Copper-catalyzed C(sp3)-H functionalization of ketones with vinyl azides: synthesis of substituted-1H-pyrroles

Article abstract of DOI:10.1039/c5ob01407g

Copper-catalyzed C(sp³)-H functionalization of ketones with vinyl azides for the synthesis of substituted pyrroles has been developed. The method is a straightforward and efficient way to access a series of 2,3,5-trisubstituted-1H-pyrroles in modest to excellent yields with broad functional group tolerance under mild conditions.

Full text of DOI:10.1039/c5ob01407g

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Copper−catalyzed C(sp3)−H functionalization of ketones
with vinyl azides: Synthesis of substituted−1H−pyrroles
Received 00th January 20xx,
Accepted 00th January 20xx
Ramachandra Reddy Donthiri, Supravat Samanta and Subbarayappa Adimurthy*
DOI: 10.1039/x0xx00000x
www.rsc.org/
Copper−catalyzed C(sp3)−H functionalization of ketones with vinyl
azides for the synthesis of substituted pyrroles has been
developed. The method is straightforward and efficient to access
series of 2, 3, 5 – trisubstituted – 1H – pyrroles in modest to
excellent yields with broad functional group tolerance under mild
conditions.
Pyrroles are considered to be the privileged heterocycles due to their
presence in biological systems and their therapeutic activities.1a
Pharmaceuticals such as the antitumor agent, 1b a potent blocker for
potassium-competitive acid,1c the leading cholesterol-lowering drug
lipitor1d and the numerous natural products1e,f are constituted with
the pyrrole core structure. Additionally, pyrroles serve as useful
building blocks in the synthesis of bioactive molecules1g and the
functionalized materials.1h-j
Scheme 1
As part of our ongoing project towards the development of novel
methods for synthesis of aza-heterocycles,7 herein we report a
convenient method for the synthesis of substituted pyrroles with
copper acetate as a sole catalyst under the mild reaction conditions
through the C(sp3)−H functionalization of ketones with vinyl azides.
Initially, we subjected deoxybenzoin 1a and (1-azidovinyl)
benzene 2a with 10 mol% of copper acetate as a catalyst in
1mL of DMF at room temperature, after 24 h no desired
product 3a formation was observed (Table 1, entry 1). In order
to check the necessity of an oxidant, same reaction was
performed under oxygen atmosphere, but it also failed to yield
the desired product (Table 1, entry 2). Surprisingly when the
reaction performed under argon atmosphere, 60 % of the
desired product 3a was isolated (Table 1, entry 3). Screening of
various solvents showed no improvement in the yield of the
product 3a (Table 1, entries 4 -14). Reaction at 40 ºC provided
78 % yield of 3a (Table 1, entry 15). Further increase in
temperature to 50 ºC does decrease the product yield (Table 1,
entry 16). Other Cu(II) salts were found to be inefficient for this
transformation (Table 1, entries 17 - 20) and no product
formation in the absence of the catalyst (Table 1, entry 21), this
indicates the crucial role of copper(II) acetate for the present
transformation. Therefore the optimized reaction conditions for
the present protocol are as follows: 10 mol % copper acetate as
the catalyst, DMF as solvent under argon atmosphere at 40 ºC
(Table 1, entry 15).
Due to the importance of pyrrole moiety, organic chemists have been
fascinated to develop the various synthetic strategies to obtain
variety of pyrrole derivatives. Paal and Knorr independently
synthesized pyrroles from condensation of 1, 4−dicarbonyl
compounds with primary amines or ammonia.2a,b Later, a three
component reaction of β-ketoesters with ammonia (or primary
amines) and α-halo ketones to obtain pyrroles was reported by
Hantzsch.2c Inspired by the aforementioned methods, over the last
decade a significant progress has been observed for the synthesis of
pyrrole derivatives.3-6 Among the reported methods the synthesis of
pyrroles from vinylazides is considered to be a convenient strategy.
Recently, Chiba and co-workers synthesized various pyrrole
derivatives starting from vinylazides and 1, 3 di carbonyl compounds
or β-keto acids under metal or metal free conditions.4b-d However, to
access 2,3,5-trisubstituted-1H-pyrroles starting from vinylazides and
ketones remain unaddressed. Although, the methods for the
synthesis of 2,3,5-triphenyl-1H-pyrroles does exist in the literature,
but the use of noble transition metals or harsh reaction conditions or
multi-step process to complete the reaction may confines the
advantage of the reported methods.5
Academy of Scientific & Innovative Research, Scale up & Process Engineering Unit,
CSIR–Central Salt & Marine Chemicals Research Institute, G.B. Marg, Bhavnagar-
364 002. Gujarat (INDIA). E-mail: adimurthy@csmcri.org
Electronic Supplementary Information (ESI) available: [Detailed experimental
procedures and spectroscopic data]. See DOI: 10.1039/x0xx00000x
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Table 2. Substrate scope for 2, 3, 5−triphenyl−1H−pyrroles
Table 1 Optimisation of reaction conditionsa
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DOI: 10.1039/C5OB01407G
aReaction conditions otherwise stated: 0.45 mmol of 1a, 0.3 mmol of 2a, 0.03
mmol of catalyst and 1mL solvent, under argon atmosphere at 40 ºC for 24 h.
bFor entries 1 and 2 the reactions performed under open air and oxygen
atmosphere respectively. cReaction at room temperature. dReaction at 50 ºC.
aReaction conditions: 0.45 mmol of 1, 0.3 mmol of 2, 0.03 mmol of
Cu(OAC)2.H2O and 1mL DMF as the solvent under argon atmosphere at 40
ºC for 24 h.b 0.9 mmol of ketone (3 equivalents w.r.t vinyl azide).
With these optimized conditions, we examined the scope of this
catalytic method for the synthesis of substituted pyrroles. As can be
seen the results of Table 2; the electron-withdrawing groups as well
as electron-donating groups in (1-azidovinyl) benzene moieties 2
were well tolerated and the reactions delivered the desired products
in moderate to good yields 3a-3k. It may be noted that, halide (F, Cl,
and Br) substituted vinyl azide derivatives 3d-3f were also well
tolerated, and provided the corresponding products in good yields.
The halide substituted products could be further applied in
traditional cross-coupling reactions. Electronic effects associated
with electron donating/withdrawing substituents at meta/para
position on the arene ring of vinyl azide do not affect the efficiency
of the process. Unfortunately, vinyl azides like [(2-
azidoallyl)oxy]benzene, (E)-(1-azidoprop-1-en-1-yl)benzene and 4-
azido-1,2-dihydronaphthalene are not amenable to this procedure.
Then the substrate scope of the substituted deoxybenzoins was also
evaluated. Deoxyanisoin reacts with various vinyl azide derivatives
and afford the desired products in moderate to good yields 3l-3r.
Halo substituted deoxybenzoins such as benzyl 4-chlorophenyl
ketone and benzyl 4-bromophenyl ketone reacts with vinyl azides
and afford the desired products in good yields 3s-3x. However, the
substrates like acetophenone and propiophenone are unreactive
under these conditions. The above examples indicates that, the
phenyl group at the α-carbon of the ketone is crucial for the present
transformation. Reaction of 1-phenylpropan-2-one with (1-
azidovinyl) benzene under similar conditions offers only 30 % of
desired product 3y. But the yield of desired product 3y was increased
to 83 % with three equivalents of ketone (w.r.t. vinyl azide).
Substituted vinyl azides also reacted smoothly with 1-phenylpropan-
2-one to provide the products 3z, 3aa and 3ab in excellent yields
(80−93%).
To understand the reaction mechanism, we performed the reaction
with TEMPO as a radical scavenger and no formation of desired
product 3l was observed, however the formation of an adduct 4 was
detected by the HRMS analysis (Scheme 2, eq.1). Further, 70% of 4
was isolated when the reaction was performed with deoxyanisoin
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and TEMPO (Scheme 2, eq 2). The adduct 4 was well characterized functional group tolerance and wide range of substrate scope with
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DOI: 10.1039/C5OB01407G
by 1H, 13C NMR and HRMS analysis (SI pages S45 and S60). modest to excellent yields of products.
Oxidation of deoxyanisoin to 1,2-bis(4-methoxyphenyl)ethane-1, 2-
dione was also observed in the presence of oxygen atmosphere
(Scheme 2, eq. 3). The above studies indicates that, the reaction may
Acknowledgements
proceed through a radical mechanism.
CSIR-CSMCRI Communication No. 101/2015. D. R. R. and S. S.
are thankful to AcSIR for their Ph. D. enrolment and the “Analytical
Discipline and Centralized Instrumental Facilities” for providing
instrumentation facilities. D. R. R. and S. S. are also thankful to
CSIR and UGC New Delhi, India for their fellowships. We thank
DST, Government of India (SR/S1/OC-13/2011), for financial
support and CSIR-CSMCRI (OLP-0076) for partial assistance.
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In conclusion we have developed an efficient protocol for the
synthesis of 2,3,5-trisubstituted-1H-pyrroles with copper as a sole
catalyst under mild reaction conditions. Present strategy shows good
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