BF3-Etherate-catalyzed tandem reaction of 2-formylarylketones with electron-rich arenes/heteroarenes: An assembly of isobenzofurans

Article abstract of DOI:10.1039/d0cc02760j

An efficient and BF₃·Et₂O-catalyzed chemoselective synthesis of diversified 1,3-diarylisobenzofuran in a high yield has been described. The reaction proceeds through sequential hydroarylation-cyclization between 2-formylarylketones and electron-rich arenes/heteroarenes. Advantageous features of the developed methodology include operational simplicity, a broad substrate scope, and applicability towards gram scale synthesis. The utility of isobenzofuran derivatives as the diene was extended to the synthesis of [4+2] cyclo-adducts with DMAD and the synthesis of 1,2-dicarbonylarenes in good yields.

Full text of DOI:10.1039/d0cc02760j

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DOI: 10.1039/D0CC02760J
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ARTICLE
BF3-Etherate-Catalyzed Tandem Reaction of 2-Formylarylketones
with Electron-rich Arenes/Heteroarenes: An Assembly of
Isobenzofurans
Received 00th January 20xx,
Accepted 00th January 20xx
Pawan K. Mishra, Ankit Kumar and Akhilesh K. Verma*
DOI: 10.1039/x0xx00000x
An efficient and BF3.Et2O-catalyzed chemoselective synthesis of diversified 1,3-diarylisobenzofuran in high yield has been
described. The reaction proceeds through sequential hydroarylation-cyclization between 2-formylarylketones and electron-
rich arenes/heteroarenes. Advantageous features of the developed methodology includes operational simplicity, broad
substrate scope, and applicability towards gram scale synthesis. The utility of isobenzofuran derivatives as diene was
extended toward synthesis of [4+2] cyclo-adducts with DMAD and synthesis of 1,2-dicarbonylarenes in good yield.
www.rsc.org/
Previous work:
Benzo[c]furans are an important class of heterocyclic scaffold
with 10π electron system having quinoid structure. They are
recognized as highly reactive dienes in the Diels-Alder reaction1-2 and
also used as standard reagent for the determination of singlet
oxygen3 and synthesis of acene species.4 They also serve as a
template for the preparation of polymers, optical devices, electro-
photographic photoreceptors, electroluminescent devices and dye
lasers.5-6 In addition, isobenzofurans have also been extensively used
as synthetic building blocks for the π-conjugated carbocycles as well
as heterocycles.7 Furthermore; benzo[c]furans also employed as
synthetic precursor of 1,3-disubstituted benzo[c]selenophenes.8
Several conventional synthetic strategies for the construction of
isobenzofurans ring system have been reported in the literature9. In
2006, Takai and co-workersl10 have reported the rhenium-catalyzed
insertion of aldehydes into a C-H bond of aromatic ketimines
towards the synthesis of isobenzofuran derivatives (Scheme 1a).
Later on, Einhorn11 and Hamura12 groups have reported the
synthesis of 1,3-disubstituted isobenzofuran via chemoselective
addition of arylmagnesium reagents/arylboronic acid to the
aldehyde function of 1,2-dicarbonyls substrates (scheme 1b).
Furthermore, Yamamuchi13 and Nishina14 groups have developed
the synthesis of 1,3-disubstituted isobenzofuran derivatives.
Although, existing methods suffer certain limitation with respect to
instability of product, substrate scopes, prefunctionalization of
nucleophiles such as Grignard reagents, boronic acid, organ lithium
and use of expensive catalysts. Therefore, the development of a
convenient and straightforward protocol for the direct synthesis of
isobenzofuran is still in demand. To overcome these shortcomings,
we hypothesized the synthesis of functionalized isobenzofurans via
tandem hydroarylation/cyclization reactions of 2-formylarylketones
with electron-rich arenes/heteroarenes under transition-metal-free
condition (Scheme c).
R2
N
R1
R1
N
R1
R1
O
R2
R3CHO
Re(I)
N
Re
H
a)
R2
O
Re
H
R3
H
R3
Rehenium Complex:
[ReBr(CO)3(thf)]2
Ar
Ar
Ar
H
CHO
Ar
ArMgX
OH
Ar
O
O
b)
THF, -78 to 0 o
HCl
C
Ar
HO
Ar
O
O
Our Concept
Nu-H
Nu
OH
Nu
Nu
O
LA
H
CHO
O
LA
O
c)
Ar
O
Ar
LA
O
Ar
Ar
O
Ar
O
LA
This work:
R1
Nu
O
BF3.Et2O (20 mol % )
O
O
R1
d)
Nu
H
+
DCM, 0 oC-rt
30 min
R2
R2
3a-w 5a-e
(74-90%)
&
2
1
R1 = H, Cl, Br, I, F, CO2Et, alkyl, aryl; R2 = aryl, (het)aryl
Me
OMe
MeO
OMe
OH
Nu
H
Me
N
N
N
N
OMe
OMe
Me
Me
Me
Me
Scheme 1. Synthetic Strategies for Isobenzofuran Derivatives
Transition-metal-free carbon-carbon bonds formation has
become emerging tool in organic chemistry.15 Using electron-rich
arenes/heteroarenes as nucleophiles towards the synthesis of
heterocyclic scaffold are less explored in the literature. In 2014,
Michelet and co-worker have reported the synthesis of
isochromenes via a cascade hydroarylation/cycloisomerization of
ortho-Alkynylbenzaldehydes using silver catalyst.16 Based on our
ongoing research towards the synthesis N–heterocycles,17 herein,
*Department of Chemistry, University of Delhi, Delhi 110007, India.
E_mail: averma@acbr.du.ac.in.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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we report a novel method for isobenzofurans synthesis via BF3.Et2O- corresponding isobenzofurans 3a-f in excellent yields. Despite the
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catalyzed tandem hydroarylation/cyclization reactions of 2- bulkiness, the 5-tert-butyl (1g) and 6-isopDroOpI:y1l0(.110h3)9s/Du0bCstCit0u2t7e6d0J2-
formylarylketones with electron-rich arenes (Scheme 1d).
formylarylketones afforded the desired product 3g-h in 81% and 90%
yields respectively. Halogen substituted o-aroylbenzaldehydes 1i-k
furnished the corresponding isobenzofurans 3i-k in 82-86% yields.
The reaction was well tolerated with substrate 1l having ester group
and afforded the desired product 3l in 80% yield which enable a
potential application in further functionalization. The 2-benzoyl-3,5-
dichloro benzaldehyde 1m are also viable substrate to provide the
desired product 3m in 79% yield. The substrate having 4-tert-butyl
(1n), 4-floro (1o) and 4-chloro (1p) substituted aryl groups as R2
afforded the corresponding products 3n-p in good yields. Reaction of
substrates (1q) and (1r) having 2-thienyl and 2-pyridinyl groups as R2
with nucleophile 2a provided the desired product 3q-r in 85% and
75% yields respectively.
To determine the optimal condition, we have commenced our
investigation with 2-formylbenzophenone 1a and 1,3,5-trimethoxy
benzene 2a as a model substrate (Table 1). The reaction of 1a with
2a in presence of 10 mol% AuCl3 catalyst in DCE at 80 oC,
isobenzofuran 3a was not observed (Table 1, entry 1). Further, other
Lewis acid catalysts such as AgNO3, AgOTf, CuBr, ZnCl2, and SnCl4
were also screened; owever, they were incapable to provide the
desired product 3a (Table 1, entries 2–6). Inferior result was
obtained on using FeCl3 as catalyst (table 1, entry 7). The product 3a
was obtained in 25 % yield when p-toluene-sulphonic acid (p-TSA)
was used as catalyst at room temperature (Table 1, entry 8). Use of
TFA slightly improved the yield of the product 3a (Table 1, entry 9).
Above result encouraged us to use BF3.Et2O as catalyst in the
reaction, the desired product 3a was obtained in 60% yield (Table 1,
entry 10). The yield of product 3a increases by the switching solvent
from DCE to DCM (Table 1, entry 11). Increasing the loading of
catalyst from 10 to 20 mol % provided the desired product 3a in 85%
yield (Table 1, entry 12). Other solvents like toluene, and CH3CN
were found to be inferior for the reaction (Table 1, entries 13–14).
No product was obtained when reaction was performed in THF
(Table 1, entry 15). In the absence of a catalyst, no cyclized product
was obtained (Table 1, entry 16).
Table 2. Scope of Substituted Isobenzofuransa,b
Nu
BF3.Et2O (20 mol % )
O
O
R1
R1
O
Nu-H
2a-g
+
DCM, rt
30 min
R2
R2
3a-y
1
OMe
OMe
OMe
R
1 = H, 85% (82%)c
3a,
1 = 5-Me, 88%
1 = 6-Me, 87%
1 = 5-Et, 84%
MeO
MeO
3b,
3c,
3d,
3e,
3f,
R
MeO
R
tBu
OMe
OMe
R
OMe
R
1 = 5-Ph, 83%
O
O
R1
O
R
1 = 7-OMe, 84%
iPr
Ph
Ph
3g,
81%
Ph
3h,
90%
Table 1. Optimization of Reaction Conditionsa
OMe
OMe
OMe
OMe
MeO
MeO
MeO
MeO
OMe
MeO
R1
OMe
OMe
OMe
Cl
O
O
Reaction Condition
OMe
O
O
O
+
Solvent, Temp,
Time
O
Ph
OMe
Ph
Cl
2
t
3n,
3o,
3p,
,
= Bu 87%
R2
1a
Ph
3a
2a
1
,
R2 = F 83%
3i,
3k,
3j,
R
= Br, 86%;
= Cl, 85%;
R
R
1 = F, 82%
1 = CO2Et, 80%
1
,
R
= Cl 86%
3l,
R
R2
Yield (%)b
3a
3m,
79%
T (oC)
t (h)
OMe
entry catalyst (equiv)
solvent
OMe
OMe
MeO
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
AuCl3 (0.1)
AgNO3 (0.1)
AgOTf (0.1)
CuBr (0.1)
ZnCl2 (0.1)
SnCl4 (0.1)
FeCl3 (0.1)
p-TSA (0.1)
TFA (0.1)
BF3.Et2O (0.1)
BF3.Et2O (0.1)
BF3.Et2O (0.2)
BF3.Et2O (0.2)
BF3.Et2O (0.2)
BF3.Et2O (0.2)
-
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCM
DCM
toluene
CH3CN
THF
80
80
80
80
80
80
80
25
25
25
25
25
25
25
25
25
12
12
12
12
12
12
12
12
4
4
1
0.5
1
1
n.r
n.r
n.r
n.r
n.r
n.r
20
25
40
60
75
85
20
10
trace
trace
Me
N
MeO
OMe
Me
OMe
OMe
O
O
O
O
S
N
3q,
3r,
85% (5 min)
Me
75%
Me
3s,
3t,
82%
80%
Me
N
OMe
N
N
Me
HO
R1
O
O
O
Ph
68%
O
Ph
Ph
3w+3w',
Ph
1 = H, 78%
3u,
R
83%
(regioisomer)
3x+3x',
R
1 = 5-Cl, 89%
54%
(regioisomer)
3v,
3y,
aReactions were performed using 1 (1.0 equiv, 0.50 mmol), 2 (1.0 equiv, 0.50
mmol) and BF3.Et2O (0.2 equiv) in 5.0 mL of DCM, bIsolated yield. cgram scale.
1
1
The scopes of other nucleophiles were also investigated to
extend the substrate scope of our established protocol. When 1,3-
dimethoxybenzene (2b) employed as nucleophile, the corresponding
isobenzofuran 3s was obtained in 80% yield. Gratifyingly, the
reaction conditions were compatible with 1,2-dimethyl-1H-indole
(2c) and 1,3-dimethyl-1H-indole (2d) as a nucleophile, and provided
the desired product 3t-v in 78-89% yields respectively. When 5-
methoxy-N-methyl-1H-indole 2e employed as nucleophile in the
reaction, regioisomers product 3w was obtained in 83% yield. Other
nucleophiles such as N-Methylpyrrole (2f) and β-naphthol (2g)
reacted well with starting substrate 1 and provide the desired
DCM
aReactions were performed using 1a (1.0 equiv, 0.5 mmol), 2a (1.0 equiv, 0.5
mmol) and catalyst (0.20 equiv) in 5.0 mL of solvent. Isolated yield. n.r = no
reaction. DCE = 1,2-dichloroethane, DCM = dichloromethane
b
With optimized condition in hand, we have examined the scope
of 2-formylarylketones (1a-s) amenable to reaction with electron-
rich nucleophile 2a-e (Table 2). The electronically neutral 1a and
electronically-rich 2-formylarylketone 1b-f reacted well with
electron-rich arene 1,3,5-trimethoxybenzene 2a and provided the
2 | J. Name., 2012, 00, 1-3
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OMe
product 3x and 3y in moderate yields. Reaction with electronically
poor nucleophile such as 3-methylbenzo[b]thiophene and 3-methyl
[b]benzofuran with 1a furnished only traces of the corresponding
isobenzofuran derivatives.
The scope of this reaction was further extended toward the
synthesis of 1, 3-substituted naphtho[1,2-c]furan18 using variety of
2-aroyl-1-naphthaldehydes (1s-u) under standard reaction
condition. Reaction of 2-pheny-1-naphthaldehyde 1s with 2a, gave
the desired product 4a in 85% yield. The corresponding products 4b-
c was obtained in good yields when 2a reacted with substrate having
R2 as 4-tbutylphenyl (1t), and 4-chlorophenyl (1u) arenes. Other
carbon nucleophile like dimethoxybenzene (2b) and 2-methyl-1-
methylindole (2c), on reaction with substrate 1s, provided the
corresponding products 4d and 4e in 78% and 74% yields
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DOI: 10.1039/D0CC02760J
MeO
OMe
O
Nu
MeO
OMe
m-CPBA
(1.2 equiv)
m-CPBA
(1.2 equiv)
O
O
O
O
OMe
DCM, rt, 1 h
R2 = Cl
DCM, rt, 1 h
R2 = H
Cl
3a 4c
,
7a,
(88%)
R2
7b
, (85%)
Scheme 4. Synthesis of 1,2-Diaroylarenes
To find out the electronic effects of two electron-rich
nucleophiles on competence with 2-formylbenzophenone 1a, an
intermolecular competitive experiment was performed. The
competitive experiment between 1,3,5-trimethoxybenzene 2a and
1,3-dimethoxybenzene 2b with 1a under the standard conditions
could provide evidence about the electronic effects of nucleophiles
in the reaction. The yield of products 3a and 3s were obtained 60%
and 20% respectively (Scheme 6), confirming that formation of
product become more favorable with high electron-rich 2a.
Likewise, intermolecular competition reaction between 2a and
phenol 2g with substrate 1a were revealed that the formation of
product 3a is more favorable. This result supports the electronic
effect of nucleophiles (Scheme 5).
respectively (Scheme 2).
MeO
OMe
O
O
O
MeO
BF3.Et2O (20 mol % )
R2
+
R2
Nu-H
2
DCM, rt, 30 min
1
4a-e
(74-85%)
MeO
MeO
MeO
OMe
OMe
OMe
O
Me
N
O
O
O
MeO
Me
MeO
Ph
R2
Ph
OMe
OMe
Cl
2 = H, (85%);
MeO
4a,
4b,
R
2
4e, (74%)
MeO
+
OMe
OMe
=
tBu, (84%)
4d,
(78%)
4c,
(82%)
R
OMe
+
OMe
BF3.Et2O (20 mol%)
DCM, rt, 30 min
+
1a
O
O
Scheme 2. Scope of 1, 3-Disubstituted Naphtho[1,2-c]furansa,b
OMe
OMe
2b
Ph
aReactions were performed using 1 (1.0 equiv, 0.50 mmol), 2 (1.0 equiv, 0.50
Ph
2a
3s,
20%
3a,
60%
mmol) and BF3.Et2O (0.2 equiv) in 5.0 mL of DCM, bIsolated yield.
OMe
HO
MeO
Further, synthetic utility of 1,3-disubstituted benzo[c]furans
were explored as a stable and reactive diene for the construction of
cyclo-addition product via Diels-Alder reaction (scheme 3). When
[4+2] cycloaddition reaction was performed between stable 1,3-
disubstituted isobenzofuran 3 with dimethyl acetylenedicarboxylate
(DMAD) 5, the desired product 6a-d was obtained in 70-85% yields
which can be used for synthesis of diversified naphthalenes. Under
acidic treatment, the cyclo-adduct can undergoes aromatization and
provide respective 1,4-diaryl naphthalenes.19
OMe
+
MeO
OMe
BF3.Et2O (20 mol%)
DCM, rt, 30 min
O
O
+
1a
+
OH
2g
Ph
3a', 5%
Ph
OMe
3a,
78%
2a
Scheme 5. Competitive Experiment
Based on the previous reports,16, 21 we have proposed a plausible
mechanism for the synthesis of the isobenzofuran 3. The mechanism
is initiated by co-ordination of aldehyde of 2-formylarylketone 1
with the BF3 which enhanced the electrophilicity at the aldehydic
Nu
Nu
CO2Me
CO2Me
CO2Me
DCM
carbon of species P. The, species
P
is available for the
on
R1
O
R1
O
+
50 oC, 12 h
(70-85%)
chemoselective attack of the electron-rich nucleophile
2
R2
CO2Me
R2
3
activated carbonyl, which would eventually result the generation of
5
6a-d
OMe
OMe
OMe
OMe
OMe
OMe
OMe
MeO
F
OMe
MeO
OMe
MeO
OMe
MeO
OMe
MeO
MeO
OMe
OMe
MeO
CO2Me
CO2Me
H
CO2Me Ph
CO2Me
C-C bond
formation
C-O bond
formation
OMe
O
O
BF3
O
O
BF3.Et2O
O
O
O
O
O
O
O
CO2Me
CO2Me
CO2Me
CO2Me
BF3
BF3
O
Ph
Ph
Ph
Ph
1
P
Q
R
6a
6b
6c
6d
(72%)
F
(85%)
(82%)
(70%)
aromatization
MeO
OMe
Scheme 3. Synthetic application of isobenzofurans. aUsing 0.30
mmol of 3; 0.30 mmol of 5 in 5.0 mL of DCM. bIsolated yield
OMe
OMe
MeO
MeO
OMe
MeO
OMe
OMe
O
aromatization
MeO
To further explore the application; synthesis of 1,2-diaroylarenes
7a-b was achieved via a facile oxidative transformation of 1,3-
disubstitutedbenzo[c]furans 3a and 4c using m-CPBA at room
MeO
H
H
BF3
O
O
O
[BF3OH]-
Ph
O
H
H2O
Ph
Ph
S
Ph
3
BF3
T
temperature in excellent yields (Scheme 4) 20
.
Scheme 6. Proposed mechanism
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Angew. Chem. Int. Ed., 2008, 47, 8380; (d) X. MV. iMewaA,rtWicle. OJ.nlWineu,
Q. Zhang, F. L. Guo, F. S. Meng and J. DL.OHI:u1a0,.1D03y9e/sDP0iCgCm0.2, 726000J9,
82, 353; (e) W. J. Wu, F. L. Guo, J. Li, J. X. He and J. L. Hua, Synth.
Met., 2010, 160, 1008; (f) M. Nandakumar, J. Karunakaran and
A. K. Mohanakrishnan, Org. Lett., 2014, 16, 3068.
species Q via C-C bond formation. Subsequently, the species Q
undergoes cyclization via nucleophilic attack of the aldehydic
carbonyl oxygen on to the second carbonyl carbon (ketonic) and
form species R, which is then transformed into species S. The
unstable species S then undergoes aromatization-isomerization
through oxonium ion T and results in the formation of desired
isobenzofurans 3, 4 (Scheme 6).
In conclusion, we have described a BF3-Et2O catalyzed
chemoselective synthesis of structurally diversified 1,3–disubstituted
isobenzofuran via tandem hydroarylation/cyclization reactions of 2-
formylarylketones in good to excellent yields. The reaction was well
tolerated in variety of functional groups with broad substrate
scopes. The reaction is also successful for the synthesis of 1,3–
disubstituted naptho[c]isobenzofurans. Further, the synthetic utility
of isobenzofuran as a reactive diene was explored in the Diels-Alder
reaction towards the synthesis of π-conjugated scaffolds and in the
synthesis of 1,2-diaroylarenes.
[8] P. Amaladass, N. S. Kumar and A. K. Mohanakrishnan,
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Conflicts of interest
The authors declare no conflicts.
Acknowledgments
[14] Y. Nishina, T. Kida and T. Ureshino Org. Lett., 2011, 13, 3960.
The Research work was supported by SERB (EMR/2017/003218/OC) [15] For selected review articles, see: (a) C.-L. Sun and Z.-J. Shi,
and University of Delhi and P. K. M and A. K., are thankful to UGC
and CSIR for fellowship, respectively..
Chem. Rev. 2014, 114, 9219; (b) S. Roscales and A. G. Csaky,
Chem. Soc. Rev. 2014, 43, 8215; (c) A. Bhunia, S. R. Yetra and
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4 | J. Name., 2012, 00, 1-3
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Graphical abstract
DOI: 10.1039/D0CC02760J
Nu
Nu
H 2
Nu
MeO2C
CO2Me
CO2Me
O
O
BF3.Et2O (20 mol % )
DCM, 0 oC-rt
5
R1
O
R1
R1
O
DCM, 50 oC, 12 h
CO2Me
(70-85%)
Synthetic utility as diene

R2
R2
R2
30 min
(74-90%)
6a-d
3a-y, 4a-e
1
R1 = H, Cl, Br, I, NO2, Me; R2 = aryl/(het)aryl
= Electron-rich arenes/(het)arenes
Metal & Additive free
Broad substrate scope Yields up to 90%



Nu
H