Selective Oxidative Decarbonylative Cleavage of Unstrained C(sp3)-C(sp2) Bond: Synthesis of Substituted Benzoxazinones

Article abstract of DOI:10.1021/acs.orglett.6b02142

A transition metal (TM)-free practical synthesis of biologically relevant benzoxazinones has been established via a selective oxidative decarbonylative cleavage of an unstrained C(sp³)-C(sp²) bond employing iodine, sodium bicarbonate, and ^tbutyl hydroperoxide in DMSO at 95 °C. Control experiments and Density Functional Theory (DFT) calculations suggest that the reaction involves a [1,5]H shift and extrusion of CO gas as the key steps. The extrusion of CO has also been established using PMA-PdCl₂.

Full text of DOI:10.1021/acs.orglett.6b02142

Letter
pubs.acs.org/OrgLett
Selective Oxidative Decarbonylative Cleavage of Unstrained C(sp3)−
C(sp2) Bond: Synthesis of Substituted Benzoxazinones
Ajay Verma and Sangit Kumar*
Department of Chemistry, IISER Bhopal, Bhopal By-pass Road, Bhauri, Bhopal, Madhya Pradesh, 462066, India
S
* Supporting Information
ABSTRACT: A transition metal (TM)-free practical synthesis of
biologically relevant benzoxazinones has been established via a
selective oxidative decarbonylative cleavage of an unstrained C(sp3)−
t
C(sp2) bond employing iodine, sodium bicarbonate, and butyl
hydroperoxide in DMSO at 95 °C. Control experiments and Density
Functional Theory (DFT) calculations suggest that the reaction
involves a [1,5]H shift and extrusion of CO gas as the key steps. The extrusion of CO has also been established using PMA−
PdCl2.
evelopment of environmentally transcendent, operation-
ally simple, and efficient strategies for the construction of
Beller et al. described a Pd-catalyzed carbonylative synthesis of
benzoxazinones from 2-bromoanilines using carbon monoxide
(Scheme 1).9a Recently, the formation of benzoxazinones has
D
privileged molecular skeletons continues to attract broad
interest.1 Transition metal (TM)-free reactions have attracted
considerable attention from researchers because such method-
ologies avoid expensive and limited feedstocks of metals. Further,
the removal of toxic heavy metals from the relevant drug
molecules is challenging.2 However, selectivity is one of the
issues in TM-free reactions, particularly; the cleavage of
unstrained C−C bonds has been a critical issue due to its
uncontrollable selectivity and needed attention. Iodine3 and
peroxide4 mediated reactions are the alternatives for the selective
cleavage of C−C bonds for the synthesis of various heterocyclic
molecules. Extensive research has been carried out for the
cleavage of strained C−C bonds;5 nonetheless, only a few reports
are available for the selective cleavage of C(sp3)−C(sp2) bonds
for the C−O bond formation.6
Scheme 1. Synthetic Routes to Benzoxazinones
The benzoxazinone core is found in many drug molecules
which possess various biological activities, namely serine
protease inhibitor, antiobesity, inhibitors of human leukocyte
elastase, and suicide inactivation of chymotrypsin inactivators
(Figure 1).7 Moreover, these moieties are intermediates for the
been realized from azidoalkynes and CO gas, catalyzed by
palladium(II) nitrate hydrate. Nonetheless, synthesis of the
substrates involves multiple steps.9b Moreover, there is a lack of
synthesis of substituted benzoxazinones from unactivated and
halogen-free readily accessible substrates under mild reaction
conditions. TM-free cleavage of a C−C bond has been
accomplished in various substrates.3f,6a,f Nonetheless, the
formation of CO has not been established. In continuation of
our work13 on TM-free synthesis via C−C13a and C−X (X = N, S,
Se, Te)13b−d oxidative coupling reactions, herein, we disclose a
practical synthetic method for the synthesis of substituted
benzoxazinones from readily accessible N-(2-acetylphenyl)aryl/
alkylamides 1 by the selective oxidative cleavage of an unstrained
C(sp3)−C(sp2) bond using iodine and TBHP under mild
reaction conditions.
Figure 1. Biologically active substituted benzoxazinones.
synthesis of various molecules such as benzoxazinethiones,
benzothiazinethiones, substituted amidobenzoates, 4-hydroxy-
quinolinones, and quinazolinones.8 Various methods have been
developed for the synthesis of benzoxazinones by organic and
medicinal chemists which involved the TM-catalyst and carbon
monoxide gas,9 halogenated substrates,10,11 and anhydrides.12
Received: July 20, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02142
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Synthesis of benzoxazinone 2a from N-(2-acetylphenyl)-2-
methylbenzamide 1a was optimized by screening various bases
and oxidants in different solvents at different temperatures
(Table 1). Initially, we applied iodine promoted C−N coupling
Scheme 2. Substrate Scope for 2-Aryl Benzoxazinones
a
Table 1. Optimization of Reaction Conditions
entry
bases
oxidants
DTBP
temp
yield, 2a/3
b
1
K2CO3
140
95
95
95
95
95
95
95
95
95
95
95
95
95
95
0/0
2
3
4
5
6
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
K2CO3
H2O2(aq)
Na2S2O8
K2S2O8
PhI(OAc)2
TBHP(aq)
TBHP
−
nd
nd
nd
15/60
26/54
72/10
nd/trace
69/10
nd/60
nd/80
nd/70
93/0
70/20
55/10
b
7
b
8
b
K2CO3
9
K2CO3
TBHP
c
10
K2CO3
−
−
−
c
11
KOtBu
12
KOtBu
13
NaHCO3
NaHCO3
NaHCO3
TBHP
TBHP
TBHP (3 equiv)
d
14
15
a
Reactions were carried out with 0.16 mmol of 1a, 0.08 mmol of I2,
0.16 mmol of a base, and 0.96 mmol of oxidant in 1.5 mL of anhydrous
DMSO. 2 equiv of I2 was used. Absence of I2. 0.2 equiv of I2 was
used. nd = not detected.
a
b
c
d
Reactions were carried out using 0.3 mmol of 1, 0.15 mmol of I2, 0.3
mmol of NaHCO3, and 1.8 mmol of TBHP in DMSO.
reaction conditions (entry 1);13b unfortunately, none of the
expected products 2a, 3, and 4 was observed, and substrate 1a
was recovered from the reaction mixture. Among various
screened oxidants (entries 2−6), DTBP, aq. H2O2, and
M2S2O8 (M = Na and K) failed to facilitate the decarbonylative
coupling reaction. PhI(OAc)2 and aqueous TBHP provided
benzoxazinone 2a in 15% and 26% yields along with undesired
aldol 2-(o-tolyl)quinolin-4(1H)-one 3 in 60% and 54% yields,
respectively (entries 5 and 6). Anhydrous TBHP led to further
improvement in the yield by 46%; however, 2-phenylquinolin-
4(1H)-one 3 was also formed albeit in low yield (entry 7).
Among various bases (entries 8−11), NaHCO3 was found to be
superior. Potassium tert-butoxide along with iodine, which could
form iodide and tbutoxyl radicals, also failed to yield any 2a, and
instead 3 was obtained exclusively (entry 12). The use of 50 mol
% of iodine together with NaHCO3 provided exclusive formation
of 2a (entry 13). Further reduction in the iodine loading to 20
mol % was not effective as this provided 2a in low yield (70%)
and also undesired 3 in 20% yield (entry 14). Worth noting, a
base, iodine, and TBHP are crucial for the reaction, as the
absence of any one of them failed to yield benzoxazinone 2a. The
temperature ranging from 90 to 100 °C was noted to be optimum
for the reaction. An excess of anhydrous TBHP seems necessary
for the quantitative yield of benzoxazinone 2a (entry 13 vs 15).
With the optimized conditions in hand, a variety of N-(2-
acetylphenyl)-2-methylbenzamide substrates 1b−1za were ex-
plored for decarbonylative coupling between acetyl and amide
moieties. As shown in Scheme 2, various benzamide ring
substituted benzoxazinones 2b−2za with electron-donating
methyl, tert-butyl, methoxy, and dimethoxy as well as electron-
withdrawing halogens, CF3, and nitro at different positions of the
benzamide ring were obtained without a significant difference in
the isolated yields. Benzoxazinone 2b has also been synthesized
practically in gram quantity in overall 76% yield. ortho-Iodo-
substituted benzoxazinone 2q possessing C1r protease inhibition
activity7c was synthesized in 88% yield under the decarbonylative
coupling reaction. Similarly, biologically relevant biaryl benzox-
azinone 2w was obtained. Further, molecule 2x with a bis-
benzoxazinones moiety, which could be used as a ligand for
various metals complexation,14 has been isolated in 87% yield.
Substitution in the benzamide ring of 2′-aminoacetophenones
with dimethoxy, dioxole groups also proceeded in the decarbon-
ylative C−O coupling reaction to generate electron-rich
benzoxazinones 2y−2za in 78−89% yields. Structures of
benzoxazinones 2i and 2p are well established by single crystal
X-ray crystallography (Figure 2).15
Next, heterocyclic amides namely 2-furan as well as 2- and 3-
thiophenes successfully underwent the TM-free decarbonylative
coupling reaction and resulted in heterocyclic benzoxazinones
5a−5c in 88−90% yields (Figure 3). Similarly, primary,
secondary, and tert-alkyl amides smoothly experienced decarbon-
Figure 2. ORTEP diagrams of benzoxazinone 2i and 2p.
B
DOI: 10.1021/acs.orglett.6b02142
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Figure 4. Qualitative analysis for the extrusion of CO gas.
Acetylphenyl)benzamide undergoes α-iodination followed by
Kornblum oxidation that led to 2-oxoacetyl intermediate I.16b
Figure 3. Substrate scope for heteroaryl/alkyl benzoxazinones.
Scheme 5. Plausible Reaction Mechanism
ylation followed by a C−O coupling reaction to form 2-alkyl-4H-
benzo[d][1,3]oxazin-4-ones 5d−5h.
Further, synthesized benzoxazinones have been functionalized
to ethyl-2-arylamidobenzoate 6a and 6b in 90% and 86% yield,
respectively, using ethanol and pyridine (1:1) in a sealed tube at
120 °C for 10 h (Scheme 3). Benzoxazinones can also be
transformed into biologically imperative quinazolinones.8
Scheme 3. Postsynthetic Modification
Mechanistic insights are gained by conducting several control
experiments, and DFT calculations (Scheme 4). Reaction of N-
a
Calculated relative Gibbs’ free energy (ΔGo in kcal mol−1) obtained
at the DFT-B3LYP/6-311+G(d,p)/CPCM, (LanL2DZ for iodine)
level of theory. Energy barrier of key steps (III−V).
Scheme 4. Characterization of Intermediates by ES-MS
The generated HI in the step oxidized to molecular iodine by
DMSO (see SI p S30). The resulting 2-oxoacetyl I could react
with iodine in the presence of NaHCO3 to give N-iodo-oxoacetyl
II. The presence of NaHCO3 seems crucial to this trans-
formation, as in its absence benzoxazinone cannot be realized. N-
Iodo-oxoacetyl II would produce amidyl radical III in the
presence of TBHP.13b Translocation of the radical to the
carbonyl carbon by a [1,5]H shift should furnish carbon-centered
radical IV, which transforms to another carbon-centered radical
V by CO elimination. An intramolecular transfer of the radical to
the amidic carbonyl carbon would provide cyclized radical VI.
The abstraction of a hydrogen atom by a tbutoxy radical or the N-
iodo-oxoacetyl II intermediate would furnish the desired
benzoxazinone.
Additionally, we complemented the proposed mechanism
with DFT computations, to study key intermediates and
transition states involved in the reaction in DMSO solvent (see
SI p S35−47). The negative Gibbs free energy changes for III−
VI except II are indicative of the thermodynamic feasibility of the
reaction (Scheme 5). The [1,5]H-shift and evolution of CO gas
seem to be crucial steps in the transformation and could occur
through transition states TS-III and TS-IV, respectively. The
energies barriers (ΔG#) for these steps are +16.00 and +10.71
kcal mol−1, respectively, which could be achievable under the
reaction conditions.3k
(2-acetylphenyl)benzamide 1b with iodine in DMSO gave 2-
oxoacetyl intermediate 7.16 Subsequently, the addition of TBHP
and NaHCO3 to in situ formed 7 provided benzaldehyde 8 and
benzoxazinone 2b by an evolution of CO gas. The addition of
TEMPO to the reaction mixture yielded TEMPO-coupled
products 9 and 10 along with benzoxazinone 2b as analyzed by
high-resolution mass spectrometry (see Supporting Information
pp S30−S34).
Evolution of CO gas from the reaction mixture was confirmed
by phosphomolybdic acid (PMA)−PdCl2 solution (Figure 4 and
a short movie is attached to SI p S29). PMA [H3PO4(MoVIO3)12]
oxidizes evolved CO gas into CO2 in the presence of catalyst
PdCl2, and yellow PMA reduced into a blue-green colored
mixed-valence heteropolymolybdate complex (MoVI MoV).17
The generated CO gas can be exploited in the synthesis of
various natural products via a carbonylation reaction.18
Based on control experiments, a plausible mechanism for the
decarbonylative reaction is depicted in Scheme 5. N-(2-
In summary, we have presented a practical synthetic method
for the preparation of diversely substituted benzoxazinones from
N-(2-acetylphenyl)benzamide via oxidative decarbonylative
cleavage of an unstrained C(sp3)−C(sp2) bond avoiding
C
DOI: 10.1021/acs.orglett.6b02142
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
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The Supporting Information is available free of charge on the
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Experimental details, spectroscopic data, mass spectra
(PDF)
X-ray crystallographic data for 2i [CCDC No. 1474945]
(CIF)
X-ray crystallographic data for 2p [CCDC No. 1474944]
(CIF)
AUTHOR INFORMATION
Corresponding Author
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*E-mail: sangitkumar@iiserb.ac.in.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
S.K. thanks DST-SERB New Delhi (EMR/2015/000061), IISER
Bhopal for generous funding and Miss Dimple Pawar for mass
experiments. A.V. acknowledges UGC, New Delhi for fellowship,
IISER Bhopal for computation facility.
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