Enone-alkyne reductive coupling: A versatile entry to substituted pyrroles

Article abstract of DOI:10.1021/ol201133n

The reductive coupling of enones or enals with alkynes, followed by olefin oxidative cleavage and Paal-Knorr cyclization, provides a versatile entry to a variety of pyrrole frameworks. A number of limitations of alternate entries to the requisite 1,4-dica

Full text of DOI:10.1021/ol201133n

ORGANIC
LETTERS
2011
Vol. 13, No. 13
3289–3291
EnoneÀAlkyne Reductive Coupling: A
Versatile Entry to Substituted Pyrroles
Benjamin B. Thompson and John Montgomery*
Department of Chemistry, University of Michigan, 930 North University Avenue, Ann
Arbor, Michigan 48109-1055, United States
jmontg@umich.edu
Received April 28, 2011
ABSTRACT
The reductive coupling of enones or enals with alkynes, followed by olefin oxidative cleavage and PaalÀKnorr cyclization, provides a versatile
entry to a variety of pyrrole frameworks. A number of limitations of alternate entries to the requisite 1,4-dicarbonyl intermediate are avoided.
Classes of pyrroles that are accessible by this approach include 2,3-, 2,4-, 1,2,3-, 1,2,4-, 2,3,5-, and 1,2,3,5-substituted monocyclic pyrroles as well
as a number of fused-ring polycyclic derivatives.
The pyrrole heterocycle is a key structural element in
numerous natural products, synthetic medicinal agents,
and novel materials.1 In addition to strategies that func-
tionalize an existing pyrrole ring, numerous cyclization
and cycloaddition strategies for constructing complex
pyrroles have been developed.1,2 The PaalÀKnorr con-
densation of 1,4-dicarbonyls with ammonia or primary
amines is among the most versatile and widely used of the
many strategies that have been developed.3 The requisite
1,4-dicarbonyl precursor may be prepared from a linear
precursor by oxidation state adjustments or alterna-
tively, attractive entries via Stetter additions4 or enolate
heterodimerizations5 have been developed in recent years
(Scheme 1). While Stetter reactions and enolate hetero-
dimerizations provide exceptionally versatile entries to 1,
4-dicarbonyls, several notable limitations exist. For exam-
ple, given the undesirable side reactions and self-condensa-
tions that occur with enals and formaldehyde in the Stetter
reaction, aldehyde products are difficult to obtain, thus
limiting access to pyrroles where R2 or R5 = H.6 Similarly,
enolate heterodimerizations that install hydrogen func-
tionality at these positions are plagued by difficulties in
avoiding homocoupling and in developing well-behaved
aldehyde enolization processes.7 Additionally, certain
classes of polycyclic pyrroles are difficult to access by
these methods given complexities in accessing the required
1,4-dicarbonyl substrates.
(1) (a) Fan, H.; Peng, J. N.; Hamann, M. T.; Hu, J. F. Chem. Rev.
2010, 110, 3850–3850. (b) Estevez, V.; Villacampa, M.; Menendez, J. C.
Chem. Soc. Rev. 2010, 39, 4402–4421. (c) Schmuck, C.; Rupprecht, D.
Synthesis 2007, 3095–3110. (d) Bellina, F.; Rossi, R. Tetrahedron 2006,
62, 7213–7256.
(2) (a) St. Cyr, D. J.; Arndtsen, B. A. J. Am. Chem. Soc. 2007, 129,
12366–12367. (b) Morin, M. S. T.; St-Cyr, D. J.; Arndtsen, B. A. Org.
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J. C.; Luh, T. Y. J. Am. Chem. Soc. 2000, 122, 4992–4993. (f) Milgram,
B. C.; Eskildsen, K.; Richter, S. M.; Scheidt, W. R.; Scheidt, K. A. J.
Org. Chem. 2007, 72, 3941–3944. (g) Galliford, C. V.; Scheidt, K. A. J.
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Werner, S.; Iyer, P. S.; Fodor, M. D.; Coleman, C. M.; Twining, L. A.;
Mitasev, B.; Brummond, K. M. J. Comb. Chem. 2006, 8, 368–380. (g)
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Chem. Soc. 2008, 130, 11546–11560. (c) Clift, M. D.; Thomson, R. J. J.
Am. Chem. Soc. 2009, 131, 14579–14583. (d) Clift, M. D.; Taylor, C. N.;
Thomson, R. J. Org. Lett. 2007, 9, 4667–4669.
(6) For alternate reactivity of enals under Stetter-type conditions,
see: (a) Sohn, S. S.; Rosen, E. L.; Bode, J. W. J. Am. Chem. Soc. 2004,
126, 14370–14371. (b) Burstein, C.; Tschan, S.; Xie, X. L.; Glorius, F.
Synthesis 2006, 2418–2439.
(7) For effective heterodimerizations involving aldehyde substrates,
see: Jang, H. Y.; Hong, J. B.; MacMillan, D. W. C. J. Am. Chem. Soc.
2007, 129, 7004–7005.
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2756.
r
10.1021/ol201133n
2011 American Chemical Society
Published on Web 06/09/2011

installed from the enone carbonyl substituent and from
an alkyne substituent. These two positions may both be
functionalized (Table 1, entries 1, 2, and 7), or alterna-
tively, hydrogen substituents may be installed from either a
terminal alkyne (Table 1, entries 3 and 4) or an enal (Table 1,
entries 5 and 6) component. The pyrrole positions remote
from nitrogen (R3 and R4) are most readily installed by
utilizing a β-substituted enone or enal as each of the
examples illustrate (shown here as an R4 substituent). While
hydrogen and aromatic functionality were the primary
focus of this study, aliphatic groups may also be installed
(entry 7). Standard PaalÀKnorr protocols for condensation
of either ammonium acetate or a primary amine under
microwave conditions easily allow the R1 position to be
substituted or unsubstituted.3 Using this simple combina-
tion of substrates (enone/enal, alkyne, and amine), a broad
array of pyrrole substitution patterns are available by choice
of the appropriate substitution pattern in each of the
requisite substrates.
In addition to monocyclic pyrroles obtained by intermo-
lecular reductive couplings, nickel-catalyzed cyclizations of
alkynyl enones provides simple access to more structurally
complex bicyclic and tricyclic pyrroles (Table 2). While
reductive cyclizations directly analogous to the intermole-
cular couplings described above (Table 1) are possible,
alkylative versions of the process are generally more
efficient for intramolecular cases.9 In the alkylative variant,
Ni(COD)2 alone is employed as a catalyst without ligand
additives. Employing dimethylzinc as the reducing agent
then transfers a methyl group to the substrate in the
exocyclic position, in contrast to the delivery of a hydrogen
substituent in the intermolecular, triethylborane protocol.
Since the exocyclic substituents are oxidatively removed in
the conversion to the pyrrole products, the exocyclic group
is of no consequence in the synthesis of pyrroles.
Scheme 1. Representative Entries to Substituted Pyrroles
Given these challenges, we were attracted to the oxidative
cleavage of γ,δ-unsaturated carbonyls as an entry to 1,
4-dicarbonyl precursors for PaalÀKnorr condensations.
Extensive recent work from our laboratory has focused on
developing entries to γ,δ-unsaturated carbonyls from nickel-
catalyzed couplings and cyclizations of enones or enals with
alkynes.8,9 These advances allow hydrogen or non-hydrogen
substituents at any of the positions R2ÀR5 (Scheme 2), and
they provide access to a broad variety of linear or cyclic
frameworks. These features provide considerable flexibility
in the types of pyrroles that could be accessed by such a
strategy. In this communication, we describe representative
entries to various classes of pyrroles by this approach to illu-
strate the pyrrole structural variations that may be accessed.
Scheme 2. 1,4-Dicarbonyls from EnoneÀAlkyne Reductive
Coupling/Oxidative Cleavage
In order to illustrate the general strategy, three intra-
molecular templates were chosen for study. In the first
example (Table 2, entry 1), substrate 6a was employed
to provide cyclization adduct 7a from dimethylzinc-
promoted cyclization. Oxidative cleavage, followed by
PaalÀKnorr condensation with ammonium acetate, pro-
vided access to tricyclic product 9a. Next, substrate 6b with
an all-carbon tether chain was employed to afford product
7b after dimethylzinc-promoted cyclization. Oxidative clea-
vage and ammonium acetate condensation provided bicyc-
lic pyrrole 9b in high yield. Finally, oxazolidinone-derived
substrate 6c was employed in a dimethylzinc-promoted
cyclization to afford adduct 7c. Conversion of this struc-
ture to tricyclic product 9c proceeded smoothly. The range
of fused-ring carbocyclic and heterocyclic arrays prepared
illustrates the variety of pyrrole derivatives that may be
accessed by this approach.10
Our studies began with an investigation of intermolecu-
lar reductive couplings of acyclic enones or enals with
alkynes (Table 1). These substrate combinations provide
the γ,δ-unsaturated carbonyls required for accessing
monocyclic pyrroles 5 with varying substitution patterns
at R1, R2, and R5. As the examples below illustrate, the
positions R2 and R5 adjacent to the pyrrole nitrogen are
(8) For reductive (H atom transfer) variants, see: (a) Herath, A.;
Thompson, B. B.; Montgomery, J. J. Am. Chem. Soc. 2007, 129, 8712–
8713. (b) Herath, A.; Montgomery, J. J. Am. Chem. Soc. 2008, 130,
8132–8133. (c) Herath, A.; Li, W.; Montgomery, J. J. Am. Chem. Soc.
2008, 130, 469–471. (d) Li, W.; Herath, A.; Montgomery, J. J. Am.
Chem. Soc. 2009, 131, 17024–17029. (e) Wang, C.-C.; Lin, P.-S.; Cheng,
C.-H. J. Am. Chem. Soc. 2002, 124, 9696–9697. (f) Chang, H.-T.;
Jayanth, T. T.; Wang, C.-C.; Cheng, C.-H. J. Am. Chem. Soc. 2007,
129, 12032–12041.
(9) For alkylative (alkyl transfer) variants, see: (a) Montgomery,
J.; Savchenko, A. V. J. Am. Chem. Soc. 1996, 118, 2099–2100. (b)
Montgomery, J.; Oblinger, E.; Savchenko, A. V. J. Am. Chem. Soc.
1997, 119, 4911–4920. (c) Montgomery, J.; Chevliakov, M. V.;
Brielmann, H. L. Tetrahedron 1997, 53, 16449–16462. (d) Montgomery,
J.; Seo, J.; Chui., H. M. P. Tetrahedron Lett. 1996, 37, 6839–6842. (e) Ni, Y.;
Kassab, R. M.; Chevliakov, M. V.; Montgomery, J. J. Am. Chem. Soc.
2009, 131, 17714–17718. (f) Ikeda, S.; Sato, Y. J. Am. Chem. Soc. 1994, 116,
5975. (g) Ikeda, S.; Yamamoto, H.; Kondo, K.; Sato, Y. Organometallics
1995, 14, 5015.
While the synthesis of pyrroles was our primary focus,
the 1,4-dicarbonyl species utilized may be readily con-
verted to the corresponding furans in a straightforward
(10) For representative studies of fused ring pyrrole derivatives, see:
(a) Jeannotte, G.; Lubell, W. D. J. Am. Chem. Soc. 2004, 126, 14334–
14335. (b) Jeannotte, G.; Lubell, W. D. J. Org. Chem. 2004, 69, 4656–
4662.
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Org. Lett., Vol. 13, No. 13, 2011

Table 1. Monocyclic Pyrroles from Intermolecular Reductive Couplings
entry
R1
R2
R5
yield (%) of 3
yield (%) of 4
yield (%) of 5
1
2
3
4
5
6
7
H
Ph
Ph
Ph
Ph
H
Ph
Ph
H
81
81
88
88
50
50
92
94
94
83
83
77
77
64
97
62
61
71
76
75
99
p-tolyl
H
Ph
H
H
Ph
Ph
Me
Ph
H
H
Ph
Table 2. Bicyclic and Tricyclic Pyrroles from Intramolecular Alkylative Coupling
a 10 mol % Ni(COD)2, 1.5 equiv of Me2Zn (2.0 M in toluene), 0.07 M THF, 0 °C. b (1) O3, À78 °C, CH2Cl2; (2) 1 equiv of PPh3, rt. c For product 9a: 3 equiv
˚
˚
of NH4OAc, 2equivofTsOH, 4AMS, THF/EtOH (1:2), reflux. For products 9b and 9c:4.5equivofNH4OAc, 4 A MS, THF/AcOH (1:1), 170 °CμW, 15 min.
fashion.3g As illustrated with compound 4d (as prepared in
Table 1, entry 7), acid-catalyzed condensation of the 1,
4-dicarbonyl species directly affords the corresponding
furan 10 in good yield (eq 1).
pyrroles, and a number of polycyclic derivatives with fused
carbocyclic or heterocyclic rings are also accessible.
A number of the classes of pyrroles that may be accessed
by this method are difficult to access by alternate ap-
proaches, and the reductive coupling approach provides
complementary characteristics to alternative procedures
including enolate heterodimerizations and Stetter reactions.
In summary, a versatile new entry to 1,4-dicarbonyl
derivatives has been developed, involving nickel-catalyzed
coupling or cyclization of enones or enals with alkynes
followed by oxidative cleavage. Further functionalization
by standard PaalÀKnorr cyclizations provides rapid ac-
cess to a variety of substituted pyrrole derivatives. Various
substitution patterns may be accessed with monocyclic
Acknowledgment. Support for this work was provided
by the National Science Foundation (CHE-1012270).
Supporting Information Available. Experimental pro-
cedures and copies of spectral data for all new compounds
are provided. This material is available free of charge via
the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 13, 2011
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