Indium(III)-Catalyzed Synthesis of Benzo[ b]furans by Intramolecular Hydroalkoxylation of ortho-Alkynylphenols: Scope and Mechanistic Insights

Article abstract of DOI:10.1021/acs.joc.8b00829

Indium(III) halides catalyze the hydroalkoxylation reaction of ortho-alkynylphenols to afford benzo[b]furans in good yields. The reaction proceeds with 5-endo-dig regioselectivity with a variety of phenols functionalized at the arene and alkyne moieties in high yields using InI₃ (5 mol %) in DCE. Experimental and computational studies support a mechanism based on the indium(III) π-Lewis acid activation of the alkyne followed by nucleophilic addition of the phenol and final protodemetalation to afford the corresponding benzo[b]furan. DFT calculations suggest that dimer In₂I₆ is the catalytic species through a novel double coordination with the alkyne and the hydroxyl group.

Full text of DOI:10.1021/acs.joc.8b00829

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Article
Indium(III)-catalyzed Synthesis of Benzo[b]furans by Intramolecular
Hydroalkoxylation of ortho-Alkynylphenols: Scope and Mechanistic Insights
Lorena Alonso-Marañon, M. Montserrat Martínez, Luis A.
Sarandeses, Enrique Gomez-Bengoa, and José Pérez Sestelo
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00829 • Publication Date (Web): 12 Jun 2018
Downloaded from http://pubs.acs.org on June 12, 2018
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Indium(III)-catalyzed Synthesis of Benzo[b]furans by Intramolecular
Hydroalkoxylation of ortho-Alkynylphenols: Scope and Mechanistic
Insights
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Lorena AlonsoꢀMarañón,‡ M. Montserrat Martínez,‡ Luis A. Sarandeses,‡ Enrique Gómezꢀ
Bengoa,*† José Pérez Sestelo*‡
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‡ Centro de Investigaciones Científicas Avanzadas (CICA) and Departamento de Química,
Universidade da Coruña, Eꢀ15071 A Coruña, Spain
†Departamento de Química Orgánica I, Universidad del País Vasco UPV/EHU,
20009 DonostiaꢀSan Sebastián, Spain
sestelo@udc.es, enrique.gomez@ehu.es
Table of Contents
Abstract
Indium(III) halides catalyze the hydroalkoxylation reaction of orthoꢀalkynylphenols to afford
benzo[b]furans in good yields. The reaction proceeds with 5ꢀendoꢀdig regioselectivity with a
variety of phenols functionalized at the arene and alkyne moieties in high yields using InI3 (5
mol%) in DCE. Experimental and computational studies support a mechanism based on the
indium(III) πꢀLewis acid activation of the alkyne followed by nucleophilic addition of the
phenol and final protodemetallation to afford the corresponding benzo[b]furan. DFT
calculations suggest that dimer In2I6 is the catalytic species through a novel double
coordination with the alkyne and the hydroxyl group.
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Introduction
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Indium, in different oxidation states, has been widely recognized as a soft σꢀLewis acid for
the activation of carbonyl groups in a variety of fundamental organic transformations.1 In
addition, indium is considered to be a green reagent based on its compatibility with aqueous
media, low toxicity and excellent tolerance to oxygenꢀ and nitrogenꢀcontaining substrates and
functional groups.2 In recent years, indium(III) has also proven to be an efficient πꢀLewis acid
for the activation of unsaturated systems, particularly alkynes.3 The synthetic utility has been
demonstrated in a variety of interꢀ and intramolecular indiumꢀcatalyzed carbonꢀcarbon4 and
carbonꢀheteroatom transformations,5 including polycyclization reactions using enynes.6 This
catalytic activity, which is often limited to transition metals, has been explained by Corey
based on the hypothesis that the 5d orbitals of In(III) may be sufficiently lowered in energy to
allow some hybridization with the vacant 5p orbital to facilitate a bidentate coordination
mode with the two orthogonal πꢀbonding orbitals of the C–C triple bonds.6 The dual Lewis
acid activity of indium(III) has found interesting applications in the synthesis of complex
organic compounds.7
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In this context, we have disclosed the ability of indium(III) halides to catalyze a 6ꢀendoꢀdig
regioselective intramolecular hydroarylation (IMHA) of aryl propargyl ethers and amines for
the synthesis of 2Hꢀchromenes and dihydroquinolines (Scheme 1a),8a a reaction that can be
combined in one pot with a palladiumꢀcatalyzed crossꢀcoupling reaction of triorganoindium
reagents.8b Further computational studies,9 support a mechanism based on the indium(III) πꢀ
Lewis activation of the alkyne. In connection with this work, we switched our attention to the
formation of carbonꢀheteroatom bonds using indium catalysis, in particular to the indium(III)ꢀ
catalyzed intramolecular hydroalkoxylation of oꢀalkynylphenols for the synthesis of
benzo[b]furans (Scheme 1b). The benzofuran ring is a privileged structure that is present in a
large number of biologically active compounds and natural products, and the development of
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practical, green and economical methods for synthesis of this unit has been widely pursued.10
One of the most straightforward approaches to benzofurans involves the hydroalkoxylation
reaction of oꢀalkynylphenols using catalysis with precious transition metals such as
palladium, 11 platinum, 12 rhodium, 13 or gold. 14 Although studies on the reactivity of oꢀ
alkynylanilines under indium(III) catalysis have been reported,5b to the best of our knowledge
this is the first example of the synthesis of benzo[b]furans by indium catalysis.
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Scheme 1. Indium(III)ꢀcatalyzed Hydroarylation and Hydroalkoxylation reactions
Results and discussion
Our investigation started with the reactivity of oꢀphenylethynylphenol (1a) with indium(III)
halides. At the outset, treatment of 1a with InI3 (5 mol%) in DCE at room temperature only
produced a small amount of 2ꢀphenylbenzo[b]furan (2a) and most of the starting phenol 1a
was recovered (Table 1, entry 1). However, upon heating at 80 °C the yield increased to 95%
yield in just 2 h (entry 2). Furthermore, it was found that on using InBr3 (5 mol%) the
cycloisomerization proceeded to give a high yield in a short reaction time (entry 3). In
addition, it was observed that the hydroalkoxylation reaction also took place on using InCl3 (5
mol%), although this reaction required 40 h at 80 °C to achieve full conversion (entry 4).
Surprisingly, the use of In(OTf)3 (5 mol%) only gave traces of the benzofuran 2a, with
unreacted starting oꢀalkynylphenol 1a recovered (entry 5). These results show that InI3 and
InBr3 are the most suitable indium(III) halides for this process. We reasoned that this result is
based on the lower oxophilicity of these halides when compared with InCl3 and In(OTf)3,
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which drives the preference for πꢀcoordination with the alkyne over the σꢀinteraction with the
hydroxyl group. This counteranion effect was previously observed in the indiumꢀcatalyzed
hydroarylation reaction8 and in the indiumꢀpromoted carboindiation of alkenes.15 On the other
hand, these results highlight the tolerance of indium(III) halides for the hydroxyl group.
During the optimization process we observed that the reaction also proceeded in toluene,
albeit with longer reaction times required (entry 6), and in CH2Cl2 at 40 °C – although this
reaction required 48 h to afford 2ꢀphenylbenzo[b]furan in excellent yield (entry 7). Evidence
for reaction was not observed in MeOH or CH3CN, probably due to coordination of the
catalyst with the solvent (entries 8 and 9).
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Table 1. Indium(III)ꢀcatalyzed Hydroalkoxylation of oꢀPhenylethynylphenol (1a).
Entry
InX3
InI3
Solvent
DCE
T (ºC)
25
t (h)
16
2
Yield (%)a
15 (85)b
95
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InI3
DCE
80
InBr3
InCl3
In(OTf)3
InI3
DCE
80
2
85
DCE
80
40
16
7
82
(99)b
DCE
80
Toluene
CH2Cl2
MeOH
MeCN
80
93
InI3
40
48
48
16
90
(99)b
(99)b
InI3
65
InI3
80
a Isolated yields. b Recovered starting material in parentheses.
With the optimal reaction conditions in hand, we proceeded to examine the scope of the
reaction using a variety of oꢀalkynylphenols functionalized at the arene and alkyne moieties.
It was found that the presence of electronꢀdonating or electronꢀwithdrawing functional groups
on the phenol ring, such as bromide, methyl or methyl ester (1b–d), did not have a significant
effect on the reactivity and the corresponding 2ꢀphenylbenzo[b]furans 2b–d were obtained in
high yield (Table 2, entries 1–3). The reactions of oꢀalkynylphenols with internal alkynes
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bearing heteroaryl groups, such as thienyl (1e), naphthyl (1f), alkenyl (1g), and alkyl groups
(1h–j), also proceeded efficiently to provide a variety of 2ꢀsubstituted benzo[b]furans (2e–j)
under the same reaction conditions (Table 2, entries 4–9). In addition, the mꢀtrifluoromethyl
oꢀphenylethynyl phenol 1k gave the corresponding benzo[b]furan 2k in 96% yield (Table 2,
entry 10). The hydroalkoxylation reaction with terminal alkynes proved to be more
problematic both in terms of reactivity and side products. Only benzo[b]furan (2l) was
obtained in toluene at 110 °C in 42% yield (Table 2, entry 11).
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Table
2.
Scope
of
the
Indium(III)ꢀcatalyzed
Hydroalkoxylation
of
oꢀAlkynylphenols.
Entry
1
oꢀAlkynylphenol
Product
Yield (%)a
95
96
94
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4
5
82
75
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90b
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96
42c
a Isolated yields b Reaction at rt. c Reaction at 110 °C.
As the next step we focused our attention on the reaction mechanism. Our first proposal
considered the πꢀcoordination of InX3 to the alkyne followed by nucleophilic attack of the
hydroxyl group. The alkenylindium compound generated during this process should undergo
a protodemetallation by the previously generated haloacid to give the corresponding
benzo[b]furan with regeneration of the InX3 (Scheme 2a). We also considered Brønsted acid
catalysis promoted by the haloacid produced by reaction of the phenol with InI3 (Scheme
2b).16
Scheme 2. Mechanistic Pathways for the Indium(III)ꢀcatalyzed Hydroalkoxylation Reaction
of oꢀAlkynylphenols
With these proposals in mind, various experiments were carried out to obtain more
information about the reaction mechanism. Firstly, the hydroalkoxylation reaction in the
presence of deuterated water was explored. Treatment of oꢀalkynylphenol 1a with InI3 (5
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mol%) and D2O (300 mol%) in toluene at 100 °C gave the 2ꢀphenylbenzofuran (2a-d) in 93%
yield with 75% deuterium incorporation at the Cꢀ3 position, a result that supports an
intermolecular protonation step (Table 3, entry 1). Several experiments were also carried out
using proton scavengers that could prevent Brønsted acid catalysis. Interestingly, the
hydroalkoxylation reaction of 1a using InI3 (5 mol%) and K2CO3 (20 mol%) gave a similar
yield, albeit with a longer reaction time (12 h) required, probably due to the slower rate for
the protonation step (Table 3, entry 2). In contrast, evidence for reaction was not observed on
using InI3 (5 mol%) and iꢀPr2NEt (20 mol%) as the catalytic system. In this case, we reasoned
that the Lewis acidꢀbase interaction between the indium(III) halide and the amine inhibited
the catalysis (Table 3, entry 3). Finally, proton catalysis using hydroiodic acid (HI, 57% aq
sol.) was evaluated. The treatment of 1a with 5 mol% of HI afforded the benzofuran 2a in 5%
yield (Table 3, entry 4) and higher amounts of HI produced the electrophilic addition to the
alkyne (Equation 1).
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Table 3. Experimental Mechanistic Studies.
Entry
Catalyst
InI3
Additive
D2O (300 mol%)
K2CO3 (20 mol%)
iꢀPr2NEt (20 mol%)
none
Yield (%)a
93 (75% D)b
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InI3
88
–
InI3
HI (57% aq)
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a Isolated yield. b Reaction in toluene at 100 °C
(1)
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The formation and reactivity of the alkenylindium species generated during the
hydroalkoxylation was also investigated. Organoindium compounds are useful in metalꢀ
catalyzed organic reactions, especially in palladiumꢀcatalyzed crossꢀcoupling reactions.17 On
applying a modified protocol described by Nakamura for the preparation of 3ꢀ
metallobenzofuran intermediates,18 the oꢀphenylethynylphenol (1a) was deprotonated using nꢀ
BuLi and the corresponding lithium phenoxide was heated under reflux in toluene in the
presence of stoichiometric amounts of InCl3. When the reaction was quenched with water the
2ꢀphenylbenzo[b]furan (2a) was obtained in 88% yield. Alternatively, the addition of 4ꢀ
iodotoluene, Pd(OAc)2 (5 mol%), and SPhos (10 mol%) afforded the crossꢀcoupling product
3a in 88% yield (Scheme 3). This result provides evidence for the formation of the
organoindium compound and represents the first example of a tandem indium(III)ꢀpromoted
hydroalkoxylation/palladiumꢀcatalyzed crossꢀcoupling for the synthesis of 2,3ꢀdisubstituted
benzo[b]furans.
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Scheme 3. Tandem Indium(III)ꢀpromoted Hydroalkoxylation/Palladiumꢀcatalyzed Crossꢀ
coupling.
Finally, the mechanism of the cycloisomerization reaction was investigated by performing
density functional theory (DFT) calculations, with particular interest in ascertaining the
coordination pattern of the indium(III) halides with the alkynyl substrate and the origin of the
catalytic activity. According to our experimental results and the proposal of indium(III) as a
soft Lewis acid, indium(III) should bind preferentially to soft basic functional groups such as
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alkynes in preference to other harder groups (i.e., hydroxyl groups).19 oꢀPhenylethynylphenol
(1a) was used as a model and it was found that the preference of indium(III) halides for the
triple bond is not total (Table 4) and equilibrium ratios close to 1:1 were computed for all
InX3 halides. Only InI3 shows a low energy difference (0.7 kcal/mol, 3.3:1, entry 1) in favour
of the alkynyl complex, whereas the chloride and bromide counterparts do not show any
measurable preference. However, the alkynophilic character of In(III) is significant in relative
terms when compared with the behavior of typical hard Lewis acids, such as MgCl2 or AlCl3.
In these cases, the HO:MX2 complex is 8 to 11 kcal/mol more stable than the alkyne:MXn
one, and these values correspond to equilibrium ratios of 107:1 (Al) and 105:1 (Mg) (entries 5
and 6), respectively. Thus, indium salts can be regarded as highly alkynophilic and this
contrasts with the oxophilic character of magnesium or aluminium. Interestingly, GaCl3
shows a relative preference that is intermediate between those of AlCl3 and InCl3, as
corresponds to its hardness, which is between those of indium and aluminium (Table 4, entry
4).
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Table 4. Computed Binding Enthalpiesa and Equilibrium Ratios for Complexation to Oxygen
vs Alkyne of oꢀPhenylethynylphenol (1a) and Lewis Acids of the Type MXn.
Entry
InX3
∆Hf1 (kcal/mol) ∆Hf2 (kcal/mol) Equilibrium
ratio
1
2
3
4
5
6
InI3
–13.8
–16.2
–17.8
–14.6
–15.6
–9.6
–13.1
–16.1
–17.7
–19.4
–26.4
–17.5
3.3 : 1
1.1 : 1
1.3 : 1
1 :103
1 : 107
1 : 105
InBr3
InCl3
GaCl3
AlCl3
MgCl2
a In the gas phase. ∆Hf1 and ∆Hf2 were calculated by subtraction of
the absolute energies of the starting compounds from the absolute
energy of the optimized complex between the substrate and the
Lewis acid.
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Next, computational studies to figure out the complete reaction mechanism were calculated
using InI3 as catalytic species.20 It was found that the formation of the complex INT-1 is
exergonic, i.e., 1.0 kcal/mol lower in energy than the separate reactants, oꢀ
(phenylethynyl)phenol (1a) and InI3, and this initiates the catalytic cycle (Figure 1, the sum of
reactants is taken as G = 0). The results of previous computational studies9 on the indiumꢀ
catalyzed intramolecular hydroarylation showed that the coordination of the triple bond to
indium activates it for the external nucleophilic attack, but this attack is not the rateꢀ
determining step of the reaction. We wanted to address this mechanistic proposal with our
own system. After INT-1, the initial transition state (TSꢀ1) for the ring closure was computed
and this showed quite a high activation energy (ꢀGǂ = 28.6 kcal/mol). In this process, which is
high in energy, an unstable zwitterionic intermediate containing the new C–O and C–In bonds
is formed (INT-2, ꢀG = 27.2 kcal/mol) and this lies 28.2 kcal/mol above the initial
intermediate and only 0.4 kcal/mol below the transition state. These data indicate that the
cyclization is a highly reversible process, and the reaction will not proceed to completion or
become an exothermic process until the oxonium cation in INT-2 is deprotonated or the
hydrogen is transferred to its final position at the Cꢀ3 atom of the benzo[b]furan 2a
(ꢀG = –29.1 kcal/mol). However, it became clear from the beginning that the proton transfer
from INT-2 to 2a is not a straightforward process. Under the experimental conditions
considered here, there is no external base that could promote it and, furthermore, the addition
of bases shuts down the reaction, thus indicating the need for the OH proton to cleave the C–
In bond and form the final adduct (2a).
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Figure 1. Computed Energy Profile for the InI3ꢀcatalyzed Hydroalkoxylation Reaction.
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Under these circumstances, we envisioned several possible mechanistic alternatives for the Hꢀ
transfer (Figure 2). For example, a double intramolecular [1,2]ꢀproton shift would place the H
first on the carbon adjacent to the oxygen (INT-3) and then in the benzofuran 2a. Indeed, the
second migration is energetically affordable (TSꢀ3, ꢀGǂ = 23.5 kcal/mol). In contrast, TSꢀ2
does not seem to exist, since the oxygen would have to adopt an extremely strained geometry
to transfer the hydrogen. Alternatively, an iodide anion, detached from indium in INT-2,
could be responsible for the abstraction of the proton to form the much more stable neutral
intermediate INT-4. However, iodide is not basic enough to play this role, as demonstrated by
the high activation energies of both the intermolecular (TSꢀ4) and intramolecular (iodide still
attached to indium, TSꢀ5) variants of the process, which can be safely ruled out. It is
noteworthy that the cleavage of the C–In bond by hydrogen iodide would be a straightforward
step, as in TSꢀ6 (ꢀGǂ = 10.9 kcal/mol), if INT-4 or a similar intermediate is formed somehow.
Figure 2. Computed Alternatives for the Hydrogen Transfer from the Oxygen atom to the
Final Position in the 2ꢀPhenylbenzo[b]furan (2a).
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I
I
I
I
ꢀ
I
In
In
I
I
I
ꢀ
In
I
H
+
+
O
Ph
O
Ph
Ph
O
H
INT-2
2a
H
TSꢀ2
nonꢀexistent
TSꢀ3
ꢀG = 27.2
INT-3
ꢀG‡ = 16.5
ꢀG = –7.0
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I
In
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I
I
I
In
+O
H
Ph
I
I
I–
In
H
I
TSꢀ4
O
Ph
G >> 40 kcal/mol
2a
INT-2
O
Ph
I
TSꢀ6
ꢀG‡ = 15.5
ꢀG = 27.2
+
H–I
I
In
I
H
+O
INT-4
ꢀG = 4.6
Ph
TSꢀ5
ꢀG‡ = 38.3
As there are no more good candidates for the deprotonation apart from iodide, we
hypothesized that the dimeric nature of In2I6 could play a significant role in stabilizing and
facilitating the different intermediates and transition states of the catalytic cycle. We therefore
reconsidered the whole scheme in the presence of the indium iodide dimer. In fact, the
complexation of the alkyne is stronger with In2I6 (INT-5, Figure 3) than with InI3 (INT-1,
Figure 2) due to the double coordination that the former is able to exert, i.e., between the
indium center and the alkyne plus a new hydrogen bond between the hydroxyl group and one
of the iodides in the second indium atom. In2I6 also has the advantage of a more flexible
structure, which increases the binding free energy to 3.4 kcal/mol. The double interaction C–
In and OH–I is even more important in the subsequent steps of the mechanism. 21 For
example, the activation energy of TSꢀ7 is only 19.7 kcal/mol (compared to 28.6 kcal/mol of
TSꢀ1 in Figure 2) due to the activation of the triple bond and the increased nucleophilicity of
the hydroxyl group. The zwitterionic intermediate INT-6 is still high in energy, but the
reversibility of the process is now compensated by the ease of hydrogen abstraction in TSꢀ8,
which is only 0.2 kcal/mol higher that the energy of INT-6. The higher flexibility of the
dimer In2I6 over the monomer InI3 plays a crucial role. The formation of the neutral species
INT-7 becomes easy and irreversible, since the forward step, namely cleavage of C–InI2 bond
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(TSꢀ9), is low in energy under these conditions. The indium dimer is recovered at the end of
the cycle. We believe that this proposal explains the experimental observations for the
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–
reaction. Alternatively, the deprotonation step could also be seen as driven by the InI4 anion,
9
which simultaneously interacts with the C–InI2 moiety.
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Figure 3. Reaction Profile of the Mechanistic Proposal for the In2I6ꢀpromoted
Hydroxyalkoxylation, and 3D Representation of the Main Transition States.22
Conclusions
Indium(III) halides catalyze the intramolecular 5ꢀendoꢀdig hydroalkoxylation of oꢀ
alkynylphenols to give benzo[b]furans. The reaction proceeds efficiently with 5 mol% of InI3
or InBr3 at 80 °C in DCE and nonꢀcoordinating solvents such as toluene or dichloromethane.
The cycloisomerization takes place with oꢀalkynylphenols substituted at the arene and internal
alkynes to provide a variety of 2ꢀsubstituted benzo[b]furans. Experimental studies support
indium(III) catalysis over Brønsted acid catalysis. The reaction of the phenoxide with
stoichiometric amounts of InCl3 followed by addition of an aryl halide under palladium
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catalysis allows the tandem cycloisomerization/crossꢀcoupling process to give the 2,3ꢀ
disubstituted benzo[b]furans in one pot. DFT calculations support a mechanism in which In2I6
acts as a catalytic species through a double coordination with the alkyne and the hydroxyl
group of the oꢀalkynylphenol. In this proposal the rateꢀlimiting step is the cyclization to give a
zwitterionic intermediate that, after losing H–I, affords a new indium organometallic that
undergoes fast protodemetallation to give the corresponding benzo[b]furan.
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Experimental section
General experimental methods.
All reactions were carried out in flameꢀdried glassware, under argon atmosphere, using
standard gastight syringes, cannulae and septa. Toluene and THF were distilled from
sodium/benzophenone. Dichloromethane was distilled from calcium hydride. Dry DCE,
MeOH, Et3N, iPr2NH and other commercially available reagents were used as received.
Reaction temperatures refer to external bath temperatures. Butyllithium was titrated prior to
use. Indium(III) iodide (99.998%), indium(III) bromide (99%), indium(III) chloride (99.99%)
and indium(III) trifluoromethanesulfonate were purchased from Aldrich and used as received
under argon. Reactions were monitored by TLC using preꢀcoated silica gel plates (Alugram®
Xtra SIL G/UV254, 0.20 mm thick), UV light as the visualizing agent and ethanolic
phosphomolybdic acid as the developing agent. Flash column chromatography was performed
with 230–400 mesh silica gel packed in glass columns. Melting points were measured in a
Stuart Scientific melting point apparatus SMP3 and are uncorrected.
General Procedure for the Preparation of ortho-Alkynylphenols.23
To a rt solution of 2ꢀiodophenol (4.54 mmol) in THF/Et3N (4:1), CuI (0.182 mmol, 4 mol%),
Pd(PPh3)2Cl2 (0.091 mmol, 2 mol%) and the alkyne (9.09 mmol, 200 mol%) were added and
stirred overnight. The reaction mixture was poured into a separatory funnel with saturated
aqueous NH4Cl (30 mL) and extracted with CH2Cl2 (2 × 30 mL). The combined organic layer
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was washed with H2O (20 mL), dried (MgSO4), filtered, and the solvent evaporated under
reduced pressure. The crude was purified by flash chromatography with silica gel
(EtOAc/hexane) to afford, after concentration and high vacuumꢀdrying, the corresponding 2ꢀ
alkynylphenols.
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2-Phenylethynylphenol (1a).11c
Following the General Procedure, the reaction of 2ꢀiodophenol (2.00 g, 9.09 mmol) with
phenylacetylene (2.00 mL, 18.18 mmol), Pd(PPh3)2Cl2 (128 mg, 0.182 mmol) and CuI (70.0
mg, 0.364 mmol) in Et3N (20 mL) and THF (80 mL) afforded, after purification by flash
chromatography (10% EtOAc/hexane), 1a (1.52 g, 86%) as a brown solid. TLC: Rf = 0.20
1
(10% EtOAc/hexane). Mp = 73–75 °C. H NMR (300 MHz, CDCl3): δ 7.58–7.55 (m, 2H),
7.45 (dd, J = 7.7, 1.6 Hz, 1H), 7.40–7.38 (m, 3H), 7.32–7.26 (m, 1H), 7.0 (dd, J = 8.2, 0.8 Hz,
1H), 6.93 (td, J = 7.5, 1.0 Hz, 1H), 5.85 (s, 1H). 13C{1H} NMR (75 MHz, CDCl3): δ 156.5
(C), 131.7 (CH), 131.6 (2 × CH), 130.5 (CH), 128.8 (CH), 128.5 (2 × CH), 122.4 (C), 120.4
(CH), 114.7 (CH), 109.6 (C), 96.4 (C), 83.0 (C). MS (EI, 70 ev): m/z (%): 194 (98) [M]+, 165
(100), 77 (62). HRMS (EI): m/z calcd for C14H10O: 194.0726 [M]+, found: 194.0726.
4-Bromo-2-(phenylethynyl)phenol (1b).24
To a rt solution of 4ꢀbromoꢀ2ꢀiodophenylacetate (460 mg, 1.35 mmol) in THF (5 mL) and
Et3N (0.750 mL, 5.40 mmol), Pd(PPh3)2Cl2 (19 mg, 0.027 mmol), CuI (12.8 mg, 0.067 mmol)
and phenylacetylene (0.440 mL, 4.05 mmol) were added. After 16 h the reaction was diluted
with CH2Cl2 (15 mL) and poured into a separatory funnel with saturated aqueous NH4Cl (15
mL). The aqueous phase was extracted with CH2Cl2 (2 × 15 mL) and the combined organic
layer was washed with H2O (10 mL), dried (MgSO4), filtered, and the solvent evaporated
under reduced pressure. The crude was purified by flash chromatography (10%
EtOAc/hexane) to afford 4ꢀbromoꢀ2ꢀ(phenylethynyl)phenylacetate (1b-OAc, 355 mg, 84%)
as a light brown solid. TLC: Rf = 0.20 (10% EtOAc/hexane). 1H NMR (300 MHz, CDCl3): δ
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7.72 (d, J = 2.4 Hz, 1H), 7.52–7.46 (m, 3H), 7.39–7.36 (m, 3H), 7.02 (d, J = 8.6 Hz, 1H), 2.37
(s, 3H). 13C{1H} NMR (75 MHz, CDCl3): δ 168.5 (C), 150.6 (C), 135.4 (CH), 132.4 (CH),
131.6 (2 × CH), 128.9 (CH), 128.4 (2 × CH), 123.8 (CH), 122.4 (C), 119.5 (C), 118.7 (C),
95.4 (C), 82.9 (C), 20.8 (CH3). MS (EI, 70 ev): m/z (%): 316 (8) [M (81Br)]+, 314 (8) [M
(79Br)]+, 274 (98) [C14H8BrO (81Br)]+, 272 (100) [C14H8BrO (79Br)]+. HRMS (EI): m/z calcd
for C16H11BrO2: 313.9937 [M+]; found: 313. 9927.
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A solution of 1b-OAc (350 mg, 1.11 mmol) in THF (2 mL) at 0 °C was added dropwise to a
solution of K2CO3 (307 mg, 2.22 mmol, 200 mol%) in MeOH (8 mL) and THF (6 mL). The
resulting mixture was stirred for 2 h. After completion, the reaction mixture was poured into a
separating funnel over saturated aqueous NH4Cl (10 mL) and extracted with EtOAc (3 × 10
mL), dried (MgSO4), filtered and concentrated in vacuo, to afford, after purification by flash
chromatography (10% EtOAc/hexane) 1b (270 mg, 0.987 mmol, 89%) as an orange solid.
TLC: Rf = 0.75 (10% EtOAc/hexane). Mp = 105–107 °C (lit.:24 mp = 82–83 °C). 1H NMR
(300 MHz, CDCl3): δ 7.56–7.53 (m, 3H), 7.41–7.35 (m, 4H), 6.89 (d, J = 8.7 Hz, 1H), 5.82 (s,
1H). 13C{1H} NMR (75 MHz, CDCl3): δ 155.1 (C), 133.8 (CH), 133.3 (CH), 131.7 (2 × CH),
129.2 (CH), 128.6 (2 × CH), 121.8 (C), 116.5 (CH), 112.0 (C), 111.7 (C), 97.5 (C), 81.7 (C).
MS (EI, 70 ev): m/z (%): 274 (98) [M (81Br)]+, 272 (100) [M (79Br)]+. HRMS (EI): m/z calcd
for C14H9BrO: 271.9831 [M]+; found: 271.9841.
4-Methyl-2-(phenylethynyl)phenol (1c).11c
To a rt solution of 2ꢀiodoꢀ4ꢀmethylphenol (600 mg, 2.56 mmol) in THF (16 mL)
Pd(PPh3)2Cl2 (18 mg, 0.026 mmol), CuI (9.8 mg, 0.051 mmol) and phenylacetylene (0.340
mL, 3.08 mmol) followed by addition of aqueous solution of NH3 (~0.5 M, 200 mol%) were
added. After 16 h, the reaction mixture was poured into a separating funnel over saturated
aqueous NH4Cl (10 mL) The aqueous layer was extracted with CH2Cl2 (2 × 20 mL) and the
combined organic layer dried (MgSO4), filtered, and the solvent evaporated under reduced
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pressure. The crude was purified by flash chromatography using (10% EtOAc/hexane) to
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afford 1c (420 mg, 2.02 mmol, 79% yield) as an orange solid. TLC: Rf = 0.26 (10%
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8
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EtOAc/hexane). Mp = 71–73 °C (lit.:11c mp = 59–60 °C). H NMR (300 MHz, CDCl3): δ
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7.57–7.54 (m, 2H), 7.40–7.38 (m, 3H), 7.26 (d, J = 1.5 Hz, 1H), 7.10 (dd, J = 8.4, 1.7 Hz,
1H), 6.91 (d, J = 8.4 Hz, 1H), 5.71 (s, 1H), 2.30 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3): δ
154.4 (C), 131.7 (CH), 131.6 (2 × CH), 131.3 (CH), 129.6 (C), 128.7 (CH), 128.5 (2 × CH),
122.5 (C), 114.5 (CH), 109.2 (C), 96.0 (C), 83.3 (C), 20.3 (CH3. MS (EI, 70 ev): m/z (%): 208
(100) [M]+. HRMS (EI): m/z calcd for C15H12O: 208.0883 [M]+; found: 208.0880.
Methyl 4-hydroxy-3-(phenylethynyl)benzoate (1d).25
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Following the General Procedure, the reaction of methyl 4ꢀhydroxyꢀ3ꢀiodobenzoate (500 mg,
1.80 mmol) with phenylacetylene (0.400 mL, 3.57 mmol), Pd(PPh3)2Cl2 (25.2 mg, 0.036
mmol) and CuI (13.7 mg, 0.072 mmol) in Et3N (4 mL) and THF (18 mL) afforded, after
purification by flash chromatography (20–30% EtOAc/hexane), 1d (189 mg, 0.756 mmol,
42%) as a yellow solid. TLC: Rf = 0.35 (30% EtOAc/hexane). Mp = 116–118 °C (lit.:25 mp =
1
114–116 °C). H NMR (300 MHz, CDCl3): δ 8.16 (d, J = 2.1 Hz, 1H) 7.97 (dd, J = 8.6, 2.1
Hz, 1H), 7.57–7.53 (m, 2H), 7.40–7.38 (m, 3H), 7.02 (d, J = 8.6 Hz, 1H), 6.25 (s, 1H), 3.90
(s, 3H). 13C{1H} NMR (75 MHz, CDCl3): δ 166.2 (C), 160.0 (C), 133.8 (CH), 132.1 (CH),
131.7 (2 × CH), 129.1 (CH), 128.6 (2 × CH), 122.7 (C), 121.9 (C), 114.8 (CH), 109.9 (C),
97.0 (C), 81.9 (C), 52.1 (CH3). MS (EI, 70 ev): m/z (%): 252 (100) [M]+, 221 (98), 193 (80)
[C14H9O]+. HRMS (EI): m/z calcd for C16H12O3: 252.0781 [M]+; found: 252.0787.
2-(Thien-3-ylethynyl)phenol (1e).26
Following the General Procedure, the reaction of 2ꢀiodophenol (250 mg, 1.14 mmol) with 3ꢀ
ethynylthiophene (0.220 mL, 2.27 mmol), Pd(PPh3)2Cl2 (16.3 mg, 0.023 mmol) and CuI (9.2
mg, 0.045 mmol) in Et3N (3 mL) and THF (12 mL) afforded, after purification by flash
chromatography (10% EtOAc/hexane), 1e (746 mg, 82%) as a brown solid. TLC: Rf = 0.21
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(10% EtOAc/hexane). Mp = 103–105 °C (lit.:26 mp = 113–115 °C). H NMR (300 MHz,
CDCl3): δ 7.58 (dd, J = 3.0, 1.1 Hz, 1H), 7.43 (dd, J = 7.7, 1.6 Hz, 1H), 7.35 (dd, J = 5.0, 3.0
Hz, 1H), 7.31–7.21 (m, 2H), 6.99 (d, J = 8.3 Hz, 1H), 6.92 (td, J = 7.5, 1.0 Hz, 1H), 5.83 (s,
1H). 13C{1H} NMR (75 MHz, CDCl3): δ 156.5 (C), 131.6 (CH), 130.4 (CH), 129.8 (CH),
129.3 (CH), 125.7 (CH), 121.4 (C), 120.4 (CH), 114.7 (CH), 109.5 (C), 91.4 (C), 82.6 (C).
MS (EI, 70 ev): m/z (%): 200 (100) [M]+, 171 (95). HRMS (EI): m/z calcd for C12H8OS:
200.0290 [M]+; found: 200.0294.
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2-[(6-Methoxynaphthalen-2-yl)ethynyl]phenol (1f).27
To a room temperature solution of Pd(PPh3)4 (39.4 mg, 0.134 mmol) and CuI (12.9 mg, 0.068
mmol) in THF (5 mL), iꢀPr2NH (3.5 mL, 23.2 mmol), 2ꢀiodophenol (300 mg, 1.36 mmol) and
6ꢀmethoxyꢀ2ꢀethynylnaphthalene (298 mg, 1.64 mmol) were added and stirred overnight. The
reaction was diluted with CH2Cl2 (15 mL) and saturated aqueous NH4Cl (15 mL). The
aqueous layer was extracted with CH2Cl2 (2 × 15 mL) and the combined organic layer were
washed with H2O (10 mL), dried (MgSO4), filtered, and the solvent evaporated under reduced
pressure. The crude was purified by flash chromatography (5–10% EtOAc/hexane) to afford
1f (252 mg, 67%) as a light yellow solid. TLC: Rf = 0.15 (10% EtOAc/hexane). Mp = 114–
116 °C (lit.:27 mp = 115–117 °C). 1H NMR (300 MHz, CDCl3): δ 7.99 (s, 1H), 7.72 (d, J = 8.7
Hz, 2H), 7.55 (d, J = 8.4 Hz, 1H), 7.48 (d, J = 7.7 Hz, 1H), 7.29 (t, J = 7.5 Hz, 1H), 7.20 (dd,
J = 9.0, 2.4 Hz, 1H), 7.13 (d, J = 2.2 Hz, 1H), 7.04 (d, J = 8.3 Hz, 1H), 6.94 (t, J = 7.5 Hz,
1H), 5.98 (s, 1H), 3.93 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3): δ 158.6 (C), 156.5 (C),
134.4 (C), 131.7 (CH), 131.5 (CH), 130.4 (CH), 129.4 (CH), 128.7 (CH), 128.4 (C), 127.0
(CH), 120.5 (CH), 119.6 (CH), 117.2 (C), 114.8 (CH), 109.9 (C), 105.9 (CH), 97.1 (C), 82.7
(C), 55.4 (CH3). MS (EI, 70 ev): m/z (%): 274 (100) [M]+. HRMS (EI): m/z calcd for
C19H14O2: 274.0988 [M]+; found: 274.0986.
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2-(Cyclohex-1-en-1-ylethynyl)phenol (1g).
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Following the General Procedure, the reaction of 2ꢀiodophenol (500 mg, 2.27 mmol) with 1ꢀ
ethynylcyclohexene (0.540 mL, 4.55 mmol), Pd(PPh3)2Cl2 (32.0 mg, 0.045 mmol) and CuI
(17.3 mg, 0.091 mmol) in Et3N (6 mL) and THF (20 mL) afforded, after purification by flash
chromatography in neutral alumina (5% EtOAc/hexane), 1g (336 mg, 75%) as an orange
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solid. TLC: Rf = 0.25 (2% EtOAc/hexane). Mp = 62–64 °C. H NMR (300 MHz, CDCl3): δ
7.33 (dd, J = 7.7, 1.7 Hz, 1H), 7.23 (td, J = 7.5, 1.6 Hz, 1H), 6.95 (dd, J = 8.2, 0.7 Hz, 1H),
6.87 (td, J = 7.5, 1.1 Hz, 1H), 6.29–6.25 (m, 1H), 5.77 (s, 1H), 2.28–2.15 (m, 4H), 1.74–1.63
(m, 4H). 13C{1H} NMR (75 MHz, CDCl3): δ 156.2 (C), 136.2 (CH), 131.3 (CH), 129.9 (CH),
120.2 (CH), 120.1 (C), 114.4 (CH), 110.1 (C), 98.5 (C), 80.2 (C), 29.3 (CH2), 25.8 (CH2),
22.2 (CH2), 21.4 (CH2). MS (EI, 70 ev): m/z (%): 198 (100) [M]+, 170 (80). HRMS (EI): m/z
calcd for C14H14O: 198.1039 [M]+; found: 198.1037.
2-(Cyclopropylethynyl)phenol (1h).28
Following the General Procedure, the reaction of 2ꢀiodophenol (500 mg, 2.27 mmol) with
ethynylcyclopropane (0.385 mL, 4.55 mmol), Pd(PPh3)2Cl2 (32.0 mg, 0.045 mmol) and CuI
(17.3 mg, 0.091 mmol) in Et3N (6 mL) and THF (20 mL), afforded, after purification by flash
chromatography (5% Et2O/hexane), 1h (238 mg, 66%) as a yellow oil. TLC: Rf = 0.18 (5%
Et2O/hexane). 1H NMR (300 MHz, CDCl3): δ 7.29 (dd, J = 7.8, 1.5 Hz, 1H), 7.20 (td, J = 7.8,
1.6 Hz, 1H), 6.93 (dd, J = 8.2, 0.9 Hz, 1H), 6.84 (td, J = 7.5, 1.1 Hz, 1H), 5.80 (s, 1H), 1.55–
1.48 (m, 1H), 0.98–0.90 (m, 2H), 0.88–0.82 (m, 2H). 13C{1H} NMR (75 MHz, CDCl3): δ
156.8 (C), 131.6 (CH), 129.6 (CH), 120.1 (CH), 114.3 (CH), 110.1 (C), 101.0 (C), 69.5 (C),
9.0 (2 × CH2), 0.2 (CH). MS (EI, 70 ev): m/z (%): 158 (100) [M]+, 131 (71). HRMS (EI): m/z
calcd for C11H10O: 158.0726 [M]+; found: 158.0724.
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2-(Hex-1-ynyl)-phenol (1i).29
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Following the General Procedure, the reaction of 2ꢀiodophenol (500 mg, 2.27 mmol) with
hexyne (0.522 mL, 4.55 mmol), Pd(PPh3)2Cl2 (32.0 mg, 0.045 mmol) and CuI (17.3 mg,
0.091 mmol) in Et3N (6 mL) and THF (20 mL) afforded, after purification by flash
chromatography (10% EtOAc/hexane), compound 1i (274 mg, 66%) as an orange oil. TLC:
Rf = 0.41 (20% EtOAc/hexane). 1H NMR (300 MHz, CDCl3): δ 7.30 (dd, J = 7.7, 1.6 Hz, 1H),
7.20 (td, J = 7.8, 1.6 Hz, 1H), 6.93 (dd, J = 8.2, 1.0 Hz, 1H), 6.84 (td, J = 7.5, 1.1 Hz, 1H),
5.79 (s, 1H), 2.72 (t, J = 7.0 Hz, 2H), 1.68–1.58 (m, 2H), 1.55–1.43 (m, 2H), 0.96 (t, J = 7.2
Hz, 3H). 13C{1H} NMR (75 MHz, CDCl3): δ 156.5 (C), 131.4 (CH), 129.5 (CH), 120.1 (CH),
114.3 (CH), 110.2 (C), 98.0 (C), 74.5 (C), 30.8 (CH2), 22.0 (CH2), 19.3 (CH2), 13.6 (CH3).
MS (EI, 70 ev): m/z (%): 174 (42) [M]+, 131 (100) [C9H7O]+. HRMS (EI): m/z calcd for
C12H14O: 174.1039 [M]+; found: 174.1039.
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6-(2-Hydroxyphenyl)hex-5-ynenitrile (1j).
Following the General Procedure, the reaction of 2ꢀiodophenol (300 mg, 1.36 mmol) with 5ꢀ
hexynenitrile (0.285 mL, 2.73 mmol), Pd(PPh3)2Cl2 (19.1 mg, 0.027 mmol) and CuI (10.4
mg, 0.054 mmol) in Et3N (5 mL) and THF (15 mL) afforded, after purification by flash
chromatography (20% EtOAc/hexane), 1j (262 mg, 99%) as a yellow solid. TLC: Rf = 0.16
(20% EtOAc/hexane). Mp = 50–52 °C. 1H NMR (300 MHz, CDCl3): δ 7.30 (dd, J = 7.7, 1.6
Hz, 1H), 7.23 (t, J = 7.0 Hz, 1H), 6.93 (d, J = 8.2 Hz, 1H), 6.86 (td, J = 7.5, 1.0 Hz, 1H), 5.75
(s, 1H), 2.69 (t, J = 6.8 Hz, 2H), 2.56 (t, J = 7.0 Hz, 2H), 2.00 (t, J = 6.9 Hz, 2H). 13C{1H}
NMR (75 MHz, CDCl3): δ 156.6 (C), 131.8 (CH), 130.1 (CH), 120.3 (CH), 119.0 (C), 114.7
(CH), 109.4 (C), 100.0 (C), 94.1 (C), 24.5 (CH2), 18.8 (CH2), 16.4 (CH2). MS (EI, 70 ev): m/z
(%): 174 (46) [M]+, 131 (100) [C9H7O]+. HRMS (EI): m/z calcd for C12H11NO: 185.0835
[M]+; found: 185.0837.
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2-(Phenylethynyl)-5-(trifluoromethyl)phenol (1k).
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To a cold solution of 2ꢀbromoꢀ5ꢀ(trifluoromethyl)phenol (300 mg, 1.25 mmol) and K2CO3
(0.69 g, 5.0 mmol, 400 mol%) in DMF (3 mL) MOMCl (0.14 mL, 1.88 mmol, 150 mol%)
was added the reaction stirred overnight at rt. The reaction mixture was quenched with H2O (4
mL), extracted with Et2O (2 x 10 mL), and the combined organic layers washed with H2O (10
mL), dried, filtered, and the solvent evaporated under reduced pressure. Concentration and
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high
vacuumꢀdrying
afforded
crude
of
1ꢀbromoꢀ2(methoxymethoxy)ꢀ4ꢀ
(trifluoromethyl)benzene. This product was transferred to a Schlenk tube under argon and
Et3N (2.5 mL, 17.8 mmol), ethynylbenzene (0.30 mL, 2.74 mmol, 200 mol%), Pd(PPh3)2Cl2
(17 mg, 0.025 mmol, 2 mol%) and CuI (12 mg, 0.063 mmol, 5 mol%) were added and the
mixture stirred for 20 h at 50 ºC. Then the reaction was filtered through a pad of Celite® and
the solvent evaporated under reduced pressure and the crude purified by flash
chromatography (5% EtOAc/hexane) to afford 2ꢀ(methoxymethoxy)ꢀ1ꢀ(phenylethynyl)ꢀ4ꢀ
(trifluoromethyl)benzene (1k-MOM, 106 mg). The 1k-MOM (106 mg, 0.35 mmol) was
dissolved in methanol (5 mL) and HCl (37%, 70 ꢁL) was slowly added. The resulting mixture
was stirred at rt for 12 h. After completion, the reaction was neutralized with saturated
NaHCO3 aq., extracted with EtOAc (3 × 10 mL), dried, filtered and concentrated in vacuo, to
afford, after purification by flash chromatography (5% EtOAc/hexane) compound 1k (82 mg,
0.088 mmol, 25% yield over three steps) as an orange solid. TLC: Rf =0.27 (5%
EtOAc/hexane). Mp = 73–75 °C. 1HꢀNMR (300 MHz, CDCl3): δ 7.60–7.52 (m, 4H), 7.44–
7.39 (m, 3H), 7.19 (dd, J = 8.1, 1.9 Hz, 1H), 6.05 (s, 1H). 13C{1H}NMR (75 MHz, CDCl3): δ
156.5 (C), 132.3 (C, q, J = 32 Hz), 132.1 (CH), 131.7 (2 × CH), 129.4 (CH), 128.6 (2 × CH),
125.4 (C), 121.4 (C, q, J = 272 Hz), 121.7 (C), 117.1 (CH, q, J = 4.1 Hz), 112.0 (CH, q, J =
4.1 Hz), 98.3 (C), 81.7 (C). MS (EI, 70 ev): m/z (%): 262 (68) [M]+. HRMS (EI): m/z calcd
for C15H9F3O: 262.0600 [M]+; found: 262.0606.
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Methyl 3-ethynyl-4-hydroxybenzoate (1l).
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Following the General Procedure, the reaction of methyl 4ꢀhydroxyꢀ3ꢀiodobenzoate (800 mg,
2.88 mmol) with ethynyltrimethylsilane (0.815 mL, 5.76 mmol), Pd(PPh3)2Cl2 (40.0 mg,
0.058 mmol) and CuI (22.0 mg, 0.115 mmol) in Et3N (4 mL) and THF (16 mL) afforded,
after purification by flash chromatography (20% EtOAc/hexane), methyl 4ꢀhydroxyꢀ3ꢀ
((trimethylsilyl)ꢀethynyl)benzoate (1l-TMS, 0.694 g, 97%) as a light yellow solid. TLC: Rf =
0.28 (20% EtOAc/hexane). Mp = 144–146 °C. 1H NMR (300 MHz, CDCl3): δ 8.07 (d, J = 2.1
Hz, 1H) 7.94 (dd, J = 8.6, 2.1 Hz, 1H), 6.98 (d, J = 8.6 Hz, 1H), 6.19 (s, 1H), 3.88 (s, 3H),
0.29 (s, 9H). 13C{1H} NMR (75 MHz, CDCl3): δ 166.1 (C), 160.5 (C), 133.7 (CH), 132.3
(CH), 122.5 (C), 114.5 (CH), 109.8 (C), 103.5 (C), 97.6 (C), 52.0 (CH3), ꢀ0.14 (3 × CH3). MS
(EI, 70 ev): m/z (%): 248 (15) [M]+, 233 (100) [C12H13O3Si]+. HRMS (EI): m/z calcd for
C13H16O3Si: 248.0863 [M]+; found: 248.0864.
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To a rt solution of 1l-TMS (440 mg, 1.77 mmol) in THF (15 mL), TBAF (2.22 mL, 1.0 M in
THF) was added and the resulting mixture was stirred for 2 h under argon. The reaction was
diluted with Et2O (20 mL) and saturated aqueous NaCl (20 mL). The aqueous layer was
extracted with Et2O (2 × 20 mL) and the combined organic layer were dried (MgSO4), filtered
and the solvent evaporated under reduced pressure to afford, after purification by flash
chromatography (20% EtOAc/hexane), 1l (0.306 g, 98%) as a brown oil. TLC: Rf = 0.25
1
(40% EtOAc/hexane). H NMR (300 MHz, CDCl3): δ 8.12 (d, J = 2.1 Hz, 1H) 7.98 (dd, J =
8.7, 2.1 Hz, 1H), 7.01 (d, J = 8.7 Hz, 1H), 6.24 (s, 1H), 3.90 (s, 3H), 3.51 (s, 1H). 13C{1H}
NMR (75 MHz, CDCl3): δ 166.0 (C), 160.9 (C), 134.2 (CH), 132.6 (CH), 122.7 (C), 114.9
(CH), 108.5 (C), 85.0 (CH), 77.2 (C), 52.1 (CH3). MS (EI, 70 ev): m/z (%): 176 (63) [M]+,
145 (100) C9H5O2]+. HRMS (EI): m/z calcd for C10H8O3: 176.0468 [M]+; found: 176.0466.
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General Procedure for the Indium(III)-catalyzed Hydroalkoxylation Reaction of ortho
-
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Alkynylphenols.
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In an ovenꢀdried Schlenk tube filled with argon, the orthoꢀalkynylphenol (100 mg scale) was
dissolved in DCE (5–7 mL) and InI3 (5 mol%) was added. The resulting mixture was heated
at 80 °C and monitored by TLC. The mixture was cooled to rt and the solvent was removed in
vacuo. The residue was purified by flash chromatography (EtOAc/hexane) to afford, after
concentration and highꢀvacuum drying, the corresponding 2ꢀsubstituted benzo[b]furan.
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2-Phenylbenzo[b
]furan (2a).30
Following the General Procedure, the reaction of 2ꢀphenylethynylphenol (1a, 100 mg, 0.515
mmol) with InI3 (12.7 mg, 0.026 mmol) in DCE (6 mL) at 80 °C overnight afforded, after
purification by flash chromatography (10% EtOAc/hexane), 2a (94 mg, 94% yield) as a white
1
solid. TLC: Rf = 0.53 (10% AcOEt/hexane). Mp = 122–124 °C (lit.:30 mp = 118–120 ºC); H
NMR (300 MHz, CDCl3): δ 7.88 (dd, J = 8.4, 1.2 Hz, 2H), 7.60 (dd, J = 7.2, 1.7 Hz, 1H),
7.53 (d, J = 8.2 Hz, 1H), 7.46 (t, J = 7.4 Hz, 2H), 7.39–7.21 (m, 3H), 7.04 (d, J = 0.8 Hz, 1H).
13C{1H} NMR (75 MHz, CDCl3): δ 155.9 (C), 154.9 (C), 130.5 (C), 129.2 (C), 128.8 (2 ×
CH), 128.5 (CH), 124.9 (2 × CH), 124.2 (CH), 122.9 (CH) 120.9 (CH), 116.2 (CH), 101.3
(CH). MS (EI, 70 ev): m/z (%): 194 (100) [M]+, 165 (40). HRMS (EI): m/z calcd for C14H10O:
194.0726 [M]+; found: 194.0726.
5-Bromo-2-phenylbenzo[b
]furan (2b).31
Following the General Procedure, the reaction of 4ꢀbromoꢀ2ꢀ(phenylethynyl)phenol (1b, 100
mg, 0.366 mmol) with InI3 (9.1 mg, 0.018 mmol) in DCE (5 mL) at 80 °C for 16 h afforded,
after purification by flash chromatography (10% EtOAc/hexane), 2b (135 mg, 95%) as a
white solid. TLC: Rf = 0.40 (10% EtOAc/hexane). Mp = 157–159 °C (lit.: 32 mp = 158–159
ºC); 1H NMR (300 MHz, CDCl3): δ 7.88 (dd, J = 8.4, 1.3 Hz, 2H), 7.72–7.71 (m, 1H), 7.50–
7.45 (m, 2H), 7.43–7.36 (m, 3H), 6.97 (s, 1H). 13C{1H} NMR (75 MHz, CDCl3): δ 157.2 (C),
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153.6 (C), 131.2 (C), 129.9 (C), 129.0 (CH), 128.8 (2 × CH), 127.1 (CH), 125.0 (2 × CH),
123.5 (CH), 116.0 (C), 112.6 (CH), 100.6 (CH). MS (EI, 70 ev): m/z (%): 274 (98) [M
(81Br)]+, 272 (100) [M (79Br)]+. HRMS (EI): m/z calcd for C14H9BrO: 271.9831 [M]+; found:
271.9832.
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5-Methyl-2-phenylbenzo[b
]furan (2c).33
Following the General Procedure, the reaction of 4ꢀmethylꢀ2ꢀ(phenylethynyl)phenol (1c, 100
mg, 0.480 mmol) with InI3 (11.9 mg, 0.024 mmol) in DCE (6 mL) at 80 °C for 16 h afforded,
after purification by flash chromatography (10% EtOAc/hexane), 2c (96 mg, 96%) as a white
solid. TLC: Rf = 0.48 (10% EtOAc/hexane). Mp = 132–134 °C (lit.:33 mp = 131–133 ºC). 1H
NMR (300 MHz, CDCl3): δ 7.88 (d, J = 7.3 Hz, 2H), 7.49–7.36 (m, 5H), 7.11 (dd, J = 8.3, 1.2
Hz, 1H), 6.97 (s, 1H), 2.47 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3): δ 156.0 (C), 153.3 (C),
132.3 (C), 130.6 (C), 129.3 (C), 128.7 (2 × CH), 128.4 (CH), 125.5 (CH), 124.8 (2 × CH),
120.7 (CH), 110.6 (CH), 101.1 (CH), 21.3 (CH3). MS (EI, 70 ev): m/z (%): 208 (100) [M]+.
HRMS (EI): m/z calcd for C15H12O: 208.0883 [M]+; found: 208.0878.
Methyl 2-phenylbenzo[b]furan-5-carboxylate (2d).
Following the General Procedure, the reaction of methyl 4ꢀhydroxyꢀ3ꢀ
(phenylethynyl)benzoate (1d, 100 mg, 0.396 mmol) with InI3 (9.8 mg, 0.020 mmol) in DCE
(5 mL) at 80 °C for 16 h afforded, after purification by flash chromatography (20%
EtOAc/hexane), 2d (92.3 mg, 92%) as a light brown solid. TLC: Rf = 0.38 (20%
1
EtOAc/hexane). Mp = 160–162 °C. H NMR (300 MHz, CDCl3): δ.32 (d, J = 1.3 Hz, 1H),
8.02 (dd, J = 8.6, 1.8 Hz, 1H), 7.87 (dd, J = 8.3, 1.2 Hz, 2H), 7.55 (d, J = 8.7 Hz, 1H), 7.49 –
7.44 (m, 2H), 7.41–7.35 (m, 1H), 7.07 (d, J = 0.7 Hz, 1H), 3.95 (s, 3H). 13C{1H} NMR (75
MHz, CDCl3): δ 167.3 (C), 157.4 (C), 157.3 (C), 129.9 (C), 129.2 (C), 129.0 (CH), 128.9 (2 ×
CH), 126.0 (CH), 125.3 (C), 125.1 (2 × CH), 123.3 (CH), 111.0 (CH), 101.5 (CH), 52.1
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(CH3). MS (EI, 70 ev): m/z (%): 252 (100) [M]+, 221 (60), 193 (27). HRMS (EI): m/z calcd
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for C16H12O3: 252.0781 [M]+; found: 252.0769.
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2-(Thien-3-yl)benzo[b
]furan (2e).34
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Following the General Procedure, the reaction of 2ꢀ(thienꢀ3ꢀylethynyl)phenol (1e, 100 mg,
0.500 mmol) with InI3 (12.3 mg, 0.025 mmol) in DCE (6 mL) at 80 °C overnight afforded,
after purification by flash chromatography (10% EtOAc/hexane), 2e (81.8 mg, 82%) as a
white solid. TLC: Rf = 0.46 (10% AcOEt/hexane). Mp = 134–136 °C (lit.:34 mp = 133–135
ºC). 1H NMR (300 MHz, CDCl3): δ 7.73 (dd, J = 2.9, 1.2 Hz, 1H), 7.58–7.56 (m, 1H), 7.51–
7.46 (m, 2H), 7.41–7.39 (m, 1H), 7.31–7.20 (m, 2H), 6.84 (s, 1H). 13C{1H} NMR (75 MHz,
CDCl3): δ 154.5 (C), 152.7 (C), 134.2 (C), 129.1 (C), 126.5 (CH), 125.1 (CH), 124.1 (CH),
122.9 (CH), 121.4 (CH), 120.8 (CH), 111.0 (CH), 101.0 (CH). MS (EI, 70 ev): m/z (%): 200
(100) [M]+, 171 (30). HRMS (EI): m/z calcd for C12H8OS: 200.0290 [M]+; found: 200.0290.
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2-(6-Methoxynaphthalen-2-yl)benzo[b
]furan (2f).35
Following the General Procedure, the reaction of 2ꢀ[(6ꢀmethoxynaphthalenꢀ2ꢀ
yl)ethynyl]phenol (1f, 100 mg, 0.364 mmol) with InI3 (9.1 mg, 0.018 mmol) in DCE (4 mL)
at 80 °C for 16 h afforded, after purification by flash chromatography (20% EtOAc/hexane),
2f (75.4 mg, 75%) as a beige solid. TLC: Rf = 0.45 (20% EtOAc/hexane). Mp = 193–195 °C
1
(lit.:36 mp = 193–195 ºC). H NMR (300 MHz, CDCl3): δ 8.31 (s, 1H), 7.91 (d, J = 8.4 Hz,
1H), 7.82 (t, J = 9.6 Hz, 2H), 7.61 (d, J = 7.6 Hz, 1H), 7.57 (d, J = 7.9 Hz, 1H), 7.31–7.17 (m,
4H), 7.10 (s, 1H), 3.96 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3): δ 158.2 (C), 156.2 (C),
154.9 (C), 134.6 (C), 129.9 (CH), 129.4 (CH), 128.9 (CH), 127.3 (CH), 125.7 (C) 124.1
(CH), 123.8 (CH), 123.4 (CH), 122.9 (CH), 120.8 (CH), 119.4 (CH), 111.1 (CH), 105.9 (CH),
101.1 (CH), 55.4 (CH3). MS (EI, 70 ev): m/z (%): 274 (100) [M]+. HRMS (EI): m/z calcd for
C19H14O2: 274.0988 [M]+; found: 274.0986.
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2-(Cyclohex-1-en-1-yl)benzo[b
]furan (2g).37
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Following the General Procedure, the reaction of 2ꢀ(cyclohexꢀ1ꢀenꢀ1ꢀylethynyl)phenol (1g,
100 mg, 0.504 mmol) with InI3 (12.5 mg, 0.025 mol) in DCE (6 mL) at 80 °C overnight
afforded, after purification by flash chromatography (5% EtOAc/hexane), 2g (90.2 mg, 90%)
as a white solid. TLC: Rf = 0.62 (5% EtOAc/hexane). Mp = 92–94 °C (lit.:37 mp = 55–57 ºC).
1H NMR (300 MHz, CDCl3): δ 7.52 (d, J = 7.6 Hz, 1H), 7.44 (d, J = 7.9 Hz, 1H), 7.27–7.16
(m, 2H), 6.64 (t, J = 4.2 Hz 1H), 6.52 (s, 1H), 2.42–2.29 (m, 4H), 1.82–1.72 (m, 4H). 13C{1H}
NMR (75 MHz, CDCl3): δ 157.5 (C), 154.4 (C), 129.2 (C), 127.2 (C), 126.1 (CH), 123.8
(CH), 122.5 (CH), 120.5 (CH), 110.7 (CH) 100.0 (CH), 25.4 (CH2), 25.0 (CH2), 22.4 (CH2),
22.1 (CH2). MS (EI, 70 ev): m/z (%): 198 (100) [M]+, 170 (71) [C12H10O]+. HRMS (EI): m/z
calcd for C14H14O: 198.1039 [M]+; found: 198.1027.
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2-Cyclopropylbenzo[b]furan (2h).
Following the General Procedure, the reaction of 2ꢀ(cyclopropylethynyl)phenol (1h, 100 mg,
0.632 mmol) with InI3 (15.7 mg, 0.032 mmol) in DCE (8 mL) at 80 °C overnight afforded,
after purification by flash chromatography (2% EtOAc/hexane), 2h (86.3 mg, 86%) as a
1
colorless oil. TLC: Rf = 0.57 (2% EtOAc/hexane). H NMR (300 MHz, CDCl3): δ 7.47–7.44
(m, 1H), 7.40–7.37 (m, 1H), 7.20–7.16 (m, 2H), 6.36 (s, 1H), 2.07– 2.02 (m 1H), 1.02–0.98
(m, 4H). 13C{1H} NMR (75 MHz, CDCl3): δ 160.5 (C), 154.3 (C), 129.1 (C), 122.9 (CH),
122.4 (CH), 119.9 (CH), 110.6 (CH), 100.3 (CH), 9.3 (CH), 7.2 (2 × CH2). MS (EI, 70 ev):
m/z (%): 158 (98) [M]+. HRMS (EI): m/z calcd for C11H10O: 158.0726 [M]+; found: 158.0728.
2-Butylbenzo[b
]furan (2i).38
Following the General Procedure, the reaction of 2ꢀ(hexꢀ1ꢀynyl)phenol (1i, 100 mg, 0.574
mmol) with InI3 (14.2 mg, 0.029 mmol) in DCE (7 mL) at 80 °C overnight afforded, after
purification by flash chromatography (5% EtOAc/hexane), 2i (86.1 mg, 86%) as a yellow oil.
1
TLC: Rf = 0.68 (10% EtOAc/hexane). H NMR (300 MHz, CDCl3): δ 7.50–7.47 (m, 1H),
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7.43–7.40 (m, 1H), 7.24–7.14 (m, 2H), 6.38 (d, J = 0.9 Hz, 1H), 2.78 (t, J = 7.6 Hz, 2H), 1.74
(quint, J = 7.5 Hz, 2H), 1.43 (sext, J = 7.4 Hz, 2H), 0.96 (t, J = 7.3 Hz, 3H). 13C{1H} NMR
(75 MHz, CDCl3): δ 159.7 (C), 154.6 (C), 129.0 (C), 123.0 (CH), 122.3 (CH), 120.1 (CH),
110.7 (CH) 101.7 (CH), 29.8 (CH2), 28.1 (CH2), 22.3 (CH2), 13.8 (CH3). MS (EI, 70 ev): m/z
(%): 174 (25) [M]+, 131 (100) [C9H7O]+. HRMS (EI): m/z calcd for C12H14O: 174.1039 [M]+;
found: 174.1040.
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4-(Benzo[b]furan-2-yl)butanonitrile (2j).
Following the General Procedure, the reaction of 6ꢀ(2ꢀhydroxyphenyl)hexꢀ5ꢀynenitrile (1j,
100 mg, 0.540 mmol) with InI3 (13.4 mg, 0.027 mmol) in DCE (7 mL) at 80 °C overnight
afforded, after purification by flash chromatography (20% EtOAc/hexane), 2j (77.9 mg, 78%)
as a yellow oil. TLC: Rf = 0.30 (20% EtOAc/hexane). 1H NMR (300 MHz, CDCl3): δ 7.54 (d,
J = 7.9 Hz, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.29–7.21 (m, 2H), 6.49 (s, 1H), 2.96 (t, J = 7.1 Hz,
2H), 2.41 (t, J = 7.1 Hz, 2H), 2.12 (quint, J = 7.1 Hz, 2H). 13C{1H} NMR (75 MHz, CDCl3):
δ 156.3 (C), 154.8 (C), 128.6 (C), 123.7 (CH), 122.7 (CH), 120.5 (CH), 119.2 (C), 110.9
(CH) 103.4 (CH), 27.1 (CH2), 23.7 (CH2), 16.5 (CH2). MS (EI, 70 ev): m/z (%): 185 (33)
[M]+, 131 (100). HRMS (EI): m/z calcd for C12H11NO: 185.0835 [M]+; found: 185.0836.
2-Phenyl-6-(trifluoromethyl)benzofuran (2k). Following the General Procedure, the
reaction of 2ꢀ(phenylethynyl)ꢀ5ꢀ(trifluoromethyl)phenol (1k, 77 mg, 0.294 mmol) with InI3
(7.3 mg, 0.015 mmol) in DCE (4 mL) at 80 ºC overnight afforded, after purification by flash
chromatography (5% EtOAc/hexane), 2k (74 mg, 96% yield) as a white solid. TLC: Rf =0.48
1
(5% EtOAc/hexane). Mp = 121–123°C (lit.: 39 mp = 120–121°C). HꢀNMR (300 MHz,
CDCl3): δ 7.89 (dd, J = 8.1, 2.0 Hz, 2H), 7.81 (s, 1H), 7.67 (dd, J = 8.1, 1.0 Hz, 1H), 7.51 (dd,
J = 8.1, 1.0 Hz, 1H), 7.49–7.42 (m, 3H), 7.08 (s, 1H). 13C{1H}NMR (75 MHz, CDCl3): δ
158.6 (C), 153.9 (C), 132.3 (C, q, J = 1.2 Hz), 129.7 (C), 129.3 (CH), 129.0 (2 × CH), 126.2
(C, q, J = 32.4 Hz), 125.2 (2 × CH), 122.8 (C, q, J = 283 Hz), 121.2 (CH), 119.9 (CH, q, J =
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4.1 Hz), 108.7 (CH, q, J = 4.1 Hz), 101.0 (CH). MS (EI, 70 ev): m/z (%): 262 (100) [M]+.
HRMS (EI): m/z calcd for C15H9F3O: 262.0600 [M]+; found: 262.0602.
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Methyl benzo[b
]furan-5-carboxylate (2l).40
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Following the General Procedure, the reaction of methyl 3ꢀethynylꢀ4ꢀhydroxybenzoate (1l)
(100 mg, 0.568 mmol) with InI3 (14.1 mg, 0.028 mmol) at 80 °C overnight afforded, after
purification by flash chromatography using (30–40% EtOAc/hexane), 2l (42.3 mg, 42%) as a
white solid. TLC: Rf = 0.56 (40% EtOAc/hexane). Mp = 79–81 °C (lit.:40 mp = 69–70 ºC). 1H
NMR (300 MHz, CDCl3): δ 8.36 (d, J = 1.2 H, 1H), 8.04 (dd, J = 8.7, 1.8 Hz, 1H), 7.70 (d, J
= 2.3 Hz, 1H), 7.54 (d, J = 8.7 Hz, 1H), 6.85 (dd, J = 2.3, 1.0 Hz, 1H), 3.95 (s, 3H). 13C{1H}
NMR (75 MHz, CDCl3): δ 167.2 (C), 157.5 (C), 146.2 (CH), 127.4 (C), 126.0 (CH), 125.2
(C), 123.7 (CH), 111.2 (CH), 107.1 (CH), 52.1 (CH3). MS (EI, 70 ev): m/z (%): 176 (44)
[M]+, 145 (100) [C9H5O2]+. HRMS (EI): m/z calcd for C10H8O3: 176.0468 [M]+; found:
176.0467.
2-Phenylbenzo[
According to the General Procedure, the reaction of 2ꢀphenylethynylphenol (1a, 100 mg,
0.515 mmol) with InI3 (12.7 mg, 0.026 mmol) at 100 °C in toluene (6 mL) with D2O (30 L,
1.54 mmol, 300 mol%) overnight afforded, after purification by flash chromatography (20%
EtOAc/hexane), 2a-3 (93.4 mg, 93%, 75%ꢀD) as a white solid. TLC: Rf = 0.53 (10%
b]furan-3d (2a-3d
).13b
ꢁ
d
EtOAc/hexane). Mp = 120–122 °C (lit.,13b mp = 118–119 ºC). 1H NMR (300 MHz, CDCl3): δ
7.90 (d, J = 7.2 Hz, 2H), 7.60 (dd, J = 6.9, 1.5 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.47 (t, J
=7.4 Hz, 2H), 7.39 (d, J = 7.4 Hz, 1H), 7.35–7.23 (m, 3H), 7.05 (s, 0.10H). 13C{1H} NMR (75
MHz, CDCl3): δ 155.9 (C), 154.9 (C), 130.5 (C), 129.2 (C), 128.8 (2 × CH), 128.5 (CH),
124.9 (2 × CH), 124.2 (CH), 122.9 (CH) 120.9 (CH), 111.2 (CH), 101.3 (CH). MS (EI, 70
ev): m/z (%): 195 (100) [M]+. HRMS (EI): m/z calcd for C14H9OD: 195.0785 [M]+; found:
195.0786.
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2-(1-Iodo-2-phenylvinyl)phenol (4).
To a solution of 1a (95 mg, 0.489 mmol) in DCE (6 mL), HI (32
ꢁL, 0.245 mmol, 57%
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aqueous solution) was added dropwise at rt and the resulting mixture was stirred for 4 h at 80
ºC. The reaction was diluted with CH2Cl2 (10 mL) and saturated aqueous NH4Cl (10 mL). The
aqueous layer was extracted with CH2Cl2 (2 × 10 mL) and the combined organic layer were
dried (MgSO4), filtered and concentrated in vacuo to afford, after purification by flash
chromatography (5% EtOAc/hexane), 2ꢀ(1ꢀiodoꢀ2ꢀphenylvinyl)phenol (4) (79 mg, 50%) as a
yellow oil. TLC: Rf = 0.17 (10% EtOAc/hexane). 1H NMR (300 MHz, CDCl3): δ 7.62 (s, 1H)
7.42–7.14 (m, 5H), 7.00–6.90 (m, 4H), 5.19 (s, 1H). 13C{1H} NMR (75 MHz, CDCl3): δ
151.1 (C), 144.9 (CH), 136.2 (CH), 130.7 (CH), 129.3 (C), 128.5 (2 x CH), 128.2 (2 x CH),
121.2 (CH), 116.5 (CH), 91.6 (C). MS (EI, 70 ev): m/z (%): 323 (3) [M (128I)]+, 322 (18) [M
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(
127I)]+, 195 (71) [C14H11O (128I)]+, 194 (100) [C14H11O (127I)]+. HRMS (EI): m/z calcd for
C14H11OI: 321.9849 [M]+; found: 321.9849.
]furan (3a).41
2-Phenyl-3-(p-tolyl)benzo[b
To a 0 ºC solution of 1a (100 mg, 0.515 mmol) in Et2O (1.0 mL) a solution of nꢀBuLi (0.220
mL, 2.40 M in hexane, 100 mol%) was added dropwise and stirred for 10 min. The resulted
yellow solution was left to reach rt and stirred for additional 30 min. Then, a solution of InCl3
(1.15 mL, 0.45 M in THF) was added, the solvents were removed in vacuo, and the residue
dried under highꢀvacuum. Toluene (2 mL) was then added and the resulting solution heated to
120 ºC for 1 h (TLC monitoring). A mixture Pd(OAc)2 (5.8 mg, 0.026 mmol), SPhos (21.1
mg, 0.052 mmol), and 4ꢀiodotoluene (94.5 mg, 0.432 mmol) in THF (2 mL) were added and
heated to 95 ºC overnight. The reaction mixture was quenched with a saturated aqueous
solution of NH4Cl (10 mL), poured into a separatory funnel and extracted with AcOEt (3 × 15
mL). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo to
afford, after purification by flash chromatography using hexane, compound 3a (88.8 mg,
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