Azaindole synthesis through dual activation catalysis with N-heterocyclic carbenes

Article abstract of DOI:10.1039/c6cc04735a

A convergent, transition-metal-free synthesis of 2-aryl-azaindoles has been developed. The interception of a reactive aza-ortho-azaquinone methide intermediate by an acyl anion equivalent generated through carbene catalysis provides high yields, a wide substrate scope, and the synthesis of previously inaccessible azaindoles.

Full text of DOI:10.1039/c6cc04735a

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Azaindole synthesis through dual activation
catalysis with N-heterocyclic carbenes†
Cite this:DOI: 10.1039/c6cc04735a
Hayden A. Sharma, M. Todd Hovey and Karl A. Scheidt*
Received 7th June 2016,
Accepted 23rd June 2016
DOI: 10.1039/c6cc04735a
www.rsc.org/chemcomm
A convergent, transition-metal-free synthesis of 2-aryl-azaindoles has
been developed. The interception of a reactive aza-ortho-azaquinone
methide intermediate by an acyl anion equivalent generated through
carbene catalysis provides high yields, a wide substrate scope, and the
synthesis of previously inaccessible azaindoles.
The azaindole and diazaindole heteroaromatic scaffolds possess
medically significant biological activity despite limited presence
in known natural products.1 In particular, C2-aryl azaindole
compounds show potent and selective inhibition of a variety of
kinases over-expressed in virulent human-cancer cell lines
(Fig. 1).1,2 Additionally, specific C2-aryl azaindoles selectively
inhibit anthelmintic activity, agonize melatonin receptors, and
downregulate expression of inflammatory cytokines.3,4 In many
cases, azaindoles can have superior pharmacokinetics when
Fig. 1 Selected biologically active 2-aryl-azaindoles.
Other existent methods emanating from Hegedus–Mori–Heck,9
compared to other heterocyclic compounds.4b From an indus- Fischer,10 or Madelung11 approaches use palladium and strongly
trial standpoint, more than 100 patents containing bioactive basic or acidic conditions with high temperatures. Many syntheses
C2-aryl azaindoles exemplify the pharmacophore potential of do not provide access to substitution of the C2-aryl moiety or
this scaffold. The continued interest in developing these molecules the full scope of azaindole regioisomers. Various milder, non-
underscores the need for robust synthetic methods to access these traditional synthetic routes have been reported, but afford multiple
structures in order to drive current and future research efforts.
azaindole regioisomers and/or display poor regiocontrol.12 While
Several classic methods for the synthesis of this heterocycle current methods allow access to a moderately diverse array of
currently exist and are analogous to established indole technology. C2-aryl azaindoles, complimentary organocatalytic approaches
The most common is the Sonogashira-type synthesis,2c,e,f,5 which with an emphasis on convergency and substitution variability
shows a broad scope for controlled C2-arylation in excellent to poor would be important to improve access to these essential molecular
yields.6 While generally dependable, this method struggles or fails scaffolds.
to generate azaindoles with hetero-, bromo-, or densely functiona-
In our program to explore the versatility and power of
lized aromatic C2 substituents.6c,7 The Larock synthesis (Fig. 2b) N-heterocyclic carbenes13 (NHCs) for new catalytic reactions,
yields 2,3-disubstituted azaindoles in a moderately reliable fashion we recently discovered a novel and efficient synthesis of C2-aryl
but can provide limited yields and regiocontrol.2d,8 Both methods indoles through reaction of a transient aza-ortho-quinone
depend on transition metal catalysts and alkyne-containing starting methide14,15 with an acyl-anion equivalent. We hypothesized
materials.
that the analogous aza-ortho-aza-quinone methide intermediate
1* could be intercepted to form the related azaindole core 3
(Table 1a). As benzaldehyde derivatives are diverse and widely
available, the success of this method could broaden the scope of
C2-aryl substitution in a concise and efficient manner. Additionally,
this proposed organocatalytic approach would compliment the
Department of Chemistry, Department of Pharmacology, Center for Molecular
Innovation and Drug Discovery, Chemistry of Life Processes Institute,
Northwestern University, Silverman Hall, Evanston, Illinois 60208, USA.
E-mail: scheidt@northwestern.edu
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6cc04735a known transition-metal catalysed syntheses.
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Table 1 Reaction approach and optimization
Fig. 2 Common approaches to C2-substituted azaindoles.
%
Equiv. Temp.
2b
(%)
3b
4b
Entrya Solvent
Cat. MsOH (1C)
(%) (%)
Our initial investigations took aza-ortho-azaquinone methide
precursor, picolyl chloride 1a, benzaldehyde and NHC A with
cesium carbonate as base (Table 1b). This mixture yielded aryl-
ketone 2a, analogous to the ketone intermediate observed in
our indole-synthesis.15 A range of ethereal solvents were found
to support the NHC-catalyzed acylation in good to excellent
yields with a catalyst loading of 20 mol% (entries 1–5). Attempts
to lower catalyst loading proved unproductive even at increased
concentration or temperature (entries 6–8). With optimized
conditions for ketone formation, we turned our focus to optimizing
the dehydrative cyclization to afford the azaindole core in a one-pot
operation. A survey of cyclization conditions revealed that methane-
sulfonic acid enables cyclization of ketone 2a in dioxane (entry 10).
This cyclization fails in other more Lewis-basic ethereal solvents, as
is illustrated in entry 9. Further optimization revealed an additional
equivalent of acid and mild heating promotes complete conversion
1
2
3
4
THF
Dioxane
20
20
—
—
—
—
—
—
—
—
6.5
6.5
7.5
rt
rt
rt
rt
rt
rt
rt
45
78
96
59
64
66
68
Trace
Trace
70
—
—
—
—
—
—
—
—
0
—
—
—
—
—
—
—
—
0
Diethyl ether 20
MTBE 20
2-Methyl THF 20
Dioxane
Dioxane
Dioxane
THF
5
6c
7d
8c
9
10
5
5
20
20
20
rt
rt
10
Dioxane
Dioxane
30
0
36
0
38
90
11e
rt, then 40
a
Optimization reactions conducted on a 0.04 mmol scale (0.1 M) using
20% catalyst, 1.2 equivalents of aldehyde, and 1.2 equivalents of Cs2CO3
b
c
unless otherwise noted. Yield of isolated material. Conducted at
0.2 M concentration. Conducted at 0.4 M concentration. Conducted
on a 0.4 mmol scale; cyclization reaction went to completion overnight.
d
e
of ketone 2a to deacylated azaindole 4 in excellent yield. Attempts the synthesis of azaindole 10; to the best of our knowledge, it has
to selectively deliver boc-protected azaindole 3a by varying reaction never been reported and would be difficult to synthesize using
conditions revealed de-acylation occurs concomitantly with the transition-metal catalyzed methods due to competing insertion
dehydrative cyclization.
reactions. The developed method also functions well with
With optimized conditions in hand, we turned our focus to aldehydes bearing chlorine (11) and fluorine (12) substitution.
surveying the reaction scope with variation of the azaindole Use of other aldehydes with ortho substitution besides hydrogen
core (Table 2). We found that 4-, 5-, 7-, and 4,7-di-azaindoles groups proved unproductive, putatively due to steric clash of the
with 2-phenyl substitution (4–7) could be delivered in excellent substitution with the catalyst.15a,17 Benzaldehydes containing
yields. Attempts to synthesize 2-phenyl-6-azaindole were unsuccess- other electron-withdrawing groups, such as those with m-trifluoro-
ful and only produced 23; the acylation reaction was found to methyl and p-cyano substitution, resulted in the efficient synthesis
proceed in poor yield, and treatment with acid in dioxane or CH2Cl2 of azaindoles 13 and 14, respectively. The use of aryl aldehydes with
led only to removal of the carbamate protecting group to yield 23. electron donating substituents in the meta and para positions
Further investigation into the reduced yield of 23 revealed competing afforded azaindoles 15–18 in high yields. Finally, polycyclic aromatic
decomposition of the picolyl chloride starting material to reaction aldehydes (19) and, in fair to good yields, heteroaromatic aldehydes
conditions.
(20–22) were competent substrates. Further expansion of aldehyde
We then turned our focus to survey the scope of substituted scope towards use of non-aryl aldehydes have proved unproductive
benzaldehydes. Aryl aldehydes with p-, m-, and di-p,m-bromine to date. Additionally, the use of secondary alkyl aldehydes afforded
substitution afforded azaindoles 8–10 in excellent yields. Of note is trace amounts of acylated product and a complex mixture of
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Table 2 Exploration of reaction scope
the reaction was studied by NMR spectroscopy and LCMS for
azaindole 4, revealing nearly full conversion of azaindole precursor
to product. For this reaction, the only discernable impurity in
greater than 5% yield in NMR spectra of the unpurified material
after basic work up was benzoin.
In conclusion, we have developed an efficient method for
the transition-metal-free synthesis of azaindoles. This method
provides access to a range of 2-aryl azaindole regioisomers as
well as to diazaindoles. A broad scope of meta- and para-
functionalization on the C2 aryl substituent is tolerated, including
halogens, other electron-withdrawing groups, and electron-
donating groups. The azaindole products were purified through
an aqueous workup followed by recrystallization or column
chromatography. To the best of our knowledge, this is the first
synthesis of the full regioisomeric family of azaindoles employing
mild temperature and conditions without transition metal catalysis.
Further expansion of NHC-catalyzed dual activation strategies to
access functionalized heterocycles are underway.
HAS, MTH, and KAS acknowledge financial support generously
provided by the NIH (NIGMS R01-GM073072). HAS thanks North-
western University for a Summer Undergraduate Research Grant.
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