Orthogonal selectivity with cinnamic acids in 3-substituted benzofuran synthesis through C-H olefination of phenols

Article abstract of DOI:10.1039/c4cc07026g

A palladium catalyzed intermolecular annulation of cinnamic acids and phenols has been achieved for the selective synthesis of 3-substituted benzofurans. Isotope labeling, competition experiments, kinetic studies, and intermediate trapping have supported a sequence of C-C bond formation and decarboxylation followed by the C-O cyclization pathway. This journal is

Full text of DOI:10.1039/c4cc07026g

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Orthogonal Selectivity with Cinnamic Acids in 3-
substituted Benzofuran Synthesis through C–H
Olefination of Phenols
Cite this: DOI: 10.1039/x0xx00000x
Received 00thSeptember 2014,
Accepted 00th XXXXX 2014
Soumitra Agasti, Upendra Sharma, Togati Naveen, and Debabrata
Maiti*
DOI: 10.1039/x0xx00000x
Scheme 1. Synthesis of benzofurans by multiple C–H bond
functionalization
A palladium catalyzed intermolecular annulation of cinnamic
acids and phenols has been achieved for the selective synthesis of
3-substituted benzofurans.
Isotope labeling, competition
We have recently reported palladium-catalyzed synthesis of 2-
substituted benzofurans by reacting phenols and olefins via
sequential C–H functionalization (Scheme 1, left side).7 Herein, 3-
substituted benzofurans are synthesized from widely available
experiments, kinetic studies, and intermediate trapping have
supported a sequence of C–C bond formation, decarboxylation
followed by C–O cyclization pathway.
Benzofurans are one of the most prevalent structural motifs in phenols and cinnamic acids. Importantly, the carboxylic acid moiety
natural products1 and synthetic compounds, which show a variety of acts as a traceless directing group8 for the exclusive synthesis of
biological activities.2
Tradionally transition-metal-catalyzed benzofuran derivatives.
inter/intra molecular condensation reactions using prefunctionalized
substrates (such as ortho-alkynyl or –halo phenol) are utilized for
bezofuran synthesis.3 Recent efforts are focused on benzofuran
synthesis via ortho C–H activation of phenols.4 Significant recent
achievement includes iron-catalyzed oxidative Pechmann
Mechanistic study of our recently reported 2ꢀsubstituted
benzofuran synthesis from phenol and olefin revealed that palladium
center is located at the α-position of the olefin substituent in the
intermediate B. Complementary to this approach, we envisioned, 3ꢀ
substituted benzofuran (E) synthesis will require intermediate D,
wherein palladium will be attached at the β-position. Formation of
this new intermediate D will be possible if C–Pd bond inserts in an
orthogonal fashion to that of the terminal olefin (Scheme 1, right
side). Cinnamic acid in conjunction with readily available phenols
will produce D since introduction of carboxylic acid group in olefin
will reverse the electronic nature of two carbon centers as compared
to simple olefin (Scheme 1).8a, 9
condensation reaction between phenol and
β-keto ester for
generating polybenzofuran in a single-step.4a Efficient synthesis of
dibenzofuran through novel C–H activation/C–O cyclization from 2-
hydroxy biphenyl has also been reported.4b An oxidative annulation
of phenol and internal alkyne has been achieved for the synthesis of
2,3-disubstituted benzofuran derivatives.4c-e
A Ru-catalyzed
dehydrative C–H alkenylation/annulation reaction of phenols with
1,2-diols has also been utilized efficiently for the synthesis of
benzofuran.4f
Triflic anhydride mediated Pummer annulation
R'
HOOC
reaction is another concise route to access substituted benzofurans.4g,
R'
R
R
Pd-cat.
This work
Pd-cat.
O
R
O
N
4h
OH
previous work, 2013 (ref. 7)
Despite these significant advances, selective synthesis of 3ꢀ
R
substituted benzofurans from readily accessible phenols remain a
challenging task.5 Notably a significant number of natural products
and synthetic compounds are based on 3-substituted benzofuran
motif.1c, 6
R
HOOC
Rh-cat.
R
R
R'
N
R
R
OPiv
N
Rh-cat.
Rovis, 2013 (ref. 9c)
R
Rovis, 2014 (ref. 8a)
R'
Scheme 2. Selective synthesis of benzofuran and pyridine
OH
our previous work7
(2013)
current strategy
H
This work in combination with our previous report on substituted
benzofuran synthesis,7 in essence, parallel the recent studies from
Rovis group for the synthesis of substituted pyridine derivatives
(Scheme 2).8a, 9c In this regard, Miura have contributed significantly
by introducing decarboxylation strategy in various synthetic
transformation like regio-selective olefination, arylation and
cyclization reactions.10
LnPdII(OAc)2
H
COOH
O
O
O
PdIILn(OAc)
Ar
PdIILn(OAc)
Ar
Ar
PdIILn
OAc
COOH
(B)
(A)
Ar
(D)
styrenes
cinnamic acids
O
O
Ar
switchable selectivity
Ar
(E)
After extensive experimentations, desired 3-arylbenzofuran in
dichloroethane (DCE) was obtained with substituted phenol and
(C)
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cinnamic acid under O2 atmosphere (Table 1).11 Notably, related 2- [a]bathophenanthroline as the ligand
arylbenzofuran was not detected even in trace amount. With
Internal alkenyl carboxylic acids were explored subsequently
cinnamic acid derivatives, substituted phenols produced 3-arylated
benzofuran in 26-82% isolated yield (3a-3v). Naphthyl- and para-
tolyl- substituted cinnamic acids gave the 3-arylbenzofuran
exclusively in 82% (3a) and 75% (3c) yields, respectively.
Thiophenylacrylic acid provided the desired benzofuran product in
moderate yield (3d, 45%). Further, nitro (3k), halogen (3f-3h), ester
(3n), and cyano (3l) groups were tolerated under the standard
condition. Next, we probed the scope of our method with different
electron rich phenols (3o-3t). Notably, lower yield of the desired
benzofuran products were obtained in every cases.
under the optimal condition.
Substituted benzofurans were
synthesized exclusively by reacting α,
β
-unsaturated carboxylic acid
with phenol (Table 2, 5a and 5b).
Ph
H
2
1
OH
HO2C
Ph
35%
Ph
Ph
Pd(OAc)2 (10 mol%)
1,10-phen (20 mol%)
Pd(OAc)2 (10 mol%)
1,10-phen (20 mol%)
Cu(OAc)2.H2O (0.25 mmol)
DCE (4 mL), O2, 130 °C, 24h
Cu(OAc)2.H2O (0.25 mmol)
DCE (4 mL), O2, 130 °C, 24h
O
O
OH
7
6
yield : 33%
3j
yield : 0%
Table 1. Scope with substituted phenols and cinnamic acids12
Scheme 3. Formation of 3-phenylbenzofuran from 6
R2
Although a C–Pd intermediate was presumed (Scheme 1),
formation of O–Pd intermediate might be suggested as an alternative
for the observed product formation. In order to gain insights into
this C-olefination vs. O-olefination pathway, two probable
R2
Pd(OAc)2 (10 mol%)
H
1,10-phen (20 mol%)
R1
+
R1
isolated yields
3
Cu(OAc)2.H2O (0.25 mmol)
DCE (4 mL), O2, 130 ºC, 24h
O
OH
1
2
HO2C
(0.75 mmol)
(0.25 mmol)
single regioisomeric product
intermediates
2-(1-phenylvinyl)phenol
(6)
and
(2-
CH3
phenoxyvinyl)benzene (7) were independently synthesized (Scheme
3). Under the reaction condition, 6 produced the expected 3-phenyl
benzofuran (3j).5b In contrary, 7 failed completely to generate this
product.
O2N
NC
O2N
O
O
O
Br
Br
3c, 75%
3a, 82%
3b, 50%
OCH3
R2
Br
S
Cl
Cl
Cl
Cl
Cl
3e, 70%; R2 = 4-OCH3
3f, 69%; R2 = 4-Cl
3g, 42%; R2 = 2-F
H
O2N
NC
Pd(OAc)2 (10 mol%)
1,10-phen (20 mol%)
+
O2N
+
3h, 49%;[a] R2 = 4-Br
O
Cu(OAc)2.H2O (0.25 mmol)
DCE (4 mL), O2, 130 °C, 24h
O
O
OH
OH
8, 32%
O
3d, 45%
3i, 57%
Cl 9, 15%
HOOC
O
O
O
std. conditions
O
O
O
30%
Br
Scheme 4. Isolation of intermediate
NC
O2N
O
Further, we succeeded in isolating the putative intermediate α,α-
disubstituted olefin 8 along with the desired 3-arylated benzofuran 9
(Scheme 4). As anticipated, isolated intermediate 8 can be converted
to 9 under the standard condition.
O
O
O
3m, 51%[a]
3l, 72%[a]
3j, 35%
3k, 81%
O
CH3
O
3p, 32%; R1 = 3-tBu
3q, 26%; R1 = 4-tBu
3r, 34%; R1 = 2-CH3
3n, 56%; R1 = 4-COOCH3
3o, 38%; R1 = 3-OMe
Cu(I)
ArOH
LnPdII(OAc)2
R1
O2 or Cu(OAc)2
R1
O
O
CH3
O
CH3
O
LnPd(0)
O
O
O
O
(I)
Cl
Cl
Ar
O2N
PdIILn
O
OAc
CO2H
O
O
O
H3C
H
tBu
O
Cl
CH3
3v, 47%
3u, 50%
3s, 36%[a]
3t, 31%
r.d.s
PdIILn(OAc)
(IV)
Ar
[a]bathophenanthroline as the ligand
Table 2. Reaction with internal alkenyl carboxylic acids
Ar
LnPdII(OAc)2
O
OH
PdIILn(OAc)
CO2
R2
COOH
H
R2
R3
Pd(OAc)2 (10 mol%)
1,10-phen (20 mol%)
Ar
+
R1
R3
(III)
Ar
LnPd(0) + AcOH
(II)
R1
O
Cu(OAc)2.H2O (0.25 mmol)
DCE (4 mL), O2, 130 °C, 24h
OH
HO2C
5
1
4
isolated yields
single regioisomeric product
(0.75 mmol)
(0.25 mmol)
Scheme 5. Suggested mechanism of 3-arylated benzofuran synthesis
Ph
Ph
O2N
O2N
A plausible mechanism of 3-arylated benzofuran synthesis is
provided in Scheme 5 based on the experimental observations.
Intermediate I can be generated upon coordination of palladium
center to the ortho-position of phenol.7, 13 This step is irreversible
5a, 41%[a]
CH3
CH3
HO2C
HO2C
O
5b, 44%
CH3
CH3
O
2 | J. Name., 2012, 00, 1-3
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since in the absence of α,β-unsaturated carboxylic acid, no D/H
exchange was observed with d5-PhOH.11 Electron withdrawing
substituents on the phenol coupling partners stabilize the phenoxide
ions. Consequently formation of intermediate I is more feasible for
electron deficient phenols. Insertion of cinnamic acids into the C–Pd
bond of I can lead to the C-olefinated intermediate II, wherein –Ar
group will be at the β-position with respect to palladium center.
Removal of CO2 from intermediate II will result in α,α-disubstituted
olefin III. This intermediate has been isolated and characterized
from reaction mixture (Scheme 4). In presence of Pd, intermediate
III will form IV, which can then undergo β-hydride elimination to
provide 3-substituted benzofuran.5b, 14
Notes and references
Department of Chemistry, Indian Institute of Technology
Bombay, Powai, Mumbai-400076, India, E-mail:
dmaiti@chem.iitb.ac.in
Electronic Supplementary Information (ESI) available: [NMR
studies, optimization table, general procedure, detailed control
experiments and the physical data for the compounds.] See
DOI: 10.1039/c000000x/
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Further, the kinetic investigation suggested a first (1.12) order
rate dependency on the cinnamic acid.11 A first order rate
dependency (1.07) was also found for phenol.11 Order with respect
to phenol and cinnamic acid indicate the probable involvement of
both the species in the rate determining step. Therefore, the
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likely to be occuring in the rate determining step (IꢀII).
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intermolecular kinetic isotope effect (KIE) of kH/kD = 1.1 (Scheme
6). Such a low kinetic isotope effect implies that C–H metalation
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Scheme 6. Studies of the kinetic isotope effect
2701-2713.
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deficient phenols were preferred over neutral and electron rich
phenols.11 In addition, electron-rich cinnamic acids were favored
compared to neutral- and electron-poor cinnamic acids.
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a
preference for the 2-arylated benzofuran over 3-arylated
benzofuran (Scheme 1).7,11
In conclusion, we have developed a straightforward synthesis of
3-substituted benzofurans from readily available phenols and
cinnamic acid. With respect to simple olefin, cinnamic acid offers
an orthogonal selectivity. An inverse insertion, compared to alkene,
has been proposed upon ortho-palladation (C–Pd) of phenol. The
equilibrium concentration of the key C–Pd intermediate is depended
on C–H bond breaking and the insertion of cinnamic acid into this
C–Pd bond is likely to be the rate determining step. Complete
regioselectivity and avoidance of expensive additive make this
method synthetically useful. Further mechanistic investigations and
expansion of such strategies are currently underway in our
laboratory.
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This activity is supported by SERB, India (No. SB/S5/GC-
05/2013). Financial support received from CSIR-India (fellowship to
S. A. and T. N.) and DST under Fast Track Scheme (U. S.) is
gratefully acknowledged.
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TOC Graphic
Ar
H
Pd-cat.
R1
R1
Ar
O
OH
free phenols
HO2C
traceless DG
4 | J. Name., 2012, 00, 1-3
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