Nickel-Catalyzed Denitrogenative Cross-Coupling Reaction of 1,2,3-Benzotriazin-4(3 H)-ones with Organoboronic Acids: An Easy Access to Ortho-Arylated and Alkenylated Benzamides

Article abstract of DOI:10.1021/acs.orglett.8b01401

A novel nickel-catalyzed approach to synthesize ortho-arylated and alkenylated benzamides in good to high yields via a denitrogenative cross-coupling reaction of 1,2,3-benzotriazin-4(3H)-ones with organoboronic acids is described. The reaction proceeds th

Full text of DOI:10.1021/acs.orglett.8b01401

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Nickel-Catalyzed Denitrogenative Cross-Coupling Reaction of 1,2,3-
Benzotriazin-4(3H)‑ones with Organoboronic Acids: An Easy Access
to Ortho-Arylated and Alkenylated Benzamides
Madasamy Hari Balakrishnan,† Kotturaja Sathriyan,† and Subramaniyan Mannathan*,†,‡
†SRM Research Institute, SRM Institute of Science and Technology, Kattankulathur, Chennai 603203, India
‡Department of Chemistry, SRM University-AP, Amaravati 522502, Andhra Pradesh, India
S
* Supporting Information
ABSTRACT: A novel nickel-catalyzed approach to synthesize ortho-arylated and alkenylated benzamides in good to high yields
via a denitrogenative cross-coupling reaction of 1,2,3-benzotriazin-4(3H)-ones with organoboronic acids is described. The
reaction proceeds through a five-membered azanickelacyclic intermediate with the extrusion of a nitrogen molecule. Moreover,
the resulting ortho-arylated benzamides were successfully converted into synthetically useful substituted fluorenones and ortho-
arylated benzylamine derivatives in high yields.
trogenative transannulation reactions.6 In this context, Mur-
iaryls are important motifs that are present in various
Bagrochemicals, dyes, organic materials, and pharmaceuti- akami et al. demonstrated a series of nickel-catalyzed
cally relevant compounds.1 Consequently, significant attention
transannulation reaction of 1,2,3-benzotriazinones with various
π-components such as alkyne, alkene, allene, benzyne, and
isocyanides to prepare isoquinolones and isoindolinones.7a−f
Recently, Liu et al. also demonstrated the asymmetric
denitrogenative transannulation reaction of 1,2,3-benzotriazi-
nones by synthesizing axially chiral isoquinolones in high yields
with high enantioselectivity.7g Interestingly, these reactions
proceed through a five-membered aza-nickelacycle intermediate
I7 (Figure 1) which is in sharp contrast to rhodium- and
palladium-catalyzed reactions of other 1,2,3-triazoles such as
pyridotriazoles, N-sulfonyl-1,2,3-triazoles, and N-aroylbenzo-
triazoles that proceed via a metallocarbene intermediate.6
Inspired by the literature reports on metallacycle-triggered
cross-coupling reactions by a nickel catalyst,8 we set out to
perform a cross-coupling reaction of 1,2,3-benzotriazin-4(3H)-
ones by trapping the aza-nickelacycle with organometallics to
prepare biaryl scaffolds. It is important to mention that cross-
coupling reactions of 1,2,3-triazoles with organometallics are
scarcely studied.9 In fact, cross-coupling reactions with 1,2,3-
benzotriazinones are yet to be developed. In 2012, Fokin and
co-workers displayed a stereoselective arylation of N-sulfonyl-
1,2,3-triazoles with organoboronic acids using rhodium
complex as the catalyst to synthesize 2,2-diaryl enamines at
ambient temperatures.9a Very recently, Tang et al. reported a
palladium-catalyzed denitrogenative Suzuki and carbonylative
has been paid toward the synthesis of these scaffolds for more
than a century.2 One of the classical methods to create such
motifs is transition-metal-catalyzed coupling reaction of aryl
halides (or pseudo halides) with organometallic reagents.3
These reactions, however, need preactivation of both aryl rings,
which is intrinsically uneconomical since it demands the
installation and later disposal of the stoichiometric activating
agent.2c On the other hand, transition-metal-catalyzed directing
group assisted C−H bond activation of substituted aromatics
with organometallics or aryl halides (pseudo halides) provides
an excellent alternate way to prepare biaryl molecules in a step-
and atom-economical fashion.4,5 Mechanistically, these reac-
tions proceed via a key metallacycle intermediate4 and, notably,
require less functionalization of coupling partners. Apparently,
this strategy is not only advantageous in minimizing the
reaction steps but also reduces byproduct (waste) formation.
However, to perform this transformation, a stoichiometric
amount of (metal) oxidant and, in most cases, the higher
reaction temperature is always necessary. Despite these
significant advances, there is always a demand for development
of a new methodology toward the synthesis of biaryl molecules
under mild reaction conditions with minimum waste
generation.
In recent years, 1,2,3-triazoles such as pyridotriazoles, N-
sulfonyl-1,2,3-triazoles, 1,2,3-benzotriazinones, and N-aroylben-
zotriozoles have been recognized as useful substrates to
synthesize various azaheterocycles via metal-catalyzed deni-
Received: May 3, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01401
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of Reaction Conditions
b
yield (%)
entry
ligand
additive
3a
4a
1
20
10
19
3
2
P(n-Bu)3
P(n-Bu)3
PPh3
81
3
H2O
88
4
H2O
81
8
f
5
TFP
H2O
62
0
6
dppe
H2O
64
26
25
4
7
dppp
H2O
75
Figure 1. Nickel-catalyzed denitrogenative reactions of 1,2,3-
benzotriazinones.
8
2,2′-bipyridine
P(n-Bu)3
P(n-Bu)3
P(n-Bu)3
P(n-Bu)3
P(n-Bu)3
P(n-Bu)3
P(n-Bu)3
H2O
4
9
NaOAc
KOH
74
26
10
4
10
11
12
13
89
Suzuki coupling reactions of benzotriazoles with organoboronic
acids to prepare structurally diverse o-amino-substituted biaryl
and biaryl ketone derivatives.9b Herein, we report a nickel-
catalyzed denitrogenative cross-coupling reaction between
1,2,3-benzotriazin-4(3H)-ones and organoboronic acids to
prepare ortho-arylated benzamides.10
Na2CO3
K2CO3
NaHCO3
Na2CO3
Na2CO3
96
92
4
95
5
d
c
14
95 (92)
80
5
e
15
4
a
All of the reactions were carried out using 1a (0.40 mmol), 2a (0.60
1,2,3-Benzotriazin-4(3H)-ones 1 are readily prepared from
commercially available methyl anthranilates and their corre-
sponding anilines via diazotization and cyclization reactions.7
After preparing the starting materials, we began our
investigation by treating 1a with phenylboronic acid (2a) in
the presence of 10 mol % of Ni(cod)2 as the catalyst with 1,4-
dioxane as solvent at 110 °C. After 12 h, the reaction afforded
the desired product 3a in 20% yield along with N-(4-
methoxyphenyl)benzamide (4a) as the byproduct in 10%
yield. To suppress the formation of byproduct and to improve
the reaction efficacy, we investigated the reaction with various
ligands and additives under similar reaction conditions. After
extensive screening, we found that the catalytic system
comprising of 10 mol % of Ni(cod)2 as the catalyst, 20 mol
% of P(n-Bu)3 as the ligand, and Na2CO3 (1.0 equiv) as an
additive was the most effective, affording the desired product 3a
in 96% GC yield. It is also noteworthy to mention that 3a was
obtained in 88% yield when water was employed as an additive.
The choice of solvent is also crucial in obtaining the desired
product in high yield (see the Supporting Information). Among
the solvents that we tested, 1,4-dioxane, and THF were the
best, producing 3a in 95 and 91% yields, respectively. Other
solvents including 1,2-dichloroethane (DCE), toluene, and
acetonitrile were less useful, giving 3a in 43−54% yields.
Delightfully, a decrease in the reaction temperature from 110 to
80 °C afforded 3a in 92% isolated yield (Table 1, entry 14).
However, further lowering the temperature led to moderate
yield due to poor conversion of 1a.
mmol), Ni(cod)2 (0.04 mmol), P(n-Bu)3 (0.08 mmol), additive (0.40
mmol), and solvent (dry) at mentioned temperature and 12 h under
b
c
d
N2. GC yields. Isolated yield. Reaction was carried out at 80 °C.
e
f
Reaction was carried out at 50 °C. TFP = tri(2-furyl)phosphine.
a,b
Scheme 1. Scope of Organoboronic Acids
With the optimized reaction conditions in hand, we have
investigated the scope of the denitrogenative cross-coupling
reaction of 1a with various organoboronic acids (Scheme 1).
From Table 1, it is clear that aryl boronic acids bearing
electron-rich substituents on the phenyl ring afforded the cross-
coupling products 3 in higher yield than electron-deficient aryl
boronic acids. Thus, the reaction of p-methoxy- (2b) and p-
tolylboronic acids (2c) with 1a gave the products 3b and 3c in
high yields. Similarly, 3-methyl-substituted boronic acid 2d
furnished the respective products in good yield. However, when
the reaction was carried out with 3-fluoro- (2e), 4-fluoro- (2f),
a
All the reactions were carried out using 1,2,3-benzotriazin-4(3H)-one
1a (0.40 mmol), organoboronic acid 2 (0.60 mmol), Ni(cod)2 (0.04
mmol), P(n-Bu)3 (0.08 mmol), and Na2CO3 (0.40 mmol) for 12 h.
b
Isolated yields.
and 4-trifluoromethyl-substituted (2g) arylboronic acids, the
desired products were obtained in 71, 80, and 73% yields,
respectively. Correspondingly, benzofuran-2-ylboronic acid
(2h) and thiophene-2-ylboronic acid (2i) afforded 3h and 3i
in 63 and 90% yields, respectively. Delightfully, alkenyl boronic
B
DOI: 10.1021/acs.orglett.8b01401
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
acids, 2j−m, also successfully participated in the reaction
providing the corresponding coupling products 3j−m in high
yields.
Scheme 3. Proposed Mechanistic Pathway
After successfully establishing the scope of the reaction with
organoboronic acid, we next investigated the denitrogenative
cross-coupling reaction with various 1,2,3-benzotriazin-4(3H)-
ones 1b−j (Scheme 2). First, the effect of substituent on the
a,b
Scheme 2. Scope of 1,2,3-Benzotriazin-4(3H)-ones
Scheme 4. Synthesis of Fluorenones and Ortho-Arylated
Benzylamine
in the presence of lithium aluminum hydride to obtain 8 in 85%
yield.11
In conclusion, we have successfully described the first
denitrogenative cross-coupling reaction of 1,2,3-benzotriazin-
4(3H)-ones with organoboronic acids using a nickel complex as
the catalyst. The present catalytic reaction provides a mild and
convenient method for the preparation of synthetically useful
ortho-arylated and alkenylated benzamides in good to high
yields. The reaction is compatible with both aryl and alkenyl
boronic acid and proceeds through a five-membered azanick-
elacyclic intermediate with the extrusion of a nitrogen molecule.
The synthetic utility of the current methodology was also
demonstrated by synthesizing substituted fluorenones and
ortho-arylated benzylamine derivatives in high yields. Currently,
cross-coupling reactions with different coupling partners are
underway in our laboratory.
a
All of the reactions were carried out using 1a (0.40 mmol),
organoboronic acid 2 (0.60 mmol), Ni(cod)2 (0.04 mmol), P(n-Bu)3
b
(0.08 mmol), and Na2CO3 (0.40 mmol) for 12 h. Isolated yields.
nitrogen atom was examined. Both N-aryl- and N-alkyl-
substituted 1,2,3-benzotriazin-4(3H)-ones 1b−f participated
well in the reaction, affording the respective ortho-arylated
benzamide derivatives in 85−92% yield. However, an N-aryl
ring bearing chloro substituent (1d) gave 3p in 72% yield.
Similarly, 1,2,3-benzotriazin-4(3H)-ones 1g−j with different
substituents on the benzene ring also provided the correspond-
ing products 3s−v in 71%, 65%, 72%, and 77% yields,
respectively. It is important to mention that in all the
denitrogenative cross-coupling reactions 5−10% yields of the
corresponding amide 4 was observed.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01401.
A possible catalytic reaction mechanism is proposed based on
the reported nickel-catalyzed denitrogenative reaction of 1,2,3-
benzotriazin-4(3H)-ones7 in Scheme 3. Oxidative addition of
nickel(0) to 1,2,3-benzotriazin-4(3H)-ones affords five-mem-
bered aza-nickelacyclic intermediate 5.7d Transmetalation of 5
with boronic acid 2 gives intermediate 6. Subsequent reductive
elimination affords 3a and regenerates the Ni(0) for the further
catalytic cycle. In the present catalytic reaction, it is believed
that sodium carbonate facilitates the transmetalation step by
cleaving the boronic acid moiety.
The synthetic utility of the present catalytic reaction is shown
in Scheme 4. Substituted fluorenones 7 are important scaffolds
in natural products and bioactive molecules. Such molecules
were readily synthesized in good yields by treating 3 in the
presence of trifluoroacetic anhydride and hydrochloric acid at
100 °C for 3 h.10c A reduction reaction of 3 was also performed
Experimental procedures and characterization of all
products (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mannathan.s@srmap.edu.in.
ORCID
Subramaniyan Mannathan: 0000-0002-3114-8265
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.8b01401
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ACKNOWLEDGMENTS
■
We thank the Department of Science and Technology (DST),
New Delhi, India (DST/INSPIRE/04/2015/002987), for
support of this research under a DST-INSPIRE faculty scheme.
We also extend our sincere thanks to Prof. M. Sasidharan, SRM
Institute of Science and Technology, Chennai, for providing
laboratory facilities.
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