Controlled oxidation of pyrroles: Synthesis of highly functionalized γ-lactams

Article abstract of DOI:10.1021/ol400491p

The oxidation of pyrroles usually leads to uncontrolled polymerization and decomposition. To overcome this problem, the controlled oxidation of substituted pyrroles with Dess-Martin periodinane is reported. This strategy yields a range of 5-aroyloxypyrrol

Full text of DOI:10.1021/ol400491p

ORGANIC
LETTERS
2013
Vol. 15, No. 7
1714–1717
Controlled Oxidation of Pyrroles:
Synthesis of Highly Functionalized
γ‑Lactams
James K. Howard,† Christopher J. T. Hyland,†,‡ Jeremy Just,† and Jason A. Smith*,†
School of Chemistry, University of Tasmania, Hobart, Tasmania, Australia,
and School of Chemistry, University of Wollongong, NSW, Australia
Jason.Smith@utas.edu.au
Received February 23, 2013
ABSTRACT
The oxidation of pyrroles usually leads to uncontrolled polymerization and decomposition. To overcome this problem, the controlled oxidation
of substituted pyrroles with Dess-Martin periodinane is reported. This strategy yields a range of 5-aroyloxypyrrolinones.
Dearomatization of substituted aromatic systems is
a powerful and widely used synthetic strategy for the
preparation of carbo- and heterocyclic rings.1,2 This
transformation may be achieved by numerous methods
including enzymatic,3 photochemical,4 radical,5 transition-
metal mediated,6 reductive7 (Birch reduction/catalytic
hydrogenation), oxidative,8 or electrochemical9 approaches.
While these processes are most widely applied to aromatic
hydrocarbons, the dearomatization of aromatic heterocycles
is a powerful method to prepare nonaromatic heterocycles
that are ubiquitous in bioactive molecules and natural prod-
ucts. Aromatic heterocycles are attractive building blocks due
to their stability and ready availability. This can be exempli-
fied by the ability of pyrroles to undergo substitution fol-
lowed by partial reduction to pyrrolines10ꢀ12 or catalytic
hydrogenation to pyrrolidines (Scheme 1, a and b).13 The
importance of these reductive methods is highlighted by their
application in the synthesis of natural products and bioactive
molecules, such as hyacinthacine A1 (1a),14 1-epiaustraline
(1b),15 and anisomycin (2).10b,16
† University of Tasmania.
‡ University of Wollongong.
(1) Roche, S. P.; Porco, J. A., Jr. Angew. Chem., Int. Ed. 2011, 50, 4068.
(2) Donohoe, T. J.; Garg, R.; Stevenson, C. A. Tetrahedron: Asym-
metry 1996, 7, 317.
(3) (a) Sono, M.; Roach, M. P.; Coulter, E. D.; Dawson, J. H. Chem.
Rev. 1996, 96, 2841. (b) Jerina, D. M.; Daly, J. W. Science 1974, 185, 573.
(4) For an example of [2þ3] photocycloadditions, see: Cornelisse, J.
Chem. Rev. 1993, 93, 615. For an example of a [2þ2] cycloaddition, see:
Hoffmann, N.; Pete, J-. P. Synthesis 2001, 8, 1236. For a thermal example,
see: Liu, R. S. H.; Edman, J. R. J. Am. Chem. Soc. 1968, 90, 213.
€
€
(5) Aulenta, F.; Berndt, M.; Brudgam, I.; Hartl, H.; Sorgel, S.;
(10) (a) Gourlay, B. S.; Ryan, J. H.; Smith, J. A. Beilstein J. Org.
Chem. 2008, 4, 3. (b) You, H. T.; Grosse, A. C.; Howard, J. K.; Hyland,
C. J. T.; Just, J.; Molesworth, P. P.; Smith, J. A. Org. Biomol. Chem.
2011, 9, 3948.
(11) Ketcha, D. M.; Carpenter, K.; Zhou, Q. J. Org. Chem. 1991, 56,
1318.
(12) Donohoe, T. J.; Thomas, R. E. Chem. Record 2007, 7, 180.
(13) Bond, T. J.; Jenkins, R.; Taylor, P. C. Tetrahedron Lett. 1994, 35,
9263. Wang, D.-S.; Ye, Z.-S.; Chen, Q-A; Zhou, Y.-G.; Jefford, C. W.
Curr. Org. Chem. 2000, 4, 205. Yu, C.-B.; Fan, H.-J.; Duan, Y. J. Am.
Chem. Soc. 2011, 133, 8866.
Reißig, H.-U. Chem.;Eur. J. 2007, 13, 6047.
ꢀ
(6) Rosillo, M.; Domınguez, G.; Perez-Castells, J. Chem. Soc. Rev.
2007, 36, 1589. Garcıa-Fortanet, J.; Kessler, F.; Buchwald, S. L. J. Am.
Chem. Soc. 2009, 131, 6676. Harman, W. D. Chem. Rev. 1997, 97, 1953.
(7) For a review on the Birch reduction, see: Mander, L. N. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon:
Oxford, 1991; Vol. 8, p 489. For a recent review on the asymmetric
reduction of aromatics and heteroaromatics, see: Wang, D.-S.; Chen,
Q.-A.; Lu, S.-M.; Zhou, Y.-G. Chem. Rev. 2012, 112, 2557.
(8) PouysEgu, L.; Deffieux, D.; Quideau, S. Tetrahedron 2010, 66,
2235. Jackson, S. K.; Wu, K. L.; Pettus, T. R. Biomimetic Organic
Synthesis 2011, 723–749.
(14) Donohoe, T. J.; Sintim, H. O.; Hollinshead, J. J. Org. Chem.
2005, 70, 7297.
(15) Donohoe, T. J.; Sintim, H. O. Org. Lett. 2004, 6, 2003.
(16) Schumacher, D. P.; Hall, S. S. J. Am. Chem. Soc. 1982, 104, 6076.
(9) Yoshida, K. The Chemistry of Functional Groups, Supplement C;
Patai, S., Rappoport, Z., Eds.; John Wiley & Sons, Ltd.: Chichester, U.K.,
1983; p 221.
r
10.1021/ol400491p
Published on Web 03/25/2013
2013 American Chemical Society

yields as a result of significant accompanying decomposi-
tion. Recently Lubricks et al. have demonstrated a con-
trolled palladium catalyzed acetoxylation of pyrrole
with phenyliodonium acetate.25 During their investiga-
tions they observed the formation of pyrrole-2,5-diones
and 5-functionalized pyrrolidin-2-ones as overoxidation
productions in some instances when the reaction was
carried out at elevated temperatures. Alp et al. also reports
the oxidation of N-tosylpyrrole with 1 equiv of pheny-
liodine bis(trifluoroacetate) (PIFA) to reveal a γ-lactam
species, and a 5-hydroxy-γ-lactam when reacted with
2 equiv of PIFA.26 However, this reaction was only
demonstrated with a single electron-poor example and it
has also been reported by Kita et al. that the oxidation of
electron-rich pyrroles with PIFA/Lewis acid combinations
results in the formation of bipyrroles via Scholl oxidation
rather than the formation of pyrrolinones.27
We envisaged that through judiscious choice of hyper-
valent iodine reagent and reaction conditions that selective
oxidation of readily available electron-rich pyrroles28 to
γ-lactams should be possible. Such a method would avoid
the limitation of using a sulfonyl protecting group at
nitrogen and provide a compliment to current reductive
methods for the synthetic manipulation of pyrroles
(Scheme 1, d). Herein, we report a metal-free, controlled
oxidation of pyrroles with the Dess-Martin periodinane
reagent yielding 5-aroyloxy-γ-lactams.
As a compliment to these reductive methods, the oxida-
tion of pyrrole has the potential to yield the important
γ-lactam skeleton. The γ-lactam skeleton is a building
block for synthesis17 and possesses useful biological
activity.18 For example, Levitiracetam (3) is currently used
in the management of epileptic disorders.19 While there are
numerous methods for the synthesis of γ-lactams, these
generally require the synthesis of specific acyclic pre-
cursors.20 As such, there is still a need for more general
methods to construct γ-lactams from simple, readily avail-
able aromatic starting materials.
Scheme 1. Potential Dearomatization Reactions of Pyrroles
Initial experiments following the PIFA method of Alp26
with N-methyl pyrrole resulted in the formation of a
complex mixture of products in poor and inconsistent
yields due to decomposition of the starting material. This
outcome was attributed to the high electron density of the
N-alkyl pyrrole in comparison to the N-tosylated species.
Due to the nonselective reactivity of PIFA, alternate
hypervalent iodine oxidants were screened and Dess-
Martin periodinane was found to be effective. Interest-
ingly, as part of Kita’s bipyrrole method development,
they found Dess-Martin periodinane to cause decomposi-
tion of electron-rich pyrroles.27 However, we found that
when N-methylpyrrole (4a) was added slowly to 2.5 equiv
of Dess-Martin periodinane at 0 °C polymerization was
prevented and the 5-aroyloxy-γ-lactam 6a was formed as
the major product after a reductive workup (Table 1). To
our surprise the compound contained an ortho-iodoben-
zoyloxy moiety at C5 and only trace amounts of a 5-acet-
oxy-derivative were observed in the crude NMR. Unlike
other oxidations with Dess-Martin periodinane, we see the
incorporation of an organic fragment of the oxidant into
the product.29
Unfortunately, in contrast to the efficient reductive
processes, controlled oxidations of pyrrole have been
hampered by the propensity for polymerization to occur
under oxidizing or acidic conditions, yielding polypyrrole
(Scheme 1, c).21 The handful of reports on the oxidation of
pyrroledemonstratedthatpyrrolinonescan be obtainedby
the use of singlet oxygen22,23 and peroxides.24 These have
not been widely adopted as synthetic protocols due to low
(17) For selected examples, see: (a) Shao, C.; Yu, H.-J.; Wu, N.-Y.;
Tian, P.; Wang, R.; Feng, C.-G.; Lin, G.-Q. Org. Lett. 2011, 13, 788.
(b) Craig, D.; Hyland, C. J. T.; Ward, S. Synlett 2006, 13, 2142.
(18) (a) Kiren, S.; Hong, X.; Levertt, C. A.; Padwa, A. Tetrahedron
2009, 65, 6720. (b) Dubernet, M.; Caubert, V.; Guillard, J.; Massuard,
M. C. Tetrahedron 2005, 61, 4585. (c) Clayden, J.; Watson, D. W.;
Helliwel, M.; Chambers, M. Chem. Commun. 2003, 2582. (d) Alizadeh,
A.; Rezvanian, A.; Zhu, L. G. Helv. Chim. Acta 2007, 90, 2414. (e) Enz,
A.; Feuerbach, D.; Frederiksen, M. U.; Gentsch, C.; Hurth, K.; Muller,
W.; Nozulak, J.; Roy, B. L. Bioorg. Med. Chem. Lett. 2009, 19, 1287.
(19) S. Shorvon, S. The Lancet 2001, 358, 1885.
(20) For example, see: Craig, D.; Hyland, C. J. T.; Ward, S. E. Chem.
Commun. 2005, 3439.
We postulate that the slow addition of pyrrole limits
polymerization due to its rapid consumption in the
(21) Myers, R. E. J. Electron. Mater. 1986, 15, 61. MacDiarmid,
A. G. Synth. Met. 1997, 84, 27. Kang, H. C.; Geckeler, K. E. Polymer
2000, 41, 6931. Calvo, P. A.; Rodriguez, J.; Grande, H.; Mecerreyes, D.;
Pomposo, J. A. Synth. Met. 2002, 126, 111. Chakrabarti, S.; Banerjee,
D.; R. Bhattacharyya, R. J. Phys. Chem. B 2002, 106, 3061.
(22) Alberti, M. N.; Vougioukalakis, G. C.; Orfanopoulos, M.
J. Org. Chem. 2009, 74, 7274.
(23) (a) Chierici, L.; Gardini, G. P. Tetrahedron 1966, 22, 53.
(b) Bocchi, V.; Chierici, L.; Gardini, G. P. Tetrahedron 1970, 26, 4073.
(24) Greger, J. G.; Yoon-Miller, S. J. P.; Bechtold, Flewelling, S. A.;
MacDonald, J. P.; Downey, C. R.; Cohen, E. A.; Pelkey, E. T. J. Org.
Chem. 2011, 76, 8203.
(25) Lubriks, D.; Sokolovs, I.; Suna, E. Org. Lett. 2011, 13, 4324.
€
€
(26) Alp, C.; Ekinci, D.; Gultekin, M. S.; Senturk, M.; Sahin, E.;
€
ꢁ
Kufrevioglu, O. I. Bioorg. Med. Chem. 2010, 18, 4468.
(27) Dohi, T.; Morimoto, K.; Maruyama, A.; Kita, Y. Org. Lett.
2006, 8, 2007.
(28) (a) Gourlay, B. S.; Molesworth, P. P.; Ryan, J. H.; Smith, J. A.
Tetrahedron Lett. 2006, 47, 799. (b) Rivera, S.; Bandyopadhyay, D.;
Banik, B. K. Tetrahedron Lett. 2009, 50, 5445.
(29) Zhdankin, V. V. J. Org. Chem. 2011, 76, 1185.
Org. Lett., Vol. 15, No. 7, 2013
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1
workup. Attempts to follow the reaction by H NMR
presence of excess oxidant. Using 1 equiv of oxidant with
N-methylpyrrole results in the formation of the same
5-aroyloxy-γ-lactam 6a in 31% yield instead of a mono-
oxidized product, indicating that the intermediate formed
is more reactive and consumed faster than the starting
pyrrole. It was also shown that trace amounts of water
helped facilitate the reaction, as demonstrated in the
comparison of bench grade solvent to anhydrous solvent
under a nitrogen atmosphere (81% yield compared to 65%
under anhydrous conditions). This is similar to previous
oxidations with Dess-Martin periodinane in which trace
amounts of water can help to promote the oxidation of
alcohols.30
and IR to observe either an iodonium intermediate or the
2,5-diaroyloxypyrrole intermediates were not successful,
as only the starting material and the resonances of the
pyrrolinone system were visible. This indicates that the
reaction intermediates are short-lived on the NMR time
scale and that the 2,5-diaroyloxypyrrole 9 intermediate is
hydrolyzed in situ, as the product pyrrolinone 6a had
formed before aqueous workup.
Scheme 2. Proposed Mechanism of Oxidation with Dess-Martin
Periodinane
A range of N-alkyl pyrroles (4) were oxidized with the
Dess-Martin periodinane reagent (5) under our conditions
to yield the corresponding 5-aroyloxy-γ-lactams 6 in good
to excellent yield (Table 1). Both N-alkyl and N-aryl
substituents are tolerated, and the parent pyrrrole (4h)
gives the lactam 6h in a 56% yield. Compound 6g was
formed as a 1:1 mixture of diastereoisomers. Compounds
of this type, which can be synthesized in two steps from
amino esters, could be used for the synthesis of the anti-
epileptic drug levitiracetam and derivatives.
Table 1. Oxidation of Pyrroles to 5-Aroyloxy-γ-lactams with
Dess-Martin Periodinanea
While the proposed mechanism is plausible, there is one
clear curiosity. The addition of trace amounts of water
to the Dess-Martin periodinane is believed to aid in the
dissociation of an acetate group from the iodine core
making iodine more electrophilic.30 This would help pro-
mote the attack of the electron-rich pyrroles to form an
iodonium intermediate. However, what is not clear is why
migration of the benzoate O-atom would be favored al-
most exclusively over one of the acetate groups. Trace
amounts of the acetoxy species are always observed; how-
ever, this is proposed to form from the in situ generation
of acetic acid, which exchanges for the benzoate group.
Support for this hypothesis is seen when the benzoate
lactam is stirred in AcOH/CH2Cl2 to slowly produce the
acetoxylated product. An alternative mechanism would be
the direct attack of the electron-rich pyrrole on the benzo-
ate O-atom of the Dess-Martin periodinane; however,
there is no precedent for such a reaction.
The Dess-Martin periodinane is commonly used to
oxidize primary and secondary alcohols to their corre-
sponding carbonyls,29,30 so, as a competitive oxidation,
N-(2-hydroxyethyl)pyrrole (9) was subjected to the oxida-
tive reaction conditions. Interestingly, the 5-aroyloxy-γ-
lactam 10 with the alcohol functionality still intact was the
major product when treated with 1 equiv of oxidant. This
gives further evidence to the reactivity of pyrroles toward
Dess-Martin periodinane, indicating a selectivity over
alcohols (Scheme 3).
Based upon the results of Lubricks25 that showed pyr-
roles react with phenyliodonium acetate to form an iodo-
nium intermediate, we postulated a similar mechanism
(Scheme 2). The electrophilic aromatic substitution of
pyrrole onto the iodine atom of Dess-Martin periodinane
would give a similar intermediate 7 to that reported by
Lubriks. This can be followed by a selective migration of
the oxygen atom of the benzoate onto C2 of the pyrrole to
give 8. Once formed, the electron-rich intermediate 8 is
more reactive than the starting pyrrole and substitution is
repeated to form 2,5-diaroyloxypyrrole 9 as an intermedi-
ate that is either hydrolyzed in situ or upon reductive
(30) Meyer, S.; Schreiber, S. J. Org. Chem. 1994, 7549.
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Org. Lett., Vol. 15, No. 7, 2013

The resulting 5-aryloxy-R,β-unsaturated-γ-lactams
6aꢀh are highly functionalized compounds, and to demo-
nstrate their potential utility in synthesis we carried out a
series of reactions typical of the functionality present
(Scheme 5). The aroyloxy group can be exchanged with
MeOH/HCl to generate the 5-methoxy-γ-lactam31 14,
while simply heating the compound in a solution of
methanol furnishes the same product but in a reduced
yield of 48%. The aminal group can be reduced with
Scheme 3. Chemoselective Oxidation of Pyrrole over a Primary
Alcohol with Dess-Martin Periodinane
BF3 OEt2/Et3SiH to yield the 5-unsubstituted-γ-lactam 15.31
3
The method has also been expanded to the oxidation of
2-substituted pyrroles. Initial oxidations of 2-benzyl-N-
methyl pyrrole (11a, R = Ph) proceeded to give the
5-benzyl-5-hydroxy-γ-lactam 12 in only 35% isolated
yield. As this decrease in yield was due to the instability
of 12 during isolation, an attempted in situ hydroxyl group
Scheme 5. Reaction of 5-Aroyloxypyrrolinones
reduction with BF3 OEt2/Et3SiH was employed. How-
3
ever, alkene 13a (R = Ph) was provided in 89% yield
(Scheme 4). This two-step methodology was also applied
to2-ethyl-N-methylpyrrole(11, R = CH3), resulting inthe
corresponding product (13, R = CH3) in 96% yield. The
formation of the E isomer 13a was supported by NMR
witha signal observed between the N-methylgroupand the
proton of the exocyclic alkene in the nOe.
In conclusion, we have developed a new method for the
controlled oxidation of N-alkylpyrroles resulting in high
yields of 5-aroyloxy-γ-lactams. These lactams are highly
functionalized and therefore are excellent building blocks
for synthesis. Further investigations to expand the sub-
strate scope of the controlled oxidation with the Dess-
Martin periodinane reagent as well as mechanistic studies
are underway in our laboratory.
Scheme 4. Oxidation of 2-Alkyl-N-methyl Pyrroles
Acknowledgment. The authors wish to thank The Uni-
versity of Tasmania for funding. J.K.H. thanks the Uni-
versity of Tasmania for a Tasmanian Graduate Research
Scholarship. The authors also thank Dr. James Horne of
the Central Science Laboratory, University of Tasmania
for assistance with nOe experiments.
The extension of the oxidation to other substitution
patterns was not as selective with 3-benzyl-N-methylpyr-
role yielding a 3:2 mixture of isomers (see Supporting
Information for details) while 2,5-dialkylpyrroles under-
went decomposition.
Supporting Information Available. Experimental de-
tails and spectral 1H NMR of compounds 6aꢀg, 10, 12,
13aꢀb, 14, and 15. This material is available free of charge
via the Internet at http://pubs.acs.org.
(31) Issa, F.; Fischer, J.; Turner, P.; Coster, M. J. J. Org. Chem. 2006,
71, 4703.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 7, 2013
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