Selective N1-Acylation of Indazoles with Acid Anhydrides Using an Electrochemical Approach

Article abstract of DOI:10.1021/acs.orglett.8b03683

An electrochemical synthesis method for the selective N1-acylation of indazoles has been developed. This "anion pool" approach electrochemically reduces indazole molecules generating indazole anions and H₂. Acid anhydrides are then introduced to the solution resulting in selective acylation of the N1-position of the indazoles. This procedure can also be applied to the acylation of benzimidazoles and indoles. The reaction can also be performed using a 9 V battery without loss of reaction efficiency.

Full text of DOI:10.1021/acs.orglett.8b03683

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Selective N1-Acylation of Indazoles with Acid Anhydrides Using an
Electrochemical Approach
D. M. M. Mevan Dissanayake and Aaron K. Vannucci*
Department of Chemistry and Biochemistry, University of South Carolina, 541 Main Street, Columbia, South Carolina 29208,
United States
S
* Supporting Information
ABSTRACT: An electrochemical synthesis method for the
selective N1-acylation of indazoles has been developed. This
“anion pool” approach electrochemically reduces indazole
molecules generating indazole anions and H2. Acid anhydrides
are then introduced to the solution resulting in selective acylation
of the N1-position of the indazoles. This procedure can also be
applied to the acylation of benzimidazoles and indoles. The
reaction can also be performed using a 9 V battery without loss of reaction efficiency.
itrogen-containing heterocycles are immensely impor-
tant building blocks for medicinally important com-
two nonequivalent nitrogen atoms of indazole should portend
the ability to form selective products. Early results, however,
showed the use of strong bases, such as NaH, to deprotonate
indazoles led to a mixture of N1- and N2-substituted
products.8,9 Selective alkyl functionalization at the N2 position
has since been achieved using weak non-deprotonating bases
to increase the nucleophilicity of the N2 position.9,10 Up to
135:1 selectivity for alkylation of the N1 position was also
achieved using Cs2CO3 base in DMF.11 Indazoles alkylated at
the N1 position have also been synthesized via ring-forming
reactions between 2-halobenzonitriles and N-alkylhydrazines.12
Recently, hetrocyclization synthesis has also achieved N2-
substituted indazoles using a phosphacycle catalyst.13
N
pounds.1 More specifically, indazole derivatives are prevalent in
pharmaceutical research with over 40 new patents being
recently filed on biologically interesting indazole compounds.2
Research has been carried out on the role of indazole as a
kinase inhibitor,3 and examples of indazole-based drugs and
drug candidates are shown in Figure 1.4−7 Such drug structures
While impressive selectivities for the alkylation of indazoles
has been achieved in the aforementioned studies, reports on
selective acylation of indazoles are much rarer. Acylation of
indoles via acyl-group transfer has been extensively inves-
tigated.14−19 However, to the best of our knowledge, just two
reports of acyl group transfer to indazoles have been
reported.17,19 In both reports, a single acylated indazole was
reported with yields between 60 and 70% and without mention
of reaction selectivity toward the N1 position. As can be seen
in Figure 1, acylated indazoles are drug targets; therefore, the
development of a general and efficient method for the selective
acylation of indazoles is important.
To address the challenges of general applicability and
operational simplicity while achieving reaction efficiency, we
have utilized an electrochemical procedure for the chemo-
selective acylation of indazoles. This electrochemical proce-
dure, called the “anion pool method” was recently developed
by our group for the electrochemical synthesis of alkylated
benzimidazoles.20 The anion pool method builds on principles
of the previously developed cation pool method21 and is base,
Figure 1. Selected examples of U.S. FDA approved pharmaceuticals
and molecules under investigation containing the indazole moiety.
The N1-position has been highlighted.
possess various substituents such as alkyl, benzyl, and acyl
moieties at the N1 position. The structurally diverse indazole
scaffolds can be synthesized by selectively manipulating the
substitution pattern. As a result, methods for the selective
functionalization of indazoles are appealing for both industry
and academia.
Selective functionalization of indazoles has been previously
explored through deprotonation of indazoles with added base,
followed by functionalization at the nitrogen positions. The
Received: November 18, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03683
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
catalyst, and precious-metal-electrode free. The procedure
generally operates via reduction of substrates to form
electrogenerated nucleophiles.22 Electrochemistry allows for
precise control of the applied reduction potentials, and the
base-free environment makes this procedure applicable to
substrates with base-sensitive, electron-withdrawing, and
electron-donating functional groups. Furthermore, in this
base-free environment, acid anhydrides can be used for
acylation reactions without being consumed by side reactions.
Lastly, the in situ generated nucleophiles can react directly with
acid anhydrides without the assistance of an acyl-transfer
catalyst.
This reported procedure was carried out through the use of
constant current electrolysis using a two-electrode setup
(Figure S2). Inexpensive reticulated vitreous carbon (RVC)
electrodes were utilized to avoid the use of expensive, rare
transition metals. The reaction conditions were optimized with
the aim of developing an efficient method for the acylation of
indazoles with high chemoselectivity for the N1 position. Table
1 summarizes the results of the optimization studies. For the
electrolysis was terminated and the reaction solution was
purified to give the desired N1-acylated indazole product in
81% yield. GC−MS analysis of the reaction mixture and NMR
analysis of the separated reaction components showed no
evidence for the N2 product isomer.
With promising initial results in hand, the experimental
conditions were varied to explore further optimizations.
Changing the applied current to 4 or 16 mA maintained the
reaction selectivity but decreased the overall yields (B and C,
Table 1). Varying the current applied after the addition of the
acetic anhydride was also explored. Lowering the current to 0.5
mA (D, Table 1) led to nearly identical yields when compared
to reaction A but is advantageous due to the lower applied
current consuming less energy over the course of the reaction.
Completely turning off the electrolysis after addition of
anhydride (E, Table 1), however, led to a sharp decrease in
product yield. It is hypothesized that the anion pool is only
stable while external current is being applied;20 thus, cutting off
the applied current leads to a loss of the indazole anions and a
decreased product yield. The use of a single-component
electrochemical cell was explored (F, Table 1), but both
selectivity and product yield for the reaction dropped. This
result implies that having a positively charged anode near the
anion pool is detrimental for this reaction. Initially adding both
the 1H-indazole and the acetic anhydride together before
generating an anion pool (G, Table 1) also led to decreased
yields and selectivity. This shows the importance of adopting a
two-step procedure to obtain the N1-acetylated product
selectively. Directly stirring the acetic anhydride and the 1H-
indazole together at room temperature without an applied
current (H, Table 1) did result in some product, but with poor
selectivity. Addition of base and heating the reaction to 55 °C
without applied current did result in 63% conversion of the
1H-indazole (I, Table 1), but once again the selectivity for the
N1 product was poor.
Table 1. Optimization of the Electrochemical Acylation
a
Reaction
% yield
conditions initial current second current N1 product N2 product
A
B
C
D
E
8.0
4.0
16.0
8.0
8.0
8.0
8.0
0.0
0.0
8.0
4.0
16.0
0.5
0.0
0.5
8.0
0.0
0.0
81
62
77
82
53
52
45
18
56
b
F
G
11
22
5
c
Having established conditions D in Table 1 as the optimized
experimental conditions, the substrate scope with respect to
acid anhydrides was explored. A range of commercially
available anhydrides delivered N1-acylated products in
consistently high yields as shown in Figure 2. In all cases, no
evidence for the N2-acylated product was observed, indicating
this electrochemical synthesis procedure is completely selective
for the desired N1 product. Acetic (1), isobutyric (3), and
pentanoic anhydride (5) substrates were all successfully used
for the acylation reactions. Anhydrides containing an aromatic
H
d
I
12
a
All reactions performed at room temperature, unless otherwise
noted, with 0.1 M Bu4NPF6 electrolyte, 0.75 mmol of 1H-indazole,
1.4 equiv of acetic anhydride in acetonitrile on the cathode side, 0.05
M Fc on the anode side. RVC anode and cathode. Current units in
b
c
mA. Single-cell setup with iron anode. 1H-Indazole and acetic
d
anhydride initially mixed. Carried out at 55 °C.
initial experimental conditions (A in Table 1), a two-
compartment electrochemical H-cell was used with a glass
frit separating the anodic and cathodic sides of the cell. The
solution in the cathodic chamber was initially composed of
only 1H-indazole substrate and 0.1 M tetrabutylammonium
hexafluorophosphate (NBu4PF6) in acetonitrile. The anodic
chamber contained 0.05 M ferrocene and 0.1 M NBu4PF6 in
acetonitrile. The ferrocene was added as an electron donor for
the system and to avoid excessive consumption/degradation of
the solvent or electrolyte. The stable ferrocenium cation
generated during the electrolysis could be reduced back to
ferrocene for recycled use, thus limiting chemical waste. With
these initial solutions set up, 8 mA of current was applied
between the two electrodes for a total of 3 h. This controlled
current electrolysis generates a “pool” of indazole anions. After
the initial 3 h, 1.4 equiv of acetic anhydride was added while
maintaining the applied 8 mA of current. The electrolysis was
continued for an additional 3 h with stirring, at which time the
Figure 2. Selective N1-acylation of indazole with various anhydrides.
B
DOI: 10.1021/acs.orglett.8b03683
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Organic Letters
Letter
group (2) and unsaturation (6) also led to high yields. Further
functional group tolerance was also illustrated with diethyl
dicarbonate (7) and 2-chloroacetic anhydride (4) substrates.
The chloroacetic acylation reaction is of added interest as the
chloro group adds another synthetic handle for potential
further functionalization of product 4. In addition to these N−
C bond-forming reactions, tosyl anhydride was also utilized to
form an N−S bond and product 8 in 73% yield.
Continuing the investigation, a series of indazoles sub-
stituted with a variety of functional groups were explored and
are shown in Figure 3. These results shed light on adopting this
Figure 4. Electrochemical acylation of various azole compounds.
address this possible shortcoming of the anion-pool approach,
the reaction used to obtain product 2 in Figure 2 was setup up
using a standard 9 V battery instead of a potentiostat (Figure
S3). For this battery-driven reaction, the same reaction
procedure was followed, where the indazole substrate was
stirred in the cell for 3 h before addition of the benzoic
anhydride. The anhydride was stirred in the reaction mixture
for another 3 h before the battery was disconnected, and the
reaction solution was analyzed. The battery-powered reaction
led to a 72% isolated yield of the N1-acylated product without
evidence for the N2 product. This result illustrates the
operational simplicity of the anion-pool approach.
Figure 3. Selective N1-acylation of a variety of substituted indazole
compounds.
To gain insight into the highly selective nature of this
reaction, acylation of 7-methylindazole was investigated
(Figure 5). The reaction proceeded with only 22% conversion
method for N-benzoylation, which is a common practice for
protection of an amine group in a multistep synthesis.23 This
anion-pool method was able to selectively acylate the N1-
position of 5-iodoindazole. Once again, the iodo group on the
ring of the indazole moiety offers an excellent synthetic handle
for further functionalization of product 9. Acylation of
indazoles containing halogen functional groups was expanded
to products 11, 12, and 13 which all contain a bromo
substitution at the 6-position of the indazole ring. Products 12
and 13 containing aldehyde and ester functionalities were also
obtained with good yields. In addition, the strong electron-
withdrawing nitro functionality also performed well under the
optimized reaction conditions (10). Furthermore, the
benzoylated products in Figure 3 can be reduced to benzylated
products through Wolff−Kishner reduction. This is an
advantageous strategy in place of direct benzylation that
produces a mixture of both isomers.24
Gratifyingly, this method could be effectively applied to
various other azole compounds, as shown in Figure 4. The
ubiquitous presence of azoles in bioactive compounds makes
new greener and broadly applicable methods for making their
derivatives in demand. Both benzimidazole (14) and 2-
methylthiobenzimidazole (15) were successfully acylated,
thus providing a base-free method for the functionalization
of the benzimidazole NH group. Numerous base-assisted
synthetic protocols for the protection of benzimidazoles have
been reported.25 Indole also reacted with both acetic (17) and
benzoic (18) anhydrides with complete selectivity to the N1
position.
Figure 5. Acylation of 7-methylindazole. Reaction conditions are
identical to conditions d from Table 1.
of the starting 7-methylindazole. In addition, GC−MS analysis
of the post reaction solution indicated both N1- and N2-
acylated products (19 and 20 respectively) formed in a 1.4:1
mixture (Figure S26). Chromatographic separation of the two
1
isomers proved difficult, but a H NMR spectrum of the
isomer mixture is shown in Figure S27. This result indicates
that steric hindrance at the 7-position of the indazole moiety is
detrimental to the reaction selectivity and efficiency.
Furthermore, the effect of countercation size was examined.
In a previous report, the selectivity for the N1 product during
the base-assisted alkylation of indazoles was greatly increased
when cesium carbonate base was used instead of potassium
and sodium bases.11 For this study, using LiClO4 supporting
electrolyte instead of NBu4PF6 led to a 2:1 ratio of the N1/N2
product as evidenced by GC−MS analysis. Thus, larger
counter cations in the supporting electrolyte increase the
selectivity for the N1 product, which is consistent with
previous reports.
In conclusion, we have developed a general and operation-
ally simple electrochemical procedure for the acylation of
indazoles and azoles in general. This “anion pool” procedure is
completely selective for the acylation of the N1-position of
indazoles with the exception of 7-substituted indazole
substrates. Since the procedure is base-free, acid anhydrides
The results in Figures 2−4 show that this anion-pool
approach is applicable for the acylation of indazoles and azole
compounds, in general. It is understood, however, that many
synthetic laboratories are not equipped with potentiostats in
order to perform highly controlled electrolysis reactions. To
C
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* Supporting Information
The Supporting Information is available free of charge on the
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glett.8b03683.
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Experimental procedures and product characterization
(PDF)
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AUTHOR INFORMATION
■
Chem. Commun. 2018, 54, 531−534.
Corresponding Author
*E-mail: vannucci@mailbox.sc.edu.
ORCID
(18) Heller, S. T.; Schultz, E. E.; Sarpong, R. Chemoselective N-
Acylation of Indoles and Oxazolidinones with Carbonylazoles. Angew.
Chem., Int. Ed. 2012, 51, 8304−8308.
(19) Zhao, J.; Li, P.; Xia, C.; Li, F. Direct N-acylation of azoles via a
metal-free catalyzed oxidative cross-coupling strategy. Chem. Commun.
2014, 50, 4751−4754.
Aaron K. Vannucci: 0000-0003-0401-7208
Notes
(20) Dissanayake, D. M. M. M.; Vannucci, A. K. Transition-Metal-
Free and Base-Free Electrosynthesis of 1H-Substituted Benzimida-
zoles. ACS Sustainable Chem. Eng. 2018, 6, 690−695.
(21) Yoshida, J.-i.; Shimizu, A.; Hayashi, R. Electrogenerated
Cationic Reactive Intermediates: The Pool Method and Further
Advances. Chem. Rev. 2018, 118, 4702−4730.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors gratefully acknowledge support for this work by
the University of South Carolina.
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Catalyzed N-Benzoylation of Amines via Aerobic C−C Bond
Cleavage. J. Org. Chem. 2015, 80, 8782−8789.
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DOI: 10.1021/acs.orglett.8b03683
Org. Lett. XXXX, XXX, XXX−XXX