Towards a Sequential One-Pot Preparation of 1,2,3-Benzotriazin-4(3H)-ones Employing a Key Cp*Co(III)-catalyzed C?H Amidation Step

Article abstract of DOI:10.1002/adsc.201800133

1,2,3-benzotriazin-4(3H)-one derivatives have been recognised for their potential application as pesticides and pharmaceuticals and new methodologies for their preparation, starting from readily accessible reagents would therefore be an attractive proposition. A wide range of differently substituted benzamides are readily available, which provide an excellent substrate scaffold for the application of direct C?H functionalization protocols. In this context, herein we report the use of a Cp*Co(III) catalyst for the amidation of these benzamides, using 1,4,2-dioxazol-5-ones as amidating agent. The isolable intermediate 2-acetamido benzamide products can thereafter be converted to the desired 1,2,3-benzotriazin-4(3H)-one derivatives through the use of tert-butyl nitrite under mild conditions. It was found to be possible to perform the second step with the crude reaction mixture obtained from the initial C?H amidation step, leading to the overall development of a facile one-pot procedure for the preparation of a range of substituted 1,2,3-benzotriazin-4(3H)-one derivatives, requiring only 5 hours of reaction time, which is also applicable on a gram scale. In addition, the key Cp*Co(III)-catalyzed C?H amidation step has been studied by DFT calculations in order to fully elucidate the mechanism. (Figure presented.).

Full text of DOI:10.1002/adsc.201800133

Title: Towards a Sequential One-Pot Preparation of 1,2,3-
Benzotriazin-4(3H)-ones Employing a Key Cp*Co(III)-catalyzed
C-H Amidation Step
Authors: Paula Chirila, Lauren Skibinski, Keith Miller, Alex Hamilton,
and Christopher Whiteoak
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800133
Link to VoR: http://dx.doi.org/10.1002/adsc.201800133

10.1002/adsc.201800133
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Towards a Sequential One-Pot Preparation of 1,2,3-
Benzotriazin-4(3H)-ones Employing a Key Cp*Co(III)-
catalyzed C-H Amidation Step
Paula G. Chirila,a Lauren Skibinski,a Keith Miller,a Alex Hamiltona*and Christopher J.
Whiteoaka*
a
Department of Biosciences and Chemistry and the Biomolecular Sciences Research Centre (BMRC), Sheffield Hallam
University, Sheffield, S1 1WB, United Kingdom.
E-Mail: c.whiteoak@shu.ac.uk or a.hamilton@shu.ac.uk
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. 1,2,3-benzotriazin-4(3H)-one derivatives have through the use of tert-butyl nitrite under mild conditions. It
been recognised for their potential application as pesticides was found to be possible to perform the second step with
and pharmaceuticals and new methodologies for their the crude reaction mixture obtained from the initial C-H
preparation, starting from readily accessible reagents would amidation step, leading to the overall development of a
therefore be an attractive proposition. A wide range of facile one-pot procedure for the preparation of a range of
differently substituted benzamides are readily available, substituted
1,2,3-benzotriazin-4(3H)-one
derivatives,
which provide an excellent substrate scaffold for the requiring only 5 hours of reaction time, which is also
application of direct C-H functionalization protocols. In this applicable on a gram scale. In addition, the key Cp*Co(III)-
context, herein we report the use of a Cp*Co(III) catalyst for catalyzed C-H amidation step has been studied by DFT
the amidation of these benzamides, using 1,4,2-dioxazol-5- calculations in order to fully elucidate the mechanism.
ones as amidating agent. The isolable intermediate 2-
acetamido benzamide products can thereafter be converted
to the desired 1,2,3-benzotriazin-4(3H)-one derivatives
Keywords: 1,2,3-benzotriazin-4(3H)-ones; C-H
functionalization; cobalt; amidation; cyclization
(a) Chang, Jiao, Ackermann, Sundararaju, Dixon
Introduction
O
R
NH
O
Cp*Co(III)
+
O
R
H
R
O
N
Formation of C-N bonds is one of the most important,
yet challenging, transformations in synthetic organic
chemistry.[1] Traditionally, both Ullman and
Buchwald-Hartwig cross-couplings have provided the
most successful routes for the preparation of these
important bonds.[2,3] Although well established and
used extensively, these methodologies suffer a major
drawback, in that a pre-functionalized starting
material is required. In this context, and with the
explosion of research in the field of direct C-H
functionalization,[4] much attention is now beginning
to focus on the development of novel C-N bond
forming reactions through direct C-H activation
approaches.[5]
R
(b)
Li, Zhu
O
O
O
NMe2
Cp*Co(III)
+
O
NMe2
R
O
R
NH
N
H
R
O
R
O
One-pot approach
HCl or TMSOTf
R
N
H
(c)
This work:
O
O
O
R
R
N
Cp*Co(III)
+
O
N
R
H
O
R
H
NH
N
H
O
O
One-pot approach
TBN/AcOH
R
N
R
N
N
Bearing in mind that the well-established
Buchwald-Hartwig methodology is based on
relatively expensive palladium catalysis, more
recently, focus has also begun to switch to the
application of cheaper, more abundant, first row
transition metals, such as iron, nickel and cobalt.[6] As
a result of this, particularly since the publication by
Kanai and Matsunaga on the powerful Cp*Co(III)
catalyst for C-H functionalization protocols in
1,2,3-Benzotriazin-4(3H)-one
Scheme 1. (a) general scheme for Cp*Co(III)-catalyzed
amidation of C-H bonds with 1,4,2-dioxazol-5-ones. (b)
Example of one-pot approaches to preparation of
quinolone products simultaneously reported by Li and Zhu.
(c) The sequential one-pot protocol reported in this work
for conversion of benzamides to 1,2,3-benzotriazin-4(3H)-
ones using Cp*Co(III) catalysis and tert-butyl nitrite
(TBN).
2013,[7]
functionalization has started to
high-valent
cobalt-catalyzed
C-H
1
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800133
Advanced Synthesis & Catalysis
Table 1. Optimization studies for Cp*Co(III)-catalyzed synthesis of 2-acetamido-N-isopropylbenzamide.a
[Cp*Co(CO)I2] (8.0 mol%)
O
O
silver salt (16 mol%)
base (20 mol %)
O
N
O
+
H
N
O
H
N
solvent, T [oC]
NH
H
O
1
1a
Entry
Silver salt
Base
Solvent [mL]
T [oC]
1a [%]b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
AgNTf2
AgOTf
Ag2O
AgBF4
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
-
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgOTf
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOPiv
CsOAc
Na2CO3
K3PO4
NaOAc
-
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
1,2-DCE [2]
1,2-DCE [2]
1,2-DCE [2]
1,2-DCE [2]
1,2-DCE [2]
1,2-DCE [2]
1,2-DCE [2]
1,2-DCE [2]
1,2-DCE [2]
1,2-DCE [2]
1,2-DCE [2]
1,2-DCE [2]
1,2-DCE [2]
Toluene [2]
1,4-Dioxane [2]
1,2-DCE [4]
1,2-DCE [2]
80
80
80
80
80
80
80
80
80
80
80
90
60
80
80
80
80
64
23
trace
65
66
42
24
63
50
trace
40
62
60
19
13
78 (77)c
23
a)
General conditions: 0.5 mmol N-isopropylbenzamide, 8.0 mol% [Cp*Co(CO)I2], 16 mol% silver salt, 20 mol% base,
1.20 equiv. 3-methyl-1,4,2-dioxazol-5-one, 2 mL solvent, T [oC], 16 hours. Yields of 1a calculated from H NMR of
b)
1
crude reaction mixture using mesitylene as internal standard. c) Yield after 4 hours.
attract significant attention, providing a wide range of
coupling protocols.[8] In the field of C-N bond
formation, several groups have successfully
could then be combined in a one-pot manner. Herein,
we report the results from this study, providing a
novel sequential one-pot procedure for the
preparation of 1,2,3-Benzotriazin-4(3H)-ones using
tert-butyl nitrite as key reagent in the second reaction.
1,2,3-benzotriazin-4(3H)-ones are a family of
heterocyclic compounds, which have been recognized
for their potential application as pesticides and
medicines, although their synthesis can be
challenging.[14] Besides their use as pesticides and
medicines, they have also been studied as useful
developed
and
applied
Cp*Co(III)-catalyzed
protocols.[9-11] One of the most intriguing protocols to
be developed involves the use of readily available,
easy to handle and bench-top stable, 1,4,2-dioxazol-
5-ones (Scheme 1a).[11] These coupling partners are
easily prepared on a gram scale and when employed
in C-H functionalization protocols, only carbon
dioxide is released as waste.
In our current research, we are focused on
developing efficient routes to more valuable
heterocyclic compounds starting from cheap, readily
available, benzamide substrates. Amides are of
interest as they are excellent directing groups for a
range of C-H functionalization protocols.[12] Indeed,
we have recently reported a facile preparation of
azepinones using acrolein as coupling partner starting
from these benzamides.[13]
precursors
for
Ni(0)-catalyzed
heterocycle
preparation.[15] Previously, these compounds have
been synthesized using a variety of complex multi-
step syntheses or from substrates which show limited
availability for diversity. The new facile approach for
their preparation described in this report would
therefore present an attractive proposition and
improve their accessibility, likely resulting in
widened applications.[16]
Recently, both the groups of Li and Zhu
simultaneously reported the one-pot preparation of
quinolone compounds using Cp*Co(III) catalysis,
aryl enaminone substrates and 1,4,2-dioxazol-5-ones
(Scheme 1b).[11j,k] It was possible to isolate the
intermediate amidation products, before a facile
second reaction takes place, which furnishes the
quinolone products. With this approach in mind, we
decided to further develop and apply the Cp*Co(III)-
catalyzed amidation of benzamides reported by
Chang,[11a] before developing a second reaction which
Results and Discussion
We initiated our studies with the optimization of the
C-H amidation coupling of N-isopropyl benzamide, 1,
with 3-methyl-1,4,2-dioxazol-5-one using the
[Cp*Co(CO)I2] catalyst, optimizing silver salt, base,
solvent, reaction temperature and time (Table 1). The
methyl substituted 1,4,2-dioxazol-5-one was selected,
2
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800133
Advanced Synthesis & Catalysis
[Cp*Co(CO)I2] (8.0 mol %)
AgSbF6 (16 mol %)
O
O
O
N
NaOAc (20 mol %)
O
R
H
N
+
O
R
H
N
NH
1,2- DCE, 80 o
4h
C
H
O
x
xa
O
O
O
O
O
O
N
H
N
N
N
N
N
H
H
H
H
H
NH
NH
NH
NH
N
NH
O
NH
O
O
2a: 77%
O
O
O
O
6a: 70%
5a: 90%
1a: 78%
3a: 81%
4a 72%
O
O
O
O
O
O
O
N
H
N
N
N
N
N
N
H
H
H
H
H
H
S
NH
F3CS
NH
I
NH
Br
NH
F3C
NH
NH
NH
O
O
O
O
O
O
O
7a: 89%
8a: 81%
9a: >99%
10a: 45%
11a: 70%
12a: 83%
13a: 62%
O
F
O
O
O
I
O
O
O
F
F
S
O
N
H
NH
N
N
H
N
H
NH
N
H
NH
N
N
H
H
H
NH
NC
NH
NH
NH
F
O
O
O
O
O
O
O
14a: 75%
15a 58%
16a: 43%
17a: Traces
18a: Traces
19a: Traces
20a: Traces
Scheme 2. Substrate scope studying the effect of variation in substituent on the aromatic moiety of the N-isopropyl
benzamide under the optimized reaction conditions; Isolated yields reported. General conditions: 1.5 mmol benzamide
substrate, 8.0 mol% [Cp*Co(CO)I2], 16 mol% AgSbF6, 20 mol% NaOAc, 1.20 equiv. 3-methyl-1,4,2-dioxazol-5-one, 24
mL
1,2-DCE,
80
oC,
4
hours.
although Chang previously observed that this was not
the optimal 1,4,2-dioxazol-5-one,[11a] as the objective
was to further react the amide in a second reaction
and
However, inclusion of cyano at the para-position
prevented the formation of the desired amidation
product, 19a. This is likely due to the competitive
coordination to the Cp*Co(III) catalyst with the
necessary substrate binding site, thus inhibiting the
amidation reaction.
The protocol also displayed meta-substituent
tolerance affording high yields for both fluoro- and
methyl-substitution in a regioselective manner (13a,
14a). The fluoro-substituted substrate was found to
react at the most sterically hindered site, whereas the
methyl-
through use of the methyl, the mass loss will be
reduced, increasing the sustainability of the
process.[17] For note, in our hands, the 3-phenyl-1,4,2-
dioxazol-5-one yielded
a
slightly decreased
conversion (63%) compared to the 3-methyl-1,4,2-
dioxazol-5-one (Scheme 2; 78%) under our optimized
conditions.
The optimized conditions were found to be similar
to those reported by Chang,[11a] although as might be
expected, upon use of increased catalyst loading it
was found that the reaction was complete in a
significantly shorter time of 4 hours (Table 1, entry
16). Decreased catalyst loadings resulted in decreased
yields (see supporting information, Table S5). In
addition to this, an increased yield was obtained when
the solvent was increased from 2.0 to 4.0 mL (Table
1, entry 5 vs. entry 16). For full details on the
optimization of the reaction conditions see the
Supporting Information.
With the optimized conditions in hand, the
substrate scope was studied, broadening the scope
reported by Chang (Scheme 2). Electron-withdrawing
groups at the para-position afforded good to excellent
yields for both weakly (8a, 9a and 10a) and highly
deactivating groups (11a). The addition of electron-
donating groups at the para position also delivered
high yields of amidation products for weakly (2a, 3a,
4a and 12a) and highly (5a, 6a) activating groups.
[Cp*Co(CO)I2] (8.0 mol %)
AgSbF6 (16 mol %)
NaOAc (20 mol %)
O
O
O
R
N
R
O
H
N
+
O
H
N
1,2- DCE, 80 o
4h
C
NH
H
O
x
xa
Cl
O
O
O
O
N
H
NH
N
N
H
NH
N
H
H
NH
NH
O
O
O
O
21a: 77%
22a: 78%
23a: 20%
24a: 30%
O
O
O
O
O
O
N
H
N
H
N
H
N
H
NH
NH
NH
NH
O
O
O
O
25a: 78%
26a: 62%
27a: 19%
28a: 20%
3
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800133
Advanced Synthesis & Catalysis
Scheme 3. Substrate scope studying the effect of variation
in substituent on the nitrogen atom of the benzamide under
the optimized reaction conditions. General conditions: 1.5
mol% AgSbF6, 20 mol% NaOAc, 1.20 equiv. 3-methyl-
1,4,2-dioxazol-5-one, 24 mL 1,2-DCE, 80 C, 4 hours.
o
mmol benzamide substrate, 8.0 mol% [Cp*Co(CO)I2], 16
O
O
R
N
TBN, AcOH
75 oC, 1h
R
R
N
H
R
NH
N
N
O
xa
xb
O
O
O
O
O
O
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
H
N
N
N
O
N
1b: 98%
2b: 80%
3b: 83%
4b: 84%
5b: 45%
6b: 98%
O
O
O
O
O
O
O
N
N
N
N
N
N
N
N
N
N
N
N
N
N
F3CS
N
F3C
N
S
N
I
N
Br
N
N
N
7b: 89%
8b: 80%
9b: 87%
10b: 90%
11b: 73%
12b: >99%
13b: 79%
O
N
F
O
O
N
O
O
N
O
N
O
N
O
F
S
N
N
N
N
N
N
N
N
N
N
N
N
N
N
F
N
N
F
14b: 90%
15b: 72%
16b: 50%
21b: 25%
22b: 98%
25b: 98%
26b: 98%
Scheme 4. Substrate scope studying the effect of variation in substituent on the aromatic moiety of the N-isopropyl
benzamide and substituent on the nitrogen atom of the benzamide under the optimized reaction conditions; Isolated yields
o
reported. General conditions: 1.0 mmol amidated benzamide, 3.0 equiv. TBN, 3.0 mL AcOH, 75 C, 1 hour.
was decreased to fluoro, the amidation reaction
proceeded in good yield (15a).
Table 2. Effect of reaction temperature variation on
conversion of 1a to 1,2,3-benzo-triazin-4(3H)-one.a
Thereafter, the effect of replacing the isopropyl
amide with other substituents was studied (Scheme 3).
Methyl, tert-butyl, cyclohexyl and tetrahydropyranyl
were tolerated providing the corresponding amidated
products, 21a, 22a, 25a and 26a, in similar yield to
the isopropyl derivative. On the other hand, aromatic
substituents provided the desired amides, 23a, 24a,
27a and 28a, in relatively poor yield. It was found
that at the end of the reaction, there was a complex
mixture between the desired amidation product and
also the amidation of the amide substituent, and
additionally a product displaying amidation of both
the aromatic moieties. We have attempted to isolate
all these products and their characterization is
included in the Supporting Information. This
observation is not unexpected as Chang also reported
amidation of acetanilides under the optimized
reaction conditions.[11a] However, the results showed
that the selectivity could be slightly controlled to
afford a higher yield of the desired product by the
addition of an electron-withdrawing groups at the
para-position of the phenylamine. Consequently,
adding a halogen at the para position affords a higher
yield of 24a compared to 23a.
O
O
TBN
AcOH
N
H
N
T [oC]
NH
N
N
O
1b
1a
Entry
T[oC]
Yield of 1,2,3-Benzo-triazin-4(3H)-
one [%]b
1
2
3
25
50
75
25
75
98
a)
General conditions: 1.0 equiv. 1a, 3.0 equiv. TBN, 3.0
mL AcOH, T, 1 hour. b) Yields of 3a calculated from crude
1H NMR using mesitylene as internal standard.
substituted substrate was found to react at the least
sterically hindered C-H. This regioselectivity is the
same as we have observed in our previous Cp*Co(III)
coupling of methyl vinyl ketone with benzamides and
has been previously reported by several groups
working
with
meta-substituted
aromatic
compounds.[13,18] In addition, the thiophene derivative
could also be converted to furnish the corresponding
amidation product, 16a.
With a library of 2-acetamido benzamides in hand
and with an interest in conversions utilizing tert-butyl
nitrite (TBN) we were pleased to see that upon
reacting 2-acetamido-N-isopropylbenzamide, 1a, with
When substituents were included in the ortho-
position of the benzamide substrate, in the case of
methyl- or iodo- (17 and 18), no amidation product
was obtained. However, when the size of substituent
o
TBN in acetic acid (AcOH) at 75 C, an intriguing
transformation towards the cyclic 1,2,3-benzo-triazin-
4
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800133
Advanced Synthesis & Catalysis
4(3H)-one was observed, in excellent yield (98%).
Reducing the temperature at which this conversion is
carried out, decreases the yield of 1,2,3-benzo-triazin-
4(3H)-one obtained (Table 2). AcOH was chosen as
solvent as in previous work we have observed that
highly reactive species are formed from the
degradation of tert-butyl nitrite to nitrogen oxide.[19]
Typically 1,2,3-benzo-triazin-4(3H)-ones can be
Figure 1. Solvent corrected Free Energy Surface (ΔG298 kcal mol-1) for the amidation of isopropyl benzamide with 3-
methyl-1,4,2-dioxazol-5-one. Free energies taken relative to the [Cp*Co(III)(AcO)2] pre-catalyst and associated reagents.
With the new facile protocol for the conversion of
[Cp*Co(CO)I2] (8.0 mol %)
AgSbF6 (16 mol %)
2-acetamido-N-isopropylbenzamide, 1a, to 1,2,3-
NaOAc (20 mol %)
O
O
O
1,2-DCE, 80 o
C
benzo-triazin-4(3H)-one developed, all the remaining
2-acetamido benzamides previously obtained were
converted (Scheme 4). Substituents at the para-
position of the original benzamide afforded excellent
yields of the desired products (2b, 3b, 4b, 6b, 8b, 9b,
10b and 11b). Intriguingly, 5b was obtained as the
secondary amine which may result from dealkylation
of the dimethylamine in the presence of tert-butoxy
radical.[21] High yields of 1,2,3-Benzotriazin-4(3H)-
one were also obtained for compounds bearing meta-
substituents (13b, 14b). A lower yield of 50% was
observed when the thiophene substrate was applied.
Furthermore, 21b was converted in low yield
compared to 1b and 22b. This is proposed to result
from a less stable intermediate during the reaction
with TBN.
N
N
O
4h
R
O
H
R
+
N
N
H
N
TBN, AcOH
75 oC, 1h
x
xb
O
O
N
O
N
N
N
N
N
N
N
N
1b: 45%
2b: 50%
13b: 45%
O
O
Gram scale reaction:
N
N
O
N
N
N
F3C
N
O
N
N
N
11b: 40%
6b: 70%
1b: 58%
Inspired by the work of Zhu and Li,[11j,k] we
attempted to synthesize some of our target molecules
in a sequential one-pot protocol, to eliminate the need
for intermediate work-up. The development of one-
pot protocols is highly attractive and attracting
increased attention.[22] The obtained yields after one
pot reaction with 1b, 2b, 6b, 11b, and 13b (Scheme
5) were comparable to the overall yields of the
combined individual steps and exemplify the
application of a facile sequential one-pot protocol for
the preparation of 1,2,3-benzo-triazin-4(3H)-ones
using Cp*Co(III) C-H functionalization catalysis as
the key step. To explore the scalability of the new
sequential one-pot protocol, a gram scale conversion
was attempted. We were delighted to observe an
Scheme 5. Examples of conversions of benzamides
towards 1,2,3-benzo-triazin-4(3H)-ones by a sequential
one-pot protocol developed in this work (including a gram
scale synthesis of 1b from 1g of benzamide 1): Isolated
yields reported. General conditions: Optimized reaction
conditions for each individual step.
prepared through the reaction of methyl-2-
aminobenzoate with sodium nitrite.[20] This route
limits the facile inclusion of substituents on the
aromatic ring, whereas the newly developed protocol
described in this report provides a methodology for a
wide substituent scope.
5
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800133
Advanced Synthesis & Catalysis
overall yield of 58%, highlighting the potential of this
new synthetic protocol. This yield is slightly higher
than the smaller scale reactions (45%) likely as a
result of the easier isolation of larger amounts of
product.
∇2 ρ and V(r) all highlight increased stabilization of
the imido-like transition state structure for the
Cp*Ir(III) catalyst (see supporting information for
full details).
At first glance this proposal for the migratory
insertion being the rate determining step contradicts
the experimentally obtained KIE results, however
taking into account the reversibility of the initial C-H
activation step having the potential to limit the
equilibrium concentration of the following
intermediates prior to this migratory insertion, a
relatively small KIE is not unexpected.[26]
The insertion step leads to Int4 with a significant
stabilization in energy. Which is in agreement with
the observed irreversibility of the reaction after the
loss of CO2. Entropically unfavorable addition of an
acetic acid to the coordination site weakly associated
to the benzamide oxygen affords Int5. Coordination
of the acetic acid facilitates the last step of the
reaction, which is the protonation of the newly
installed amide group, with a barrier of 7.8 kcal mol-1,
forming Int6.
To further understand the initial Cp*Co(III)-
catalyzed amidation step, both deuterium exchange
and parallel Kinetic Isotope Effect (KIE) experiments
were performed (Scheme 6). The results obtained
(a) H/D exchange
[Cp*Co(CO)I2] (8.0 mol %)
AgSbF6 (16 mol %)
NaOAc (20 mol %)
D
O
H
O
N
H
N
H
D
1,2- DCE/CD3OD (2 mL/0.1 mL)
80 oC, 4h
50% D incorporation
H
a
a[D2]
(b) KIE study
[Cp*Co(CO)I2] (8.0 mol %)
AgSbF6 (16 mol %)
NaOAc (20 mol %)
O
O
O
N
O
H
N
H
+
O
H5/D5
N
1,2- DCE, 80 o
4h
C
NH
O
a or a[D5]
1a or 1a[D5]
KIE = 2.09
Parallel experiments
Dissociation of Int6 releases the 2-acetamido
benzamide product and regenerates the active
[Cp*Co(OAc)]+ catalyst, completing the catalytic
cycle. This mechanism is also in agreement with the
DFT study provided by Kim and Chang for the
amidation of arylpyridines under Cp*Rh(III) catalysis
using the same 1,4,2-dioxazol-5-one amidating agents,
although the energies are not directly comparable due
to the different substrates being used.[27,28] For
completeness, the triplet surface was also analyzed
for this mechanism, with all structures being
significantly higher in energy, see supporting
information for full details. Scheme 7 summarizes the
proposed catalytic cycle for the formation 2-
acetamido benzamides using both the experimental
and the DFT results obtained in this study.
Scheme 6. Experimental insights into mechanism of the
Cp*Co(III)-catalyzed C-H amidation step.
demonstrate that the C-H activation step is clearly
reversible and that C-H cobaltation is kinetically
relevant in the rate-determining step of the
mechanism.
In addition to the experimental results, and in order
to gain an in-depth insight into the mechanism of
formation for the new C-N bond, DFT calculations
were carried out (Figure 1). The formation of the
cationic active catalyst [Cp*Co(OAc)]+ species forms
as a result of the loss of acetate ion from the neutral
[Cp*Co(OAc)]2 pre-catalyst.[23] Subsequently, the
[Cp*Co(OAc)]+ coordinates to the lone pair of the
oxygen of the isopropyl benzamide substrate to form
the first intermediate (Int1). This is in agreement
with our previous DFT study.[13] Subsequent C-H
activation leads to the 5 membered cobaltacycle, Int2.
This C-H activation step takes place via an energy
barrier of 21.5 kcal mol-1. Loss of acetic acid and
coordination of the amidating agent, dioxazolone,
yields Int3.
2 OAc-
2 AgSbF6
[Cp*Co(CO)I2
]
[Cp*Co(CO)](SbF6
)
[Cp*Co(OAc)2
- OAc-
]
2
-
- 2AgI
- 2 SbF6
Generation of cationic catalyst species
O
O
+
R
N
R
N
H
OAc
H
H
NH
O
Co
*Cp
Cp*
The following migratory insertion of the 1,4,2-
dioxazol-5-one, with formation of the new C-N bond
and concomitant loss of CO2, into the Co(III)-C bond
is the rate determining step for the reaction with a
barrier of 25.2 kcal mol-1. It should be noted that a
stepwise barrier has also been calculated and is 0.5
kcal mol-1 higher in the energy. Interestingly, both the
Cp*Co(III)-catalyzed concerted and stepwise
mechanisms are significantly higher in energy than
the equivalent Cp*Ir(III)-catalyzed CO2 extrusion
reported by Chang for the same benzamide
substrates.[24] In an effort to understand this difference
between the two catalyst systems QTAIM[25]
topological analysis of the equivalent transition state
structures was carried out. The bond critical point
connecting the metal and the 1,4,2-dioxazol-5-one
nitrogen was located and the QTAIM parameter for ρ,
Substrate coordination
+
Co OAc
O
+
R
OAc
N
H
Co
O
*Cp
NH
R
N
H
O
H
Proto-demetallation
CMD step
+
Cp*
Co
+
O
AcOH
O
N
O
*Cp
R
Co
R
N
H
N
H
AcOH
Dioxazolone insertion
CO2
O
O
O
N
6
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800133
Advanced Synthesis & Catalysis
provide the analytically pure 1,2,3-benzo-triazin-4(3H)-
Scheme 7. Proposed catalytic cycle for Cp*Co(III)-
catalyzed coupling of 1,4,2-dioxazol-5-ones and
benzamides for the preparation of 2-acetamido benzamides.
one product
Sequential one-pot procedure for conversion of
benzamides to 1,2,3-benzotriazin-4(3H)-ones
The mechanism for the conversion of 2-acetamido
benzamides to the corresponding 1,2,3-benzotriazin-
4(3H)-ones is less clear. It is well known that alkyl
nitrites are a source of nitrogen oxide (NO)[29] and it
is likely that this species reacts with the amide of the
2-acetamido benzamides generating a highly reactive
N-nitrosoamide intermediate, reported recently by
Bhanage.[30] This intermediate is thereafter able to
cyclize, furnishing the observed heterocyclic products.
Under air, a 20 mL vial was charged with benzamide (0.5
mmol), [Cp*Co(CO)I2] (8.0 mol%, 0.04 mmol), AgSbF6
(16 mol%, 0.08 mmol), NaOAc (20 mol%, 0.10 mmol), 3-
methyl1,4,2-dioxazol-5-one (1.2 equiv., 0.6 mmol) and
1,2-DCE (8 mL). The vial was sealed and the mixture was
stirred at 80 oC for 4 hours. After this time, the solvent was
evaporated under reduced pressure and tert-butyl nitrite
(3.0 equiv., 1.5 mmol) and AcOH (3.0 mL) were added to
the crude reaction mixture. The reaction was then stirred at
o
75 C for a further 1 hour. The AcOH was then removed
under reduced pressure and the crude was purified by
column chromatography using hexane/EtOAC (1/1) as
eluent to provide the analytically pure 1,2,3-benzo-triazin-
4(3H)-one.
Conclusion
1
Full characterization data (including original H, 13C {1H},
19F {1H} and COSY NMR for all products) can be found in
the Supporting Information.
In summary, we have demonstrated that using a
[CoCp*(CO)I2] catalyst, a wide library of substituted
benzamides can be successfully amidated employing
readily available 3-methyl-1,4,2-dioxazol-5-one.
Furthermore, we have disclosed a novel approach to
synthesize valuable 1,2,3-benzotriazin-4(3H)-ones
from the intermediate 2-acetamido-N-benzamides
through a single step reaction using TBN. The two
steps can be combined to provide a sequential one-
pot synthesis of 1,2,3-benzotriazin-4(3H)-ones,
starting from the readily available and cheap
benzamides. Finally, the mechanism of the
Cp*Co(III)-catalyzed C-H amidation step has been
elucidated for the first time using DFT studies,
wherein it has been found that despite an
experimentally obtained KIE of 2.09, the migratory
insertion is the rate limiting step. This observable
KIE arises from the reversibility of the C-H
cobaltation step.
Computational details
All DFT calculations undertaken using the ORCA 3.03
computational software. Optimisations were performed at
the BP86-D3BJ/def2-TZVP level of theory and final single
point energies and solvation corrections calculated at
M06/def2-TZVP. Frequencies calculations approximated
the ZPE correction and entropic contributions to the free
energy term as well as confirming all intermediate were
true with no imaginary modes and all transition states had
the correct critical frequency of decomposition (imaginary
mode). Solvation correction was implemented with the
COSMO model for 1,2-DCE. Graphical visualisation using
Gabedit 2.4.8 and Avogadro 1.2.0 programs. For full
computational details see the Supporting Information.
Acknowledgements
The authors would like to thank the Department of Biosciences
and Chemistry and the Biomolecular Sciences Research Centre
(BMRC) at Sheffield Hallam University for funding. We would
also like to thank Dr Daniel Allwood from Sheffield Hallam
University for his insightful comments. CJW and PGC would also
like to thank COST Action CA15106 (CHAOS) for funding and
providing a fruitful platform for discussion.
Experimental Section
General procedure for amidation of benzamides
Benzamide substrate (1.5 mmol), [Cp*Co(CO)I2] (8.0
mol%, 0.12 mmol), AgSbF6 (16 mol%, 0.24 mmol),
NaOAc (20 mol%, 0.30 mmol), 3-methyl-1,4,2-dioxazol-
5-one (1.2 equiv., 1.8 mmol) and 1,2-DCE (24 mL) were
added to a 40 mL vial under air. The vial was sealed, and
the mixture stirred at 80 oC for 4 hours. The crude reaction
mixture was purified by column chromatography, using
hexane/EtOAc (8/2) as eluent to provide the analytically
pure amidation product.
References
[1](a) R. Hili, A. K. Yudin, Nat. Chem. Biol., 2006, 2, 284.
(b) J. Bariwalab, E. Van der Eycken, Chem. Soc. Rev.,
2013, 42, 9283.
[2] G. Evano, N. Blanchard, M. Toumi, Chem. Rev., 2008,
108, 3054.
General procedure for synthesis of 1,2,3-benzotriazin-
4(3H)-ones from the amidated benzamides
[3] P. Ruiz-Castillo, S. L. Buchwald, Chem. Rev., 2016,
116, 12564.
To an 8 mL vial, under air, was added amidated benzamide
(1.0 mmol), AcOH (3.0 mL) and tert-butyl nitrite (3.0
equiv., 3.0 mmol). The vial was sealed, and the reaction
[4] a) J. Wencel-Delord, F. Glorius, Nat. Chem., 2013, 5,
369. b) C-H Bond Activation in Organic Synthesis (Ed.:
J. J. Li), 2015, CRC Press, Boca Raton, FL. c) H. M. L.
Davies, D. Morton, J. Org. Chem., 2016, 81, 343. d) H.
Yi, G. Zhang, H. Wang, Z. Huang, J. Wang, A. K.
o
mixture was stirred at 75 C for 1 hour. After this period,
the acetic acid was removed under reduced pressure and
the crude reaction mixture was purified by column
chromatography using hexane/EtOAc (1/1) as eluent to
7
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800133
Advanced Synthesis & Catalysis
Singh, A. Lei, Chem. Rev., 2017, 117, 9016. e) J.-P.
X.-Y. Liu, ACS Catal., 2016, 6, 3496. d) V. H. Thorat,
N. S. Upadhyay, M. Murakami, C.-H. Cheng, Adv.
Synth. Catal., 10.1002/adsc.201701143
Wan, L. Gan, Y. Liu, Org. Biomol. Chem., 2017, 15,
9031. f) Y. Qin, L. Zhu, S. Luo, Chem. Rev., 2017, 117,
9433.
[16] For an example of the potential of 1,2,3-benzotriazin-
4(3H)-ones as precursors for accessing more complex
compounds see: J. J. A. Campbell, S. J. Noyce, R. C.
Storr, J. Chem. Soc., Chem. Commun., 1983, 22, 1344.
[5] a) J. Jiao, K. Murakami, K. Itami, ACS Catal., 2016, 6,
610. b) K. Shin, H. Kim, S. Chang, Acc. Chem. Res.,
2015, 48, 1040.
[6] G. Pototschnig, N. Maulide, M. Schnürch, Chem. Eur.
J. 2017, 23, 9206.
[17] P Anastas, N. Eghbali, Chem. Soc. Rev., 2010, 39,
301.
[7] T. Yoshino, H. Ikemoto, S. Matsunaga, M. Kanai,
[18] See for examples: a) T. Gensch, S. Vásquez-Céspedes,
D.-G. Yu, F. Glorius, Org. Lett., 2015, 17, 3714. b) J.
Li, L. Ackermann, Chem. Eur. J., 2015, 21, 5718. c) Y.
Bunno, N. Murakami, Y. Suzuki, M. Kanai, T. Yoshino,
S. Matsunaga, Org. Lett., 2016, 18, 2216. d) B. Sun, T.
Yoshino, M. Kanai, S. Matsunaga, Angew. Chem. Int.
Ed., 2015, 54, 12968.
Angew. Chem. Int. Ed., 2013, 52, 2207.
[8] For an overview of cobalt-catalyzed C-H
functionalization, see: a) M. Moselage, J. Li, L.
Ackermann, ACS Catal., 2016, 6, 498. b) D. Wei, X.
Zhu, J.-L. Niu, M.-P. Song, ChemCatChem, 2016, 8,
1242. c) T. Yoshino, S. Matsunaga, Adv. Synth. Catal.,
2017, 359, 1245. d) S. Wang, S.-Y. Chen, X.-Q. Yu,
Chem. Commun., 2017, 53, 3165. e) P. G. Chirila, C. J.
Whiteoak, Dalton Trans., 2017,46, 9721. f) T. Yoshino,
S. Matsunaga, Adv. Organomet. Chem., 2017, 68, 197.
g) S. Prakash, R. Kuppusamy, C.-H. Cheng,
ChemCatChem, 2018, 10, 683.
[19] C. J. Whiteoak, O. Planas, A. Company, X. Ribas,
Adv. Synth. Catal., 2016, 358,1679.
[20] T. S. Ibrahim, A. A. Rashad, Z. K. Abdel-Samii, S. A.
El-Feky, M. K. Abdel-Hamid, W. Barakat, Med. Chem.
Res., 2012, 21, 4369.
[21] For an example of the tert-butoxy radical involved in
demethylation of alkyl amines see: R. K. Kawade, D. B.
Huple, R.-J. Lin, R.-S. Liu, Chem. Commun., 2015, 51,
6625.
[9] For examples using azides as coupling partners see: a)
B. Sun, T. Yoshino, S. Matsunaga, M. Kanai, Adv.
Synth. Catal., 2014, 356, 1491. b) B. Sun, T. Yoshino,
S. Matsunaga, M. Kanai, Chem. Commun., 2015, 51,
4659.
[22] For examples and a discussion the advantages of one-
pot procedures see: Y. Hayashi, Chem. Sci., 2016, 7,
866
[10] For an example using carbamates as amidating agents
see: P. Patel, S. Chang, ACS Catal., 2015, 5, 853.
[23] For an example of a DFT study where cationic
cobalt(III) species has been proposed as the active
catalyst see: S. Qu, C. J. Cramer, J. Org. Chem., 2017,
82, 1195.
[11] For examples using 1,4,2-dioxazol-5-ones as
amidating agents see: a) J. Park, S. Chang, Angew.
Chem. Int. Ed., 2015, 54, 14103. b) Y. Liang, Y. Liang,
C. Tang, Y. Yuan, N. Jiao, Chem. Eur. J., 2015, 21,
16395. c) X. Wang, A. Lerchen, F. Glorius, Org. Lett.,
2016, 18, 2090. d) R. Mei, J. Loup, L. Ackermann,
ACS Catal., 2016, 6, 793. e) F. Wang, H. Wang, Q.
Wang, S. Yu, X. Li, Org. Lett., 2016, 18, 1306. f) N.
Barsu, M. A. Rahman, M. Sen, B. Sundararaju, Chem.
Eur. J., 2016, 22, 9135. g) X. Yu, Q. Ma, S. Lv, J. Li, C.
Zhang, L. Hai, Q. Wang, Y. Wu, Org. Chem. Front.,
2017, 4, 2184. h) J. Huang, Y. Huang, T. Wang, Q.
Huang, Z. Wang, Z. Chen, Org. Lett., 2017, 19, 1128.
i) P. W. Tan, A. M. Mak, M. B. Sullivan, D. J. Dixon, J.
Seayad, Angew. Chem. Int. Ed., 2017, 56, 16550. j) F.
Wang, L. Jin, L. Kong, X. Li, Org. Lett., 2017, 19,
1812. k) P. Shi, L. Wang, K. Chen, J. Wang, J. Zhu,
Org. Lett., 2017, 19, 2418.
[24] Y. Hwang, Y. Park, S. Chang, Chem. Eur. J., 2017, 23,
11147.
[25] T. Lu, F. Chen, J. Comput. Chem., 2012, 33, 580.
[26] For a discussion on the interpretation of KIE values in
transition metal-catalyzed C-H functionalization, see: E.
M. Simmons, J. F. Hartwig, Angew. Chem. Int. Ed.,
2012, 51, 3066.
[27] Y. Park, K. T. Park, J. G. Kim, S. Chang, J. Am.
Chem. Soc., 2015, 137, 4534.
[28] It appears from a review of the literature that the
significance of the C-H cobaltation step as the rate-
determining step varies widely with substrate; for
example, the KIE for arylpyridines and anilides
observed experimentally by Chang was 1.1 and 3.8,
respectively, from parallel experiments. See Ref 11a.
[12] R.-Y. Zhu, M. E. Farmer, Y.-Q. Chen, J.-Q. Yu,
Angew. Chem. Int. Ed. 2016, 55, 10578.
[13] P. G. Chirila, J. Adams, A. Dirjal, A. Hamilton, C. J.
[29] Tert-butyl nitrite is a known source of nitrogen
monoxide, see: P. G. Wang, T. B. Cai, N. Taniguchi,
in: Nitric Oxide Donors: for Pharmaceutical and
Biological Application, (Eds.: P. G. Wang, T. B. Cai, N.
Taniguchi), Wiley-VCH, Weinheim, 2005.
Whiteoak, Chem. Eur. J., 2018, 24, 3584.
[14] Z. Khalid, H. A. Ahmad, M. A. Munawar, M. Khan,
S. Gul, Heterocycles, 2017, 94, 3.
[15] a) T Miura, M Yamauchi, M. Murakami, Org. Lett.,
2008, 10, 3085. b) T. Miura, M. Morimoto, M.
Yamauchi, M. Murakami, J. Org. Chem., 2010, 75,
5359. c) N. Wang, S.-C. Zheng, L.-L. Zhang, Z. Guo,
[30] S. L. Yedage, B. M. Bhanage, J. Org. Chem., 2017,
82,
5769.
8
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800133
Advanced Synthesis & Catalysis
FULL PAPER
Towards a Sequential One-Pot Preparation of 1,2,3-
Benzotriazin-4(3H)-ones Employing a Key
Cp*Co(III)-catalyzed C-H Amidation Step
O
R
N
R
H
H
Adv. Synth. Catal. 2018, Volume, Page – Page
tBuONO
Cp*Co(III)
O
O
O
Paula G. Chirila, Lauren Skibinski, Keith Miller,
Alex Hamilton* and Christopher J. Whiteoak*
N
O
N
R
N
R
N
9
This article is protected by copyright. All rights reserved.