Preparation of highly functionalised benzofurans from ortho-hydroxyphenones and dichloroethylene: Applications and mechanistic investigations

Article abstract of DOI:10.1002/chem.201201505

Highly functionalised benzofurans have been prepared from ortho-hydroxyphenones and 1,1-dichloroethylene. The key intermediate, a chloromethylene furan, smoothly rearranged into the corresponding benzofuran carbaldehyde under acidic conditions. Some mechanistic investigations have been performed and several biologically active benzofurans have been synthesised. Copyright

Full text of DOI:10.1002/chem.201201505

FULL PAPER
DOI: 10.1002/chem.201201505
Preparation of Highly Functionalised Benzofurans from ortho-
Hydroxyphenones and Dichloroethylene: Applications and Mechanistic
Investigations
Florian Schevenels,[a] Bernard Tinant,[b] Jean-Paul Declercq,[b] and Istvꢀn E. Markꢁ*[a]
Abstract: Highly functionalised benzofurans have been prepared from ortho-hy-
droxyphenones and 1,1-dichloroethylene. The key intermediate, a chloromethylene
furan, smoothly rearranged into the corresponding benzofuran carbaldehyde
under acidic conditions. Some mechanistic investigations have been performed and
several biologically active benzofurans have been synthesised.
Keywords: acid catalysis · benzo-
furans · heterocycles · NMR spec-
troscopy · rearrangement
Introduction
Benzofurans are important heterocyclic compounds. Their
widespread occurrence and powerful biological activities
have stimulated the development of numerous synthetic
methods. These approaches can be divided into four main
strategies. The dehydration–cyclisation of o-hydroxybenzyl
ketones 3 or a-(phenoxy)alkyl ketones[1–3] 1 are two well-
Scheme 2. One-pot etherification and dehydration–cyclisation.
known methods (Scheme 1), described among others, by
Boehme and Adams.
Patel, Cacchi and many others (Scheme 3). At this stage, it
is important to point out that several alternative, though less
general, methodologies[14–24] have also been described. These
involve ring fragmentations[25–27] and oxidative process-
es.[28–30]
Scheme 1. Dehydration–cyclisation pathways.
The one-pot etherification and dehydration–cyclisation of
o-hydroxyacetophenones 4 under basic conditions[3–6] is an-
other general approach that has been described, for exam-
ple, by Bogdal and Katrizky (Scheme 2).
Scheme 3. Arylacetylene cyclisation using transition metals.
Finally, a last approach consists of the cyclisation of aryla-
cetylenes using transition-metal catalysts[7–13] as described by
Recently, we reported some preliminary results on a
novel benzofuran synthesis,[31] based upon our previous in-
cursion into the largely unexplored Z-chloromethylene ketal
chemistry.[32] Thus, starting from a variety of o-hydroxyphe-
nones 9 and 1,1-dichloroethylene, a range of chloromethy-
lene furans 10 could be obtained in high yield. These labile
intermediates were then rearranged under acidic conditions,
yielding benzofurans 11 in excellent overall yields
(Scheme 4).
Herein, we disclose our results in full and discuss the
scope and limitations of our method, with respect to both
reaction partners. In addition, some of the mechanistic infor-
mation gathered during our studies will be presented.
[a] F. Schevenels, Prof. Dr. I. E. Markꢀ
Laboratory of Organic and Medicinal Chemistry
Universitꢁ catholique de Louvain, Place Louis Pasteur 1 bte L4.01.02
1348 Louvain-la-Neuve (Belgium)
Fax : (+32)10-472788
E-mail: istvan.marko@uclouvain.be
[b] Prof. Dr. B. Tinant, Prof. Dr. J.-P. Declercq
IMCN-MOST, Universitꢁ catholique de Louvain
Place Louis Pasteur 1 bte L4.01.03
1348 Louvain-la-Neuve (Belgium)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201201505.
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Scheme 4. Transformation of o-hydroxyphenones into benzofuran carbal-
dehydes.
Results and Discussion
Scheme 7. Proposed mechanism for the rearrangement step.
The rearrangement: When an a-hydroxyphenone is treated
with 1,1-dichloroethylene and a base, such as tBuOK, a
rapid reaction ensues and leads to a chloromethylene furan.
Our previous study demonstrated that potassium tert-butox-
ide deprotonated dichloroethylene 13, which led to the in
situ generation of the corresponding chloroacetylene
anion.[33,34] This intermediate then adds to the ketone, for
example, 2-acetylnaphth-1-ol (12; Scheme 5). At this stage,
a spontaneous 5-exo-dig ring closure of the alkoxide occurs,
leading to the formation of the chloromethylene furan 14 in
95% estimated yield. Much to our surprise, only aldehyde
15 was isolated after purification by chromatography on
silica gel.
Several acids were screened under homogeneous and het-
erogeneous conditions. Sulfuric acid in CH2Cl2/H2O eventu-
ally provided optimum conditions. When the rearrangement
was carried out in a homogeneous medium, or neat and
without acid, a 1:1 mixture of the aldehyde 17 and of the di-
chlorinated product 22 was consistently obtained. When hy-
drochloric acid was used, adduct 22 could be isolated as the
major product (Scheme 8).
Scheme 8. Preparation of the dichlorinated adduct.
Scheme 5. Formation of the naphthylfuran carbaldehyde.
According to our mechanistic hypothesis, HCl is released
during the rearrangement. This acid can then competitively
react with the chloromethylene ketal, thereby leading to the
dichlorinated adduct 22. Our hypothesis also explains the
observed 1:1 ratio of 17 and 22. Indeed, if one molecule of
water adds to the exomethylene position of oxonium 19, a
chloride ion is produced. In a homogeneous medium, this
ion will be rapidly consumed by its addition onto a second
oxonium cation, which provides the dichlorinated product
22. Therefore, a biphasic system containing dichloromethane
and water was used. It proved to be quite successful.
Indeed, in this system, the hydrochloric acid is rapidly hy-
drated by water, thus minimising the re-addition of the
chloride ion. Moreover, aldehyde 17 is extracted in the or-
ganic layer as soon as it is generated.
The same conditions were applied to o-hydroxyacetophe-
none (16; Scheme 6). This time, the rearrangement did not
occur spontaneously on silica gel. Therefore, a biphasic
acidic hydrolysis protocol was developed. Under these con-
ditions, aldehyde 17 could then be obtained in 97% yield.
These results suggest that, under acidic conditions, oxoni-
um cation 19 is formed by water elimination from 18
(Scheme 7). Water then adds back at the terminal position
of 19, which leads to a-chlorohydroxybenzofuran (20),
which spontaneously eliminates HCl, generating aldehyde
17.
Mechanistic investigations: To lend some more support to
our mechanistic proposal, the formation of chloromethylene
1
furan 21 was followed by H NMR spectroscopy in deuterat-
ed THF (Scheme 9). As expected, no aldehyde could be de-
tected during this step, thereby confirming that the rear-
rangement occurred during the acidic treatment. Moreover,
Scheme 6. Formation of the methylbenzofuran carbaldehyde.
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Highly Functionalised Benzofurans
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Scheme 9. Chloromethylene furan formation followed by 1H NMR spec-
troscopy.
Scheme 12. NMR spectroscopy experiment for the rearrangement step
(aliphatic area).
it can be seen that the chloromethylene proton appeared
slowly after the disappearance of the dichloroethylene pro-
tons, which reinforces our previously postulated mecha-
nism.[31]
The rearrangement of the chloromethylene furan 21 was
studied in a similar way (Scheme 10). The reaction was per-
formed in THF, at a concentration of 1.0 m, at room temper-
the aromatic region, the characteristic protons of aldehyde
17 (d=10.04 ppm), dichlorinated adduct 22 (d=7.50 ppm)
and chloromethylene reactant 21 (d=5.86 ppm) are indicat-
ed (Scheme 11). A similar analysis was performed for the
aliphatic region. The methyl protons of 17 (d=2.63 ppm),
22 (d=2.35 ppm) and 21 (d=1.64 ppm) were assigned
(Scheme 12). As expected, the signals of 17 and 22 appeared
in a 1:1 ratio, proportionally to the disappearance of the
chloromethylene signals.
The mechanistic pathway can be considered as shown in
Scheme 13. The chloromethylene furan 21 is protonated re-
versibly (k1), leading to hydronium cation 18. An oxonium
ion 19 is then formed (k2) by elimination of water. Addition
of water to this oxonium cation (k3) leads to the intermedi-
ate 23. A chloride anion can also competitively react with
Scheme 10. Conditions for the NMR spectroscopy investigations of the
rearrangement step.
ature. Water (2 equiv) and sulfuric acid (0.3 equiv) were
then added and the transformation was monitored. These
conditions are known to produce adducts 17 and 22 in a 1:1
ratio. The spectra are displayed in Schemes 11 and 12. In
Scheme 11. NMR spectroscopy experiment for the rearrangement step
(aromatic area).
Scheme 13. Detailed mechanistic pathway for the rearrangement step.
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I. E. Markꢀ et al.
this molecule (k6) or add to the oxonium species 19 (k7) to
form the dichlorinated product 22. Intermediate 23 may lose
a proton (k4), yielding the a-chloroalcohol 20. Finally, alde-
hyde 17 would be obtained after loss of HCl (k5).
Another NMR spectroscopy study was performed to in-
vestigate the effect of water. As mentioned earlier, perform-
ing the reaction in THF, at a concentration of 1.1m, at room
temperature, in the presence of water (0.2 equiv) and sulfu-
ric acid (0.35 equiv), led to the formation of adducts 17 and
22 in a 1:1 ratio (Scheme 16).
The NMR spectroscopy data also enabled us to obtain
some kinetic values for this mechanistic scheme. As an ini-
tial hypothesis, we suspected the oxonium cation formation
(k2) to be the rate-determining step of the whole process.
Therefore, the disappearance of the starting material was
1
followed by H NMR spectroscopy, using the methyl signal
located at d=1.64 ppm. The obtained exponential curve is
depicted in Scheme 14.
Scheme 16. Increasing the amount of water in the rearrangement step.
Surprisingly, the reaction reached completion within
15 min but a confident kinetic correlation could not be ob-
tained. However, this experiment indicates that the addition
of water to the oxonium cation (k3) could not be the rate-
determining step. Indeed, when the amount of water is low-
ered, the reaction proceeds faster. This effect could be due
to the hydration and dilution of the HCl, lowering the effec-
tive concentration in acid and thus decreasing the reaction
rate.
In conclusion, our NMR spectroscopy studies enabled us
to observe the formation of the chloromethylene furan inter-
mediate. We have also established a first-order kinetic pro-
file, strongly suggesting the generation of the oxonium
cation 19 to be the rate-determining step.
Scheme 14. Concentration of the chloromethylene furan versus the reac-
tion time.
Interestingly, a first-order correlation was obtained by
plotting the logarithm of the concentration ratio (lnACHTNUTRGNE(NUG C0/C)
Preparation of benzofurans: Using our two-step procedure,
several commercially available o-hydroxyphenones 24 were
successfully transformed into the corresponding benzofurans
25 in 78 to 97% isolated yield (Scheme 17).
versus the reaction time (Scheme 15). As aldehyde 17 and
chlorinated product 22 are always formed in a 1:1 ratio,
even after 8 min, k4, k5, k6 and k7 are high compared to the
rate-determining step, and all the HCl is immediately con-
sumed. Therefore, H2SO4 becomes rapidly the catalytically
active acid and its concentration remains essentially con-
stant. With this information, the first-order kinetics match
the oxonium cation formation perfectly.
Scheme 17. Extension of our methodology to several hydroxyphenones.
The reaction appears to be rather general and is efficient
for both alkyl- and aryl-substituted phenones (Table 1). It
also tolerates several functions such as halides and alkoxy
groups. We noticed a significant effect of the substituents on
the kinetics of the rearrangement. Indeed, for electron-with-
drawing groups, the reaction is slow. In contrast, when elec-
tron-donating substituents are present, this step is rather
fast. These observations are in agreement with the forma-
tion of an oxonium cation as the rate-determining step.
To extend our method to the corresponding aldehydes, we
had to modify slightly our system, as a fast degradation oc-
curred using the standard procedure. Thus, lithium diisopro-
pylamide (LDA) was used to prepare the chloroacetylene
Scheme 15. Linear regression (ln
rearrangement.
ACHTUNGRTEN(NUNG C/C0)) for the chloromethylene furan
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Highly Functionalised Benzofurans
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Table 1. Preparation of benzofuran carbaldehydes.
Entry
Substrate
Product
Yield[a] [%]
97
1
Scheme 18. Formation of the benzofuran-2-carbaldehyde with LDA.
2
3
93
78
4
5
6
92
94
88
Scheme 19. Synthesis of nerolione.
tallised. A single-crystal X-ray diffraction analysis confirmed
our assignment (Scheme 20); the previous data in the litera-
ture are thus incorrect.
7
93
80
89
94
95
8
9
Scheme 20. X-ray plot of nerolione oxime 40.
10
11
Starting from the benzofuran aldehyde 31, the lipoxyge-
nase inhibitor 43 was also prepared (Scheme 21). Alcohol 41
was obtained in good yield by the addition of the propyl
Grignard reagent. It was then oxidised using our copper-cat-
[a] All yields are for pure, isolated products.
anion and salicylaldehyde 36 was added dropwise to the sol-
ution containing this lithiated anion. After an acid-catalysed
rearrangement, benzofuran-2-carbaldehyde 37 was isolated
in 84% yield (Scheme 18).
Using our methodology, nerolione 39 was readily assem-
bled as shown in Scheme 19. However, our spectroscopic
data did not match those reported in the literature.[35] There-
fore, to establish unambiguously the structure of our com-
pound, the corresponding oxime 40 was prepared and crys-
Scheme 21. Synthesis of a lipoxygenase inhibitor.
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I. E. Markꢀ et al.
alysed method.[36] Finally, demethylation of ketone 42 pro-
ceeded smoothly, using a standard protocol,[37] delivering the
desired compound in high overall yields.
Aware that the conditions used to rearrange the chloro-
methylene furans require a prolonged period of time, we
varied the acid concentration and the reaction temperature
to speed up the process. Chloromethylene furan 21 was
chosen as a model substrate and was transformed into the
benzofuran aldehyde 17 (Scheme 22).
could not deprotonate this acetylene, treatment with LDA
afforded the corresponding diols 46 and 48. Both diols were
then reacted with tBuOK. Alas, no ring closure was ob-
served.
To verify that an alternative mechanism does not occur
when a haloalkene is used as the alkyne precursor, b-bro-
mostyrene (2.2 equiv) was reacted with an excess amount of
LDA (4.4 equiv) in the presence of ketone 47. As expected,
and in perfect agreement with our proposed mechanism,
adduct 48 was obtained in essentially quantitative yields,
hence ruling out a possible cyclisation pathway not involving
the intramolecular addition of the alkoxide anion on the in
situ generated alkyne intermediate.
A similar lack of reactivity was noticed in the case of tri-
methylsilyl (TMS)-acetylene (49; Scheme 24) and LDA had
to be used to remove the acetylenic proton. Diols 50 and 51
were obtained from the corresponding ketones 47 and 44.
Scheme 22. Optimisation of the rearrangement step.
As can be seen from the Table 2, increasing the concen-
tration of H2SO4 results in a significant decrease in the reac-
tion time, without deleterious effects on the yield of the
final adduct. In a similar manner, raising the temperature to
838C and using dichloroethane instead of dichloromethane
led to a reasonable increase in the reaction rate. These con-
ditions were then selected as the optimum ones and used in
all subsequent experiments.
Table 2. Conditions for the rearrangement of the chloromethylene furan
21.
Scheme 24. Reaction of trimethylsilylacetylene with model substrates.
H2SO4(aq) [m]
Solvent
T [8C]
t [h]
Yield [%]
0.01
0.1
1.0
0.01
0.01
0.01
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
20
20
20
40
83
24
10
6
8
<1
<1
98
93
97
97
98
93
Treatment of diol 50 with tBuOK led to the recovery of the
starting material. Under the same conditions, loss of the
TMS group was observed in the case of diol 51. It thus tran-
spires that the TMS substituent, as the phenyl group, is
unable to stabilise the formal negative charge generated at
its a position during the 5-exo-dig ring closure.
toluene
110
[a] DCE=1,2-dichloroethane.
When 44 was treated with the thiophenylacetylene precur-
sor 52,[38] in the presence of tBuOK, the corresponding exo-
methylene furan 53 was obtained in 66% yield (Scheme 25).
Acetylene chemistry: As chloroacetylene proved to be an
efficient partner in our transformation, we wondered wheth-
er other substituted acetylenes could also be used in this
benzofuran synthesis.
At the onset of our study, phenylacetylene was treated
with 4-hydroxy-2-butanone (44) and 5-bromo-2-hydroxyace-
tophone (47; Scheme 23). Although potassium tert-butoxide
Scheme 25. From 4-hydroxy-2-butanone to
furan.
a thiophenyl-substituted
To our surprise, this intermediate was found to aromatise
under acidic conditions, albeit in a modest yield. A similar
sequence was attempted with 47 but no reaction occurred. It
thus transpires that the thiophenyl acetylene anion is not re-
active enough to add to the less electrophilic 5-bromo-2-hy-
droxyacetophenone. In the presence of other bases, such as
LDA, degradation of the thiophenylacetylene precursor was
observed and the desired product was not obtained.
Scheme 23. Reaction of phenylacetylene with model substrates.
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Highly Functionalised Benzofurans
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The use of 2-chloroacrylonitrile (63) as a precursor of cya-
noacetylene proved to be successful and cyanomethylenes
64 and 65 could be isolated in moderate yields (Scheme 29).
Extensive polymerisation was observed and further attempts
to optimise this reaction failed.
Scheme 26. Reaction of 4-hydroxy-2-butanone with dibromoethylene.
As 1,1-dichloroethylene provides chloroacetylene,[33,34] we
wondered whether 1,2-dibromoethylene (55) could be a pre-
cursor for bromoacetylene (Scheme 26). Unfortunately,
rapid decomposition was observed in the presence of
tBuOK. Formation of bromoacetylene could, however, be
accomplished with LDA. The subsequent addition of 4-hy-
droxy-2-butanone (44) provided the desired diol 56 in excel-
lent yield. Treatment of 56 with tBuOK, at À248C, to pro-
mote the 5-exo-dig cyclisation, resulted in the formation of
bromomethylene furan 57 in a modest yield. A sequential
process in which intermediate adduct 56 was not purified
but directly treated with tBuOK resulted in an improved
yield of 39%.
Scheme 29. Reaction of 2-chloroacrylonitrile with model substrates.
Using an alkyne substituted by an ester group proved to
be even more interesting. When methyl propiolate 66 was
reacted with tBuOK, polymerisation occurred. However,
using LDA, the corresponding exo-methylene ester 67, de-
rived from 4-hydroxy-2-butanone 44, could be obtained in a
modest yield (Scheme 30). However, and for the first time,
When aromatic ketone 47 was treated under the same
conditions, a rather unexpected transformation occurred
(Scheme 27) and two products could be identified. The first
one proved to be the dibromomethylene benzofuran 58 and
the second one the non-brominated acetylenic diol 59.
Scheme 30. Reaction of 4-hydroxy-2-butanone with methyl propiolate.
Scheme 27. Reaction of 5-bromo-2-hydroxyacetophenone with dibromo-
ethylene.
the double-bond geometry was determined as E, a dramatic
deviation from all the previous examples. It is possible that
the ring closure, in this case, proceeded through an allenyl
enolate, which was subsequently protonated. In contrast, se-
quential treatment (LDA, workup, then tBuOK) of 44 led to
the Z-methylene ester 68. Both unsaturated esters 67 and 68
underwent the Michael addition of methanol, followed by a
spontaneous lactonisation, to afford the interesting adduct
69.
In the aromatic series, the coupling between 5-bromo-2-
hydroxyacetophenone 47 and methyl propiolate afforded
the two methylene ester isomers 70 and 71 in a combined
70% yield (Scheme 31). Lactone formation was also ob-
served when 72 was treated with methanol (1.5 equiv) and
tBuOK (1.8 equiv). Further optimisation, using a sequential
process, provided the tricyclic lactone 72 in 53% overall
yield from 47. This transformation was extended to 2-hy-
droxyacetophenone 16. The corresponding lactone 73 was
obtained in 50% yield.
This result can be rationalised as follows: during the ring
closure of bromoacetylene intermediate 60, the bromine
atom of 60 is transferred to the growing partial negative
charge generated on a second molecule of 60. This negative-
charge buildup results from the intramolecular addition of
the phenoxide anion onto the triple bond (Scheme 28). This
reaction should provide anions 61 and 62 in a 1:1 ratio. Pro-
tonation during the workup ultimately afforded the final ad-
ducts 58 and 59.
Scheme 28. Bromine-exchange reaction.
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I. E. Markꢀ et al.
Experimental Section
3-Methylbenzofuran-2-carbaldehyde (17): Potassium tert-butoxide (1.30 g,
11.4 mmol, 3.8 equiv) was added portionwise to a solution of 2-hydroxya-
cetophenone (0.37 mL, 3 mmol, 1 equiv) and vinylidene dichloride
(0.34 mL, 4.2 mmol, 1.4 equiv) in THF (15 mL). After 4 h, water (20 mL)
was added. The aqueous phase was neutralised with diluted sulfuric acid.
The aqueous layer was extracted with dichloromethane (3ꢃ20 mL). The
organic phase was dried, filtered and concentrated. The crude mixture
was dissolved in dichloromethane (100 mL) and aqueous sulfuric acid
(100 mL, 0.01m) was added. After 16 h under vigorous stirring, the aque-
ous layer was extracted with dichloromethane (2ꢃ60 mL). The organic
layer was dried, filtered and concentrated. The crude mixture was then
purified over silica gel yielding 17 as a yellow solid (0.465 g, 2.90 mmol,
1
97%). Rf =0.64 (petroleum ether/ethyl acetate 5:1); m.p. 628C; H NMR
(300 MHz): d=9.94 (s, 1H), 7.60 (m, 1H), 7.45 (m, 2H), 7.27 (m, 1H),
2.53 ppm (s, 3H); 13C NMR (75 MHz): d=179.5, 155.2, 148.0, 129.2,
128.5, 123.5, 121.7, 112.3, 8.2 ppm; MS (CI): m/z: 159.8; IR (neat): n˜ =
3310, 3067, 3036, 2920, 2862, 1661, 1612 cmÀ1; elemental analysis calcd
(%) for C10H8O2: C 74.99, H 5.03; found: C 75.05, H 4.64. Other benzo-
furans were similarly prepared. For full details see the Supporting Infor-
mation.
Scheme 31. Reaction of acetophenones with methyl propiolate.
The successful addition/cyclisation sequence described
above depends critically upon the nature of the electron-
withdrawing group attached to the in situ generated alkyne.
This reactivity correlates particularly well with the Hammett
sI coefficients, also known as the induction sigma coeffi-
cients or electron-withdrawing (donating) degree.[39] For ex-
ample, ring closure proceeds when this group is a chlorine,
bromine, nitrile, ester and sulfide substituent. Conversely,
no cyclisation is observed in the case of phenyl, trimethylsil-
yl, hydrogen or alkyl residues (Table 3).
Acknowledgements
The Universitꢁ catholique de Louvain (UCL), the Fonds pour la Recher-
che Industrielle et Agronomique (F.R.I.A.) and the Action de Recherch-
es Concertꢁes (ARC 08/13-012) are gratefully acknowledged for their fi-
nancial support.
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MeS
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Alkyl
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In summary, we have reported a unique, efficient and con-
nective reaction leading to highly functionalised benzofurans
in good to excellent yields. Starting from o-hydroxyphe-
nones, the corresponding Z-chloromethylene furans are ini-
tially obtained. These intermediates rearrange promptly into
the corresponding benzofuran carbaldehydes under mild
acidic conditions (0.01m H2SO4). To illustrate the synthetic
potential of our new method, some biologically active ben-
zofurans have been efficiently assembled. Several mechanis-
tic investigations have been carried out, the results of which
support our mechanistic hypotheses. An incursion into the
use of other acetylenes showed that interesting structures,
such as bi- or tricyclic lactones, could be readily constructed,
even though in some cases, the yields were rather modest.
Further investigations are on-going and the application of
this methodology to other heterocyclic structures is being
actively pursued. These results will be reported in due
course.
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Highly Functionalised Benzofurans
FULL PAPER
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Received: April 30, 2012
Revised: November 12, 2012
Published online: && &&, 0000
Chem. Eur. J. 2013, 00, 0 – 0
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www.chemeurj.org
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I. E. Markꢀ et al.
Heterocycles
F. Schevenels, B. Tinant, J.-P. Declercq,
I. E. Markꢀ* ..................... &&& — &&&
Smooth operator: A unique, efficient
and connective reaction is found to
lead to highly functionalised benzofur-
ans in good to excellent yields (see
scheme). The key intermediate, a
chloromethylene furan, smoothly rear-
ranged into the corresponding benzo-
furan carbaldehyde under acidic condi-
tions. Mechanistic investigations have
been performed and several biologi-
cally active benzofurans have been
synthesised.
Preparation of Highly Functionalised
Benzofurans from ortho-Hydroxyphe-
nones and Dichloroethylene: Applica-
tions and Mechanistic Investigations
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ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
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These are not the final page numbers!