrrole (3) system was then prepared
by heating a mixture of the 1-methoxy-5-oxopentylcarbamate
12 and an appropriate primary amine in the presence of a
trace amount of p-TsOH in a microwave reactor at 150 °C
(Scheme 4). In all cases, the desired 2,4-disubstituted pyrrole
More than likely, the transient vinyl oxypentylcarbamate 13 that
is first formed reacts with excess benzyl amine to eventally give
enamine 14. Protonation of 14 to iminium ion 15 followed by
loss of PhCH2N ) CH2 under the reaction conditions furnishes
16 which is readily isomerized to pyrrole 3f.
Scheme 4
In summary, we have discovered a new and efficient
approach to a variety of 2,4-disubstituted pyrroles based on
an oxidative rearrangement of a furanyl carbamate followed
by sequential reaction of the resulting 5-methoxypyrrol-
2(5H)-one with alkyl lithiates. The final step of the procedure
involves heating the ring opened 1-methoxy-5-oxopentyl-
carbamate with a primary amine. The overall process can
be carried out under mild conditions and complements
existing methods to prepare substituted pyrroles.
Acknowledgment. We appreciate the financial support
provided by the National Science Foundation (CHE-
0742663).
Supporting Information Available: Spectroscopic data
and experimental details for the preparation of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
was obtained in good yield with no evidence of any products
arising from simple hydrolysis or alternatively, by furan
formation. On the other hand, heating an aqueous DMF
solution of 12a (R1 ) Ph; R2 ) n-C4H9) in a microwave
reactor afforded an almost quantitative yield of the NH-
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