Pyrrole synthesis via allylic sp3 C-H activation of enamines followed by intermolecular coupling with unactivated alkynes

Article abstract of DOI:10.1021/ja104305s

A conceptually novel pyrrole synthesis is reported, efficiently merging enamines and (unactivated) alkynes under oxidative conditions. In an intermolecular Rh catalyzed process, the challenging allylic sp³ C-H activation of the enamine substrates is followed by the cyclization with the alkyne (R³ = CO₂R). Alternatively, in some cases (R ³ = CN), the enamine can be utilized for a vinylic sp² C-H activation. A total of 17 examples with yields above 60% is presented, together with the results of an initial mechanistic investigation.

Full text of DOI:10.1021/ja104305s

Published on Web 06/28/2010
Pyrrole Synthesis via Allylic sp3 C-H Activation of Enamines Followed by
Intermolecular Coupling with Unactivated Alkynes
Souvik Rakshit, Frederic W. Patureau, and Frank Glorius*
NRW Graduate School of Chemistry, Organisch-Chemisches Institut, Westfa¨lische Wilhelms-UniVersita¨t Mu¨nster,
Corrensstrasse 40, 48149 Mu¨nster, Germany
Received May 18, 2010; E-mail: glorius@uni-muenster.de
Table 1. Enamine Scope in the Rhodium Catalyzed Oxidative
Pyrrole Synthesisa
Abstract: A conceptually novel pyrrole synthesis is reported,
efficiently merging enamines and (unactivated) alkynes under
oxidative conditions. In an intermolecular Rh catalyzed process,
the challenging allylic sp3 C-H activation of the enamine
substrates is followed by the cyclization with the alkyne (R3
)
CO2R). Alternatively, in some cases (R3 ) CN), the enamine can
be utilized for a vinylic sp2 C-H activation. A total of 17 examples
with yields above 60% is presented, together with the results of
an initial mechanistic investigation.
Arguably, pyrroles represent one of the most important classes
of heterocycles found in biologically active compounds.1,2 Con-
sequently, a plethora of methods for their synthesis has been
developed over the years,3 with metal-catalyzed ones becoming
increasingly popular.4 Recently, the groups of Jones, Miura, and
Fagnou have independently reported Rh(III)-catalyzed oxidative
couplings using a directing group for aryl C-H bond activation
followed by insertion of an internal alkyne leading to various
annulated heterocycles,5 e.g. indoles.5g Along the same lines, the
selective synthesis of multisubstituted pyrroles by oxidative com-
bination of enamines and (unactivated) alkynes would constitute a
powerful method (eq 1).
a Conditions: 1 (1.3 mmol), 2 (1.0 mmol), [Cp*RhCl2]2 (2.5 mol %),
AgSbF6 (10.0 mol %), Cu(OAc)2 (2.1 equiv), DCE (0.2 M), 120 °C,
16 h; isolated yield is given. b Determined by 1H NMR. c Only one
regioisomer was observed by 1H NMR and GC-MS analysis of crude
product mixture. d [Cp*RhCl2]2 (5.0 mol %), AgSbF6 (20.0 mol %), at
140 °C for 24 h.
Ag salt, a noncoordinating but solubilizing solvent, and the
choice of oxidant (several Cu salts fail) were found to be
important.11 Whereas the presence of chloride anions shuts down
the reaction completely, AgSbF6 is essential.5g In addition, a
Rh(I) catalyst precursor ([RhCl(cod)]2) also provided product,
but only in low yield.11
With these optimized conditions in hand, we embarked on an
investigation of the enamine scope of this interesting transformation
(Table 1). First, several different N-substituents were compared and
the acetyl group was found to be critical for success, with other
common groups providing only trace amounts of product. Further-
more, using ꢀ-substituted enamines 1b and 1c together with the
unsymmetrical alkyne 2a resulted in the smooth cyclization to 3b
and 3c, intriguingly, as single regioisomers.
Enamines are of great importance in organic chemistry and play
a prominent role in organocatalysis.6 Recently, the utility of
enamines in transition metal catalysis for the oxidative formation
of valuable indoles has been shown.7 Inspired by this work, we
investigated the Rh catalyzed reaction of enamines with unactivated
alkynes, finding surprising results. Herein, we report the challenging
allylic sp3 C-H activation8 and also an alternative vinylic sp2 C-H
activation9 of enamines and the subsequent coupling with unacti-
vated alkynes yielding pyrroles (eq 2).
Good results were also obtained with diphenyl acetylene,
providing the products 3d-f in up to 81% yield. Even the formation
of pentasubstituted pyrroles was achieved (3g), although under more
forcing conditions (5 mol % catalyst and 140 °C) and in quite low
yield. Whereas the ester could be varied, replacement with a ketone
failed (Table 1, 3h,i).
In view of these results, we turned our attention to investigate several
differently substituted alkynes. A variety of internal alkynes with
aromatic substituents were successfully coupled (Table 2). Electron-
neutral, electron-deficient, and electron-rich aromatic groups on the
alkyne gave moderate to good yields (3j-u). Gratifyingly, functional
We commenced our investigation with the coupling of
N-acetyl enamine 1a (R1 ) Ac; R3, R6 ) H; R2 ) CO2Me) and
1-phenyl-1-butyne 2a. The use of a combination of [Cp*RhCl2]2
and AgSbF6 as the catalyst together with Cu(OAc)2 as the oxidant
in DCE resulted in the formation of pyrrole 3a as the single
regioisomer10 (Table 1). A less coordinating counterion in the
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C O M M U N I C A T I O N S
Table 2. Alkyne Scope in the Rhodium Catalyzed Oxidative
Scheme 1. Proposed Modes of Activation
Pyrrole Synthesisa
Furthermore, deprotection of the ester and acetyl moieties of
3l proceeds under mild conditions (4 N aq NaOH in MeOH at
45 °C) to provide the free CO2H and free N-H pyrrole in a
single step in 96% yield.11 These pyrrole products are valuable
building blocks for medicinal chemistry and natural product
synthesis.13
a Conditions: 1a (1.3 mmol), 2 (1.0 mmol), [Cp*RhCl2]2 (2.5 mol %),
AgSbF6 (10.0 mol %, Cu(OAc)2 (2.1 equiv), DCE (0.2 M), 120 °C,
16 h; isolated yields are given; regioisomeric ratios for 3q-s were
determined by 1H NMR analysis of crude product mixture. b Reaction
was carried out on a 0.75 mmol scale. c Reaction was carried out at 140
°C for 24 h. d Regioisom. ratio 61:39. e Regioisom. ratio 75:25.
f Regioisom. ratio 56:44.
groups like bromide, chloride, and carboxylic ester were well tolerated.
These functional groups provide ample opportunity for further
functional group manipulations, for example, by modern cross-coupling
reactions. More sterically demanding alkynes like 1-naphthyl (2q) can
also be employed. When two electronically unsymmetrical aromatic
groups were present as in alkynes 2r and 2s, moderate regioselectivities
of 75:25 to 56:44 were observed for the formation of 3r and 3s,
respectively. Heterocyclic substituents, such as pyrazoles and thiophenes
may transform into the pyrrole products (3t,u). However, activated
alkynes bearing esters (R4 ) CO2Et) or propargylic alcohol derivatives
(PhCCCH2OR; R ) H, Me, or TBS) did not yield the corresponding
pyrrole, maybe due to poisoning of the catalyst by chelation.12
Competition experiments showed a slight preference for electron-poor
alkynes [electron-poor 2k > 2b > electron-rich 2p].11
In addition, to probe the nature of the reaction mechanism, two
reactions between 1a and 2a were performed in the absence of
Cu(OAc)2 at 120 °C:
(i) 20 mol % [Cp*RhCl2]2 with 80 mol % AgSbF6 and
(ii) 2.5 mol % [Cp*RhCl2]2 with 10 mol % AgSbF6.
After 16 h, 3a was formed in 18% and 2% yield (1H NMR),
respectively. After this time, addition of 2.1 equiv of Cu(OAc)2 to
these mixtures and prolonged heating for 24 h at 120 °C resulted
in continued turnover and 54% and 48% yield (1H NMR),
respectively. These results indicate that Cu(II) is not essential for
product formation.11
In conclusion, we have successfully formed pyrroles by a
novel Rh catalyzed sp3 C-H bond activation of enamines and
successive coupling with unactivated alkynes. Studies are
ongoing to understand the reaction mechanism and apply this
C-C/C-N bond formation cascade to the synthesis of other
heterocycles.
Acknowledgment. We thank the NRW Graduate School of
Chemistry (S.R.), the Alexander von Humboldt Foundation (F.W.P.),
and AstraZeneca for generous support. The research of F.G. was
supported by the Alfried Krupp Prize for Young University
Teachers of the Alfried Krupp von Bohlen und Halbach Foundation.
Supporting Information Available: Experimental and characteriza-
tion details. This material is available free of charge via the Internet at
http://pubs.acs.org.
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