Dioxazolones as masked ester surrogates in the Pd(ii)-catalyzed direct C-H arylation of 6,5-fused heterocycles

Article abstract of DOI:10.1039/c9cc05563k

A simple and effective Pd(ii)-catalyzed regioselective C(2)-H arylation of 6,5-fused heterocycles with dioxazolones as a masked ester surrogate under mild conditions is reported. The significance of the arylation is highlighted by the new reactivity demonstrated in dioxazolones via proximal C-H activation of the cyclic carbonate of the hydroxamic acid functionality under protic conditions.

Full text of DOI:10.1039/c9cc05563k

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DOI: 10.1039/C9CC05563K
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Dioxazolones as Masked Ester Surrogates in the Pd(II)-
Catalyzed Direct C-H Arylation of 6,5-Fused
Heterocycles.
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Paridhi Saxena, Neha Maida and Manmohan Kapur*
A simple and effective Pd(II)-catalyzed regioselective C(2)-H formation of 2-aryl benzo[b]furans have been relatively
arylation of 6,5-fused heterocycles with dioxazolones as masked scarcely reported.5-6 In 2014, Schnürch and co-workers
ester surrogate under mild conditions is reported. The significance reported the C-H bond arylation of benzo[b]furans using aryl
of the arylation is highlighted by the new reactivity demonstrated bromides as the arylating agents.6c Recently, Noel and co-
in dioxazolones via proximal C-H activation of the cyclic carbonate workers described a selective C-H arylation of benzo[b]furans
of hydroxamic acid functionality under protic conditions.
using aryldiazonium salts.7b Although this is most selective
protocol so far, there is still a demand for exploring simple and
efficient methods for arylation employing highly reactive and
atom-economical aryl donors.
Over the past two decades, transition-metal-catalysed C−H
bond functionalization has revolutionized organic synthesis in
delivering straightforward approaches for the rapid
construction of carbon-carbon and carbon-heteroatom bonds.1
Heterobiaryl scaffolds widely exist in natural products and
pharmaceuticals, while also serving as intermediates in organic
synthesis. In this context, 2-aryl benzo[b]furans and their
derivatives are of considerable interest as they possess
remarkable biological activities (Figure 1).2-3 Despite the great
progress in C-H bond arylation,4 methods for the construction
of C-2 arylated benzo[b]furans are rather limited. Conventional
methods focus on cross-coupling strategies which strongly rely
on pre-functionalized substrates. In contrast to cross-coupling
reactions, the direct C-H bond functionalization of
heteroarenes with aryl (pseudo) halides and aryl boronic acids
have been developed to enable C-H arylation.
Our continuous effort in C-H functionalization, to develop
direct and site-selective C-C bond formation prompted us to
investigate 1,4,2-dioxazol-5-ones as masked ester surrogates
under protic conditions.8 The limited exploration of esters as a
directing group in C-H functionalizations can be attributed to
the poor coordination ability of the ester functionality.9
Meanwhile, as highly reactive precursors, dioxazolones have
been intensively studied as a coupling partner for direct C-N
bond forming reactions. It would therefore be intriguing to
determine whether 1,4,2-dioxazol-5-ones can be employed as
activated aryl targets, which to the best of our knowledge, has
not been reported previously. Therefore, the challenge
remains to explore the other reactivity pattern of dioxazolones
unlike their efficiency for imido insertion. We describe herein a
site-selective C-2 arylation of benzo[b]furans assisted via 1,4,2-
dioxazol-5-ones as masked ester equivalents, under mild
conditions (Scheme 1).
OH
O
Me
H2N
Br
HO
OH
N
O
N
N
O
Previous work: Pd-catalyzed C-2 arylation of benzo[b]furans
HN
O
O
Me
O
S
OH
O
O
Pd(OAc)2
Ar
CF3
HO
Saprisartan
SKF-64346
Ar-N2BF4
O
Amurensin H
O
AT1- receptor antagonist:
treatment for heart failure
Multifunctional drug for
alzheimer's disease
This work: Site-selective C-2 arylation using dioxazolones as masked-ester equivalents
Figure 1: Selected bioactive molecules containing 2-Aryl benzo[b]furans.
O
Regioselective Pd(II) catalysis
C-2 arylation of benzofurans, benzothiophenes
and benzoselenophenes
N
Pd(II)
ROH
O
+
O
X
X
Ar
Dioxazolone as a masked ester surrogate
X = O, S, Se
ROOC
However, some of these reported methods require the use of
rather harsh conditions which limits their functional group
compatibility. In spite of the advances in C-H arylation, the
Scheme 1: Pd-catalyzed C-2 arylation of 6,5- fused heterocycles.
We initiated our studies with benzo[b]furan (1) and 3-phenyl-
1,4,2-dioxazol-5-one (2) as the model substrates for this C-2
arylation and after considerable optimization (Table 1),10 the
desired coupled product methyl 2-(benzofuran-2-yl)benzoate
a. Department of Chemistry, Indian Institute of Science Education and Research
Bhopal, Bhauri, Bhopal Bypass road, Bhopal 462066, MP, India
Electronic
Supplementary
Information
(ESI)
available:
See
DOI: 10.1039/x0xx00000x
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(3aa) was obtained in 55% yield using Pd(OAc)2 (10 mol%), substituents at various positions of benzo[b]furanVsieawnAdrtitchleeOnCli-n2e
DOI: 10.1039/C9CC05563K
Cu(OTf)2 (1.0 equiv.) and KF (1.5 equiv.) in MeOH at reflux selectivity was confirmed by X-ray crystallography of 3j (CCDC
temperature under inert conditions (Table 1, entry 2). Control 1897155). C-3 substituted benzo[b]furans gave desired
experiments revealed that both Pd(OAc)2 and the KF additive products (Table 2, 3a, 3o) in moderate yields under different
i
are indispensable in this transformation (Table 1, entries 3-4). protic solvents (MeOH, PrOH). Diverse substituents at the C-4
Different oxidants were then investigated but Cu(OTf)2 was and C-5 positions of benzo[b]furans (1) were well-tolerated
found to perform much better than AgOTf and Cu(OAc)2 (entry with good yields (Table 2, 3b-3d, 3h-3n). It was found that
7).10 Besides Pd(OAc)2, other transition metal catalysts (Rh and benzo[b]furans
bearing
electron-donating,
electron-
Ru) failed to catalyze this transformation. Among the other withdrawing substituents as well as halogens reacted smoothly
additives investigated, KF most-efficiently provided the C-2 with dioxazolones to afford C-2 arylated products in moderate
arylated product 3.
yields. Disubstituted benzo[b]furans were also successfully
reacted to afford C-2 arylated product (Table 2, 3f, 3g) in
decent yields. C-7 substituted benzo[b]furan was also found to
be compatible and furnished the corresponding product 3e
with slightly decreased yield. To our delight, the methodology
could also be successfully applied to synthesis C-2 selective
arylated benzothiophenes (Table 2, 3q-3s). However, much to
our disappointment, N-Me indole, N-Me imidazole as well as
the electron-poor pentafluorobenzene when subjected to the
reaction conditions did not provide the desired arylation
product (Table 2, 3t, 3u).
Table 1. Optimization of the reaction conditionsa
ROOC
O
O
N
catalyst, additive
ROOC
+
O
solvent, 80 o
C
3
O
O
Ph
O
O
4
1
2
O
NH
5
Entry
Catalyst/oxidant
Pd(OAc)2 / Cu(OTf)2
Pd(OAc)2 / Cu(OTf)2
Pd(OAc)2 / Cu(OTf)2
Cu(OTf)2
Additive
KF
Solvent
DCE
Yieldb (%) of 3aa
1
NR
2
KF
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
toluene
MeOH
DCE
55
3
-
<10
Table 2. Substrate Scope of benzo[b]furansa,b
4
KF
NR
Me
Me
5
Pd(OAc)2
-
NR
60c
Pd(OAc)2 (5 mol%), Cu(OTf)2 (1.0 equiv.)
R1
R1
+
6
Pd(OAc)2 / Cu(OTf)2
Pd(OAc)2 / AgOTf
Pd(TFA)2 / AgOTf
Pd(OAc)2 / Cu(OTf)2
Pd(OAc)2 / Cu(OTf)2
Pd(OAc)2 / Cu(OTf)2
[RhCp*Cl2]2 / AgSbF6
[RhCp*Cl2]2 / AgSbF6
[Ru(p-cym)Cl2]2/ AgSbF6
KF
O
KF (1.5 equiv.), MeOH, reflux
X
O
X
7
KF
41
N
ROOC
O
2
1
3
(X = O, S)
8
KF
20
R1
Me
Me
Me Me
Me
Me
9
KOAc
KF
NR
10
11
12
13
14
Complex mixtured
O
O
O
O
KF
NRe
NR
NR
NR
MeOOC
MeOOC
Me
MeOOC
MeOOC
Me
1 = Me, 61%
1 = Br, 52%
KOAc
KOAc
KOAc
3a,
3e
3f
60%
, 42%
, 55%
3b
R
3c
R
MeOH
MeOH
3d
R
1 = OMe, 55%
Me
R1 = Me, 65%
Br
Me
3h
3i
Me
Me
R1
aUnless otherwise noted, all reactions were carried out using 1 (0.15 mmol), 2 (0.22
R1 = t-Bu, 58%
R1 = Ph, 51%
R1 = Cl, 55%
R1 = Br, 60%
3j
mmol), catalyst (10 mol %), oxidant (1.0 equiv.) in the presence of additive (1.5 equiv.)
in a solvent (1.0 mL) at 80 °C for 12 h under N2. bIsolated yields. Pd(OAc)2 (5 mol%),
Cu(OTf)2 (1.0 equiv.), KF (1.5 equiv.). dThe reaction temperature is 110 °C. eReaction
under oxygen atmosphere.
O
O
O
Me
R1
3k
3l
c
MeOOC
MeOOC
3o
MeOOC
, 61%
3g,
64%
Me
3m
3n
Me
R
1 = I, 45%
R1 = OMe, 60%
Me
Me
Me
N
Me
N
N
S
MeOOC
Nature of the solvent had a noteworthy influence on this
reaction, as the use of protic solvents such as MeOH, EtOH and
iPrOH resulted in the desired product (3). Non-alcoholic
solvents such as DCE, acetonitrile, THF, DMF, DCM and
toluene did not give desirable results (Table 1, entries 1, 10).10
Decreasing the catalyst loading, and the amount of KF additive,
as well as the oxidant, resulted in better product yield (Table 1,
entry 6).10 No product 3 was detected when the reaction was
performed under an oxygen atmosphere (Table 1, entry 11).10
Finally, the optimal conditions were found to be Pd(OAc)2 (5
mol%), Cu(OTf)2 (1.0 equiv.) and KF (1.5 equiv.) in MeOH at
reflux temperature and 3 was obtained in 60% yield (Table 1,
entry 6). It should be noted that in all the above reactions,
exclusively C-2 arylated product 3 was obtained, neither the C-
3 arylated product 4 or the amidation product 5 was detected
in any of the cases.10
MeOOC
MeOOC
, 0%
3p
, 0%
R
1 = H, 58%
3q
3r
3t
R1 = Me, 62%
Me
N
R
1 = Cl, 57%
3s
N
MeOOC
3j
3u
, 0%
aUnless otherwise specified, all reactions were carried out using 1 (0.17 mmol), 2 (0.22
mmol), Pd(OAc)2 (5 mol %), Cu(OTf)2 (1.0 equiv.), KF (1.5 equiv.) at reflux temperature
for 6 h-10 h under N2. bIsolated yields after column chromatography purification.
Next, the reactivity of various substituted 1,4,2-dioxazol-5-
ones were tested with benzo[b]furan 1 as the coupling
partner. Dioxazolones bearing both electron-donating as well
as electron-withdrawing aryl substitutents were found to react
efficiently to give the corresponding arylated product 3 in
good yields (Table 3, 3ac-3ai). Notably, the methyl group at
various positions of 3-phenyl-1,4,2-dioxazol-5-ones gave the C-
2 selective product (Table 3, 3aj, 3al). Interestingly, this
protocol was also applicable to benzoselenophene (3ao-3aq),
affording the corresponding products with moderate yields. To
With the optimized conditions in hand, we investigated the
scope of the reaction with respect to substituted
benzo[b]furans and 1,4,2-dioxazol-5-ones as the coupling
partner (Table 2). Good to moderate yields were obtained with
2 | J. Name., 2012, 00, 1-3
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test the practicality of this protocol, the reaction of 1a with 2 was measured. In the parallel reaction as well as in the
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was carried out in 1 mmol scale which worked smoothly (Table intramolecular competition experimentD, OpIe: 1r0fo.1r0m39e/dC9CuCsi0n5g5613aK
3, 3ac (55%)).
and 1a-[D2] with the coupling partner 2a, a value of kH/kD = 1.0
(Scheme 3c) was obtained.
Table 3. Substrate Scope of 1,4,2-dioxazol-5-onesa
O
N
O
a) Reaction with benzoic ester
O
Pd(OAc)2 (5 mol%), Cu(OTf)2 (1.0 equiv.)
R1
CO2Me
Pd(OAc)2, Cu(OTf)2
+
+
R1
KF (1.5 equiv.), ROH, reflux
X
X
O
KF, MeOH, reflux
ROOC
O
MeOOC
1
2
3
(X = O, Se)
1
6
3aa
= 0%
Me
Me
R1
b) Arylation with deutrated protic solvent
O
N
R1
O
Pd(OAc)2, Cu(OTf)2
O
ROOC
R = Me, 61%
R = Et, 52%
O
ROOC
O
O
+
O
KF, MeOH-d4 , reflux
MeOOC
R1 = OMe, 60%
1 = Br, 48%
1 = Cl, 45%
R1 = F, 45%
Br
MeOOC
R1 = Me, 64%
R
1 = OMe, 61%
3ak
O
O
b
3aa
3ab
Me
D3COOC
3a'
3ac
3ad
3ae
3af
3ag
3ah
3ai
3aj
R = Me, 58%, 55%
1
2a
= 60%
R
i
R = Pr, 55%
R = nBu, 51%
R
c) Intermolecular Competition Experiments
O
R1
R
Me
N
Me
O
Pd(OAc)2, Cu(OTf)2
KF, MeOH, reflux
Se
ROOC
+
O
O
O
1 = p-Me, R = Me, 58%c
1 = p-Me, R = Et, 41%c
1 = p-Cl, R = Me, 41%c
O
O
3ao
3ap
3aq
R
R
R
R
MeOOC
MeOOC
Me
MeOOC
O
1a
R = Me/Br
3a
3ar
(R = Br) = 2:1
(R = Me):
MeOOC
3al
3am
3an
, 48%
, 57%
, 48%
Scheme 2: Control Experiments
aIsolated yields after column chromatography purification. bReaction carried at 1
mmol scale. cReaction time 24 h.
This suggested that the cleavage of C(2)-H bond of the
benzofuran is not involved in the rate-determining step and
that a concerted metalation deprotonation may not be
involved. Unfortunately for us, despite our best efforts, we
were unable to synthesize the C-2 deuterated dioxazolone.
In attempts to gain an insight into the reaction mechanism,
control experiments were performed as described in Scheme
2. Initially to understand the role of dioxazolone, C-2 arylation
was conducted with benzoate ester and it did not afford any of
the desired product 3aa (Scheme 2a). This result excludes the
possibility of the ester being involved in the reaction
mechanism.
a) Radical trap experiments:
O
N
O
Pd(OAc)2, Cu(OTf)2
KF, MeOH, reflux
Radical scavenger
+
O
O
O
With the unprecedented mode of action of dioxazolone in the
C-2 arylation reaction, we tried to delineate the role of the
protic solvent in the reaction. For this we employed CD3OD as
the solvent under standard arylation conditions, which
exclusively gave 3a’ with deuterium incorporation in the ester
functionality of the C-2 aryl ring (Scheme 2b). To rationalize
the mechanism, intermolecular competition experiments were
carried out between differently substituted dioxazolones with
3-methyl benzofuran 1a (Scheme 2c). This indicated electron-
rich dioxazolones to be intrinsically reactive substrates. To
further investigate the catalytic mechanism, several
experiments were conducted. Radical trap experiments were
undertaken with different radical scavengers, and the
corresponding C-2 arylation product was obtained with only
minor loss in the yield (Scheme 3a). This clearly excludes the
possibility of a single electron transfer process being involved
in the reaction pathway. Subsequently, the H/D exchange
experiments were conducted in the presence of D2O and
CD3OD as the co-solvent without arylation source, and these
did not lead to deutration. This observation is indicative of an
irreversible C−H metalation under optimized reaction
conditions (Scheme 3b). Similarly, to examine the reversibility
of C-H activation step, deuterium-labelling experiment was
also performed on dioxazolone with D2O as the co-solvent but
no deuterium incorporation was observed on the starting
material (Scheme 3b). Furthermore, when the benzofuran and
dioxazolone was subjected to the standard conditions under
D2O as the co-solvent, no deuterium incorporation was
observed, and the corresponding product was obtained with
58% yield (Scheme 3b). To further understand this C-H
activation process, kinetic isotope effect on the benzofuran
MeOOC
TEMPO (1.0 equiv.)
BHT (1.0 equiv.)
47%
52%
1
2
Ph2CH=CH2 (1.0 equiv.) 55%
b) Reversibility of metalation:
R
R
Pd(OAc)2, Cu(OTf)2
D2O : 0% D
KF, MeOH, reflux
H/D
(0% D)
MeOH-d4 : 0% D
O
O
1a'
1
R = H, Me
O
O
H/D
N
(0% D)
Me
N
O
O
O
Pd(OAc)2, Cu(OTf)2
O
KF, MeOH, D2O, reflux
H/D
(0% D)
Me
2a
2a'
(0%)
R
O
N
Me
Me
R
O
Pd(OAc)2, Cu(OTf)2
KF, MeOH, D2O, reflux
O
+
O
O
Me
MeOOC
3a
(58%) (0% D)
1
R = H, Me
2a
c) Kinetic isotope effect studies:
Me
O
N
Me
O
Pd(OAc)2, Cu(OTf)2
KF, MeOH, reflux
+
O
H/D
O
O
Me
MeOOC
3a
Parallel reaction: kH/kD = 1.0
Competition reaction: kH/kD = 1.0
1a 1a
/
-[D2]
2a
Scheme 3: Mechanistic Studies
Based on the mechanistic studies conducted and the literature
reports,12 we propose a plausible catalytic cycle as depicted in
Scheme 4. Initially the reaction pathway may involve
formation of A where the dioxazolone 2 undergoes ring
opening with CO2 extrusion in presence of the protic solvent
and the fluoride. C-H activation occurs to form the 5-
membered palladacycle B via chelation-assistance of imine
nitrogen atom on N-hydroxybenzimidate. Next, 1 directly
coordinates with palladacycle B and via an electrophilic
palladation leads to C. Subsequent 1,2-migration results in the
intermediate D, followed by deprotonation.12b,c Finally,
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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V. Gupta, Tetrahedron Lett., 2009, 50, 7180; (c) Y. Xia, Y. L.
reductive elimination and hydrolysis yields the desired product
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Jin, N. Kaur, Y. Choi and K. Lee, Eur. J.DMOeI:d1.0C.1h03e9m/C.,92C0C1015,56436K,
2386; (d) M. Thévenin, S. Thoret, P. Grellier and J. Dubois,
Bioorg. Med. Chem., 2012, 21, 4885; (e) C. Salomé, N.
Ribeiro, T. Chavagnan, F. Thuaud, M. Serova, A. de Gramont,
S. Faivre, E. Raymond and L. Désaubry, Eur. J. Med. Chem.,
2014, 81, 181.
For some recent papers on the synthesis of 2-aryl
benzo[b]furans via cyclization strategy: (a) P. K. Mandali, D.
K. Chand, Synthesis, 2015, 47, 1661; (b) S. -X. Sun, J. -J.
Wang, Z. -J. Xu, L. -Y. Cao, Z. -F. Shi and H. -L. Zhang,
Tetrahedron, 2014, 70, 3798; (c) J. -X. Chen, J. J. Li and W.-K.
Su, Org. Biomol. Chem., 2014, 12, 4078; (d) R. Zhou, W.
Wang, Z. -J. Jiang, K. Wang, X. -L. Zheng, H. -Y. Fu, H. Chen
and R. -X. Li, Chem. Commun., 2014, 50, 6023; (e) X. -Y.
Wang, M. -C. Liu, L. Xu, Q. -Z. Wang, J. -X. Chen, J. -C. Ding
and H. -Y. Wu, J. Org. Chem., 2013, 78, 5273; (f) U. Sharma,
T. Naveen, A. Maji, S. Manna and D. Maiti, Angew. Chem.,
Int. Ed., 2013, 52, 12669.
For selected papers on the transition-metal-catalyzed direct
C−H bond arylation: (a) N. R. Deprez, D. Kalyani, A. Krause
and M. S. Sanford, J. Am. Chem. Soc., 2006, 128, 4972; (b) T.
A. Dwight, N. R. Rue, D. Charyk, R. Josselyn and B. DeBoef,
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(a) A. Ohta, Y. Akita, T. Ohkuwa, M. Chiba, R. Fukunaga, A.
Miyafuji, T. Nakata, N. Tani and Y. Aoyagi, Heterocycles,
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3aa and Cu(II) regenerates the catalyst.
Cu(II)
3aa
O
OMe
O
O
Pd(II)
hydrolysis
HO
O
O
N
MeOH/KF
N
O
N
Reductive
elimination
H
OMe
Ph
CO2
A
Directed C-H
Activation
4
Ph
2
MeOH
OMe
H
N
Pd
OAc
OH
Pd
HON
OMe
B
O
H
D
OMe
HON
1
1,2-migration
H
O
Pd
Electropalladation
C
O
Scheme 4: Proposed Reaction Mechanism
In summary, we have developed a palladium-catalyzed, site-
selective C-2 arylation of 6,5-fused heterocycles with
dioxazolones as the arylating agents. This methodology unveils
a completely different mode of action of dioxazolones as a
masked ester surrogate. This transformation proceeds
smoothly with wide range of substrates and typically works
with excellent levels of site-selectivity (C-2 arylation of
benzofurans, benzothiophenes as well as benzoselenophenes)
with good functional group tolerance. Thus, the method
illustrates a convenient strategy for synthesis of 2-arylated-6,
5-fused heterocycle derivatives.
5
6
Conflicts of interest
There are no conflicts to declare.
7
8
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9
10. See the Supporting Information for more details.
11. Crystal Structures submitted to Cambridge Cystallographic
2
3
Data
Centre,
CCDC
deposition
number:
CCDC
1897155(Compound 3j).
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4 | J. Name., 2012, 00, 1-3
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