Cobalt-Catalyzed, Directed Intermolecular C-H Bond Functionalization for Multiheteroatom Heterocycle Synthesis: The Case of Benzotriazine

Article abstract of DOI:10.1021/acs.orglett.1c01741

Transition-metal-catalyzed, directed intermolecular C-H bond functionalization is synthetically useful but heavily underexplored in multiheteroatom heterocycle synthesis. Herein we report a cobalt catalytic method for the formation of a three-nitrogen-bearing benzotriazine scaffold via the coupling of arylhydrazine and oxadiazolone. This synthetic protocol features a low-cost base metal catalyst, a maximum number of heteroatoms built into a heterocycle, a distinct synthetic logic for benzotriazines, a superior step economy, and a broad substrate scope.

Full text of DOI:10.1021/acs.orglett.1c01741

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Letter
Cobalt-Catalyzed, Directed Intermolecular C−H Bond
Functionalization for Multiheteroatom Heterocycle Synthesis: The
Case of Benzotriazine
Weiping Wu, Shuaixin Fan, Tielei Li, Lili Fang, Benfa Chu, and Jin Zhu*
Cite This: Org. Lett. 2021, 23, 5652−5657
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ABSTRACT: Transition-metal-catalyzed, directed intermolecular C−H bond functionalization is synthetically useful but heavily
underexplored in multiheteroatom heterocycle synthesis. Herein we report a cobalt catalytic method for the formation of a three-
nitrogen-bearing benzotriazine scaffold via the coupling of arylhydrazine and oxadiazolone. This synthetic protocol features a low-
cost base metal catalyst, a maximum number of heteroatoms built into a heterocycle, a distinct synthetic logic for benzotriazines, a
superior step economy, and a broad substrate scope.
1,2,4-Triazines constitute an important class of heterocyclic
compounds that exhibit a broad spectrum of intriguing
biological, medicinal, electronic, and photonic properties.1 In
particular, the benzo-fused analogs, 1,2,4-benzotriazines
(referred to herein as benzotriazines), have witnessed
tremendous success in pharmacology and materials science
(Scheme 1a).2,3 Thus far, the vast majority of synthetic
methods rely on the complex multistep preassembly of an
open-chain molecular precursor before the final occurrence of
intramolecular ring-closure reaction. The earliest Bischler
synthesis4 proceeds via the initial flux reaction of o-nitro-
phenylhydrazine and formic acid and the subsequent intra-
molecular reductive cyclization. The classic Bamberger syn-
thesis involves the coupling of an aryldiazonium salt and the
hydrazone of pyruvic acid and the acid-driven intramolecular
cyclization.5 Many of the ensuing methods follow the same
synthetic logic, differing only by the synthetic course of how
the open-chain molecular precursor is assembled.6 The harsh
reaction conditions, low synthetic efficiency, and functional
group incompatibility issues have prompted the search for
alternative synthetic solutions.
not-self-evident rearrangement pathway.8 The highly speci-
alized preparative reagent, very narrow substrate scope, and
challenge in its routine implementation significantly limit its
synthetic practicality. The third type emulates yet contrasts
with the preassembly method by accommodating preassembly
and ring closure into a single cascade (Scheme 1b-I).9 An
apparent drawback of the protocol is the necessity of the
preinstallation of a halide group, an undesired synthetic aspect
that is often cited for compromising the step economy. The
fourth type fashions a radical cascade, C−H abstraction-based
ring-closure process (Scheme 1b-II).10 The harsh tert-butyl
peroxide oxidative condition and a relatively ill-defined
reaction course can hamper its utility in rational retrosynthetic
planning. In an effort to pursue a fundamentally different,
rational synthetic logic for benzotriazine and to push the limit
of the number of heteroatoms that can be incorporated into a
heterocycle in a transition-metal-catalyzed, directed intermo-
lecular C−H functionalization reaction, herein we report the
Received: May 24, 2021
Published: July 14, 2021
Four types of reactions have emerged in the quest for
innovative synthesis. The first type executes the synthesis via
the direct intermolecular compilation of a nonaromatic scaffold
and then, separately, aromatization.7 The second type achieves
the goal by committing the reaction course into an intuitively
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© 2021 American Chemical Society
Org. Lett. 2021, 23, 5652−5657
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group to a coupling partner, herein in hydrazine-directed C−H
functionalization reaction. Reaction development supports our
hypothetical analysis and the achievement of this reaction
course.
Scheme 1. Applications of Benzotriazines and Their
Synthetic Strategies
We commence our study by investigating the coupling
reaction between 1-methyl-1-phenylhydrazine (1a) and 3-
phenyl-1,2,4-oxadiazol-5(4H)-one (2a), drawn upon previ-
ously used metal/halide abstraction reagent/base/acid combi-
nations.11 The initial screening of a metal catalyst in
trifluoroethanol (TFE), with 1-adamantanecarboxylic acid
(AdCOOH, 20 mol %) and KOAc (30 mol %) as the
additives, indicates that [RhCp*Cl2]2 (2 mol %) and [Ru(p-
cymene)Cl2]2 (5 mol %) fail to effect any transformation after
20 h reaction at 120 °C in N2, whereas [CoCp*(CO)I2] (10
mol %) enables the formation of 3-phenyl-1,2,4-benzotriazine
(3aa) in 5% yield.16 The change of AdCOOH to AgOAc (20
mol %) increases the yield to 28%. The further addition of
AgSbF6 (20 mol %) leads to a 35% yield. The replacement of
KOAc with LiOAc (30 mol %) affords a 40% yield. The
switching of LiOAc to HOAc (1.2 equiv, 2.4 equiv) further
escalates the yield to 45 and 42%, respectively. Variation of the
quantity of AgOAc from 20 to 10 mol %, 1.0 equiv, and 2.0
equiv diminishes the yield to 38, 34, and 25%, respectively.
With [CoCp*(CO)I2] (10 mol %), AgOAc (20 mol %),
AgSbF6 (20 mol %), and HOAc (1.2 equiv) fixed, virtually no
reaction occurs in toluene, dichloroethane, methanol, 1,4-
dioxane, DMF, hexafluoroisopropanol, or N-methyl-2-pyrroli-
done. A final survey of the reaction temperature back in TFE
shows a 36% yield at 80 °C, a 52% yield at 100 °C, and a 60%
yield at 110 °C (referred to herein as the optimized reaction
conditions). The nonideal yield is likely caused by the
existence of side reactions, as evidenced by the faint spots
observed on the thin layer chromatography; however, no side
products can be structurally unambiguously assigned. A control
experiment using 1-phenylhydrazine in the replacement of 1a
leads to no product, emphasizing the importance of a methyl
group in this transformation. A 1 mmol scale experiment of 1a
and 2a currently stands at a yield of 42% for 3aa.
cobalt-catalyzed coupling of arylhydrazines and 1,2,4-oxadia-
zol-5(4H)-ones (referred to herein as oxadiazolones) that
provides convenient synthetic access to benzotriazines
(Scheme 1b).
Transition-metal-catalyzed, directed intermolecular C−H
functionalization has been increasingly utilized as an
indispensable tool for practicing synthetic chemistry.11 A key
challenge in this area is the expansion of the heterocycle
structural space via the simultaneous integration of multiple
heteroatoms from a C−H bond activation event. Indeed, the
bulk of the developed methods can only allow access to single-
heteroatom heterocycles,12 and the multiheteroatom hetero-
cycle synthesis is relatively unexplored. (One example is
cobalt-catalyzed entry into two nitrogen-containing pyrimi-
dines.13) For the construction of the three-heteroatom
heterocycle, one portion of the heteroatoms can originate
from the directing group, and the other portion needs to come
from the coupling partner. The coordination of the transition
metal from both portions of the heteroatoms can easily put the
reaction in the stalled state. To unleash the reactivity of two
coordinated heteroatom-containing structural motifs, a ther-
modynamically downhill pathway is desired that can both
expose the otherwise unreactive intermediate sites and drive
the reaction forward. In this context,14 we have developed the
use of hydrazine (N-amino) and oxadiazolone as directing
groups in rhodium- and cobalt-catalyzed C−H bond activation
and functionalization reactions.15 A tantalizing feature of
oxadiazolone is the ability to release CO2 as a catalytic step,
which fulfills the thermodynamic sink requirement, thus
potentially enabling the switching of its role from a directing
With the optimized reaction conditions in hand, we
examined the substrate scope for hydrazines by using 2a as
the coupling partner (Scheme 2). The reaction can proceed
equally efficiently with the change of the N-methyl group in 1a
to N-ethyl (1b) and N-n-pentyl (1c) groups, delivering the
a b
,
Scheme 2. Substrate Scope of Hydrazines
a
Reaction conditions: 1a−1j (0.24 mmol, 1.2 equiv), 2a (0.2 mmol,
b
1.0 equiv), TFE (2.0 mL), N2. Isolated yields.
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same product 3aa in 53 (3ba) and 56% (3ca) yields,
respectively. Single-crystal X-ray analysis unambiguously
confirms the structure of 3aa. This suggests the cleavage of
the N-alkyl bond as a crucial transformation step and the
absence of electronic and steric effects from the N-alkyl
substituent. In contrast, no product is detected for the
hydrazine bearing a second N-phenyl group, likely as a
consequence of conjugation stabilization. For the para
substituent on the phenyl ring, the electronic character can
slightly influence the reaction outcome. The electron-donating
methyl group (1d) exerts basically no impact on the product
yield (58%). The electron-withdrawing group decreases the
yield to the ∼50% level, and only a minute difference in the
product yield is observed. For the simple halide substituent, Cl
(1e, 53%) is superior to Br (1f, 47%) in imparting the
reactivity. Gratifyingly, the yield stands at 49% even for the
highly electron-withdrawing CF3 group (1g). For the meta
substitution, a single regioisomer is obtained, and the ring
closure occurs at the sterically less hindered site. The
electronic effect largely mirrors that of the para analog, with
the electron-rich group comparing favorably against the
electron-poor group. The product yield follows the descending
order of methyl (1h, 52%), Cl (1i, 49%), and Br (1j, 43%)
substitution. Under the reaction conditions used herein, the
ortho substitution and electron-rich methoxy group seem to
disfavor the target transformation. Thus a more thorough
search of the reaction space is warranted.
similar product yield, 53%, is acquired in the case of phenyl
substitution (2c). The methoxy group (2d) confers an
essentially identical reactivity as the unsubstituted one,
enabling the achievement of a 60% yield. The F group (2e)
retards the reaction and drops the yield to 42%. The Cl
substitution (2f) is higher yielding by ∼10% (53%). The
impact of meta-substituted CF3 (2o, 52%) is comparable to
that of the para analog (2h, 48%). The COOMe substitution
(2i) also provides a competent substrate, with the product
yield reaching 45%. The ortho substitution displays a
contrasting reactivity pattern. Although the F-substituted
oxadiazolone (2j, 53%) reacts efficiently, as expected, the Cl-
(2k, 51%) and Br-substituted (2l, 48%) oxadiazolones get both
halide groups extruded, thus affording product 3aa. Consid-
ering the retention of these two groups in the para
counterparts, a proximal metal coordination-mediated oxida-
tive addition mechanism or, alternatively, a steric repulsion-
induced instability effect is likely to be operating here. For the
meta substitution, the electron-donating group still excels over
the electron-withdrawing group. With the methoxy group
(2m), the product is obtained in 54% yield. With the F group
(2n), only a 43% yield is attained. In comparison, the CF3-
bearing oxadiazolone (2o) outperforms by ∼10% (52%). The
reaction also proceeds well for a variety of di- and
trisubstituted substrates. The attachment of an additional
meta methoxy group to 2m (2p, 58%) is beneficial for the
reaction. The substitution with a meta,para-disubstituted
methylenedioxy group (2q) causes a notable decrease in the
yield to 41%. An extra meta-F group on 2n (2r, 42%) imposes
virtually no influence on the product yield. The further
inclusion of a para-F group into 2r (2s) reverses the yield to
49%. The complete alteration of the phenyl ring to other
aromatic systems proves compatible with the transformation.
The synthetic efficiency is only slightly attenuated for the 1-
naphthyl ring (2t, 53%), whereas a vast reduction is witnessed
for the 2-thienyl ring (2u, 31%). Significantly, a direct linkage
to an alkene moiety also provides a viable substrate (2v, 52%);
however, the alkyl linkage completely impedes the reaction.
The ability to incorporate three nitrogen atoms into a
heterocyclic framework warrants a mechanistic understanding
(Scheme 4). 15N-labeling of 1a at the N2 site (1a-15N) allows
the tracing of the source of N2 in product 3aa. The reaction of
The substrate scope for oxadiazolones is then scrutinized by
reacting with 1a (Scheme 3). The synthesis exhibits
compatibility for a broad range of both electron-donating
and electron-withdrawing functional groups for the para
substitution on the phenyl ring. The reaction accomplishes a
52% yield for the methyl-substituted oxadiazolone (2b). A
a b
,
Scheme 3. Substrate Scope of Oxadiazolones
1
1a-15N and 2a generates a compound with H, 13C, and 15N
Scheme 4. Mechanistic and Derivatization Studies
a
Reaction conditions: 1a (0.24 mmol, 1.2 equiv), 2b−2v (0.20 mmol,
b
1.0 equiv), TFE (2 mL), N2. Isolated yields.
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NMR spectra identical to those of 3aa and a single 15N NMR
signal, consistent with the formation of 3aa-15N. In addition,
high-resolution mass spectrometry (HRMS) also signified the
generation of 3aa-15N. This supports the conclusion that the
two neighboring nitrogen atoms, N1 and N2, are both derived
from the hydrazine group (Scheme 4, panel 1). As a further
proof of the feasibility of retention of the N−N bond and
demethylative aromatization, a reaction between 1a and 2-
diazo-5,5-dimethylcyclohexane-1,3-dione (5) under rhodium
catalysis affords 6 as the product (Scheme 4, panel 2). In
addition, the viability of demethylative aromatization is also
supported by a previous observation in the manganese-
mediated oxidation of aporphines.17
arylhydrazines and oxadiazolones. The ability to simulta-
neously incorporate three heteroatoms into a heterocyclic ring
system demonstrates the synthetic prowess of C−H bond
activation chemistry and allows the expansion of chemical
space through a straightforward, rational synthetic logic.
ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01741.
Experimental procedures and full analysis data for new
compounds (PDF)
On the basis of this, we infer that aromatization can be a
driving force for the demethylation process (Scheme 5). The
Accession Codes
CCDC 2087643−2087644 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Scheme 5. Proposed Reaction Mechanism
AUTHOR INFORMATION
Corresponding Author
■
Jin Zhu − Department of Polymer Science and Engineering,
School of Chemistry and Chemical Engineering, State Key
Laboratory of Coordination Chemistry, Nanjing University,
Nanjing 210023, China; orcid.org/0000-0003-4681-
7895; Email: jinz@nju.edu.cn
Authors
Weiping Wu − Department of Polymer Science and
Engineering, School of Chemistry and Chemical Engineering,
State Key Laboratory of Coordination Chemistry, Nanjing
University, Nanjing 210023, China
Shuaixin Fan − Department of Polymer Science and
Engineering, School of Chemistry and Chemical Engineering,
State Key Laboratory of Coordination Chemistry, Nanjing
University, Nanjing 210023, China
Tielei Li − Department of Polymer Science and Engineering,
School of Chemistry and Chemical Engineering, State Key
Laboratory of Coordination Chemistry, Nanjing University,
Nanjing 210023, China
Lili Fang − Department of Polymer Science and Engineering,
School of Chemistry and Chemical Engineering, State Key
Laboratory of Coordination Chemistry, Nanjing University,
Nanjing 210023, China
Benfa Chu − Department of Polymer Science and Engineering,
School of Chemistry and Chemical Engineering, State Key
Laboratory of Coordination Chemistry, Nanjing University,
Nanjing 210023, China
following catalytic pathway is therefore proposed:14f−i
Abstraction of the iodide ligand from [CoCp*(CO)I2] by
AgSbF6 and AgOAc furnishes [CoCp*(CO)(OAc)2] (I) as the
catalytically active species. C−H bond activation of 1a by I
gives a five-membered cobaltacycle II. Coordination of 2a onto
II affords III. 1,1-Migratory insertion of III delivers a six-
membered cobaltacycle IV, with the concomitant ring opening
of oxadiazolone and the liberation of CO2. Proto-demetalation
releases an open-chain intermediate V and regenerates I.
Nucleophilic attack of hydrazine on imine closes the ring and
breaks the C−N bond for V, resulting in the creation of VI.
Demethylative aromatization of VI provides 3aa as the
product. An alternative mechanistic pathway might involve
cobalt-imido-based 1,1-migratory insertion;18 however, the
mere trace formation of 3aa from 1a and 3-phenyl-1,4,2-
dioxazol-5-one seems to argue against such a proposal.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01741
As a demonstration of the ability to further expand the
structural space of benzotriazines, derivatization is performed
through triazine-directed C−H activation.19 ortho-C−H
acetoxylation (3aa to 7, 3at to 9) and benzoylation (3aa to
8) can be facilely achieved on the three-aromatic ring under
palladium catalysis (Scheme 4, panel 3).
In summary, a cobalt-catalyzed, directed intermolecular C−
H bond functionalization strategy has been developed for the
synthesis of benzotriazines, via the coupling reaction between
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
J.Z. gratefully acknowledges support from the National Natural
Science Foundation of China (21774056, 52073141) and the
Science and Technology Department of Jiangsu Province
(BK20181255).
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Phenyl-1,2,4-triazoline-3,5-dione (PTAD) as a dienophilic dinitrogen
equivalent: A simple synthesis of 3-amino-1,2,4-benzotriazines from
arylcarbodiimides. Eur. J. Org. Chem. 2010, 2010, 694−704.
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