Direct access to benzo[b]furans through palladium-catalyzed oxidative annulation of phenols and unactivated internal alkynes

Article abstract of DOI:10.1002/anie.201210217

2,3-Disubstituted benzo[b]furans are prepared in one step from commercially available phenols and readily accessible unactivated internal alkynes (see scheme). This Pd-catalyzed oxidative annulation has a broad substrate scope and allows access to a wide range of benzo[b]furans. Copyright

Full text of DOI:10.1002/anie.201210217

Angewandte
Chemie
DOI: 10.1002/anie.201210217
Synthetic Methods
Direct Access to Benzo[b]furans through Palladium-Catalyzed
Oxidative Annulation of Phenols and Unactivated Internal Alkynes**
Malleswara Rao Kuram, M. Bhanuchandra, and Akhila K. Sahoo*
The ubiquitous benzo[b]furan is a privileged structure found
in numerous natural products[1] and biologically active com-
pounds.[2] Highly substituted benzo[b]furan motifs are also
present in various drug leads[2] and organic materials.[3] As
a result, there is considerable interest from the synthetic
organic community to access the benzo[b]furan motif by
efficient methodologies,[4] and indeed, various synthetically
viable strategies have been devised for the construction of
benzo[b]furan and its derivatives. Some of the conceptually
most interesting synthetic strategies toward benzo[b]furans
are shown in Scheme 1.[5]
benzo[b]furans (path b, Scheme 1).[8] A recent report dem-
onstrated the synthesis of 2-methyl-3-aryl-benzofurans
through Zn(OTf)2-catalyzed coupling and cyclization of
phenols with terminal propargyl alcohols.[9] Larock et al.
and other research groups demonstrated an elegant approach
to benzo[b]furans, which involved the Pd-catalyzed intermo-
lecular cyclization of ortho-halogenated phenols with unac-
tivated alkynes (path d, Scheme 1).[10] The sigmatropic rear-
rangement of aryl oxime ethers,[11a] [3+2] cycloaddition of
hydroquinones with enol ethers,[11b] and Ir-catalyzed cyclo-
dehydration of a-aryloxy ketones[11c] are a few noteworthy
approaches that have been developed subsequently and
expand the synthetic versatility of the oxidative cyclization
protocol. Unfortunately, the synthetic potential of this
strategy is limited by the requirement of functionalized
precursors, which can only be obtained through specialized
protocols involving multistep procedures.[5]
The TM-catalyzed oxidative annulation of anilines, phe-
nols, and thiols with activated or unactivated alkynes offers
a unique platform for the atom-efficient formation of hetero-
cycles in a limited number of steps.[12] The groups of Miura
and Ackermann have independently demonstrated the syn-
thesis of naphthopyrans by employing the Rh- and Ru-
catalyzed oxidative annulation between a-naphthol and
alkynes, respectively.[13] An interesting disclosure from Trost
and co-workers describes the synthesis of coumarin involving
the Pd-catalyzed annulation between phenols and alkyno-
ates.[14] Recently, Yu and co-workers reported an intramolec-
Scheme 1. Strategies toward benzo[b]furans.
The typical method for the synthesis of oxygen-bearing
heterocycles involves Lewis acid (LA) catalyzed condensa-
tion of phenol or halogenated arenes with ketones or
aldehydes (path a, Scheme 1).[6] The Fe-catalyzed oxidative
Pechmann-type condensation of phenols with b-keto esters is
a notable strategy, enabling the single-step synthesis of
polybenzofurans.[7] Unfortunately, this method does not give
access to 2,3-diarylbenzo[b]furans. The transition-met-
al(TM)-catalyzed oxidative cyclization of ortho-disubstituted
arene precursors, such as 1,2-dihaloarenes, o-hydroxybenzo-
phenones, and o-bromobenzylbromides with ketones or
aldehydes also furnishes benzo[b]furans (paths a and c,
Scheme 1),[6] while regioselective cyclization of o-alkynylphe-
nols and o-allylphenols readily gives 2- and/or 3-substituted
À
À
ular C H activation/C O cyclization method toward dihy-
drobenzofurans directed by aliphatic alcohols.[15] An efficient
approach to dibenzofurans is realized through intramolecular
[16]
À
À
phenol-directed C H activation/C O cyclization protocols.
À
The Ru-catalyzed dehydrative ortho-C H alkenylation and
cyclization of phenols with 1,2-diols is a direct route to
benzofurans recently disclosed by Yi and co-workers.[17]
While the TM-catalyzed annulation between aniline and
unactivated alkynes provides indole and its derivatives with
ease,[12] a detailed survey of the literature reveals that the one-
step synthesis of benzofurans from readily available phenols
and unactivated alkynes has so far remained elusive (path e,
Scheme 1). The reactivity of phenol toward unactivated
alkynes presents the following challenges: 1) the participation
of an unfavorable four-membered oxygen-containing metalla-
[*] M. R. Kuram, M. Bhanuchandra, Dr. A. K. Sahoo
School of Chemistry, University of Hyderabad
Hyderabad (India)
E-mail: akhilchemistry12@gmail.com
akssc@uohyd.ernet.in
Homepage: http://chemistry.uohyd.ernet.in/~aks/
cycle,[18] 2) difficulties associated with the formation of the C
À
O bond through reductive elimination of the putative PdII
intermediates,[19] and 3) sensitivity of phenols to strong
oxidants, which undergo homocoupling in the presence of
TMs.[16a,20] Despite these cumulative challenges, herein we
report the development of an unprecedented one-step syn-
thesis of benzo[b]furans by the Pd-catalyzed oxidative
[**] We thank the CSIR, INDIA, the University of Hyderabad, and
ACRHEM for financial support. M.R.K. and M.B. thank CSIR, India
for fellowship. Support of R. Kishore, C. C. Gupta, and Dr. P.
Raghavaiah for the X-ray crystallographic analysis is appreciated.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201210217.
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Table 1: Optimization of the reaction conditions.[a]
annulation of readily accessible phenols and unactivated
internal alkynes.
We started the investigation by reacting 4-nitrophenol
(1a) with diphenylacetylene (2a) in the presence of different
combinations of palladium catalysts and phosphine ligands. In
the presence of Pd(OAc)2, JohnPhos (L1) or dppe (L2) as
ligands, K2CO3 or Ag2CO3 as bases, and Cu(OAc)2·H2O as
oxidant in 1,4-dioxane, no reaction occurred or dimerization
of the phenol and/or alkyne was observed (entries 1 and 2).[21]
To our delight, the desired product 3a was formed in 40%
yield (GC analysis) under the catalytic conditions comprising
of [Pd2(dba)3], bathophenanthroline (L3), Ag2CO3, and
AgOAc in dioxane (entry 3). Interestingly, the use of Cu-
(OAc)2·H2O as oxidant and Ag2CO3 as base led to 3a with an
enhanced yield (entry 4). Among the range of Pd0 catalysts
and solvents that were surveyed, [Pd2(dba)3] and 1,4-dioxane
appeared to be optimal.[21] An extensive screening of various
combinations of catalysts, bases, and oxidants led to effective
catalytic conditions (conditions A: [Pd2(dba)3], L3, AgOAc,
and Cu(OAc)2·H2O), and 3a was isolated in 92% yield
(entry 5). Examination of other bidented ligands showed that
the 1,10-phenanthroline (L4) was equally efficient (entry 6),
while bathocuproine (L5) and 2,2’-bipyridyl (L6) produced
trace amounts of 3a (entries 7 and 8). These results show that
the Pd0 catalysts and the N-bearing bidented ligands are
pivotal to this transformation and 3a was not produced in the
absence of either [Pd2(dba)3] or L3.[21]
Entry
1
Catalyst
Ligand
Base
Yield of 3 [%][b]
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
Pd(OAc)2
Pd(OAc)2
L1
L2
L3
L3
L3
L4
L5
L6
L3
L3
L4
L4
L4
L4
K2CO3
n.d.
Ag2CO3
Ag2CO3
Ag2CO3
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
n.d.
[Pd2(dba)3]
[Pd2(dba)3]
[Pd2(dba)3]
[Pd2(dba)3]
[Pd2(dba)3]
[Pd2(dba)3]
[Pd2(dba)3]
[Pd2(dba)3]
[Pd2(dba)3]
[Pd2(dba)3]
[Pd2(dba)3]
Pd(OAc)2
40[c]
60
100 (92)[d]
90
10
trace
trace
20
25
40
9
10
11
12[e]
13[f]
14[f]
100 (88)[d]
100 (51)[d]
[a] Reaction conditions: 1 (2.0 equiv), 2 (20 mg, 1.0 equiv, 0.11 mmol),
catalyst (5 mol%), ligand (10 mol%), base (2.0 equiv), Cu(OAc)2·H2O
(2.0 equiv), and 1,4-dioxane (2.0 mL) at 1308C for 24–48 h. n.d.=not
detected. [b] Conversion based on analysis of the crude by gas
chromatography (GC) using dodecane as internal standard. [c] AgOAc
was used as oxidant. [d] Yield of isolated product on 1.0 mmol scale.
[e] 1b (4.0 equiv) and base (4.0 equiv) was used. [f] 1b (5.0 equiv) and
base (5.0 equiv) was used. Entries in bold mark optimized reaction
conditions.
We recently demonstrated the hydrophenoxylation of
phenols with alkynes for the synthesis of arylvinyl ethers.[22]
A
suitable combination of base and solvent was essential for this
reaction to proceed, and we speculated that the acidity of the
phenol is crucial.[22] Therefore, we studied the reaction
between the electron-rich 4-methoxyphenol (1b) and 2a
under optimized conditions (entry 5, Table 1). Unfortunately,
only a trace of the desired benzofuran 3b was formed (GC
analysis; entry 9). Thus, various combinations of bases,
catalysts, ligands, and solvents were screened to find accept-
able catalytic conditions for the synthesis of 3b (see the
Supporting Information, Table S5).[21] Among the bases
examined, NaOAc was the most suitable (entry 10). The
yield of 3b was marginally enhanced to 25% when L4 was
employed (entry 11). Interestingly, performing the reaction
with 4.0 equivalents of phenol afforded 3b in 40% yield
(entry 12). Notably, an increased amount of 4-methoxyphenol
(5.0 equiv) with respect to 2a (1.0 equiv) significantly
enhanced the efficiency of the reaction and produced 3b in
88% yield (entry 13, conditions B). The catalyst Pd(OAc)2
was found to be moderate (entry 14).
We next turned our attention to the scope and functional-
group tolerance of this transformation. Scheme 2 summarizes
the annulation of various phenols with 2a. The nitro-
substituted benzofuran 3a was obtained in excellent yield
under conditions A in 24 h; in contrast, the known methods
for the synthesis of 3a involve multiple steps with overall poor
yield.[23] The presence of a cyano group did not affect the
reaction outcome, providing 3c in 70% yield. Interestingly,
ketone, aldehyde, and ester functionalities on the phenol were
inert to the reaction conditions, and the desired products 3d–f
were isolated in good yields. Surprisingly, conditions B were
superior over conditions A in the case of 4-hydroxybenzalde-
hyde (1e) and 4-hydroxymethylbenzoate (1 f); the reason for
this observation is unclear. The halogen functionalities (F and
Cl) were tolerated, and the reactions of 4-fluorophenol (1g)
and 4-chlorophenol (1h) with 2a under conditions B deliv-
ered the desired benzofurans. X-ray crystallographic analysis
confirms the structure of 3g.[24] We studied the relative
stability of common N- and O-protecting groups under the
current catalytic conditions. Unfortunately, 4-aminophenol or
N-methyl-4-aminophenol failed to react with 2a, whereas the
annulation between N-acetyl-4-aminophenol and 2a pro-
ceeded smoothly under conditions B, and 3i was exclusively
obtained, leaving the NHAc moiety untouched. We next
envisaged the reaction of a hydroquinone with 2a, which
would enlarge the molecular diversity; unfortunately, our
efforts to incorporate multiple benzofurans on hydroquinone
failed. Gratifyingly, the desired product 3j was obtained from
the mono-O-benzoyl protected hydroquinone (1j) and 2a in
good yield with the O-benzoate protecting group intact.
The electron-rich 4-methoxyphenol (1b) and 4-methyl-
phenol (1k) were both reacted with 2a under conditions B to
provide 3b and 3k in 88% and 70% yield, respectively.
Remarkably, when meta-substituted phenols were annulated
with 2a, highly regioselective benzofuran products 3l–n were
À
produced through the formation of C C bonds at the less-
hindered side of the phenol (Scheme 2). As expected, the
reaction of 2a with the structurally demanding ortho-sub-
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Scheme 3. Substrate scope of alkynes. Reaction conditions A and B
summarized in Scheme 2.
formed with high regioselectivity when phenols and alkyl,
aryl-substituted alkynes were reacted. Reaction of 4-nitro-
phenol (1a) with phenyl- and n-butyl-substituted alkyne 2 f
exclusively delivered 3-butyl-5-nitro-2-phenylbenzofuran
(4 f) in 81% yield. The structure of 4 f was established
based on NOESY studies and X-ray diffraction analysis.[24,26]
The use of a bulky internal alkyne, such as 1-(hex-1-
ynyl)naphthalene (2g), did not affect the regioselectivity,
giving 4g in 64% yield.[26] Similarly, the desired regioselective
product 4h was isolated in good yield from the reaction of
meta-substituted 3-methoxyphenol (1l) with 2 f.[26] To our
delight, our results consistently agree with the observations of
the groups of Larock[27] and Fagnou:[25a] the aryl moiety is
incorporated adjacent to the oxygen functionality in benzo-
furans. Similarly, the annulation between the electron-rich 4-
methoxyphenol (1b) and 1-(hex-1-ynyl)-4-methoxybenzene
(2h) proceeded smoothly and regioselectively produced the
benzofuran product 4i in good yield.[26] Unfortunately,
terminal alkynes were incompatible and largely produced
the corresponding alkyne homocoupling products.[25a]
Various complex phenol derivatives of pharmaceutical
importance were examined to prove the synthetic potential of
this strategy (Scheme 4).[28] The N-Boc-l-tyrosine methyl
ester successfully underwent annulation with 2a and gave the
desired benzofuran derivative 3s in 65% yield. Gratifyingly,
the base-mediated reaction did not affect the stereointegrity
of the l-tyrosine moiety, even at the elevated temperature.
Despite its complex structure, estrone reacted with 2a and
afforded 3t in good yield.[28d,24] A moderate amount of the
desired benzofuran product 3u was obtained from umbelli-
ferone and 2a, without affecting the lactone functionality of
the coumarin moiety. Pleasingly, the ortho-substituted vanil-
lylidenacetone, the chief constituent of the fragrant vanilla
derivative,[28b] reacted sluggishly with 2a to provide 3v in poor
yield.
Scheme 2. Substrate scope of phenols. Reaction conditions A:
1 (2.0 equiv), 2 (178 mg, 1.0 equiv, 1.0 mmol), [Pd2(dba)3] (5.0 mol%),
L3 (10 mol%), AgOAc (2.0 equiv), Cu(OAc)2·H2O (2.0 equiv), 1,4-
dioxane (8.0 mL) at 1308C; conditions B: 1 (5.0 equiv), 2 (178 mg,
1.0 equiv, 1.0 mmol), [Pd2(dba)3] (5.0 mol%), L4 (10 mol%), NaOAc
(5.0 equiv), Cu(OAc)2·H2O (2.0 equiv), 1,4-dioxane (8.0 mL) at 1308C.
stituted phenols 1o and 1p led to moderate amounts of the
corresponding benzofurans 3o and 3p. On the other hand, the
electron-neutral phenol (1q) reacted sluggishly with 2a under
both optimized conditions and provided 3q in poor yield even
with the extended reaction time. Pleasingly, heterocyclic,
substituted phenol 1r efficiently annulated with 2a and
afforded 3r in 91% yield.
Next, we examined the effect of electron-rich and
electron-deficient aryl-substituted alkynes (Scheme 3). Annu-
lation of the electron-poor 4-fluorophenol (1g) or the
electron-rich 4-methoxyphenol (1b) with the electron-rich
4-methoxyphenyl-substituted alkyne 2b produced the desired
benzofurans 4a and 4b in 69% and 67% yields, respectively.
Similarly, the electron-poor 4-chlorophenyl-substituted
alkyne 2c underwent annulation with 1b efficiently. Under
conditions B, 1,2-di(thiophen-2-yl)ethyne (2d) was efficiently
reacted with 1a, resulting in 4d in 55% yield. Because of the
lack of conjugation, the alkyl-substituted alkyne is less
reactive.[25] Interestingly, the desired 2,3-dialkyl-substituted
benzofuran 4e was furnished from 4-chlorophenol (1h) and 4-
octyne (2e) in 63% yield. The benzofuran products were
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Scheme 4. Derivatives of biologically important molecules.
When a-naphthol (1w) was reacted with 2a under
conditions B, the naphthofuran product 3w was exclusively
isolated, albeit in poor yield, instead of the naphthopyran
(Scheme 5).[13,21] Pleasingly, the desired naphthofuran 3x was
obtained with an enhanced yield from the annulation between
1w and electron-rich alkyne 2b.[21] Similarly, the electron-
poor alkyne 2c reacted with 1w under conditions B and
delivered the napthofuran 3y in moderate yield.[21] Thus, two
distinct products can be produced independently under Rh or
Pd catalysis.
Scheme 6. Proposed mechanistic cycle.
isotope effect was observed (KH/KD = 3.0) when a 1:1 mixture
of phenol (1q) and [D5]phenol ([D5]-1q) was reacted with 2a,
thus supporting the participation of Pd-mediated C H bond
À
cleavage (cycle A).[21,30] Furthermore, as reported by van
Koten and co-workers, bis(aryloxo)–PdII complexes will form
adducts with phenols through hydrogen bonding, a require-
ment for the completion of the reaction,[29] thus clearly
supporting the need for an excess amount of phenol (see the
Supporting Information).
Because the catalytic conditions of the benzofuran syn-
thesis did not affect the NHAc moiety, we envisioned the
installation of the indole and carbazole skeletons on molec-
ular templates following known synthetic protocols. The
procedure established by Fagnou and co-workers for the
synthesis of indoles under Rh catalysis was applied, and the
oxidative coupling between aniline precursor 3i and 2a was
performed first. Gratifyingly, the three-ring-fused heterocycle
13 was isolated in 60% yield (Scheme 7).[32a] The Pd-catalyzed
Scheme 5. Switching the site selectivity.
Although a precise reaction mechanism remains to be
established, a plausible mechanism is outlined in Scheme 6.
Even though a Pd0 source was used under optimized reaction
conditions, we assume that the reaction is initiated by a PdII
intermediate, as Pd0 is readily oxidized to PdII in the presence
of Cu(OAc)2.[14] Thus, coordination of the N-bearing biden-
tate ligand to [Pd2(dba)3], followed by Cu(OAc)2-assisted
oxidation of 5, generates the active PdII species 6.[14] At this
stage, attack of phenol onto the electrophilic PdII species may
occur in two different ways. Mechanistic cycle A (Scheme 6)
involves the attack of phenol onto 6 to produce PdII–
phenoxide species 7 and liberate AcOH.[29] Subsequently,
the coordination of the alkyne to 7 would induce its
À
anilide-directed arylation at the less-hindered ortho-C H
bond in 3i with trimethoxyphenylsilane under the conditions
developed by Shi and co-workers gave 14 in 75% yield.[32b]
À
Finally, Buchwaldꢀs intramolecular C N arylation of 14
delivered novel four-ring-fused heteroaromatic compound
15 with ease (Scheme 7).[32c]
In summary, we have developed a novel one-step syn-
thesis of 2,3-disubstituted benzofurans involving Pd-catalyzed
oxidative annulations of commercially available phenols with
phenoxypalladation to afford 8. Base-assisted intramolecular
[30]
À
ortho-C H insertion by the Pd catalyst then leads to 9.
Finally, reductive elimination delivers the benzofuran 3q and
regenerates the Pd0 species for the next catalytic cycle. On the
other hand, mechanistic cycle B involves the ortho pallada-
tion of phenol by electrophilic PdII species 6, giving the
quinone-type intermediate 10.[14,31] Alkyne coordination fol-
lowed by carbopalladation then affords 11, whereupon base-
induced rearomatization yields 12. The catalytic cycle is
completed by the liberation of the product along with Pd0
through reductive elimination of 12. A significant kinetic
Scheme 7. Extending the molecular framework.
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produced the naphthofurans rather than naphthopyrans.
The inertness of the NHAc functional group in this benzo-
furan synthesis allows the creation of novel extended p-
conjugated heterocycles. Efforts are under way to develop
milder reaction conditions and unravel mechanistic details.
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Published online: March 25, 2013
Keywords: alkynes · benzo[b]furans · oxidative annulation ·
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Angew. Chem. Int. Ed. 2013, 52, 4607 –4612
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