Radical-Induced, Palladium-Catalyzed C–H Activation: An Approach to Functionalize 4H-Benzo[d][1,3]oxazin-4-one Derivatives by Using Toluenes, Aldehydes, and Benzyl Alcohols

Article abstract of DOI:10.1002/ejoc.201800263

Toluenes, aldehydes, and benzyl alcohols have been utilized in the radical-induced direct functionalization of 4H-benzo[d][1,3]oxazin-4-one derivatives by using a palladium-catalyzed C–H activation strategy. The stability, low toxicity, and ease of access

Full text of DOI:10.1002/ejoc.201800263

A Journal of
Accepted Article
Title: Radical-Induced, Palladium-Catalyzed C-H activation: A New
Approach to Functionalize 4H-Benzo[d][1,3]oxazin-4-one
Derivatives with Toluenes, Aldehydes and Benzyl Alcohols
Authors: Prashant Kumar, Mohit Gupta, Vijay Bahadur, Virinder S.
Parmar, and Brajendra Kumar Singh
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800263
Link to VoR: http://dx.doi.org/10.1002/ejoc.201800263
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10.1002/ejoc.201800263
European Journal of Organic Chemistry
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Radical-Induced, Palladium-Catalyzed C-H activation: A New
Approach to Functionalize 4H-Benzo[d][1,3]oxazin-4-one
Derivatives with Toluenes, Aldehydes and Benzyl Alcohols
Prashant Kumara, Mohit Guptaa, Vijay Bahadura,b, Virinder S. Parmara,c and Brajendra K. Singha,*
aBioorganic Laboratory, Department of Chemistry, University of Delhi, Delhi 110 007, India
bSRM University Delhi-NCR, Sonepat, Haryana 131 029, India
cDepartment of Chemistry, Central University of Haryana, Mahendragarh, Haryana 123 031, India
*Corresponding-Author. Tel: +91-11-27666646, Ext: 136, Fax: +91-11-27667206, E-mail address:
singhbk@chemistry.du.ac.in (Dr. Brajendra Kumar Singh); URL: http://people.du.ac.in/~singhbk/
alcohols in metal catalyzed C-H functionalization processes,
Abstract: In the present work, toluenes, aldehydes and benzyl
however there are still several areas which need to be explored
further towards their application in C-C and C-N bond formation
reactions for the synthesis of structurally diverse interesting
scaffolds.
alcohols have been exploited in the radical-induced direct
functionalization of heterocyclic molecules, in particular 4H-
benzo[d][1,3]oxazin-4-one derivatives via the palladium-catalyzed C-
H activation strategy. Greater stability, low toxicity and the easy
access to toluenes, aldehydes and benzyl alcohols have made them
suitable candidates for this transformation. The reaction in general
proceeded smoothly and afforded the desired products in moderate
to good yields with high functional group compatibility. Mechanistic
investigations have illustrated the radical pathway and have
highlighted the importance of both catalyst and oxidant.
4H-Benzo[d][1,3]oxazin-4-one represents ubiquitous and highly
significant scaffold, widely spread in natural products, drugs and
pharmacologically active compounds with interesting biological
properties.7 Interestingly, 4H-benzo[d][1,3]oxazin-4-one is a key
pharmacophore of the drug (under phase-III clinical trial) cetilistat,
being developed as an anti-obesity agent.8 Some derivatives of
4H-benzo[d][1,3]oxazin-4-one have been found to display various
biological activities such as antimicrobial,9 inhibitors of HSV-1
protease,10 inhibitors of human Chymase,11 serine protease
inhibitors,12 potent inhibitors of DAPK (death-associated protein
kinase),13 inhibitors of leucocyte clarase, etc.14 Although, the
synthesis of 4H-benzo[d][1,3]oxazin-4-one and its derivatives15
have received significant attention, however simple and general
route for the direct functionalization of 4H-benzo[d][1,3]oxazin-4-
one is still unknown. In this regard, very recently, Majhi et al. have
Introduction
In the past decade, remarkable progress has been made on the
transition metal catalyzed direct oxidative carbon-carbon and
carbon-heteroatom bond formation reactions via the C-H
activation strategies because of the accompanied atom-economy,
fewer reaction steps and utilization of readily available cheap
starting materials.1 Amongst several substrates explored till date,
toluenes, aldehydes and benzyl alcohols have gained
considerable attention as elegant reaction partners in the direct
functionalization of important organic molecules owing to their
exceptional advantages such as high stability, low toxicity and
easy availability.2-4 Moreover, these substrates do not require any
pre-functionalization when used as reaction coupling partners and
thus have changed the landscape of organic synthesis.5 Recently,
they have been extensively employed in directing group assisted
catalytic and selective acylation of numerous aromatic systems
as they provide a sustainable strategy for atom-economical C-C
bond formation protocols.6 Although, tremendous progress has
been made in the application of toluenes, aldehydes and benzyl
reported
the
first
regioselective
acylation
of
4H-
benzo[d][1,3]oxazin-4-one derivatives with -oxo carboxylic acids
using Pd-catalyzed cyclic imine-N-directed C-H activation
approach.16 Although this group has developed a new strategy for
the direct functionalization of 4H-benzo[d][1,3]oxazin-4-ones,
however the use of additional co-catalyst AgNO3, low atom-
economy and limited substrate scope is bottleneck to this protocol.
Our group is currently involved in developing novel approaches
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10.1002/ejoc.201800263
European Journal of Organic Chemistry
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for sustainable chemical approaches towards the synthesis of
bioactive molecules.17 In continuation of this endeavor, we report
herein (Scheme 1) a general, expedient and simple method for
the direct C-H functionalization of 4H-benzo[d][1,3]oxazin-4-one
derivatives using abundantly and easily available substrates such
as toluenes, aldehydes and benzyl alcohols as reaction partners,
Pd-catalyst and a radical-inducer oxidant to synthesize 6a-
phenyl-5H-benzo[4,5][1,3]oxazino[2,3-a]isoindole-5,11(6aH)-
diones,18 analogues of biologically significant molecules.19
screened solvents gave improved yield (Table 1, entries 2-8).
However, when toluene was used as solvent, slight improvement
in the product yield was observed (Table 1, entry 9).
Subsequently, various oxidants were screened (Table 1, entries
10-14) and we observed that TBHP is the most effective oxidant
(Table 1, entry 9). Moreover, amongst other screened oxidants
such as TBPB, K2S2O8, DTBP and H2O2, etc., only TBPB provided
the desired product 3a in 7% yield along with 45% hydrolyzd
product (Table 1, entries 11). Rest of the oxidants yielded only
the hydrolyzed product along with the starting materials and failed
to deliver the desired product 3a (Table 1, entries 12-14). Further,
various salts of metals like Pd, Cu, Ni and Co were screened to
influence this transformation (Table 1, entries 15-20). None of
them, except palladium salts yielded the desired product.
Amongst the screened Pd-salts, Pd(OAc)2 showed the best result
and yielded the desired product 3a in 40% yield (Table 1, entry
9). It is interesting to mention here that in all the screened systems,
formation of the hydrolyzed product 4a was observed (Table 1).
Scheme
1.
Synthesis
of
6a-phenyl-5H-
by
benzo[4,5][1,3]oxazino[2,3-a]isoindole-5,11(6aH)-diones
radical-induced catalytic direct C-H functionalization of 4H-
benzo[d][1,3]oxazin-4-ones.
Table 1. Optimization of reaction conditions.a
Although, few reports are available towards the synthesis of
similar types of compounds, however these protocols suffer from
several serious limitations such as pre-functionalization of starting
materials, poor substrate scope, use of ligand and toxic reagents
like CO gas, etc.20 To the best of our knowledge, this is the first
report exploiting toluenes, aldehydes and benzyl alcohols for the
Entry
Catalyst
(mol%)
Oxidant
(mmol)
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHPf
TBPB
DTBP
H2O2
Solvent
Yield
(%)b 3a
32
Yieldb
(%)b 4a
28
1
2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
DCE
DCM
direct
functionalization
of
4H-benzo[d][1,3]oxazin-4-one
16
35
derivatives involving a simple and general radical promoted, Pd-
catalyzed protocol.
c
3
CH3CN
1,4-Dioxane
DMSO
DMF
-
15
4
30
25
d
5
-
10
d
6
-
12
c
7
H2O
-
10
Results and Discussion
c
8
EtOH
-
10
e
We began our investigation by testing the reaction between
commercially available or easily prepared 2-phenyl-4H-
benzo[d][1,3]oxazin-4-one (1a, 0.5 mmol) 16 and toluene (2a) (2
mL, 15 mmol) using 3 mol% of Pd(OAc)2 and 70% aqueous tert-
butyl hydrogen peroxide solution (TBHP) (6 mmol) as a radical
initiator oxidant in 1,2-dichloroethane (DCE, 0.5 mL). These
9
-
40
33
7
20
e
10
11
12
13
14
15
16
17
18
19
20
-
30
e
-
45
e
d
-
-
30
e
d
-
-
35
e
d
K2S2O8
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
-
-
20
e
-
27
31
15
e
o
Pd(TFA)2
CuO
-
20
reactants were stirred at 80 C for 18 h. The experimental result
e
d
-
-
35
revealed that the product 3a could be obtained in 32% yield along
with a highly valuable hydrolyzed product21 4a (28%) (Table 1,
entry 1). The formation of the product 3a encouraged us to make
the reaction conditions better to furnish improved product yield by
firstly screening several solvents. Disappointingly, none of the
e
d
Cu(OAc)2.H2O
CoCl2
-
-
40
e
d
-
-
45
e
d
NiCl2
-
-
45
aReaction conditions: a mixture of 2-phenyl-4H-benzo[d][1,3]oxazin-4-one (1a)
(0.5 mmol), toluene (2a) (2 mL, 15 mmol), catalyst (3 mol%), oxidant (6 mmol)
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10.1002/ejoc.201800263
European Journal of Organic Chemistry
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in the indicated solvent (0.5 mL) was stirred at 80 oC for 18 h; bisolated yields;
cproduct was obtained in traces; ddesired product 3a formation was not
observed, only the starting materials and hydrolyzed product 4a were obtained
after 24 h; etoluene (2 mL, 15 mmol) was used as solvent; fTBHP in decane.
cisolated yields; d4a was isolated in 7% yield; e1.5 mL (11 mmol) of toluene was
used.
With the aim to generalize and expand the substrate scope of this
newly developed protocol, different toluene derivatives were
treated with 2-phenyl-4H-benzo[d][1,3]oxazin-4-one (Table 3). All
the toluene derivatives yielded the targeted products in good
yields and unsubstituted toluene provided the highest product
yield (75%) among all the screened toluene derivatives (Table 3,
entry 1). This protocol nicely tolerated both kinds of substituents,
i.e. electron withdrawing as well as electron donating functional
groups on the benzene ring (Table 3, entries 2-6).
We also evaluated the effect of catalyst concentration to improve
the yield of compound 3a and observed that the product yield
significantly increased from 40% to 62% on increasing the
concentration of Pd(OAc)2 from 3 mol% to 5 mol% (Table 2, entry
1). However, further increase in the catalyst concentration had an
adverse effect on the reaction (Table 2, entry 2). Then the role of
the reaction temperature was explored. On increasing the
reaction temperature, the product yield increased and at 120 oC,
the targeted product 3a was obtained in 75% yield along with 7%
of hydrolyzed produt 4a (Table 2, entries 3 and 4), however any
further increase in temperature retarded the product yield (Table
2, entries 5 and 6). Further, the effect of reaction time,
concentration of TBHP and toluene was examined. Any change,
increase or decrease either in reaction time or in TBHP
concentration had an adverse effect on the outcome of the
reactions (Table 2, entries 7-11). Moreover, decreasing the
amount of toluene decreased the product yield (Table 2, entry
12).
Table 3. Substrate scope of toluenes and 2-phenyl-4H-benzo[d][1,3]oxazin-4-
ones.a,b
Entry
R1
R2
R3
Product
Yield (%)c
3/4
1
2
H
H
H
H
H
2-Cl
4-Cl
2-F
4-F
4-OCH3
H
3a/4a
3b/4a
3c/4a
3d/4a
3e/4a
3f/4a
75/7
52/16
54/14
56/13
65/14
52/18
60/19
52/18
38/22
64/19
3
H
H
Table 2. Effect of temperature, time and concentration of Pd(OAc)2 and TBHP
on the reaction yield.a
4
H
H
5
H
H
6
H
H
7
5-Br
4-Br
H
H
3g/4b
3h/4c
3i/4d
8
H
H
9
4-Cl
4-CH3
H
10
H
H
13j/4e
aReaction conditions: a mixture of 2-phenyl-4H-benzo[d][1,3]oxazin-4-ones (1)
(0.5 mmol), toluenes (2) (2 mL, 15 mmol), Pd(OAc)2 (5 mol%); 70% aqueous
TBHP (6 mmol) was stirred at 120 oC temperature for 18h; bisolated yields.
Entry
Pd(OAc)2
TBHP
Time
(h)
18
18
18
18
18
18
15
24
18
18
18
18
Temp.
(oC)
80
Yield (%)c
3a
(mol %)
(mmol)
1
2
5
7
5
5
5
5
5
5
5
5
5
5
6
6
6
6
6
6
6
6
4
5
8
6
62
80
53
It was observed that the para-halo substituted toluenes provide
better product yield as compared to ortho-halo substituted
toluenes and that could be because of steric hindrance caused by
the substituent at the ortho-position (Table 3, entries 2-5). It was
further noticed that the fluoro derivatives were more effective as
compared to chloro ones and that could be because of higher
electronegativity of fluorine. The substrate scope of variously
substituted 2-phenyl-4H-benzo[d][1,3]oxazin-4-ones with toluene
was also investigated and we found that 2-phenyl-4H-
benzo[d][1,3]oxazin-4-one derivatives have good compatibility
under these reaction conditions. The substituents such as Br, Cl
and Me on the aromatic ring furnished the target compounds in
3
95
66
4
120
130
150
120
120
120
120
120
120
75d
71
5
6
61
7
68
8
63
9
65
10
11
12
67
72
69e
aReaction conditions: a mixture of 2-phenyl-4H-benzo[d][1,3]oxazin-4-one (1a)
(0.5 mmol), toluene (2a) (2 mL, 15 mmol), Pd(OAc)2 as indicated, 70% aqueous
TBHP as indicated was stirred at given temperature and time; bformation of 4a
was obsereved in all the screened systems; isolation was not attempted;
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10.1002/ejoc.201800263
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moderate to good yields (Table 3, entries 7-10). The structures
of the compounds 3a and 3f were also confirmed by the single
crystal X-ray analysis (Figure 1).
Table 4. Optimization of reaction conditions for aldehydes.a
Entry
Solventb
Oxidant
(mmol)
Yield (%)b
Yield (%)b
3a
55
62
64
59
45d
55
79
4a
17
14
14
18
20
20
3
1
2
3
4
5
6
7
DCE
DCE
6
5
4
2
4
4
5
DCE
DCE
DCE
1,4-dioxane
1,4-dioxane
aReaction conditions: a mixture of 2-phenyl-4H-benzo[d][1,3]oxazin-4-one (1a)
(0.5 mmol), benzaldehyde (5a) (0.55 mmol), catalyst (5 mol%), 70% aqueous
TBHP in the indicated solvent was stirred at 120 oC temperature for 18 h; b2mL
of solvents was used; cisolated yields; dunder nitrogen atmosphere.
Figure 1. Single crystal X-ray structures of compounds 3a and 3f.
Encouraged by these results, we further explored the
compatibility of this protocol with various aldehydes. In this regard,
primarily, we optimized the reaction conditions by varying only
solvents and concentration of TBHP to achieve better product
yields (Table 4). To our delight, best reaction condition was
obtained when 2-phenyl-4H-benzo[d][1,3]oxazin-4-one (1a) (0.5
mmol) was reacted with benzaldehyde (5a) (0.55 mmol) using
Pd(OAc)2 (5 mol%), TBHP (5 mmol) in 1,4-dioxane (2 mL) at 120
oC for 18 h which yielded the target compound in 79% yield (Table
4, entry 7). With this gratifying result, numerous benzaldehydes
substituted by electron donating groups as well as electron
withdrawing groups were reacted with 2-phenyl-4H-
benzo[d][1,3]oxazin-4-one (1a) and all these fruitfully provided the
target compounds in good yields, regardless of the position of the
substituents on the phenyl ring of benzaldehydes (Table 5). The
poor yield in case of chlorine and bromine substituted
benzaldehydes in comparison to the fluorine substituted
benzaldehydes could be attributed to higher electronegativity of
fluorine (Table 5, entries 3, 5, 11-13, 15 and 16). Not merely
Further, the substrate scope for the functionalization of 2-phenyl-
4H-benzo[d][1,3]oxazin-4-ones was investigated with benzyl
alcohols. Delightfully, when 2-phenyl-4H-benzo[d][1,3]oxazin-4-
one (1a) was treated with benzyl alcohol (7a) under the same
reaction conditions as were used for aldehydes, the target product
was obtained in 57% yield (Scheme 2, compound 3a).
Encouraged by this result, we next explored the structural
diversity of benzyl alcohols in this protocol. Various benzyl
alcohols yielded the desired products in significant yields
(Scheme
2).
Notably,
substituted
2-phenyl-4H-
benzo[d][1,3]oxazin-4-one also led to the product formation in
49% yield when reacted with benzyl alcohol (7a) (Scheme 2,
compound 3j).
Table 5. Substrate scope of aldehydes.a,b
Entry
R4
Ph
Product
3a
Yield (%)c
Yield (%)c 4a
monosubstituted
benzaldehydes,
but
disubstituted
1
2
79
58
60
58
66
69
62
53
57
37
3
benzaldehydes also were well tolerated under these conditions
(Table 5, entries 2, 3 and 13-17). When aliphatic aldehydes such
as cyclohexanecarbaldehyde and isovaleraldehyde were allowed
to react with 2-phenyl-4H-benzo[d][1,3]oxazin-4-one (1a), the
desired products were obtained in 48% and 33% yield,
respectively (Table 5, entries 18 and 19), which indicated that the
reaction condition is not limited to aromatic aldehydes.
2-Cl-Ph
3b
15
15
17
12
10
17
19
17
26
3
4-Cl-Ph
3c
4
2-F-Ph
3d
5
4-F-Ph
3e
6
4-OCH3-Ph 4
4-CH3-Ph
3,4-di-CH3-Ph
3,4-di-OCH3-Ph
3-Cl-Ph
3f
7
6a
8
6b
9
6c
10
6d
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11
12
13
14
15
16
17
18
19
2-Br-Ph
4-Br-Ph
6e
6f
22
30
70
58
53
48
21
48
33
31
27
13
17
19
14
38
17
21
and the reaction yielded the product 3a (Scheme 3, e), that
supported our hypothesis.
2,4-di-F-Ph
2,6-di-F-Ph
4-Cl-2-F-Ph
4-Br-2-F-Ph
3,4-di-Cl-Ph
cyclohexyl
isobutyl
6g
6h
6i
6j
6k
6l
6m
aReaction conditions: a mixture of 2-phenyl-4H-benzo[d][1,3]oxazin-4-ones (1a)
(0.5 mmol), aldehydes (5) (0.55 mmol), Pd(OAc)2 (5 mol%), 70% aqueous
TBHP solution (5 mmol) was stirred at 120 oC temperature for 18 h; bisolated
yields.
Scheme 3. Control experiments.
Scheme 2. Substrate scope of benzyl alcohols.a,b
aReaction conditions: a mixture of 2-phenyl-4H-benzo[d][1,3]oxazin-4-ones (1)
(0.5 mmol), benzyl alcohols (7) (0.55 mmol), Pd(OAc)2 (5 mol%), 70% aqueous
TBHP solution (5 mmol) was stirred at 120 oC temperature for 18 h; bisolated
yields are given in parentheses.
On the basis of above control experiments and literature reports,16
a plausible mechanism has been proposed as shown in Scheme
4. We believe that initially, the complex 11 is formed by the ortho-
palladation of compound 1a with Pd(OAc)2 with the liberation of
AcOH, which resulted in the hydrolysis of compound 1a into 4a.
At the same time, acyl radical 12 is generated from the other
reactant viz toluene or aldehyde or benzyl alcohol in the presence
of TBHP. This step is followed by the reaction of complex 11 and
the acyl radical which leads to the formation of complex 13
containing either palladium (III) or palladium (IV). Thereafter,
complex 13 undergoes reductive elimination process to give
compound 10. It is presumed that compound 10 may then
undergo aryl ring migration22 in the presence of oxidant TBHP via
the intermediate 14 and forms a bi-radical compound 15 which
then undergoes C-N bond formation to give the final compound
3a.
In order to predict and postulate the plausible reaction pathway,
some control experiments were carried out using 2-phenyl-4H-
benzo[d][1,3]oxazin-4-one (1a) and toluene (2a) (Scheme 3).
Initially, we carried out a blank experiment where the reaction
contents were stirred in the absence of the catalyst (Scheme 3,
a) and the desired product was detected in trace amounts on TLC.
Subsequently, when the reaction was carried out in the absence
of the oxidant TBHP (Scheme 3, b), the reactants remained
unchanged. Moreover, addition of radical scavenger TEMPO to
the reaction mixture under the optimized reaction conditions
yielded the TEMPO-trapped intermediate 9 (Scheme 3, c). Under
this condition no desired product formation was observed, which
clearly demonstrates that the reaction is progressing through a
free radical pathway. Furthermore, when the reaction between 2-
phenyl-4H-benzo[d][1,3]oxazin-4-one (1a) and toluene (2a) was
carried out at 80 oC, compound 1016 was obtained after 15
minutes (Scheme 3, d) which got converted into the product 3a
when reaction was continued further. Moreover, to ascertain that
the reaction product formation involves the migration of phenyl
ring and proceeds through the formation of compound 10, the
o
compound 10 was further treated with TBHP at 120 C for 18 h
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10.1002/ejoc.201800263
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hexane/ethyl acetate (8:2) as eluent to give the pure targeted
product 3.
General procedure for the synthesis of 6
An oven dried 10 mL reaction tube with a small stirring bar was
charged with a mixture of 4H-benzo[d][1,3]oxazin-4-one (1) (0.5
mmol), aldehyde (4) (0.55 mmol), Pd(OAc)2 (5 mol%), 70%
aqueous TBHP solution (5 mmol) and 1,4-dioxane (2 mL). The
o
tube was capped tightly and heated at 120 C for 18 hours. The
progress of the reaction was monitored by TLC. After completion
of the reaction, the reaction mixture was cooled upto ambient
temperature and passed through a short plug of celite, washed
with EtOAc (3 x 10 mL). The combined organic filtrate was further
diluted with 30 mL EtOAc and washed with 20 mL saturated
NaHCO3 solution two times, followed by distilled water (2 x 15 mL).
The organic layer was separated, dried over solid anhydrous
Na2SO4 and concentrated on a rotary evaporator to obtain the
crude product which was further purified on a silica gel column
using hexane/ethyl acetate (8:2) as eluent to give the pure
targeted product 6.
Scheme 4. Plausible mechanism.
General procedure for the synthesis of 8
Conclusions
An oven dried 10 mL reaction tube with a small stirring bar was
charged with a mixture of 4H-benzo[d][1,3]oxazin-4-one (1) (0.5
mmol), benzyl alcohol (6) (0.55 mmol), Pd(OAc)2 (5 mol%), 70%
aqueous TBHP solution (5 mmol) and 1,4-dioxane (2 mL). The
To summarize, we have developed a “Pd-catalyzed, free radical
promoted efficient and general protocol” for the direct
functionalization of 4H-benzo[d][1,3]oxazin-4-one derivatives by
C-H activation process. In this strategy, non-toxic and readily
available toluenes, aldehydes and benzyl alcohols were used as
reaction partners that proficiently resulted in the formation of the
final products in good yields. Mechanistic studies revealed that
both Pd(OAc)2 and TBHP were very important for this
transformation and reaction proceeded through radical pathway.
This protocol provides a new direction to the applicability of
toluenes, aldehydes and benzyl alcohols in the functionalization
of heterocyclic molecules by sustainable C-H activation strategies.
o
tube was capped tightly and heated at 120 C for 18 hours. The
progress of the reaction was monitored by TLC. After completion
of the reaction, the reaction mixture was cooled upto ambient
temperature and passed through a short plug of celite, washed
with EtOAc (3 x 10 mL). The combined organic filtrate was further
diluted with 30 mL EtOAc and washed with 20 mL saturated
NaHCO3 solution two times, followed by distilled water (2 x 15 mL).
The organic layer was separated, dried over solid anhydrous
Na2SO4 and concentrated on a rotary evaporator to obtain the
crude product which was further (8:2) purified on a silica gel
column using hexane/ethyl acetate as eluent to give the pure
targeted product.
Experimental Section
Acknowledgements
General procedure for the synthesis of 3
An oven dried 10 mL reaction tube with a small stirring bar was
charged with a mixture of 4H-benzo[d][1,3]oxazin-4-one (1) (0.5
mmol), toluene (2) (2 mL, 15 mmol), Pd(OAc)2 (5 mol%) and 70%
aqueous TBHP solution (6 mmol). The tube was capped tightly
and heated at 120 oC for 18 hours. The progress of the reaction
was monitored by TLC. After completion of the reaction, the
reaction mixture was cooled upto ambient temperature and
passed through a short plug of celite and washed with EtOAc (3
x 10 mL). The combined organic filtrate was further diluted with
30 mL EtOAc and washed with 20 mL saturated NaHCO3 solution
2 times, followed by distilled water (2 x 15 mL). The organic layer
was separated, dried over solid anhydrous Na2SO4 and
concentrated on a rotary evaporator to obtain the crude product
The authors acknowledge the financial assistance from the
University of Delhi (India) under its strengthening R & D Doctoral
Research Programme and the DST-DU Purse Grant Phase-II.
P.K. is thankful to the University Grants Commission (UGC, New
Delhi, India) for providing a Junior Research Fellowship.
Keywords Free radical, C-H activation, Direct functionalization,
6a-Phenyl-5H-benzo[4,5][1,3]oxazino[2,3-a]isoindole-5,11(6aH)-
diones, Cetilistat
1. a) T. Gensch, M. N. Hopkinson, F. Glorius, J. Wencel-
Delord, Chem. Soc. Rev. 2016, 45, 2900-2936; b) X.
which was further purified on
a silica gel column using
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Toluenes, aldehydes and
benzyl alcohols have been
exploited in radical-induced
direct functionalization of
4H-benzo[d][1,3]oxazin-4-
one derivatives via the
palladium-catalyzed C-H
activation strategy.
Prashant Kumar, Mohit Gupta,
Vijay Bahadur, Virinder S.
Parmar and Brajendra K.
Singh*
Page No. – Page No.
Radical-Induced, Palladium-
Catalyzed C-H activation: A
New
Approach
to
Mechanistic investigations
have illustrated the radical
pathway and have
Functionalize
4H-
Benzo[d][1,3]oxazin-4-one
Derivatives with Toluenes,
Aldehydes
Alcohols
and
Benzyl
highlighted the importance
of both catalyst and oxidant.
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