Synthesis of fused oxazole-containing coumarin derivatives via oxidative cross coupling reaction using a combination of CuCl2 and TBHP

Article abstract of DOI:10.1039/c5ra27993c

Various fused oxazoles containing coumarin derivatives were synthesized via an oxidative cross coupling reaction by employing 20 mol% CuCl₂ as the catalyst and TBHP as an oxidant. The reaction proceeds through functionalization of a C-H bond by

Full text of DOI:10.1039/c5ra27993c

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Synthesis of fused oxazole containing coumarin derivatives via
oxidative cross coupling reaction using a combination of CuCl2 and
TBHP
Received 00th January 20xx,
Accepted 00th January 20xx
Md. Belala and Abu T. Khana,b*
DOI: 10.1039/x0xx00000x
www.rsc.org/
OH
N
Various fused oxazoles containing coumarin derivatives was
O
MeO
O
N
O
O
accomplished via oxidative cross coupling reaction by employing
20 mol% CuCl2 as the catalyst and TBHP as an oxidant. The
reaction proceeds through functionalization of a C-H bond by
cross-dehydrogenative coupling (CDC) pathway to produce
various oxazole derivatives. The reaction protocol gives an easy
access to a number of oxazole derivatives containing coumarin
moiety at room temperature from various 3-(benzylamino)-2H-
chromen-2-one derivatives.
N
OH
OH
OH
O
MeO
N
O
Bengazole A
Hennoxazole A
HN
O
O
O
OH
O
O
O
N
N
HO
MeO
N
Oxaprozin
Siphonazole A
N
O
O
O
N
O
O
Coumarins are biologically active compounds widely distributed
in nature. Many biologically important fused coumarin
derivatives have been reported by our research groups as well as
by others.1 Also, a number of naturally occurring fused coumarin
derivatives having oxazole moiety exhibit interesting biological
properties such as anticancer, antifungal, antiviral, which is
shown in Figure 1.2 Many methods have been reported for the
synthesis of various oxazole derivatives in the literature.3 But, a
very few methodologies are available for the synthesis of fused
oxazoles containing coumarin derivatives except some classical
methods (scheme 1).4 Therefore, there is a scope to synthesize
these compounds by a simpler approach avoiding harsh reaction
condition.
N
N
H
O
Pimprinin
Texamine
Selvianen
Figure 1. Some biologically active oxazole derivatives2a, 2d
Earlier reported methods: by traditional methods
O
O
1. ROCl
O
O
2. KCN/ 18-Crown-6
3. NH4OH
N
(1)
(2)
4. Glycerol, reflux
OH
O
O
O
Cs2CO3
O
O
DMSO
130 oC
Transition metal catalysed oxidative coupling reactions have
been widely explored for functionalization of C-H bond.5 These
methodologies are being used for formation of diverse
heterocyclic molecular entities in recent time.6 Functionalization
of a sp3 C-H bond through cross dehydrogenative coupling
reaction adjacent to a nitrogen atom is an interesting approach
Br
Ar
O
NH
N
Ar
O
This Work: by cross dehydrogenative coupling
CuCl2(20 mol%)
O
O
O
O
R1
(3 equiv)
TBHP
R1
N
DCM, RT
18-24 h
N
H
O
R2
R2
Scheme 1. Methods for synthesis of various coumarin fused
oxazoles
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to access various molecular transformations.7 Literature survey
reveals that a number of oxidants have been employed for
oxidative coupling reaction to avoid the use of stoichiometric
amount of the catalyst.8 TBHP has been extensively used as a
useful oxidant for oxidative cross coupling reactions.9 Li et al.
have reported the use of TBHP and a copper salt to achieve
various C-C bond formation adjacent to a nitrogen atom.10
The present protocol gives access to various oxazoles derivatives
of coumarin through cross dehydrogenative coupling at room
temperature. Initially, 3-(benzylamino)-2H-chromen-2-one (1a)
was synthesized using 3-aminocoumarin and benzyl bromide in
presence of K2CO3 in DMF at 100 oC by a previously reported
Figure 2 ORTEP diagram of 2a (CCDC number 1405370)
method by our group (ref: 1a)The substrate 1a was treated with
10 mol% CuI and TBHP in DCM at room temperature and the
desired the product 2a was obtained in 50 % yield (entry 1, Table
1). The product was characterized by H1 NMR, 13C NMR and
HRMS spectra. Further, the structure of 2a was also established
from single XRD data (Figure 2)
Table 1. Optimization of reaction condition
Catalyst
O
O
O
O
N
Oxidant
N
H
Solvent
O
To find out the optimal reaction condition, a number of reactions
were executed using different copper salts like CuBr, CuBr2,
Cu(OAc)2.H2O,CuCl2, CuCl, Cu(NO2)2, CuSO4 as the catalyst
and TBHP as the oxidant in DCM at room temperature. The
desired product 2a was obtained from moderate to good yields
(entries 2-5 and 9-11). Among various copper salts, CuCl2 was
found to be the optimized catalyst for the reaction. The desired
product 2a was obtained in 64%, 66% and 72% yield with 10
mol%, 15 mol% and 20 mol% of CuCl2 respectively employing 3
equivalent of TBHP as oxidant in DCM at room temperature
(entry 5-7). Lowering the amount of catalyst from 10 mol% to 5
mol%, yield of desired product was decreased to 61% (entry 8).
Apart from DCM, the desired oxazole product was also obtained
in 1,2-dichloroethane (DCE), acetonitrile and chloroform (entries
12-15) whereas no product was formed in DMF or DMSO (entry
16 and 17). Furthermore, iron salts like FeCl2 and FeCl3 were
found ineffective to produce the desired product (18 and 19).
Also, the reaction was unsuccessful without any catalyst or
oxidant (entry 20 and 21) indicating that both are crucial for the
formation of product. The reaction was not feasible with other
oxidants like H2O2 and benzoyl peroxide (entry 22 and 23).
1a
2a
Catalyst
(mol%)
Yield
(%)b
Entry
Solvent
Oxidant
Time/h
1
2
3
CuI (10)
DCM
DCM
DCM
TBHP
TBHP
TBHP
18
18
20
50
50
52
CuBr (10)
CuBr2 (10)
Cu(AcO)2.H2O
(10)
4
DCM
TBHP
24
10
5
CuCl2 (10)
CuCl2 (15)
CuCl2 (20)
CuCl2 (5)
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCE
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
-------
18
18
20
18
12
20
20
14
14
24
32
32
32
24
24
24
64
6
66
7
72
8
61
9
CuCl (10)
Cu(NO2)2 (10)
CuSO4 (10)
CuCl2(10)
CuCl2(20)
CuCl2 (10)
CuCl2 (10)
CuCl2 (10)
CuCl2 (10)
FeCl2 (10)
FeCl3 (10)
CuCl2 (10)
58
10
11
12
13
14
15
16
17
18
19
20
60
57
62
DCE
69
CH3CN
CHCl3
DMF
DMSO
DCM
DCM
DCM
45
45
A number of 3-(benzylamino)-2H-chromen-2-one derivatives
were synthesized using various 3-aminocoumarin and benzyl
bromide derivatives and was examined to evaluate the substrates
scope of the present protocol. At first, the group tolerance on the
benzyl moiety was studied. Interestingly, the desired oxazole
derivatives of coumarin were afforded in good yield with both
electron donating-(2b, 2e, 2h and 2i, Scheme 2) and withdrawing
substituents (2c, 2d, 2f and 2g,). Product 2j was obtained in 68 %
yield containing a heteroatom in the benzyl ring. Whereas
replacing benzyl moiety with naphthyl moiety, the desired
product 2k were obtained in significant yield, but in lesser time
compared to the benzyl derivatives under the optimized
condition. The yield was comparable with substituent at the
meta- and para position of the benzyl group indicating no
NR
NR
NR
NR
NR
21
22
23
-------
DCM
DCM
DCM
TBHP
24
24
24
NR
NR
NR
CuCl2 (10)
CuCl2 (10)
H2O2
(PhCO)2O2
aUnless otherwise stated all the reactions were carried out with 3
mmol of 1a , 3 equiv. of oxidant, in 3 mL of solvent at RT.
bIsolated yield
2 | J. Name., 2012, 00, 1-3
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coupling reaction. All the reaction were carried out with 0.3 mmol of 1
,3 equiv. of TBHP, 20 mol % of the CuCl2 in 3 mL of DCM at RT.
bIsolated yield.
significant role of steric hindrance for the formation of products
(2e, 2f. 2g and 2h).
CuCl2(20 mol%)
O
O
H2O
O
O
R1
(3 equiv)
TBHP
R1
N
DCM, RT
18-24 h
N
H
CuCl2
O
t-BuOOH
R2
R1
O
O
O
O
HCl
R1
R2
tBuO
N
H
N
R2
CuCl
O
2
1
R2
O
O
O
O
N
H
R1
R2
R1
NH
A
D
O
t-BuOOH
R2
O
O
O
O
O
H
R1
NH
R1
NH
R2
O
O
C
R2
B
O
H
O
R1
H
NH
O
O
t-BuO
R2
R1
Cu(I)
Cu(II)
R2
R1
O
O
O
O
N
H
N
R2
H
1
_
H
cu(II)
Cu(I)
R1
O
O
O
O
N
N
R1
H
H
R2
A
R2
Scheme 3. Plausible reaction mechanism
Notably, no product was obtained on replacing benzyl moiety
with alkyl moiety.
Similarly, 3-(benzylamino)-2H-chromen-2-one with substituents
on the coumarin moiety such as 7-MeO, 8-MeO and 8-EtO were
also examined and the desired products 2l-u were isolated in
satisfactory yield (scheme 2). Unfortunately, the present protocol
is not feasible with electron withdrawing substituents like 6-NO2,
6-Cl and 6-Br on the coumarin moiety.
From literature survey11 and our experimental results, a plausible
mechanism is presented for the formation of 2 from 1. Initially
an iminium ion A (Scheme 3) might be formed from 1 with the
help of TBHP/CuCl2 and then another molecule of TBHP attacks
the electrophilic centre of A to form intermediate B. Intermediate
B cyclizes to intermediate D through C and finally D on aerial
oxidation provides the desired product 2.
Conclusions
Scheme 2. Synthesis of various oxazole derivatives via oxidative cross
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Glasnik Hemicara i Tehnologa Bosne i Hercegovine, 1976, 23-24,
95.
In conclusion we have demonstrated a novel approach for the
construction of various fused oxazole containing coumarin
derivatives under mild reaction conditions. We do hope that the
synthesized compounds may exhibit interesting biological
activity.
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Acknowledgemen
t
M.B is thankful to IIT Guwahati for his research fellowship.
A.T.K is thankful to CSIR, New Delhi for research grant no.:
02(0181)/14/EMR-II for financial support. The authors are
grateful to the Department of Science and Technology, New
Delhi for financial assistance for creating single XRD facility in
the Department of Chemistry under FIST programme. We are
thankful to the referees’ for their valuable comments and
suggestions.
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Graphical Abstract
Synthesis of fused oxazole containing coumarin derivatives via oxidative cross
coupling reaction using a combination of CuCl2 and TBHP
Md. Belal and Abu T. Khan