COMMUNICATION
DOI: 10.1002/chem.201201027
Catalyst- and Halogen-Free Regioselective Friedel–Crafts a-Ketoacylations
Kishor Mohanan, Marc Presset, Damien Mailhol, Yoann Coquerel,* and
[
a]
Jean Rodriguez*
Pyrroles, indoles and their derivatives are found in many
biologically active compounds, originating from both natural
[1]
and synthetic sources. The primary functionalization of
pyrroles and related aromatic nuclei usually relies on a Frie-
del–Crafts acylation to introduce a carbonyl group amenable
[2]
for further post-functionalization reactions. Friedel–Crafts
acylation of heteroaromatic compounds traditionally re-
quires activation of a carboxylic acid and most often an acyl
halide combined with a Lewis acid activating agent, often
[3]
used in greater than stoichiometric amounts.
Recent advancements have led to the development of
some efficient metal-based catalytic Friedel–Crafts acyla-
[4]
tions. Lately, the advent of organocatalysis has opened
new opportunities, and one example of an organocatalyzed
Friedel–Crafts acylation has been reported using 1,5-
Scheme 1. Schematic summary of a) standard Friedel–Crafts acylation,
and b) the work described here.
diazabicyclo ACHTUNGTRENNUNG[ 4.3.0]non-5-ene (DBN) and simple benzoyl
[5]
chlorides. However, these reactions are often complicated
by regioselectivity and/or efficiency issues, and the standard
relatively harsh reaction conditions of Friedel–Crafts acyla-
tions hamper the direct introduction of reactive functional
groups onto the heteroaromatic nucleus.
tive under halogen-free conditions. Although electrophilic
substitutions with simple ketenes have been described (es-
[10]
sentially intramolecular reactions),
there are only a few
known examples of CÀC bond formation by nucleophilic ad-
dition to a-oxo ketenes. From a practical point of view,
these are limited to 6p-electrocyclic rearrangements of mes-
In the context of ꢀeconomies in synthesisꢁ (step-, atom-,
[6]
redox-, pot-, time-economies), Friedel–Crafts acylations
using less-demanding and nontoxic materials while provid-
ing a selective and rapid route to structurally more complex
products are highly desirable. Herein, we report highly effi-
cient and regioselective intermolecular Friedel–Crafts a-ke-
toacylations of heterocyclic compounds leading to heterocy-
cles functionalized with a very versatile 1,3-dicarbonyl
[
8]
oionic compounds and a-oxo-a’-arylimino ketenes, the use
of Meldrumꢁs acid (2,2-dimethyl-1,3-dioxane-4,6-dione) de-
rivatives in intramolecular decarboxylative Friedel–Crafts-
[11]
type acylation reactions, nucleophilic addition of enolates
[12]
to a-carboxy ketenes, and very specific cases of electro-
philic substitutions with highly electrophilic perfluoroacylke-
[
7]
[13]
moiety
Scheme 1).
We hypothesized that a-keto ketenes, generated by a mi-
crowave-assisted Wolff rearrangement of 2-diazo-1,3-dike-
under halogen- and catalyst-free conditions
tenes.
(
A possible obstacle to our plan is that a-keto ketenes nor-
[8]
mally react with electron-rich olefins as 1-oxa dienes in in-
[8,14]
verse-demand oxa-Diels–Alder [4+2] cycloadditions.
[
9]
tones, could be valuable electrophilic reaction partners in
direct Friedel–Crafts a-ketoacylations of heteroaromatic
compounds, which would not require any catalyst or addi-
Therefore, we selected the reaction between the a-keto
ketene derived from 2-diazo-dimedone (1a) and N-methyl-
pyrrole (2a) as a test for our hypothesis. Rewardingly, after
[15]
a short optimization study, it was found that regulated mi-
crowave-assisted heating at 2008C of a solution of 1a and
[
a] Dr. K. Mohanan, Dr. M. Presset, Dr. D. Mailhol, Dr. Y. Coquerel,
Prof. Dr. J. Rodriguez
2
a in toluene (sealed reaction vessel) for ten minutes clean-
Institut des Sciences Molꢂculaires de Marseille
UMR CNRS 7313 iSm2, Aix-Marseille Universitꢂ
Centre Saint Jꢂrꢃme, Service 531, 13397 Marseille cedex 20 (France)
Fax : (+33)491-289-187
ly gave the expected product 3a, incorporating a 1,3-dike-
tone functional group at the 2-position (Scheme 2). The
Friedel–Crafts a-ketoacylation product 3a was obtained in
high yield and regioselectivity following a domino Wolff re-
arrangement/Friedel–Crafts a-ketoacylation sequence. No
competitive [4+2] oxa-Diels–Alder cycloaddition product
was detected in the crude reaction mixture. Remarkably,
E-mail: yoann.coquerel@univ-amu.fr
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201201027.
Chem. Eur. J. 2012, 00, 0 – 0
ꢄ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
1
&
ÞÞ
These are not the final page numbers!