Direct C3 Carbamoylation of 2H-Indazoles

Article abstract of DOI:10.1002/ejoc.202100461

We developed a novel method for direct C3 carbamoylation of 2H-indazoles using oxamic acids as carbamoyl radical sources. In the presence of ammonium persulfate, carbamoyl radicals were generated from oxamic acids, then used for further reactions with 2H-indazoles to afford the desired products. The reaction proceeds under metal- and catalyst-free conditions. This simple process allows for the efficient synthesis of C3 carbamoylated 2H-indazoles, which are important scaffolds in organic synthesis.

Full text of DOI:10.1002/ejoc.202100461

Communications
doi.org/10.1002/ejoc.202100461
Direct C3 Carbamoylation of 2H-Indazoles
Vighneshwar Shridhar Bhat[a] and Anna Lee*[a]
We developed a novel method for direct C3 carbamoylation of
2H-indazoles using oxamic acids as carbamoyl radical sources.
In the presence of ammonium persulfate, carbamoyl radicals
were generated from oxamic acids, then used for further
reactions with 2H-indazoles to afford the desired products. The
reaction proceeds under metal- and catalyst-free conditions.
This simple process allows for the efficient synthesis of C3
carbamoylated 2H-indazoles, which are important scaffolds in
organic synthesis.
Indazoles, nitrogen-containing heterocycles, are important scaf-
folds in organic synthesis and have been found in many
biologically active compounds.[1] 2H-Indazoles are of particular
interest, as they have recently been confirmed to exhibit many
significant biological activities, including antitumor and anti-
inflammatory properties (Figure 1).[2] While there have been no
Figure 1. Bioactive compounds containing the 2H-indazole moiety.
shortage of attempts to synthesize indazole scaffolds, many
studies on the synthesis of 2H-indazoles have some limitations
due to their thermodynamically less favored properties.[3] Direct
functionalization of 2H-indazoles at the C3 position has been
particularly challenging because of low reactivity at that site.[4]
Nevertheless, direct C3 functionalization of 2H-indazoles
remains a target worth pursuing, as it would provide an
efficient route for the synthesis of various 2H-indazole deriva-
tives. Very recently, some remarkable breakthroughs concerning
C3 functionalization of 2H-indazoles through acylation,[4c,5]
arylation,[4d,6] alkylation,[5b] alkenylation,[7] trifluoromethylation,[8]
selenylation,[9] and phosphorylation,[10] have been achieved
using pioneering approaches, including visible-light-mediated
reactions (Scheme 1, I).[11,12] While
a number of different
approaches to the synthesis of C3 functionalization of 2H-
indazoles have been developed, successful direct C3 carbamoy-
lation of 2H-indazoles is comparatively rarely reported
(Scheme 1, II). Carbamoylation is one of the most efficient
methods to introduce an amide motif into a molecule.[13]
Carbamoylation reactions provide rapid CÀ H carbamoylated
heterocycles that would typically otherwise be synthesized
from conventional amide-coupling reactions, which require the
use of prefunctionalized starting compounds and wasteful
coupling reagents.[14] Amide motifs have been found in many
natural products, pharmaceuticals, and specialized materials,
Scheme 1. Synthesis of C3 carbamoylated 2H-indazoles.
and amide-functionalized N-heterocycles are important scaf-
folds in medicinal chemistry. 2H-indazoles containing amide
motifs also demonstrate biological properties (Figure 1).
With this in mind, the development of a direct and efficient
method for the carbamoylation of 2H-indazoles that relies on
simple processes would be significant. We envisioned that
direct C3 carbamoylation of 2H-indazoles might be possible
[a] V. S. Bhat, Prof. Dr. A. Lee
Department of Chemistry
Jeonbuk National University
Jeonju 54896, Republic of Korea
E-mail: annalee@jbnu.ac.kr
http://top.jbnu.ac.kr/leelab
Supporting information for this article is available on the WWW under
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using in situ-generated carbamoyl radicals.[15] Herein, we report
water in this reaction, we employed a molecular sieve,
an efficient direct carbamoylation of 2H-indazoles using oxamic
acids as carbamoyl radical sources (Scheme 1, III). Notably, the
reaction proceeds without using any catalysts or metal
reagents.
ultimately observing no improvement in reaction yield (en-
try 15). Then, we tested the role of oxidants. Importantly, no
reaction was observed when the reaction was carried out in the
absence of (NH4)2S2O8 (entry 16). Therefore, we concluded that
the presence of an oxidant is necessary to this transformation.
We speculated that the decomposition of persulfate would be
important to the generation of the carbamoyl radicals under
the reaction conditions.[16] The reaction yield was diminished
when K2S2O8 was used instead of (NH4)2S2O8 (entry 17). The
reaction still occurred under air atmosphere, though we noted
a slightly decreased yield (entry 18).
Our initial studies of C3 carbamoylation of 2H-indazoles
involved a reaction between 2-phenyl-2H-indazole (1a) and
oxanilic acid (2a) in the presence ammonium persulfate. We
assumed that carbamoyl radicals would be generated by
ammonium persulfate under proper reaction conditions. Ac-
cordingly, we examined various reaction conditions, and
selected examples of the optimization studies are summarized
in Table 1. Solvent screening revealed that the desired reaction
did not take place in DCM, CH3CN, and DMF (Table 1, entries 1–
3). However, the desired products were obtained when the
reactions were performed in DMSO (entries 4–13 and en-
tries 15–16). Notably, improved yield was observed when the
With the optimized reaction conditions identified, we
explored the substrate scope of the synthesis of C3 carbamoy-
lated 2H-indazoles. The reaction proved to be tolerant to
various 2H-indazoles and oxamic acids (Table 2). First, we
examined various aryl substituents at N2 of the 2H-indazoles
(3a–3e). Aryl substituents with either electron-donating (3b
and 3c) or electron-withdrawing (3d and 3e) groups afforded
the target products in moderate to good yields (59–73% yields).
Notably, an alkyl-substituted 2H-indazole also proved to be a
suitable substrate in this reaction even though the reaction
yield was relatively low (3f, 30%). We then determined the
electronic effect of the 2H-indazole structures. The electronic
effect on the arene structure of 2H-indazole seems to be crucial;
7-methoxy-2-phenyl-2H-indazole provided the product with a
diminished yield compared with 5-fluoro-2-phenyl-2H-indazole
(3g: 61% vs. 3h: 30%). Next, various oxamic acids were
employed in this transformation (3j–3s). N-Aryl oxamic acids
with either electron-donating (3j and 3k) or electron-with-
drawing (3l) groups provided the desired products in 49–71%
yields. A diminished yield was observed with electron-with-
drawing substituent at the para-position of the oxamic acid (3l,
49%). The use of N-naphthyl oxamic acid 2m gave the desired
product 3m in 45% yield. The decrease in the yield of 3m
might be due to the substituent’s steric effect. Furthermore, the
products starting from N-alkyl oxamic acids were obtained in
52–72% yields (3n–3s). Various alkyl groups, including benzyl
(3n, 62%), cyclohexyl (3o, 66%), cyclopentyl (3p, 62%), and
tert-butyl (3q, 62%) groups, provided the desired products in
good yields even though a slightly diminished reaction yield
was observed with sterically hindered 2-adamantan-2-yl-amino-
2-oxoacetic acid (3r, 52% yield). In addition, the reaction using
2-oxo-2-(piperidin-1-yl) acetic acid 2s successfully provided the
desired product 3s in 72% yield. Moreover, other heterocyclic
compounds such as quinoline (3t), phenanthridine (3u), and
quinoxalin-2(1H)-one (3v) also provided the desired products in
this transformation.
°
reaction was carried out in DMSO at 60 C for four hours
(entry 4, 71%). Higher temperatures did not improve the
reaction yield (entries 5 and 6). In contrast, lower yields were
observed as the reaction temperature decreased (entries 7 and
°
°
8, 50 C: 56% and 23 C 20% yields respectively). A slightly
diminished reaction yield was observed as reaction time was
shortened (entry 9, 3 h: 67%), although a longer reaction time
did not improve the reaction yield (entry 10, 5 h: 70%). Varying
the amount of ammonium sulfate did not improve the reaction
yields (entries 11–14). As we were curious about the role of
Table 1. Optimization of the reaction conditions.[a]
Entry
Solvent
Temp. [ C]
Reaction time [h]
Yield [%][b]
°
1
2
3
4
5
6
7
8
DCM
CH3CN
DMF
60
60
60
60
70
80
50
23
60
60
60
60
60
60
60
60
60
60
4
4
4
4
4
4
4
4
3
5
4
4
4
4
4
4
4
4
Trace
Trace
Trace
71
70
69
56
20
67
70
65
63
42
69
69
0
21
58
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
9
10
11[c]
12[d]
13[e]
14[f]
15[g]
16[h]
17[i]
18[j]
To gain mechanistic insight into this transformation, we
performed control experiments (Scheme 2). We employed
TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) and BHT (buty-
lated hydroxytoluene) as radical inhibitors.[17] These conditions
did not provide the desired products, suggesting that this
transformation primarily involved a radical pathway.
[a] Conditions: 1 a (0.5 mmol, 1.0 equiv.), 2a (4.0 equiv.), (NH4)2S2O8
(4.0 equiv.), solvent (0.25 M) under Ar. [b] Isolated yield after column
chromatography. [c] 3.0 equiv. of (NH4)2S2O8 was added. [d] 3.0 equiv. of
(NH4)2S2O8 and 3.0 equiv. of 2a were added. [e] 2.0 equiv. of (NH4)2S2O8 and
2.0 equiv. of 2a were added. [f] 5.0 equiv. of (NH4)2S2O8 was added. [g] 4 Å
molecular sieve (50 mg) was added. [h] The reaction performed in the
absence of (NH4)2S2O8. [i] K2S2O8 was used instead of (NH4)2S2O8. [j] Under
air atmosphere.
On the basis of previous reports and our results, a plausible
reaction pathway is shown in Scheme 3.[4c,10a,16,18] The reaction
2À
begins with the decomposition of persulfate S2O8 in DMSO to
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Table 2. Substrate scope.[a]
Scheme 2. Control experiments.
Scheme 3. Proposed reaction pathway.
Scheme 4. Gram-scale synthesis.
reaction conditions (Scheme 4). A good yield of the desired
product 3a was obtained without loss.
In summary, we have developed an efficient and direct
means of C3 carbamoylation of 2H-indazoles. We also confirmed
that this process can be applied to gram-scale reactions.
Notably, this transformation did not require any metal reagents
or catalysts. This simple process would provide a facile access to
C3 carbamoylated 2H-indazoles, which are important scaffolds
of various bioactive compounds.
[a] Conditions: 1 a (0.5 mmol, 1.0 equiv.), 2a (4.0 equiv.), (NH4)2S2O8
°
(4.0 equiv.) in DMSO (0.25 M) at 60 C for 4 h under Ar. Isolated yield after
column chromatography.
Acknowledgements
*
generate the sulfate radical anion SO4 À . The subsequent CO2
emission and hydrogen atom transfer from oxamic acid by the
This work was supported by the National Research Foundation of
Korea (NRF) grant funded by the Korea government (MSIT)
(2019R1A2C1008297). This paper was also supported by research
funds for newly appointed professors of Jeonbuk National
University in 2020.
*
À
sulfate radical anion SO4 provides the carbamoyl radical I.
Then, a Minisci-type radical addition to 2H-indazole 1 affords
intermediate II.[19] Single electron transfer (SET) and deprotona-
tion finally furnish desired product 3.
To show the utility of this transformation, we performed a
gram-scale reaction with model substrates 1a and 2a under
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Keywords: Carbamoylation · 2H-Indazoles · Minisci reaction ·
Radical reaction · Synthetic methods
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Manuscript received: April 15, 2021
Revised manuscript received: May 25, 2021
Accepted manuscript online: May 27, 2021
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