2-substituted benzo[b]furans from (E)-1,2-dichlorovinyl ethers and organoboron reagents: Scope and mechanistic investigations into the one-pot Suzuki coupling/direct arylation

Article abstract of DOI:10.1002/ejoc.201000787

2-Substituted benzo[b]furans can easily be assembled from simple phenols, boronic acids or other organoboron reagents, and trichloroethylene. The overall process requires only two synthetic steps, with the key step being a one-pot sequential Suzuki cross-coupling/direct arylation reaction. The method tolerates many useful functional groups and does not require the installation of any other activating functionality. The modular nature of the process permits the rapid synthesis of many analogues using essentially the same chemistry, of particular value in drug development. Results of kinetic isotope effect studies and investigations into the regioselectivity of the process indicate that the direct arylation step most likely does not involve an electrophilic palladation. The most likely mechanism lies somewhere on the continuum between a C-H bond metathesis and an assisted palladation or concerted metallation-deprotonation pathway. A very efficient modular approach to the construction of benzo[b]furans using trichloroethylene as a scaffold is described. This method gives easy access to highlysubstituted heterocycles in only two synthetic operations, and is especially suitable for rapid construction of compound libraries.

Full text of DOI:10.1002/ejoc.201000787

FULL PAPER
DOI: 10.1002/ejoc.201000787
2-Substituted Benzo[b]furans from (E)-1,2-Dichlorovinyl Ethers and
Organoboron Reagents: Scope and Mechanistic Investigations into the One-Pot
Suzuki Coupling/Direct Arylation
Laina M. Geary[a] and Philip G. Hultin*[a]
Dedicated to the memory of Professor Keith Fagnou (1971–2009)
Keywords: Oxygen heterocycles / C-H activation / Cross-coupling / Palladium
2-Substituted benzo[b]furans can easily be assembled from
simple phenols, boronic acids or other organoboron reagents,
and trichloroethylene. The overall process requires only two
synthetic steps, with the key step being a one-pot sequential
Suzuki cross-coupling/direct arylation reaction. The method
tolerates many useful functional groups and does not require
the installation of any other activating functionality. The
modular nature of the process permits the rapid synthesis of
many analogues using essentially the same chemistry, of par-
ticular value in drug development. Results of kinetic isotope
effect studies and investigations into the regioselectivity of
the process indicate that the direct arylation step most likely
does not involve an electrophilic palladation. The most likely
mechanism lies somewhere on the continuum between a C–
H bond metathesis and an assisted palladation or concerted
metallation-deprotonation pathway.
Introduction
Heterocyclic structures play significant roles in the bio-
logical activities of pharmaceuticals. The benzo[b]furan ring
system in particular is an important scaffold for drug devel-
opment.[1] Several 2-substituted benzofurans have shown
antifungal[2] and antiplasmodial[3] as well as antioxidant,
anti-HIV, anticancer and estrogenic activities.[4]
Several retrosynthetic disconnections to commercially
available starting materials for the synthesis of benzo[b]-
furans are shown in Figure 1.[5] Common starting materials
include 2-allylphenols,[6] α-bromocresols,[7] 1,2-dihalo-
arenes,[8] o-bromo benzylbromides,[9] and other 2-substi-
tuted phenols.[10] Benzo[b]furans bearing alkyl or aryl sub-
stituents at the R2 and/or the R3 positions have been ac-
cessed from 2-alkynylphenols, frequently obtained via
Sonogashira couplings of 2-halophenol precursors.[11]
Cross-coupling approaches[12] require both components
to be activated by the installation of halide or similar func-
tionality (Figure 1). An efficient alternative route to the
benzo[b]furan nucleus could employ direct metal-catalyzed
cyclization[13] of an arene precursor, thus avoiding prelimi-
nary functionalization steps. To this end, Stoltz[14] and later
Youn[15] have reported a useful palladium-catalyzed oxidat-
Figure 1. Simplified disconnections of benzo[b]furans to commer-
cially available arene scaffolds.
ive cyclization of O-allylphenols to give benzofurans. Liu
has reported a zinc-catalyzed coupling and cyclization of
phenol with a variety of propargylic alcohols.[16] Naito has
demonstrated the sigmatropic rearrangement of aryl oxime
ethers to give 2-substituted benzofurans.[17] Janin et al. used
a [2+3] cycloaddition of in situ oxidized hydroquinone with
an enol ether to give benzofurans.[18] Most recently Shibata
used a directed, iridium-catalyzed cyclodehydration of α-
aryloxyketones to make benzofurans,[19] and Li employed
an iron-catalyzed sequential oxidative coupling and cycliza-
tion between phenols and β-keto esters.[20] While these re-
sults point in the direction of a broad and general route
View this journal online at
[a] Department of Chemistry, University of Manitoba,
Winnipeg, Manitoba, Canada R3T 2N2
Fax: +1-204-474-7608
E-mail: hultin@cc.umanitoba.ca
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000787.
wileyonlinelibrary.com
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to benzofurans, all reported routes suffer from restrictive Table 1. Synthesis of 1,2-dichlorovinyl ethers from phenols and tri-
chloroethylene.
functional group requirements, limited scope, multistep syn-
thesis or some combination thereof.
We have devised a simple strategy [Equation (1)] that
generates 2-functionalized benzofurans in only two steps
from minimally activated materials with no functional
group manipulations prior to the two key C–C bond form-
ing events. We recently reported preliminary results,[21] and
now describe our detailed studies of the scope of the reac-
tion as well as some mechanistic investigations.
(1)
Results and Discussion
Synthesis of (E)-1,2-Dichlorovinyl Ethers
Our preparation of the 1,2-dichlorovinyl aryl ether pre-
cursors (Scheme 1) was based on Greene’s method for the
synthesis of aliphatic vinyl ethers.[22]
Scheme 1. Regio- and stereoselective substitution reactions of
phenols with trichloroethylene.
We found that this procedure was quite general for phe-
nols bearing electron-donating groups (Table 1, entries 1–
6). However, when we used phenols with electron-with-
[a] Previously published results.[21] [b] Conditions A: 2.05 equiv.
KH, 1.5 equiv. TCE, –50 °C to room temp.; Conditions B: 3 equiv.
drawing groups, we found that the success of the reaction
was highly dependent on the position of the group. Both
3-nitro- and 3-cyanophenol reacted smoothly under these
conditions (Table 1, entries 7 and 8), but 4Ј-hydroxy-3Ј-
K2CO3, 3 equiv. TCE, DMF, 70 °C. [c] Required the addition of
catalytic amounts of methanol. [d] Isolated yields.
methoxyacetophenone (acetovanillone), 2- and 4-cyano-, reported that the reactions of salicylaldehydes with TCE
and 4-nitrophenol failed to react at all under these condi- promoted by K2CO3 in DMF at 70 °C gave good yields of
tions (Table 1, entries 9, 11, 13, 15).
the corresponding dichlorovinyl ethers.[10i] When we applied
This result can be rationalized by considering the pKas their conditions to the reactions of electron-poor phenols,
of the phenols; while electron-poor phenols are in general adducts 9, 10 and 11 were isolated in excellent yields
more acidic and less nucleophilic, those with electron-with- (Table 1, entries 10, 12 and 14). However, adduct 12 from
drawing groups in the 3-position are not quite as influenced p-nitrophenol was not detected at all. Sales and Mani like-
as those with electron-withdrawing groups in the 2- or 4- wise had noted that 5-nitrosalicylaldehyde failed to add to
positions. The potassium salts of those phenols are either trichloroethylene.[10i] When we added catalytic amounts of
not basic enough to deprotonate trichloroethylene (step A methanol to the reaction of p-nitrophenol with TCE (based
in Scheme 1) or not nucleophilic enough to add to dichlo- on an observation by Greene et al.[23]) smooth substitution
roacetylene (step B in Scheme 1) under our standard condi- occurred giving adduct 12 in excellent isolated yields
tions (Table 1, entries 9, 11, 13, 15). Sales and Mani recently (Table 1, entry 16). This suggests that potassium p-nitro-
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Construction of Benzo[b]furans
phenolate is nucleophilic enough to add across dichloroac- dition of palladium occurs at the most electrophilic carbon
etylene, but not sufficiently basic to deprotonate trichloro- position.[25] A variety of conditions were found to be appro-
ethylene.
priate for selective C1–Cl functionalization. Prolonged heat-
ing after completion of the Suzuki coupling led to subse-
quent cyclization to produce the benzo[b]furan. Reactions
performed at high concentration proceeded at 65 °C, while
those carried out at lower concentrations required heating
One-Pot Preparation of 2-Aryl Benzo[b]furans from
Dichlorovinylaryl Ethers and Boronic Acids
We next explored the reactivity of dichlorovinylaryl at 100 °C to occur at an acceptable rate.
ethers 1–12 as electrophiles in Suzuki couplings.[21,24] Su-
The sequential cross-coupling/direct arylation was first
zuki cross-coupling always occurred at C1–Cl and the ad- examined for unsubstituted (Table 2, entries 1–7) and sym-
ducts were always isolated as single regio- and stereoiso- metrically substituted phenols (Table 2, entries 8–20). The
mers, consistent with other observations that oxidative ad- majority of our experiments employed arylboronic acids to
Table 2. One-pot preparation of 2-substituted benzo[b]furans from symmetrical phenols.
[a] Isolated yield. [b] Previously published results.[21] [c] Reactions could be run as 0.4  (with respect to dichlorovinyl ether, see Experimen-
tal) solutions in dioxane at 100 °C or 1.0  solutions in THF at 65 °C with comparable results.
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form 2-aryl benzofurans, but a few examples of 2-alkenyl 84% conversion from the DPEphos system).[28] In contrast,
benzofurans were also prepared (entries 6, 7 and 11). This the complexes formed from Pd2dba3 and PhDavePhos, S-
method proved particularly successful for highly oxygenated Phos or JohnPhos were less efficient catalysts in Suzuki
benzofurans (entries 12–15), including the core structure couplings between 11 and p-tolylboronic acid under these
(24) of the Ebenfuran family of estrogen receptor modula- conditions; incomplete conversion to 33 was observed by
tors[1c,4] and the natural product Corsifuran C (25).[26]
crude 1H NMR, and no benzofuran could be detected
There have not been many reported syntheses of benzo- (Table 3, entries 3, 4 and 5). These observations, combined
furans bearing electron-withdrawing groups such as nitro, with our previously-published results[21] led us to select the
cyano or carbonyl.[8c,8f,11l,27] We therefore examined the reaction conditions shown in Table 2 as our “standard con-
coupling and cyclization of dichlorovinylaryl ethers 7–12. ditions” for all subsequent experiments.
The behaviour of these compounds was not as straightfor-
Using the Pd/DPEphos catalyst under our standard con-
ward as that of their more electron-rich analogues.
ditions, the p-cyanophenyl ether 11 reacted very smoothly
Several ligands were tested in the cross-coupling/direct with p-fluorophenyl, p-tolyl and 3,5-dimethyl-4-ethoxy-
arylation between p-cyanophenol derivative 11 and p-tolyl- phenylboronic acids, leading to benzofurans 30, 31, and 32
boronic acid (Table 3). The amounts of remaining starting in good yields (Table 2, entries 18–20). However, the Suzuki
material and the product ratios were determined after 16 cross-coupling reactions of 11 with several other boronic
hours of reaction, using 1H NMR spectroscopy. Under acids [2-fluoro-3-formylphenyl, 3,5-bis(trifluoromethyl)-
these conditions DPEphos appeared to be the best ligand phenyl, m-nitrophenyl, o-(methylthio)phenyl] were sluggish
(Table 3, entry 1); while the cyclization was not complete and incomplete even after prolonged reaction times. More-
during this time, the starting material was completely con- over, no evidence of benzofuran formation could be ob-
sumed and converted to intermediate 33. PCy3·HBF4 also served in these stalled reactions.
led to clean conversion from 11 to 33, but cyclization from
Dichlorovinyl ethers 9, 10 and 12 proved challenging as
33 to 31 was slower (only 67% conversion compared to well and the one pot protocol did not afford benzofurans
from these compounds (Scheme 2). Again, the initial Su-
zuki couplings were sluggish and there was substantial com-
Table 3. Ligand screen for the conversion of 11 to benzofuran 31.
peting homocoupling and/or protiodeboration[29] of the bo-
ronic acids used.
To determine whether the intermediates were intrinsically
unreactive in the cyclization step, they were isolated and re-
subjected to the cyclization conditions (Scheme 2). 5-Nitro-
benzofuran 38 was isolated in excellent yield after a 12 hour
reaction time but the o-cyano compound afforded the 7-
cyanobenzofuran 37 in only 45% yield with 38% recovered
starting material after 40 hours. Curiously, the aceto-
phenone compound 36 did not cyclize and was isolated un-
changed.
The results in Table 3 and Scheme 2 above suggest that
the major restriction on the one pot protocol for benzofu-
ran formation is the efficiency of the initial cross-coupling
reaction. In our experience, if the cross-coupling step was
incomplete, then subsequent cyclization did not occur un-
der these conditions. We did not observe degradation of the
unreacted starting material by 1H NMR analysis of the
crude products. The absence of protonolysis by-products
suggests that oxidative insertion of palladium into the C1–
Cl bond may be reversible. Increasing the number of equiv-
alents of boronic acid in problem cases might improve the
efficiency of the Suzuki coupling step, and permit one pot
conversion to the benzofurans.[30]
Enynes can easily be formed by Sonogashira cross-cou-
pling between the dichlorovinyl ethers and terminal al-
kynes.[21] Thus, for example, phenylacetylene derivative 39
could be prepared in good yields from 1. Unfortunately,
palladium(0) tetrakis(triphenylphosphane), the catalyst
used in the Sonogashira reaction, failed to mediate cycliza-
tion to 40. Therefore a two-pot procedure was necessary
to obtain 2-alkynyl benzofurans. Desiring a direct, one-pot
synthesis, we turned to alkynyl boronic acids or alkynyl tri-
[a] A similar trend was observed when the reaction was performed
in toluene rather than dioxane.
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Construction of Benzo[b]furans
Scheme 2. One-pot Suzuki-coupling/cyclizations of 9, 10 and 12 failed when cross-coupling was incomplete, but cyclization of purified
intermediates is successful.
fluoroborate salts.[31] Unfortunately, in our hands attempts
to cross-couple alkynyl boronic acids with 1 were unsuc-
cessful. Several attempts to couple alkynyl trifluoroborates
with 1 only produced 40 in low yields (Scheme 3), ac-
companied by substantial amounts of a black, gummy ma-
terial that hampered both stirring and product isolation.
Scheme 4. Initial studies on the preparation of 2-alkylbenzofurans.
Scheme 3. Preparation of 2-alkynylbenzo[b]furan 40.
Scheme 5. One pot preparation of 2-alkylbenzofuran 44.
Alkyl compounds also proved not as straightforward.
Any attempt at cross-coupling 2-cyclohexylboronic acid
Mechanistic Investigations
with 1 proved unsuccessful,[32] so we turned our attention
to other aliphatic organometallic donors.
We started our mechanistic studies by taking a brief look
Alkyl groups could be installed via Negishi coupling[33] at the C1–Cl functionalization step in the one pot procedure
or using Suzuki coupling of an alkyl borane[34] but the one- (Table 4 and Scheme 6). Intermolecular competition experi-
pot conversion to benzofurans 42 and 44 was incomplete ments were carried out using the Pd2dba3/DPEphos catalyst
even after days of reflux (Scheme 4). Subjecting the isolated in hot THF. Equimolar mixtures consisting of a dichloro-
intermediates 41 or 43 to these conditions did not improve vinyl ether (one of 1, the electron-rich 5 or the electron-
the result. However, Pd(OAc)2/S-Phos[33] afforded complete poor 11), p-fluorophenylboronic acid and p-methoxyphen-
cyclization of 43 to 44 in under 8 hours. Moreover the one ylboronic acid were allowed to react in the presence of the
pot cross-coupling/direct arylation in the presence of this catalyst and stopped after 4.5 hours, before any significant
catalyst produced the 2-alkyl benzofuran in excellent iso- conversion to the benzofuran could be observed by tlc. In
lated yield (Scheme 5). It is interesting to contrast this result all three cases (Table 4), the p-methoxyphenyl derivative
with that obtained using the Pd2dba3/S-Phos catalyst in hot was produced faster than was the p-fluorophenyl derivative,
dioxane, which did not appear to be a promising system for consistent with a faster rate of transmetallation with the
coupling and cyclization (Table 3, entry 4).
electron-rich boronic acid.
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Table 4. Initial Suzuki coupling step: Intermolecular competition
experiments with electron-rich and electron-poor boronic acids.
Entry
S.M.
Fluoro
Methoxy
1
2
3
R = H
R = CN
R = OMe
0.26
0.062
0.00
0.66
0.53
0.61
1.0
1.0
1.0
Figure 2. Mechanistic possibilities proposed for Pd-catalyzed intra-
molecular aryl C–H functionalization processes.
Based on these alternative proposals, we devised a series
of intramolecular competition experiments to probe the in-
fluence of electronic effects on the rate of cyclization. We
also examined the regioselectivity in cyclization reactions of
unsymmetrically-substituted dichlorovinyl aryl ethers. Fi-
nally, we measured deuterium-hydrogen primary kinetic iso-
tope effects (KIEs) in selected reactions.
Scheme 6. Initial Suzuki coupling step: Intermolecular competition
experiments between electron-rich and electron-poor dichlorovinyl
phenyl ethers.
Intermolecular Competition Experiments
Three intermolecular competition experiments were car-
ried out using 1-aryl-2-chlorovinyl aryl ethers 45–48.[21] The
When we subjected an equimolar mixture of 1, 5, 11 and reactions were carried out under our standard Pd2dba3/
p-methoxyphenylboronic acid to the cross-coupling condi- DPEphos conditions in hot dioxane. The reactions were
tions, the p-cyanophenol derivative 11 was both consumed stopped when tlc clearly indicated the presence of both ben-
fastest and converted into the monoaryl intermediate fast- zofuran products as well as unreacted starting materials. 1H
est (Scheme 6). The cyano group in 11, while remote from NMR spectra of the crude materials obtained after workup
the reacting C1 site, presumably renders the C1–Cl bond allowed the product ratios to be determined. The cycliza-
less electron-rich and hence better able to act as an oxidant tions of the unsubstituted precursors 48 or 45 to form ben-
towards Pd0. The results of the experiments shown in zofurans 14 or 16 were taken as standards for comparison.
Table 4 and Scheme 6 are consistent with the standard pal-
Competition between 45 and 48 probed the long-range
ladium-catalyzed cross-coupling mechanism.[29]
influence of para substitution in the C1 aryl component
The mechanism of aryl C–H functionalization[35] during (Scheme 7). We observed that p-fluoro-substituted 14 was
the cyclization step was less obvious. We deemed an oxidat- formed substantially faster than was p-methoxy substituted
ive pathway via PdIV intermediates unlikely, especially since 16. This may indicate faster oxidative addition of Pd into
our reactions were performed without obvious oxidants, the C2–Cl bond of 48, paralleling results from Table 4 re-
under argon in degassed solvents. We also discarded the lated to the C1–Cl arylation. The striking difference in the
possibility of a Heck-type carbopalladation on geometric reaction rates suggests that the rate-determining step in the
grounds. Other mechanisms for C–H activation which have direct arylation may be oxidative insertion of palladium
been proposed are summarized in Figure 2.[13a,35]
into the C2–Cl bond.
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Construction of Benzo[b]furans
In contrast, reaction between m-nitrophenol-based 8 and
boronic acids afforded mixtures of regioisomeric products
(Table 5, entries 7–9), favouring the formation of 6-nitro-
benzofurans in 3.3–5.9:1.0 ratios. We were therefore sur-
prised to find that reaction of m-cyanophenol 7 and p-
methoxyphenylboronic acid (Table 5, entry 10) formed the
4-substituted benzofuran predominantly (i.e. C–C bond for-
mation ortho to the cyano group rather than para). Fagnou
reported a similar switch in regioselectivity between nitro-
or chloro-substituted aryl substrates on the one hand and
similar fluoro-substituted compounds on the other.[37] In
these studies, C–C bond formation occurred preferentially
para to a nitro group, but ortho to a fluorine. It is evident
that the regioselectivity of the cyclization is not simply de-
pendent on the electron-donating or withdrawing character
of the aryl substituent.
The cyclization mechanism was further probed in a set
of intramolecular kinetic isotope effect studies (Scheme 9).
The dichlorovinyl ether derived from 6-deuteriophenol was
prepared and subjected to the one-pot coupling/cyclization
protocol with several boronic acids using the Pd2dba3/
DPEphos catalyst in hot dioxane. In all cases the KIE was
approximately 3. We also observed a KIE of 4.0 using the
Pd(OAc)2/S-Phos catalyst in hot toluene to obtain 48–d and
48. This KIE is not consistent with an electrophilic pallad-
ation mechanism[38] but rather suggests a mechanism in
Scheme 7. Competition in cyclization of 48 and 45 favours the less
electron-rich compound 48.
A set of intermolecular kinetic isotope effect experiments
(Scheme 8) revealed no detectable KIE in three different
cases. This is consistent with previous observations by Hen-
nessy and Buchwald in a related situation, which they inter-
preted as indicating rate-limiting oxidative insertion of Pd
into the C–X bond.[36] Taken together with the competition
results from Scheme 7, these KIE data strongly support a
similar conclusion in our reactions: oxidative insertion is
likely the overall rate-determining step in the cyclization.
1
Scheme 8. H/2H intermolecular kinetic isotope effect experiments
reveal no effect of deuteration on overall cyclization rates.
Regioselectivity of the Cyclization
To get a better understanding of the influence of elec-
tronic factors on the cyclization, we explored the regioselec-
tivity of cyclization of unsymmetrical derivatives. We pre-
viously reported one-pot preparations of benzofurans from
dichlorovinyl ethers from m-methoxyphenol or m-nitrophe-
nol and p-methoxyphenylboronic acid and found that these
reactions afforded a single regioisomer for the electron-rich
methoxy substituted, but 6.0:1.0 regioselectivity for the elec-
tron-deficient nitro-substituted compounds[21] (reproduced
in Table 5, entries 4 and 7). The high regioselectivity in the
cyclization step was also observed with other electron-rich
arenes: reaction of either m-methylphenol derivative 2 or m-
methoxyphenol derivative 4 with all boronic acids explored
always led exclusively to the 6-substituted benzofuran in
high yields (Table 5, entries 1–6). In all cases, only a single
1
Scheme 9. Intramolecular H/2H kinetic isotope effects in the Pd-
1
benzofuran isomer could be identified in H NMR spectra
catalyzed cyclization reaction indicate that C–H bond scission is
of the crude products.
rate-determining in the palladation of the aryl ring.
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Table 5. Regioselectivity in the synthesis of benzofurans from unsymmetrical monosubstituted precursors.
1
[a] Isolated yield. [b] Previously published results.[21] [c] Only one isomer was detected by crude H NMR spectroscopy. [d] Combined
yield of both isomers. Isomers were isolated, purified and independently characterized. [e] Estimated from 1H NMR of the crude material.
which C–H bond scission may be product-determining (al- tions for saturated compounds. The method is modular in
though not necessarily rate-limiting overall).[37a,39] Base-as- that different components are assembled around the central
sisted palladation of the aryl ring (via either C or D in Fig- core derived from trichloroethylene. This method provides
ure 2) might be facilitated by increased aryl C–H acidity,[40] rapid access to substituted benzofurans, compounds with
although theoretical work by Gorelsky, Lapointe and Fag- potential for the development of therapeutic agents against
nou[41] did not support a simple correlation. Transition a number of diseases.
states B – D in Figure 2 are plausible in light of our KIE
observations.
The reaction mechanism of the direct arylation process
involves a rate-determining oxidative insertion of palladium
into a vinyl C–Cl bond. The mechanism of the second step,
palladation of the aryl ring, proved more challenging to elu-
cidate. The observed KIEs and the regioselectivity of cycli-
Conclusions
We have developed a very general and efficient route to zation in unsymmetrical cases argue against an electrophilic
2-alkyl, alkenyl and alkynyl benzofurans by combining a palladation mechanism in the C–H functionalization event.
cross-coupling reaction with a direct arylation process. The Our data are consistent with a C–H metathesis or assisted
overall one-pot reaction employs one set of catalytic condi- palladation pathway, although we cannot as yet determine
tions for unsaturated compounds, and another set of condi- where on this mechanistic continuum our reaction lies.
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Construction of Benzo[b]furans
Supporting Information (see footnote on the first page of this arti-
Experimental Section
cle): Full experimental procedures and characterization data for all
1
new compounds, including original H and 13C NMR spectra, as
General Comments: Full details of materials, experimental proto-
cols and the spectroscopic characterization of products are avail-
able in the Supporting Information. All glassware was oven dried
at 140 °C overnight and cooled in a desiccator before use. All reac-
tions were carried out under argon using standard syringe tech-
niques. All materials were purchased from standard commercial
sources and were generally used as received, with the following ex-
ceptions: THF was dried by passage through activated alumina un-
der argon pressure (PureSolv system); both THF and anhydrous
dioxane were degassed by sparging with argon before use; K2CO3
was stored in an oven at 140 °C and cooled in a desiccator prior
to use; phenylacetylene was passed through a short column of acti-
vated alumina immediately before use.
well as details of the competition and kinetic isotope effect experi-
ments.
Acknowledgments
This work was supported by a Discovery Grant to P. G. H. from
the Natural Sciences and Engineering Research Council of Canada,
and by NSERC Post-graduate Fellowships to L. M. G. We thank
Dr. Kirk Marat (NMR), Mr. Wayne Buchannon (GC–MS) and
Mr. Xiao Feng (Dalhousie University, HRMS).
General Procedure for the Substitution Reactions of Phenols with
Trichloroethylene (Conditions A): KH (2.05 equiv.) was weighed
into a round-bottom flask and washed with 3 portions of pentane
or petroleum ether. The KH was then suspended in THF (ca.
2.4 mL per mmol of KH). A solution of the phenol (1.0 equiv.) in
THF (ca. 1.25 mL per mmol of phenol) was added drop wise (vig-
orous gas evolution was noted) and the reaction was allowed to stir
for 30 to 120 min. The suspension was cooled to –50 °C [CHCl3/
CO2(s) bath]. Trichloroethylene (1.5 equiv.) was then added drop
wise, after which the reaction was warmed to room temperature
overnight.
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The reaction was diluted with petroleum ether and quenched with
ice-cold water. The phases were separated and the aqueous phase
was extracted once more with petroleum ether. The organic layers
were combined, dried with sodium sulfate, filtered and concen-
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to a silica column pre-treated with triethylamine (ca. 2.5 vol.-%
with respect to the volume of dry silica) and eluted with an appro-
priate solvent to give a colourless oil or solid.
General Procedure for the Substitution Reactions of Phenols with
Trichloroethylene (Conditions B): Powdered K2CO3 (3 equiv.) and a
phenol (1.0 equiv.) were weighed into an oven-dried round-bot-
tomed flask. Anhydrous DMF (0.75 mL/mmol phenol) was added
and the suspension was heated to 60 °C while stirring. Trichloroeth-
ylene (3 equiv.) was added drop wise and the reaction was heated
at 70 °C overnight. The reaction was then cooled to room tempera-
ture, transferred to a separatory funnel and partitioned between
ethyl acetate and water (75:25 mL). The phases were separated and
the organic layer was dried with magnesium sulfate, filtered and
concentrated to give a viscous oil. The crude oil was applied to a
silica column pre-treated with triethylamine (ca. 2.5 vol.-% with
respect to the volume of dry silica) and eluted with an appropriate
solvent to give a colourless oil or solid.
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ation: The boronic acid, Pd2dba3, DPEphos, CsF and Cs2CO3
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denser, sealed with a septum and purged with argon for 20–30 min.
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until judged complete by tlc. The cooled reaction mixture was par-
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column and the benzofuran product was eluted with the appropri-
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Eur. J. Org. Chem. 2010, 5563–5573
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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Received: June 1, 2010
Published Online: July 28, 2010
Eur. J. Org. Chem. 2010, 5563–5573
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5573