p-Toluenesulfonic acid-promoted selective functionalization of unsymmetrical arylalkynes: a regioselective access to various arylketones and heterocycles

Article abstract of DOI:10.1016/j.tet.2010.03.055

Regioselective hydration of a wide range of internal alkynes has been afforded in high to good yields by using PTSA in EtOH. The scope of the reaction of alkynes has been delineated. Arylaliphatic alkynes and diarylalkynes were regioselectively hydrated in good to excellent yields and short reaction times when the reaction was achieved under microwave irradiation. Moreover, diarylalkynes, arylenynes as well as diaryldiynes bearing a methoxy- or a thiomethyl substituent on the ortho position underwent a regioselective 5-endo-dig-cyclization to give a variety of 2-aryl- and 2-styrylbenzofuran or benzothiphene derivatives. We believe that, this new environmentally metal-free procedure combined to microwave irradiation would be in importance in the search of green laboratory-scale synthesis.

Full text of DOI:10.1016/j.tet.2010.03.055

Tetrahedron 66 (2010) 3775–3787
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
p-Toluenesulfonic acid-promoted selective functionalization of unsymmetrical
arylalkynes: a regioselective access to various arylketones and heterocycles
*
*
ˆ
Maud Jacubert, Olivier Provot , Jean-François Peyrat, Abdallah Hamze, Jean-Daniel Brion, Mouad Alami
ˆ
Univ Paris-Sud, CNRS, BioCIS, UMR 8076, Laboratoire de Chimie The´rapeutique, Faculte´ de Pharmacie, rue J.-B. Cle´ment F-92296 Chatenay-Malabry, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Regioselective hydration of a wide range of internal alkynes has been afforded in high to good yields by
using PTSA in EtOH. The scope of the reaction of alkynes has been delineated. Arylaliphatic alkynes and
diarylalkynes were regioselectively hydrated in good to excellent yields and short reaction times when
the reaction was achieved under microwave irradiation. Moreover, diarylalkynes, arylenynes as well as
diaryldiynes bearing a methoxy- or a thiomethyl substituent on the ortho position underwent a re-
gioselective 5-endo-dig-cyclization to give a variety of 2-aryl- and 2-styrylbenzofuran or benzothiphene
derivatives. We believe that, this new environmentally metal-free procedure combined to microwave
irradiation would be in importance in the search of green laboratory-scale synthesis.
Received 22 January 2010
Received in revised form 12 March 2010
Accepted 15 March 2010
Available online 20 March 2010
Keywords:
Alkynes
Hydration
p-Toluenesulfonic acid
Ketone
Ó 2010 Elsevier Ltd. All rights reserved.
Benzofuran
Benzothiophene
Cyclization
1. Introduction
not applicable for oxygenated alkynes12 where the triple bond
remained absolutely inert.
The hydration of alkynes is an important tool to construct
a carbon–oxygen bond,1 and provides a direct access to carbonyl
compounds with a perfect atom economy. Historically, this
reaction was described by Kucherov since 1881,2 and required
the use of mercury(II) salts. The necessity of strongly acidic
conditions however, associated to the use of stoichiometric
amounts of toxic mercury salts had always been an inherent
problem of the process, making this reaction unsuitable for
modern applications. In recent years, numerous attempts have
been made to develop non-mercury alkyne hydration methodo-
logy. To this end, transition-metal complex catalysts including
Au,3 Ru,4 Ir,5 Rh,6 Pt,7 and Pd8 have been employed with varying
degrees of success, but the use of high loading of expensive
transition-metal catalysts limits the exploitation of these
methods. Beside enzymatic hydration of alkynes,9 metal-free
procedures using a catalytic Brønsted acid such as TfOH or
Tf2NH10 or concentrated H2SO4,11 or HCO2H12 have been reported.
While these latter hydration reactions are suitable in the case of
robust substrates, they are limited to terminal alkynes and are
As part of our research program directed to a selective
functionalization of unsymmetrically disubstituted alkynes,13 we
had to investigate the tetrahydropyranyl/ether cleavage of 1a in
EtOH under p-toluenesulfonic acid (PTSA) conditions.14 Contrary
to our expectations, the reaction did not afford 1b. We seren-
dipitously found that, besides the THP/ether cleavage, the in-
ternal carbon–carbon triple bond of 1a was hydrated together
with a concomitant etherification to give regioselectively 2a as
the only product in a 90% yield. Under these conditions, per-
forming the reaction from 1b assisted both etherification of free
hydroxyl group and carbonyl formation, producing 2a in an ex-
cellent 94% isolated yield. One can note that in both cases, the
hydration reaction is chemoselective, as it occurred exclusively
on the internal carbon–carbon triple bond keeping terminal al-
kynes unchanged (Scheme 1).
O
PTSA 10 mol%
EtO
N
EtOH, 78°C, 3 h
N
RO
1
2a
1a: R = THP
1b: R = H
* Corresponding authors. Tel.: þ33 14683 5847; fax: þ33 14683 5828 (O.P.);
tel.: þ33 14683 5887; fax: þ33 14683 5828 (M.A.); e-mail addresses: olivier.provot@
u-psud.fr, mouad.alami@u-psud.fr.
Scheme 1.
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.03.055

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M. Jacubert et al. / Tetrahedron 66 (2010) 3775–3787
Because the discovery of metal-free alkynes hydration pro-
2. Results and discussion
cedures remain as an intriguing challenge, the above observations
led us to experiment the PTSA/alcohol system as a new and
regioselective access to carbonyl compounds. Herein we wish to
detail our results with a variety of unsymmetrical internal alkynes
including, aliphatic arylalkynes or alkynols, diarylalkynes, 1,3-
enynes and 1,3-diynes.
2.1. Hydration/etherification of aliphatic arylalkynols15
The required alkynols 1c–h were readily prepared by Sonoga-
shira/Linstrumelle (S/L) coupling reactions.16 The reactivity of
model alkyne 1c was first examined in the presence of different
Brønsted acids and solvents; the results are listed in Table 1. Thus,
Table 1
Screening of catalysts and solvents for hydration of 4-methoxyphenyl alkynols 1c–h
Entry
Alkyne 1
Catalyst
(20 mol %)
ROH
(time)
Ketone 2
Yielda (%)
94
O
OH
EtOH
(5 h)
OEt
OEt
1
1c
1c
PTSA
2b
2b
MeO
MeO
MeO
MeO
O
OH
2
MeSO3H
EtOH
(5 h)
85
O
OH
OH
OH
EtOH
(5 h)
3
4
5
1c
1c
1c
CF3SO3Hb
3a
2c
2d
60
98
66
MeO
MeO
MeO
MeO
O
O
MeOH
(6 h)
OMe
OiPr
PTSA
MeO
MeO
iPrOH
(7 h)
PTSA
OH
OH
6
7
1c
1c
PTSA
PTSA
tBuOH
(24 h)
d
0
MeO
MeO
O
OH
OH
HO
(17 h)
O
2e
33
MeO
O
OH
OH
H2O
(10 h)
OH
8
1c
1c
1d
1e
1f
PTSA
PTSA
PTSA
PTSA
PTSA
2f
79
96
90
85
90
MeO
MeO
MeO
MeO
O
CD3OD
(5 h)
OCD3
9
D-2c
2b
2g
D
D
MeO
O
OMe
OH
EtOH
(8 h)
OEt
OEt
10
11
12
13
MeO
O
EtOH
(24 h)
MeO
MeO
OH
O
EtOH
(36 h)
OH
2h
MeO
MeO
OH
OH
O
EtOH
(24 h)
OEt
1g
1h
PTSA
PTSA
2i
91
73
MeO
MeO
O
EtOH
(10 h)
14
3b
MeO
MeO
a
Isolated yield.
30 mol % of catalyst were used.
b

M. Jacubert et al. / Tetrahedron 66 (2010) 3775–3787
3777
reaction of 1c with PTSA or MeSO3H (20 mol %) in refluxing EtOH
2.2. Mechanism of PTSA-catalyzed hydration
and etherification of arylalkynols in CD3OD
for 5 h provides 2b resulting from a regioselective hydration and
etherification of the free alcohol (entries 1 and 2). It is noteworthy
that enone 3a was formed when CF3SO3H was used as catalyst
(entry 3, 60%). All of the other tested catalytic systems (H2SO4,
CF3COOH, HCO2H) were unsuccessful, and in better cases, yields in
hydration products 2 were not satisfactory (e.g., HCOOH, 50%, data
not shown). The influence of the solvent was next examined with 1c
and PTSA (entries 4–9). The hydration and etherification of 1c oc-
curred efficiently in refluxing MeOH (entry 4) yielding 2c in 98%. The
process was slower and less effective in iPrOH or 1,2-ethyleneglycol
(entries 5 and 7) whereas, in tBuOH no reaction occurred, even after
a prolonged reaction time (entry 6). Interestingly, when the hydra-
The formation of arylketones 2 is believed to proceed initially
through a deuterium exchange between CD3OD and PTSA followed
by acidic deuterium activation of the triple bond as outline in
Scheme 2. The intermediate species of type I should evolve
according to an intra or an intermolecular addition process
depending on the longer alkynol chains. With substrates having
a propyn-3-ol or a butyn-4-ol chain (1c; n¼1 or 1e; n¼2) the
reaction would evolved according to an intramolecular oxygen
atom-addition to provide a four or a five membered cyclic oxonium
intermediate II. Nucleophilic ring opening with CD3OD and
( )n
MeO
OH
1
TsOH + CD3OD
TsOD
( )n
MeO
OD
TsOD
D
OCD3
D
D
CD3OD
n > 3
( )n
MeO
C
O
MeO
( )n n = 1, 2
( )n
OD
III
D
DO
D
MeO
I
II
intramolecular
addition
intermolecular
addition
CD3OD
Hydrolysis
- D
Hydrolysis
- D
O
O
( )n
( )n
OH
OCD3
D
D
D
D
MeO
MeO
n = 1
D-2c
Scheme 2. Mechanism proposed for PTSA-catalyzed hydration of alkynols in CD3OD.
tion was performed in refluxing water for 10 h, the triple bond was
regioselectively hydrated giving ketone 2f with a free-alcohol
function in a 79% yield (entry 8). Carrying out the reaction with 1c in
CD3OD as a solvent, besides a deuterated methylether formed,
a quantitative deuterium incorporation on the a-carbon of the keto
group was observed yielding D-2c (entry 9, 96%).
subsequent hydrolysis regenerated the catalyst and produced
a deuterated enol intermediate immediately rearranged to the
corresponding keto tautomer D-2c (entry 9, Table 1). From sub-
strate 1f having longer alkynol chain (n¼4, entry 12, Table 1), direct
alcoholic media addition7c,18 on I is preferred in comparison with
thermodynamically disfavored seven-membered cyclic oxonium
intermediate formation, keeping free the hydroxyl group. As
a check on our mechanistic interpretation, we also examined
hydration of a substrate 1i bearing a pentyl-5-ol chain (n¼3). Under
the same reaction conditions, hydration of 1i evolved according to
the two routes to give a mixture of alcohol 2j and ether 2k
(Scheme 3).
Next, the PTSA/EtOH system was used for the hydration of
alkyne 1d bearing a methylether function. In this case, 1d also
underwent hydration of the triple bond together with a trans-
etherification reaction by the solvent resulting in a 90% yield of the
ethylether carbonyl compound 2b (entry 10). Finally, the influence
of alkynol chains on the hydration/etherification process was in-
vestigated. As shown in entry 11, compound 1e bearing on the ar-
omatic ring a butyn-4-ol chain, was transformed into the expected
ketone 2g in a good yield but with a prolonged reaction time (24 h).
Similarly, hydration of alkyne 1f having on the aromatic nucleus
a hexyn-6-ol chain was still effective (entry 12). In this case, no
etherification of the hydroxyl group occurred and 2h with a free-
alcohol function was isolated in a good 90% yield. Reaction from
arylalkyne 1g having a secondary propargylic alcohol function
provided the expected carbonyl ether 2i (91%, entry 13). Under
these conditions, tertiary propargyl alcohol 1h leads in 73% yield to
the corresponding conjugated ketone 3b, well known as the Rupe’s
rearrangement17 adduct (entry 14).
O
OH
MeO
2j (45%)
PTSA 10 mol%
EtOH, reflux, 5 h
MeO
OH
O
1i
OEt
MeO
2k (44%)
Scheme 3. Hydration of alkynol 1i.

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M. Jacubert et al. / Tetrahedron 66 (2010) 3775–3787
2.3. Hydration of aliphatic arylalkynes
to give arylketones 2p and 2q. In this latter case, 1.2 equiv of PTSA
were necessary to achieve the complete hydration of the alkyne
substrate 1o (entry 6). However, in agreement with the proposed
mechanism, meta anisole derivative 1p as well as non-substituted
arylalkyne 1q did not react under the above experimental condi-
tions, even with stoechiometric amount of PTSA and prolonged
reaction times. In these cases, starting arylalkynes were recovered
unchanged (entries 7 and 8). These findings were illustrated with
the selective hydration of alkyne 1r having two carbon–cabon triple
bonds. As expected, besides the etherification of the free-alcohol
function by the solvent, only the activated triple bond underwent
the hydration reaction leading to 2t in 76% yield (Scheme 4).
The scope of this PTSA-catalyzed hydration reaction was next
investigated with several arylalkyne substrates and the results of
this study are summarized in Table 2.
Table 2
PTSA catalyzed synthesis of various arylketones 2
O
R2
PTSA 0.2 equiv.
R2
R1
Solvent, reflux
R1
1
2
Entry
1
Alkyne 1
ROH (reflux)
Time
Ketone 2
Yielda (%)
O
PTSA 0.2 equiv.
EtOH
O
C4H9
EtO
HO
C H
reflux, 10 h
4
9
EtOH
60 h
O
O
90
H3CO
H CO
3
1j
2l
2t (76%)
1r
Scheme 4. Selectivity in triple bond hydration of 1r.
OH
( )4
O
OH
EtOH
6 h
2
3
78b
H2N
To circumvent the low reactivity of ortho-substituted ary-
lalkynes and the lack of reactivity of non-substituted arylalkynes as
well as meta-substituted derivatives, we envisioned to use micro-
wave irradiation (MWI)19 that could enhance this process and
expand the substrate scope. Moreover, with cooperative para-
substituted arylalkynes, the use of MWI should accelerate the rate
of this hydration reaction.
H2N
2m
1k
1l
O
OH
H2O
8 h
OH
79
HO
HO
2n
Initial efforts focused on optimizing microwave conditions for
the formation of 2s from 1q. After screening the quantity of PTSA,
temperature and reaction time, we found that complete conversion
of 1q required the use of PTSA (1 equiv) in EtOH, for 30 min at 170 ꢀC
under MWI to give 2s in 89% yield (entry 1, Table 3). Performing the
reaction at a lower temperature (120 ꢀC or 150 ꢀC) or using a cata-
lytic amount of PTSA (20 mol %) resulted in lower yields of 2s
(15–35%, data not shown). The optimized reaction conditions found
for 1q were applied to meta substituted arylalkyne 1p, which was
transformed into 2r within 30 min in a satisfactory 60% yield (entry
2, Table 3). To evaluate the significant benefit of MWI, model ary-
lalkyne 1c with a cooperative para methoxy substituent was heated
in EtOH and PTSA (0.2 equiv) at different temperatures. The best
result was obtained when 1c was heated at 120 ꢀC for 30 min under
MWI (entry 3, 98%). Similarly, we have applied this protocol to var-
ious arylalkynes. In most cases studied, hydration and etherification
process successfully occurred (entries 3, 4, 6, and 7), except with
secondary propargylic alcohol 1s (entry 5) where the Rupe’s rear-
rangement predominated to give the conjugated ketone 3c. With
1,1-dichloroenyne 1u, beside the triple bond hydration, alcoholysis
of the carbon–chlorine bonds occurred to produce the ketoester 2v
in a 51% isolated yield (entry 8). Silylated arylalkyne 1v reacted well
and furnished 4-methoxyacetophenone 2w in 77% yield (entry 9).
Replacing the 4-methoxy by a 4-NH2 substituent has no deleterious
effect on this acidic hydrationprocess and ketone 2x was obtained in
a 91% yield (entry 10) Finally hydration of ortho methoxyarylalkyne
1o successfully occurred within only 1 h at 170 ꢀC (entry 11),
whereas under conventional heating (entry 6 Table 2) 144 h were
required to complete the hydration of the alkyne substrate.
O
OH
H2O
12 h
OH
4
5
73
73
OH
1m
OH
2o
O
OH
EtOH
144 h
OEt
OMe
1n
OMe
2p
O
C H
4
9
C4H9
EtOH
144 h
6
7
80c
OMe
1o
OMe
2q
O
C4H9
MeO
MeO
C H
4
EtOH
144 h
9
0
1p
1q
2r
O
C4H9
EtOH
72 h
C H
4
9
8
0
2s
a
Isolated yield.
b
When the reaction was achieved with the corresponding ortho-NH2 derivative,
12 h were required to give the ketone with a modest 30% yield.
c
1.2 equiv of PTSA were used.
Arylalkyne 1j bearing a hexynyl side chain was successfully
hydrated (entry 1, 90%) but 60 h were required for complete con-
version. Next, other p-electron-donating groups on the aromatic
ring were evaluated to assist the hydration process. As shown in
entries 2 and 3, a para NH2 and a para-OH substituents on the ar-
omatic ring activated the triple bond, as suggested in the mecha-
nism, and the corresponding ketones 2m and 2n were obtained in
EtOH or H2O in good yields. On switching the electron-donating
OH-group from the para to the ortho position on the aromatic nu-
cleus, the hydration in H2O was still efficient but required a pro-
longed reaction time (compare entries 3 and 4, Table 2). In refluxing
EtOH, ortho anisole alkyne derivatives 1n and 1o reacted smoothly
The PTSA-assisted hydration of unsymmetrical diarylalkynes
4a–f under MWI was next evaluated (Table 4, entries 1–6). By using
1.2 equiv of PTSA at 120 ꢀC in EtOH, diarylalkyne 4a was regiose-
lectively hydrated within 30 min (entry 1, 97%). As shown in entry
2, the presence of a bromine atom was tolerated and ketone 5b was
regioselectively obtained in a nearly quantitative yield (entry 2,
98%). Diarylalkynes 4c and 4d, bearing respectively a methyl and
a NH2-substituent on the aromatic rings reacted smoothly under
the previous conditions (120 ꢀC). After some trials, we were pleased

M. Jacubert et al. / Tetrahedron 66 (2010) 3775–3787
3779
Table 3
Table 4
PTSA-promoted hydration of arylalkynes 1 under MWI
PTSA-promoted hydration of substituted diarylalkynes 4 under MWI
Yielda
(%)
O
Entry
Diarylalkyne 4
(Equiv)
T (ꢀC)
Product 5
PTSA 0.2-1.0 equiv.
EtOH
R3
R2
R1
R1
MWI, 30 min
1
2, 3c
MeO
(1.2)
97b
MeO
1
120 ꢀC
O
4a
4b
5a
Entry
1
Alkyne 1
PTSA (equiv)
Temp
Ketone 2
Yielda
(%)
O
Br
MeO
Br
(1.2)
120 ꢀC
2
98c
MeO
C4H9
C4H9
(1.0)
170 ꢀC
O
89
60
5b
1q
1p
2s
O
MeO
(1.0)
150 ꢀC
MeO
MeO
C4H9
(1.0)
3
4
80
79
C4H9
O
2
170 ꢀC
4c
5c
2r
H2N
(1.0)
150 ꢀC
O
H2N
MeO
MeO
O
OH
OH
(0.2)
120 ꢀC
OEt
OEt
4d
5d
3
4
5
98
51b
90
1c
1g
MeO
MeO
MeO
MeO
MeO
MeO
2b
(1.0)
170 ꢀC
5
68
O
O
(0.2)
120 ꢀC
4e
5e
MeO
MeO
MeO
2i
MeO
MeO
MeO
MeO
MeO
MeO
OMe
O
OMe
(1.0)
170 ꢀC
6
55d
O
(0.2)
120 ꢀC
MeO
MeO
OH
4f
5f
1s
1e
3c
a
Isolated yield.
b
c
Obtained as an inseparable 90/10 mixture with the other regioisomer.
Reaction was run for 1 h.
Obtained as an inseparable 87/13 mixture with the other regioisomer.
O
OH
OEt
(0.2)
120 ꢀC
d
6
79
69
51
77
91
2g
MeO
2.4. PTSA-promoted hydration of ortho-substituted
arylalkynes under MWI
O
(0.2)
HO
7
120 ꢀC
OEt
MeO
MeO
2u
Having succeeded in developing an efficient hydration process
of low reactive diarylalkynes, we next examined the reaction with
ortho substituted diarylalkynes under MWI at 170 ꢀC in the pres-
ence of 1 equiv of PTSA in EtOH.21 The results of this study are
summarized in Table 5. Under the above conditions, diarylalkyne 6a
bearing an ortho methoxy substituent on the aromatic ring sur-
prisingly, provided the cyclized 2-arylbenzo[b]furan 7a with no
trace of the hydration products (entry 1, 76%). This result clearly
showed that the nature of the substituents attached to the triple
bond has a major impact on the behavior of the reaction (cycliza-
tion versus hydration). A para methoxyphenyl ring attached to the
triple bond of 6a favors the benzofuran formation whereas, alkyne
1o with an aliphatic chain fail to undergo cyclization but provides
exclusively the hydration adduct (see entry 11, Table 3). The unique
formation of 7a is believed to proceed according to an electrophilic
activation of the alkyne carbon–carbon triple bond with PTSA to
give hypothetic species IV or VI (Scheme 5). Subsequent intra-
molecular oxygen cyclization from IV would form the furan nucleus
of type V, which evolves into 7a via a dealkylation step by the
solvent. According to this hypothesis, the intermolecular ethanol
addition from species VI is disfavored.
The scope and limitation of this cyclization was next studied
with a variety of ortho substituted diarylalkynes. Substrates 6b–e
bearing in the ortho position a methoxy substituent were suc-
cessfully transformed into the corresponding benzofuran de-
rivatives 7b–e in good yields (entries 2–5, Table 5). One can note
that a regioselective cyclization occurred from 6e to give a single
benzofuran product 7e although alkyne substrate contains two
ortho methoxy substituents (entry 5). We believe that the aromatic
ring with two methoxy groups increase the electron density on the
1t
O
MeO
MeO
H2N
Cl
(0.2)
120 ꢀC
CO2Et
8
Cl
1u
1v
2v
O
SiMe3
C4H9
(0.2)
120 ꢀC
9
MeO
2w
O
C4H9
(0.2)
120 ꢀC
10
H2N
1w
2x
O
C4H9
C4H9
(1.0)
170 ꢀC
OMe
11
60
OMe
2q
1o
a
Isolated yield.
b
27% of conjugated ketone (Rupe’s rearrangement) was also isolated.
to observe the total conversion of these substrates into the corre-
sponding ketones 5c and 5d within 30 min using 1.0 equiv of PTSA
under microwave heating at 150 ꢀC (entries 3 and 4). Surprisingly,
the 3,4,5-trimethoxyphenyl nucleus frequently found in many an-
ticancer substances,13g,20 deactivated the triple bond. In these
cases, a microwave heating at 170 ꢀC in the presence of 1 equiv of
PTSA were needed to achieve a total conversion. Substrate 4e fur-
nished regioselectively ketone 5e (entry 5) whereas, a mixture of
ketones was obtained from alkyne 4f having methoxy substituents
on both aromatic nucleus (entry 6).

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M. Jacubert et al. / Tetrahedron 66 (2010) 3775–3787
Table 5
distal end of the triple bond. Subsequent electrophilic attack oc-
curred with the ortho methoxy group of the other aromatic ring.
This protocol was applied to ortho-(alkynyl)thioanisole derivatives
6f–h. As expected, in EtOH, the reaction provided the benzothio-
phenes 7f–h in good to excellent yields (88 to 94%, entries 6–8). It
should be noted, that this metal-free procedure, which proceeds
under environmentally friendly conditions is amenable for large
scale synthesis of 2-arylbenzofuran and 2-arylbenzothiphene de-
rivatives, which are prevalent in many compounds of biological
interest.22 The reaction with substrate 6i bearing both an ortho
electron-donating methoxy and an electron-withdrawing
methoxycarbonyl substituent was also examined. The cyclization
proceeded with high selectivity and isocoumarin 7i was obtained
as the sole product23 (95%, entry 9). This result corroborates our
mechanism hypothesis as the methoxy substituent regioselectively
directed the activation of the triple bond thus allowing the elec-
trophilic cyclization to proceed by the ortho methoxycarbonyl
group.
PTSA-promoted cyclization of ortho substituted diarylalkynes 6 in EtOH under MWI
R1 PTSA, 1.0 equiv
R1
EtOH, MWI
X
XR
6
7
Entry
1
Diarylalkyne 7
Time (h)
T (ꢀC)
Product 8
Yielda (%)
OMe
OMe
1
O
76
OMe
130
7a
6a
MeO
O
MeO
2
160
2
3
83
93
OMe
7b
6b
O
2
160
OMe
7c
HO
6c
2.5. PTSA-promoted hydration of enynes 8 and diynes
9 under MWI
TBDMSO
1
160
4
61
O
In addition to the above substrates, 1,3-enynes and 1,3-diynes
were subjected to the previously established and already optimized
electrophilic cyclization (Table 6). Enyne 8a was readily prepared by
Pd/Cu-catalyzed coupling16b of 2-methoxyphenyl acetylene with
1-bromo-2-methylpropene in a 72% yield.
For enynes 8b–e, they were obtained in good yields (See
Experimental section) from iron24 or palladium25 catalyzed re-
action of (E)-chloroenynes16 and Grignard reagents. The desired
diynes 9a–e were synthesized by the coupling of 1-iodoethynyl-
2-methoxybenzene with terminal arylalkynes in good yields
(64–81%).26
The PTSA protocol for the cyclization of ortho-substituted aryl-
alkynes 6 was then applied to enynes 8 and diynes 9. The results of
this study are reported in Table 6. Reaction of enyne 8a was carried
out with PTSA (1 equiv) under MWI in EtOH and gave 2-alke-
nylbenzofuran 10a in a satisfactory 72% yield (entry 1). Similarly,
the reaction of (E)-enynes 8b–e gave also the corresponding 2-
substituted benzofuran derivatives 10b–e with comparable yields.
All the compounds synthesized were characterized by the E double
bond geometry as judged by 1H NMR analysis (entries 2–5). The
present approach seems undoubtedly promising because it allows
a quick entry to a variety of 2-alkenylbenzofurans of biological in-
terest.27 The reaction was then applied to 1,3-diynes 9. Compounds
9a and 9b were readily transformed into the corresponding bis-
benzofuran 11a and 2-(benzothiophenyl) benzofuran derivative
11b (entries 6 and 7). One can note that no reaction occurred when
OMe
7d
6d
MeO
MeO
O
OMe
OMe
OMe
1
160
5
6
7
65
94
93
OMe
6e
6f
7e
OMe
S
1
130
SMe
7f
2
160
S
SMe
7g
6g
TBDMSO
HO
1
160
8
88
95
S
SMe
6h
7h
O
MeO2C
O
1
130
9
OMe
OMe
7i
6i
a
Isolated yield.
Scheme 5. Mechanism proposed for the formation of 7a.

M. Jacubert et al. / Tetrahedron 66 (2010) 3775–3787
3781
Table 6
friendly procedure was successfully extended to non cooperative
alkynes when carrying out the reaction under microwave irradia-
tion. Moreover, unsymmetrical diarylalkynes bearing various
functional groups on the aromatic nucleus were regioselectively
and rapidly hydrated in good to excellent yields. Under the opti-
mized conditions, diarylalkynes bearing on the ortho position
a methoxy- or a thiomethyl substituent allowed an electrophilic
cyclization to produce a variety of benzofuran and benzothiophene
derivatives. Similarly, ortho-methoxy arylenynes were successfully
transformed into the corresponding 2-alkenylbenzofurans in good
yields. Although, this procedure requires high temperatures (from
80 ꢀC to 170 ꢀC), it involves non-toxic PTSA, EtOH as solvent, short
reaction times, high to excellent yields, low cost and with minimum
waste. All of these advantages are in a total agreement with the
green chemistry philosophy.
Reaction of enynes 8 and diynes 9 with PTSA in EtOH under MWIa
Entry
1
Alkyne
Product
Yieldb (%)
72
O
OMe
10a
8a
2
3
4
C4H9
47c
73
C4H9
O
OMe
10b
10c
10d
10e
8b
O
OMe
8c
OMe
O
OMe
75
OMe
8d
4. Experimental
S
5
6
7
8
9
78
58d
76
SMe
OMe
OMe
8e
4.1. Instrumentation
O
O
The compounds were all identified by usual physical methods,
i.e., 1H NMR, 13C NMR, IR, and elemental analysis. 1H and 13C NMR
spectra were measured in CDCl3 with a Bruker Avance 300
(300 MHz). 1H chemical shifts are reported in parts per million from
an internal standard TMS or of residual chloroform (7.27 ppm). The
MeO
11a
9a
O
S
MeS
11b
9b
9c
following abbreviations are used:
m (multiplet), s (singlet),
O
d (doublet), t (triplet), dd (doublet of doublet). 13C chemical shifts
are reported in parts per million from the central peak of deuter-
iochloroform (77.14). IR spectra were measured on a Bruker Vector
22 spectrophotometer (neat, cmꢁ1). Mass spectra were obtained
with a Esquire LC Bruker spectrometer. Elemental analyses were
performed with a Perkin-Elmer 240 analyzer. Analytical TLC were
performed on Merck precoated silica gel 60F plates. Merck silica gel
60 (230–400 mesh) was used for column chromatography. Melting
points (mp) were recorded on a Bu¨chi B-450 apparatus and were
uncorrected.
OMe
OMe
94
OMe
O
O
11c
28e
OMe
9d
11d
MeO2C
O
O
10
0f
O
OMe
11e
9e
a
Reaction conditions: 8 or 9 (0.2 mmol); PTSA(0.2 mmol); EtOH (2 mL); 160 ꢀC; 2 h.
b
c
d
e
f
Isolated yield.
Reaction time 0.5 h.
24% of 2-(benzofuran-2-yl)-1-(2-methoxyphenyl)ethanone were also isolated.
Unoptimized yield.
Mixture of unidentified products.
4.2. Preparation of arylalkynes
4.2.1. N,N-di(prop-2-ynyl)-4-(3-(tetrahydro-2H-pyran-2-yloxy)prop-
1-ynyl)benzenamine 1a. To a stirred solution of 4-iodo-aniline
(2.19 g, 10 mmol) in THF (20 mL) under an argon atmosphere was
added, CuI (190 mg, 1.0 mmol), PdCl2(PPh3)2 (350 mg, 0.5 mmol),
Et2NH (7.3 g, 100 mmol), and 2-(prop-2-ynyloxy)-tetrahydro-2H-
pyran (16.8 g, 12 mmol). The stirred mixture was stirred for a 5 h at
room temperature and ether (30 mL) was added. After filtration on
a pad of Celite, the organic layer was washed with H2O. After ex-
traction and concentration to dryness, the crude mixture was dis-
solved in DMF (30 mL). Then, propargyl bromide (3 mL; 27.6 mmol;
80% in toluene), K2CO3 (3.24 g), KI (0.3 g) were added to the mixture,
which was stirred at 50 ꢀC for 15 h. After cooling, the crude mixture
was diluted in diethylether (30 mL), filtered. The organic layer was
washed with H2O (3ꢂ10 mL), dried with MgSO4, and evaporated to
dryness. Purification by flash chromatography afforded 1a (675 mg,
2.22 mmol calculated from 4-iodoaniline).
heating 9a at 160 ꢀC under MWI in acidic solvents (e.g., AcOH,
HCOOH, TFA). Starting material 9a was recovered totally unchanged
(data not shown). 1,3-Diyne 9c bearing a 4-methoxy substituent on
one of the aromatic rings was next evaluated (entry 8). As expected,
the cyclization-process occurred together with the regioselective
hydration of the second carbon–carbon triple bond to furnish 11c.
With a less electron-donating 2-naphtyl substituent attached to the
triple bond (entry 9), the process was less efficient and benzofuran
11d was isolated with a modest 28% yield. Finally, when carrying
out the reaction with diyne 9e, bearing both a methoxy and car-
bomethoxy substituents on the ortho position of the aromatic rings,
no trace of benzofuran or isocoumarin derivatives were detected.
3. Conclusion
Yield: 22%. IR (cmꢁ1) 3287, 2942, 1606, 1514, 1340. 1H NMR
(CDCl3, 300 MHz, 298 K):
d ppm 1.40–1.90 (m, 6H), 2.25 (t, 2H,
In summary, the use of PTSA in alcoholic media is a simple and
efficient protocol, that is, easy to carry out. It appears to be pre-
dictable, regardless of the diverse array of starting materials that
can be employed. Electron-rich aliphatic arylalkynes are regiose-
lectively hydrated using a catalytic amount of PTSA in refluxing
EtOH to provide carbonyl compounds. The substrate scope of this
J¼2.3 Hz), 3.50–3.90 (m, 2H), 4.11 (d, 4H, J¼2.3 Hz), 4.47 (d, 2H,
J¼3.3 Hz), 4.89 (t, 1H, J¼3.3 Hz), 6.84 (d, 2H, J¼9.0 Hz), 7.37 (d, 2H,
J¼9.0 Hz). 13C NMR (CDCl3, 75 MHz, 298 K):
d ppm 18.9, 25.2, 30.1,
40.0 (2), 54.7, 61.8, 72.7 (2), 78.7 (2), 83.4, 85.9, 96.5, 112.9, 114.4 (2),
132.8 (2), 147.2. Anal. Calcd for C20H21NO2: C, 78.15; H, 6.89; N, 4.56.
Found C, 78.01; H, 6.71; N, 4.49.

3782
M. Jacubert et al. / Tetrahedron 66 (2010) 3775–3787
4.2.2. 6-(4-Aminophenyl)hex-5-yn-1-ol 1k. TEA (1.5 equiv) was
used in place of Et2NH.
129.5, 133.5, 133.8, 156.3, 160.0. MS (APCI) m/z¼339 [MþH]þ. Anal.
Calcd for C21H26O2Si: C, 74.51; H, 7.74. Found C, 74.16; H, 7.48.
Yield: 45%. IR (cmꢁ1) 3367, 2936, 1608, 1513, 1431, 1288, 1176,
1059, 829. 1H NMR (CDCl3, 300 MHz, 298 K):
d
ppm 1.50–1.85 (m,
4.2.9. 2,4-Dimethoxy-1-((2-methoxyphenyl)ethynyl)benzene
6e. Yield: 69%; brown solid; mp 98 ꢀC. IR (cmꢁ1) 2934, 1606, 1508,
1457, 1299, 1243, 1208, 1161, 1024, 751. 1H NMR (CDCl3, 300 MHz,
4H), 2.40 (t, 2H, J¼5.9 Hz), 3.70 (t, 2H, J¼5.2 Hz), 6.58 (d, 2H,
J¼6.7 Hz), 7.19 (d, 2H, J¼6.7 Hz). 13C NMR (CDCl3, 75 MHz, 298 K):
d
ppm 19.2, 25.2, 31.9, 62.5, 81.4, 87.2, 114.7 (2), 132.7 (2), 145.9 (one
298 K): d ppm 3.82 (s, 3H), 3.90 (s, 3H), 3.92 (s, 3H), 6.45–6.50 (m, 2H),
C missing). Anal. Calcd for C12H15NO: C, 76.16; H, 7.99; N, 7.40.
Found C, 76.05; H, 8.15; N, 7.19.
6.86–6.96 (m, 2H), 7.22–7.31 (m,1H), 7.45 (dt,1H, J¼8.7 Hz, J¼1.2 Hz),
7.50 (dd, 1H, J¼7.5 Hz, J¼1.6 Hz). 13C NMR (CDCl3, 75 MHz, 298 K):
d
ppm 55.5, 56.1, 88.5, 90.0, 98.6,104.9,105.6,110.8,113.3,120.5,129.3,
4.2.3. 2-(3-Hydroxyprop-1-ynyl)phenol 1m. Compound 1m was
prepared from the coupling of tert-butyl(2-iodophenoxy)-
dimethylsilane with 1-propyn-3-ol as above and the crude mixture
was desilylated using TBAF (5 equiv) in THF at room temperature.
Yield: 59% (for the two steps). IR (cmꢁ1) 3290, 2938, 1605, 1510.
133.5, 134.4, 159.9, 161.2, 161.3. MS (APCI) m/z¼269 [MþH]þ. Anal.
Calcd for C17H16O3: C, 76.10; H, 6.01. Found C, 75.87; H, 5.88.
4.2.10. Methyl(2-(2-(naphthalen-1-yl)ethynyl)phenyl)sulfane
6g. Yield: 30%; colorless oil.1H NMR (CDCl3, 300 MHz, 298 K):
d 2.71
1H NMR (CDCl3, 300 MHz, 298 K):
d
ppm 4.70–4.90 (br s, 3H), 7.01–
(s, 3H), 7.33 (m, 2H), 7.49 (dt, 1H, J¼1.2 Hz, J¼7.9 Hz), 7.69 (m, 4H),
7.99 (m, 3H), 8.77 (d, 1H, J¼8.3 Hz). MS (APCI) m/z¼275 [MþH]þ.
Anal. Calcd for C19H14S: C, 83.17; H, 5.14. Found C, 82.82; H, 4.95.
7.23 (m, 2H), 7.45 (td, 1H, J¼7.8 Hz, J¼1.3 Hz), 7.51 (dd, 1H, J¼7.8 Hz,
J¼1.2 Hz). 13C NMR (CDCl3, 75 MHz, 298 K):
d ppm 50.4, 79.9, 93.3,
109.9, 115.3, 119.5, 129.8, 132.5, 157.9. Anal. Calcd for C9H8O2: C,
72.96; H, 5.44. Found C, 72.87; H, 5.34.
4.2.11. tert-Butyldimethyl(2-(2-(2-(methylthio)phenyl)ethynyl) phe-
noxy)silane 6h. Yield: 52%; yellow oil. IR (cmꢁ1) 2361, 2218, 1994,
1574, 1497, 1482, 916, 838, 806, 780, 744. 1H NMR (CDCl3, 300 MHz,
4.2.4. 1-(4-isoPropylphenyl)-4-(4-methoxyphenyl)but-3-yn-1-ol
1t. Yield: 88%. Mp 72–73 ꢀC. IR (cmꢁ1) 3454, 2967, 1607, 1508,1283,
1242, 1175, 1065, 1037, 1016, 830. 1H NMR (CDCl3, 300 MHz, 298 K):
298 K):
d 0.06 (s, 6H), 0.83 (s, 9H), 2.29 (s, 3H), 6.64 (dd, 1H,
J¼1.0 Hz, J¼8.2 Hz), 6.73 (dt, 1H, J¼1.0 Hz, J¼7.5 Hz), 6.89 (dt, 1H,
J¼1.2 Hz, J¼7.4 Hz), 7.06 (m, 3H), 7.24 (dd, 1H, J¼1.4 Hz, J¼7.6 Hz),
7.34 (dd, 1H, J¼1.8 Hz, J¼7.7 Hz). 13C NMR (CDCl3, 75 MHz, 298 K):
ꢁ4.0 (2), 15.2, 18.4 (3), 25.9, 88.5, 90.6, 112.9, 119.9, 121.3, 124.2,
128.5, 129.7, 132.0, 133.9, 134.5. MS (APCI) m/z¼355 [MþH]þ. Anal.
Calcd for C21H26OSSi: C, 71.13; H, 7.39. Found C, 70.89; H, 7.10.
d
ppm 1.24 (d, 6H, J¼6.9 Hz), 2.42 (d, 1H, J¼3.3 Hz), 2.82 (d, 2H,
J¼6.3 Hz), 2.91 (q, 1H, J¼6.9 Hz), 3.79 (s, 3H), 4.88–4.93 (m, 1H),
6.81 (d, 2H, J¼8.5 Hz), 7.22 (d, 2H, J¼8.1 Hz), 7.32 (d, 2H, J¼8.5 Hz),
7.35 (d, 2H, J¼8.1 Hz). 13C NMR (CDCl3, 75 MHz, 298 K):
d ppm 24.0,
30.6, 33.8, 55.3, 72.5, 82.9, 84.6, 113.7, 115.4, 125.8, 126.5, 133.0,
140.1, 148.6, 159.3. MS (ESIþ) m/z¼317 [MþNa]þ. Anal. Calcd for
C20H22O2: C, 81.60; H, 7.53. Found C, 81.47; H, 7.31.
4.2.12. (E)-1-Methoxy-2-(oct-3-en-1-ynyl)benzene 8b. Yield: 82%;
yellow oil. IR (cmꢁ1) 1673, 1603, 1510. 1H NMR (CDCl3, 300 MHz,
4.2.5. 4-(Hex-1-ynyl)benzenamine 1w. Yield: 65%. IR (cmꢁ1) 3374,
298 K):
d
ppm 0.95 (t, 3H, J¼6.9 Hz), 1.34–1.44 (m, 4H), 2.16 (q, 2H,
2957, 2931,1620,1512, 828.1H NMR (CDCl3, 300 MHz, 298 K):
d
ppm
J¼6.8 Hz), 3.89 (s, 3H), 5.75 (d, 1H, J¼15.5 Hz), 6.21–6.31 (m, 1H),
0.94 (t, 3H, J¼7.0 Hz),1.46–1.65 (m, 4H), 2.38 (t, 2H, J¼6.8 Hz), 3.35 (s,
6.85–6.92 (m, 2H), 7.23–7.29 (m,1H), 7.39 (d,1H, J¼7.5 Hz). 13C NMR
2H), 6.58 (d, 2H, J¼8.4 Hz), 7.20 (d, 2H, J¼8.4 Hz). 13C NMR (CDCl3,
(CDCl3, 75 MHz, 298 K): d ppm 14.0, 22.3, 31.0, 33.0, 55.9, 84.1, 92.6,
75 MHz, 298 K):
d
ppm 13.6,19.0, 21.9, 31.0, 80.7, 87.7,113.6 (2),114.7,
109.9, 110.6, 112.9, 120.5, 129.4, 133.5, 145.1, 159.8. MS (ESI)
m/z¼237.3 [MþNa]þ. Anal. Calcd for C15H18O: C, 84.07; H, 8.47.
Found C, 83.93; H, 8.33.
132.6 (2), 146.9. MS (ESIþ) m/z¼192.3 [MþNa]þ. Anal. Calcd for
C12H15N: C, 83.19; H, 8.73; N 8.08. Found C, 82.66; H, 8.44; N 7.68.
4.2.6. 4-(p-Tolylethynyl)benzenamine 4d. Yield: 92%. White solid
4.2.13. (E)-1-Methoxy-2-(4-phenylbut-3-en-1-ynyl)benzene
8c. Yield: 91%; yellow oil. IR (cmꢁ1) 3029, 1592, 1489, 1462, 1433,
1274, 1258, 1239, 1119, 1024, 951, 745, 690. 1H NMR (CDCl3,
mp 172–174 ꢀC. IR (cmꢁ1) 3467, 3375, 2209, 1616, 1599, 1515, 1295,
814. 1H NMR (CDCl3, 300 MHz, 298 K):
d ppm 2.35 (s, 3H), 3.81 (s,
2H), 6.63 (d, 2H, J¼8.5 Hz), 7.12 (d, 2H, J¼8.0 Hz), 7.33 (d, 2H,
300 MHz, 298 K):
d
ppm 3.92 (s, 3H), 6.47 (d,1H, J¼16.2 Hz), 6.90 (d,
J¼8.5 Hz), 7.38 (d, 2H, J¼8.0 Hz). 13C NMR (CDCl3, 75 MHz, 298 K):
1H, J¼8.3 Hz), 6.94 (td, 1H, J¼7.5 Hz, J¼0.8 Hz), 7.07 (d, 1H,
d
ppm 21.4, 87.4, 89.3, 112.8, 114.7, 120.8 (2), 129.0 (2), 131.2 (2),
J¼16.2 Hz), 7.27–7.38 (m, 4H), 7.42–7.48 (m, 3H). 13C NMR (CDCl3,
132.8 (2), 137.7, 146.4. MS (APCI) m/z¼208 [MþH]þ. Anal. Calcd for
75 MHz, 298 K): d ppm 56.0, 88.2, 93.1, 108.6, 110.8, 112.8, 120.7,
C15H13N: C, 86.92; H, 6.32; N, 6.76. Found C, 86.68; H, 6.33; N, 6.66.
126.4, 128.6, 128.8, 129.8, 133.6, 136.6, 141.1, 160.0. MS (APCI)
m/z¼235 [MþH]þ. Anal. Calcd for C17H14O: C, 87.15; H, 6.02. Found
C, 87.01; H, 5.97.
4.2.7. 1-(2-(2-Methoxyphenyl)ethynyl)naphthalene 6c. Yield: 79%;
yellow oil. IR (cmꢁ1) 3057, 2834, 1574, 1491, 1461, 1433, 1397, 1275,
1242, 1180, 1161, 1113, 1047, 1022, 934, 799, 772. 1H NMR (CDCl3,
4.2.14. (E)- 4-(2-Methoxyphenyl)-1-(4-methoxyphenyl)but-1-en-3-
300 MHz, 298 K):
d
ppm 3.82 (s, 3H), 6.80 (s, 2H), 7.18 (ddd, 1H,
yne 8d. Yield: 59%; yellow solid; mp 69 ꢀC. IR (cmꢁ1) 2935, 1604,
J¼1.7 Hz, J¼7.5 Hz, J¼8.3 Hz), 7.38 (m, 4H), 7.67 (m, 3H), 8.41 (dd,
1H, J¼1.7 Hz, J¼8.3 Hz). 13C NMR (CDCl3, 75 MHz, 298 K): 56.0, 90.9,
91.8, 110.8, 112.8, 120.2, 120.6, 121.4, 125.3, 126.4, 126.6, 126.8, 128.3,
128.6, 129.9, 130.1, 133.3, 133.4, 160.2. MS (APCI) m/z¼259 [MþH]þ.
Anal. Calcd for C19H14O: C, 88.34; H, 5.46. Found C, 88.04; H, 5.28.
1510,1491,1247,1028, 752. 1H NMR (CDCl3, 300 MHz, 298 K):
d ppm
3.82 (s, 3H), 3.91 (s, 3H), 6.31 (d, 1H, J¼16.2 Hz), 6.86–6.95 (m, 4H),
7.02 (d,1H, J¼16.2 Hz), 7.26–7.31 (m,1H), 7.37 (d, 2H, J¼8.7 Hz), 7.44
(dd,1H, J¼7.5 Hz, J¼1.6 Hz). 13C NMR (CDCl3, 75 MHz, 298 K):
d ppm
55.5, 56.0, 87.4, 93.5, 106.2, 110.7, 112.9, 114.3 (2), 120.6, 127.8 (2),
129.5, 129.6, 133.6, 140.7, 159.9, 160.1. MS (APCI) m/z¼265 (MþH)þ.
Anal. Calcd for C18H16O2: C, 81.79; H, 6.10. Found C, 81.55; H, 5.91.
4.2.8. tert-Butyl(2-((2-methoxyphenyl)ethynyl)phenoxy)dimethyl
silane 6d. Yield: 45%; brown oil. IR (cmꢁ1) 2930, 2857, 1593, 1574,
1497, 1482, 1461, 1444, 1285, 1249, 1181, 1161, 1113, 1096, 1025, 916,
4.2.15. (E)-Methyl(2-(4-phenylbut-3-en-1-ynyl)phenyl)sulfane
838, 806, 780. 1H NMR (CDCl3, 300 MHz, 298 K):
d
ppm 0.00 (s, 6H),
8e. Yield: 82%; yellow oil. IR (cmꢁ1) 3026,1463,1434, 952, 746, 690.
0.77 (s, 9H), 3.63 (s, 3H), 6.60 (m, 4H), 6.98 (m, 2H), 7.23 (dt, 2H,
J¼1.7 Hz, J¼7.7 Hz). 13C NMR (CDCl3, 75 MHz, 298 K): ꢁ4.1 (2), 18.4,
25.8 (3), 55.7, 89.2, 90.9, 110.7, 113.1, 116.3, 119.8, 120.4, 121.1, 129.3,
1H NMR (CDCl3, 300 MHz, 298 K):
d
ppm 2.52 (s, 3H), 6.47 (d, 1H,
J¼16.2 Hz), 7.08–7.19 (m, 3H), 7.27–7.38 (m, 4H), 7.43–7.46 (m, 3H).
13C NMR (CDCl3, 75 MHz, 298 K):
ppm 15.3, 89.3, 95.5, 108.1, 116.9,
d

M. Jacubert et al. / Tetrahedron 66 (2010) 3775–3787
3783
121.7, 124.3, 124.4, 126.5 (2), 128.8 (2), 128.9, 132.4, 136.5, 141.6. MS
(APCI) m/z¼251 (MþH)þ. Anal. Calcd for C17H14S: C, 81.56; H, 5.64.
Found C, 81.39; H, 5.51.
7.90 (d, 2H, J¼8.9 Hz). 13C NMR (CDCl3, 75 MHz, 298 K):
d
ppm 38.1,
55.2, 58.6, 67.9, 113.5 (2), 130.0, 130.2 (2), 163.4, 196.6. MS (EI)
m/z¼194 (23%) [M]þ.
4.2.16. (2-(4-(2-Methoxyphenyl)buta-1,3-diynyl)phenyl)(methꢁy1l)
2938, 1594, 1492, 1464, 1433, 1248, 1022, 703. 1H NMR (CDCl3,
4.3.4. 3- (2H)-Methoxy-1-(4-methoxyphenyl)-(2,2-2H)propan-1-one
sulfane 9b. Yield: 70%; light brown solid; mp 82–83 ꢀC. IR (cm
)
D-2c. Yield: 98%; yellow oil. 1H NMR (CDCl3, 300 MHz, 298 K):
d
ppm 3.77 (s, 2H), 3.83 (s, 3H), 6.91 (d, 2H, J¼8.8 Hz), 7.92 (d, 2H,
300 MHz, 298 K): ppm 2.51 (s, 3H), 3.91 (s, 3H), 6.89 (d, 1H,
d
J¼8.8 Hz). 13C NMR (CDCl3, 75 MHz, 298 K):
d ppm 37.5 (q,
J¼8.7 Hz), 6.92 (t, 1H, J¼7.5 Hz), 7.09 (t, 1H, J¼7.5 Hz), 7.17 (d, 1H,
J¼7.9 Hz), 7.29–7.36 (m, 2H), 7.48–7.51 (m, 2H). IR (cmꢁ1) 15.4, 56.0,
77.7, 79.5, 80.1, 80.4, 110.8, 111.2, 120.5, 120.7, 124.5, 124.6, 129.5,
130.9, 133.7, 134.6, 143.2, 161.5. MS (APCI) m/z¼279 [MþH]þ. Anal.
Calcd for C18H14OS: C, 77.66; H, 5.07. Found C, 77.66; H, 5.01.
J¼19.3 Hz), 55.2, 57.8 (m, J¼21.5 Hz), 67.8, 113.6 (2), 130.0, 130.2 (2),
163.4, 196.7. MS (ES) m/z¼222 [MþNa]þ.
4.3.5. 3-Isopropoxy-1-(4-methoxyphenyl)propan-1-one 2d15. Yield:
66%; pale yellow oil.1H NMR (CDCl3, 300 MHz, 298 K):
d ppm 1.13 (d,
6H, J¼6.1 Hz), 3.15 (t, 2H, J¼6.8 Hz), 3.59 (m,1H), 3.81 (s, 3H), 3.82 (t,
4.2.17. 1-(2-Methoxyphenyl)-4-(4-methoxyphenyl)buta-1,3-diyne
9c. Yield: 64%; colorless solid; mp 109–110 ꢀC. IR (cmꢁ1) 2936, 2837,
1601, 1508, 1489, 1247, 1171, 1024, 750. 1H NMR (CDCl3, 300 MHz,
2H, J¼6.8 Hz), 6.89 (d, 2H, J¼8.9 Hz), 7.92 (d, 2H, J¼8.9 Hz). 13C NMR
(CDCl3, 75 MHz, 298 K):
d ppm 21.7 (2), 38.6, 55.0, 63.2, 71.4, 113.3
(2), 129.9, 130.0 (2), 163.1, 196.6. MS (ESI) m/z¼245 [MþNa]þ.
298 K): d ppm 3.82 (s, 3H), 3.90 (s, 3H), 6.84–6.94 (m, 4H), 7.32 (t,1H,
J¼7.6 Hz), 7.45–7.48 (m, 3H). 13C NMR (CDCl3, 75 MHz, 298 K):
d
ppm
4.3.6. 3-(2-Hydroxyethoxy)-1-(4-methoxyphenyl)propan-1-one
55.4, 55.9, 73.2, 77.7, 78.0, 82.5, 110.8, 111.3, 114.0, 114.2 (2), 120.6,
130.6,134.1 (2),134.4,160.4,161.5. MS (APCI) m/z¼263 [MþH]þ. Anal.
Calcd for C18H14O2: C, 82.42; H, 5.38. Found C, 82.11; H, 5.20.
2e15. Yield: 33%; colorless oil. 1H NMR (CDCl3, 300 MHz, 298 K):
d
ppm 2.50–2.70 (s, 1H), 3.17 (t, 2H, J¼6.2 Hz), 3.56 (t, 2H, J¼4.8 Hz),
3.69 (t, 2H, J¼4.8 Hz), 3.83 (s, 3H), 3.88 (t, 2H, J¼6.2 Hz), 6.89 (d, 2H,
J¼8.9 Hz), 7.91 (d, 2H, J¼8.9 Hz). 13C NMR (CDCl3, 75 MHz, 298 K):
4.2.18. 1-(4-(2-Methoxyphenyl)buta-1,3-diynyl)naphthalene
d ppm 38.1, 55.3, 61.5, 65.9, 72.0, 113.7 (2), 129.9, 130.3 (2), 163.6,
9d. Yield: 75%; beige solid; mp 82–83 ꢀC. IR (cmꢁ1) 3059, 1491, 1279,
196.9. MS (ESI) m/z¼225 [MþNa]þ.
1253, 748.1H NMR (CDCl3, 300 MHz, 298 K):
d
ppm 3.93 (s, 3H), 6.89–
6.96 (m, 2H), 7.32–7.38 (m,1H), 7.49–7.55 (m, 4H), 7.78–7.83 (m, 3H),
8.06 (s, 1H). 13C NMR (CDCl3, 75 MHz, 298 K):
ppm 56.0, 74.7, 77.9,
4.3.7. 3-Hydroxy-1-(4-methoxyphenyl)propan-1-one
2f28. Yield:
d
75%; yellow solid; mp 62 ꢀC. 1H NMR (CDCl3, 300 MHz, 298 K):
78.5, 82.7, 110.8, 111.2, 119.4, 120.7, 126.9, 127.3, 127.9, 128.0, 128.3,
128.6, 130.9, 133.0, 133.3, 134.6, 161.6. MS (APCI) m/z¼283 (MþH)þ.
Anal. Calcd for C21H14O: C, 89.34; H, 5.00. Found C, 89.01; H, 4.79.
d
ppm 2.50–2.70 (s, 1H), 3.16 (t, 2H, J¼5.5 Hz), 4.72 (s, 3H), 4.00 (t,
2H, J¼5.5 Hz), 6.93 (d, 2H, J¼9.0 Hz), 7.93 (d, 2H, J¼9.0 Hz). 13C NMR
(CDCl3, 75 MHz, 298 K): d ppm 39.9, 55.4, 58.1,113.7 (2),129.8,130.3
(2), 163.7, 198.9. MS (ESI) m/z¼181 [MþH]þ.
4.3. Typical procedure for the PTSA-catalyzed hydration
of arylalkynes under classical heating
4.3.8. 4-Ethoxy-1-(4-methoxyphenyl)butan-1-one 2g15. Yield: 85%;
yellow oil. 1H NMR (CDCl3, 300 MHz, 298 K):
d ppm 1.16 (t, 3H,
To a stirred solution of alkyne 1a (307 mg; 1 mmol) in EtOH
(2 mL), was added PTSA monohydrate (38 mg; 0.2 mmol). The
mixture was refluxed for 3 h, diluted in H2O and extracted with
EtOAc. The combined organic layer was washed with brine and
dried over Na2SO4. After removal of the solvent under vacuo, the
crude product was purified by column chromatography on silica gel
to afford 242 mg of 2a.
J¼7.0 Hz), 1.17 (m, 2H), 2.99 (t, 2H, J¼7.2 Hz), 3.35–3.50 (m, 4H),
3.83 (s, 3H), 6.90 (d, 2H, J¼8.7 Hz), 7.93 (d, 2H, J¼8.7 Hz). 13C NMR
(CDCl3, 75 MHz, 298 K):
d ppm 15.0, 24.4, 34.6, 55.2, 65.4, 69.5,
113.5 (2), 130.0, 130.1 (2), 163.3, 198.4. MS (ESI) m/z¼245 [MþNa]þ.
4.3.9. 6-Hydroxy-1-(4-methoxyphenyl)hexan-1-one
90%; yellow solid; mp 60 ꢀC. 1H NMR (CDCl3, 300 MHz, 298 K):
ppm 1.40–1.60 (m, 6H), 2.92 (t, 2H, J¼7.3 Hz), 3.65 (t, 2H,
J¼6.4 Hz), 3.85 (s, 3H), 6.91 (d, 2H, J¼8.9 Hz), 7.92 (d, 2H, J¼8.9 Hz).
2h15. Yield:
d
4.3.1. 1-(4-(Diprop-2-ynylamino)phenyl)-3-ethoxypropan-1-one
2a. Yield: 90%; yellow solid; mp 90 ꢀC. IR (cmꢁ1) 3271, 2957, 2871,
13C NMR (CDCl3, 75 MHz, 298 K):
d ppm 24.1, 25.5, 32.5, 38.0, 55.4,
1655, 1595, 1562. 1H NMR (CDCl3, 300 MHz, 298 K):
d
ppm 1.18 (t,
62.6, 113.7 (2), 130.1, 130.2 (2), 163.4, 199.0. MS (EI) m/z¼222 [M]þ.
3H, J¼7.0 Hz), 2.27 (t, 2H, J¼2.3 Hz), 3.16 (t, 2H, J¼6.8 Hz), 3.51 (q,
2H, J¼7.0 Hz), 3.82 (t, 2H, J¼6.8 Hz), 4.17 (d, 4H, J¼2.3 Hz), 6.88 (d,
2H, J¼9.1 Hz), 7.91 (d, 2H, J¼9.1 Hz). 13C NMR (CDCl3, 75 MHz,
4.3.10. 3-Ethoxy-1-(4-methoxyphenyl)butan-1-one 2i15. Yield: 91%;
yellow oil. IR (cmꢁ1) 2973, 2930, 1675, 1600, 1576, 1510. 1H NMR
298 K):
d
ppm 14.9, 38.1, 39.8 (2), 65.9, 66.2, 72.9 (2), 78.3 (2), 112.9
(CDCl3, 300 MHz, 298 K):
d
ppm 1.14 (t, 3H, J¼7.0 Hz), 1.24 (d, 3H,
(2), 127.6, 129.9 (2), 150.6, 196.3. MS (ESI) m/z¼292 [MþNa]þ. Anal.
Calcd for C17H19NO2: C, 75.81; H, 7.11; N, 5.20. Found C, 75.66; H,
7.02; N, 5.05.
J¼6.1 Hz), 2.86 (dd, 1H, J¼6.2 Hz, J¼15.8 Hz), 3.28 (dd, 1H, J¼6.2 Hz,
J¼15.8 Hz), 3.50 (quint, 1H, J¼7.0 Hz), 3.51 (dd, 1H, J¼7.0 Hz,
J¼7.0 Hz), 3.86 (s, 3H), 4.06 (m, 1H), 6.92 (d, 2H, J¼8.9 Hz), 7.94 (d,
2H, J¼8.9 Hz). 13C NMR (CDCl3, 75 MHz, 298 K):
d ppm 15.5, 20.4,
4.3.2. 3-Ethoxy-1-(4-methoxyphenyl)propan-1-one
94%; yellow oil. IR (cmꢁ1) 2974, 1673, 1599, 1575, 1510. 1H NMR
(CDCl3, 300 MHz, 298 K):
2b19e. Yield:
45.5, 55.4, 64.1, 72.0, 113.7 (2), 130.5, 130.6 (2), 163.5, 197.4. MS (ESI)
m/z¼223 [MþH]þ.
d
ppm 1.14 (t, 3H, J¼7.0 Hz), 3.14 (t, 2H,
J¼6.7 Hz), 3.47 (d, 2H, J¼8.9 Hz), 3.78 (s, 3H), 3.79 (t, 2H, J¼6.8 Hz),
4.3.11. 5-Hydroxy-1-(4-methoxyphenyl)pentan-1-one
45%; colorless solid; mp 50 ꢀC. IR (cmꢁ1) 3470, 1671, 1605. 1H NMR
(CDCl3, 300 MHz, 298 K): ppm 1.50–2.05 (m, 5H), 3.01 (t, 2H,
2j29. Yield:
6.87 (d, 2H, J¼8.9 Hz), 7.89 (d, 2H, J¼8.9 Hz). 13C NMR (CDCl3,
75 MHz, 298 K):
d
ppm 14.9, 38.4, 55.2, 65.8, 66.3, 113.5 (2), 130.0,
d
130.2 (2), 163.3, 196.7. MS (EI) m/z¼208 (18%) [M]þ.
J¼6.5 Hz), 3.80–3.60 (m, 2H), 3.75 (s, 3H), 6.85 (d, 2H, J¼8.8 Hz),
7.92 (d, 2H, J¼8.8 Hz).
4.3.3. 3-Methoxy-1-(4-methoxyphenyl)propan-1-one
2c15. Yield:
98%; yellow oil. IR (cmꢁ1) 2986, 2905, 2842, 2816, 1665, 1598, 1513.
4.3.12. 5-Ethoxy-1-(4-methoxyphenyl)pentan-1-one
44%; colorless solid; mp 46 ꢀC. IR (cmꢁ1) 1673, 1603, 1510. 1H NMR
(CDCl3, 300 MHz, 298 K):
ppm 1.20 (t, 3H, J¼7.1 Hz), 1.50–2.01 (m,
2k29. Yield:
1H NMR (CDCl3, 300 MHz, 298 K):
(s, 3H), 3.76 (t, 2H, J¼6.6 Hz), 3.81 (s, 3H), 6.88 (d, 2H, J¼8.9 Hz),
d
ppm 3.14 (t, 2H, J¼6.6 Hz), 3.32
d

3784
M. Jacubert et al. / Tetrahedron 66 (2010) 3775–3787
4H), 2.95 (t, 2H, J¼6.5 Hz), 3.45 (t, 2H, J¼6.5 Hz), 3.50 (q, 2H,
J¼7.1 Hz), 3.86 (s, 3H), 6.92 (d, 2H, J¼8.9 Hz), 7.91 (d, 2H, J¼8.9 Hz).
(1 mL). The reaction vessel was then placed in the Emrys Optimizer
and exposed to microwave irradiation according to the following
specifications: temperature, time (see tables), fixed hold time: on,
sample absorption: high, pre-stirring: 60 s. After cooling to room
temperature, H2O (3 mL) was added to the crude and the mixture
was extracted with EtOAc (3ꢂ2 mL). Organic layers were dried,
concentrated and the crude mixture was purified by column
chromatography on silica gel.
4.3.13. 1-(4-Methoxyphenyl)hexan-1-one 2l30. Yield: 81%; yellow
solid; mp 60 ꢀC. IR (cmꢁ1) 3077, 3011, 2956, 2931, 1676, 1601, 1254.
1H NMR (CDCl3, 300 MHz, 298 K):
d
ppm 0.90 (t, 3H, J¼5.6 Hz), 1.36
(m, 4H),1.70 (quint, 2H, J¼7.3 Hz), 2.89 (t, 2H, J¼7.3 Hz), 3.85 (s, 3H),
6.91 (d, 2H, J¼8.8 Hz), 7.93 (d, 2H, J¼8.8 Hz). 13C NMR (CDCl3,
75 MHz, 298 K):
d ppm 13.8, 22.4, 24.2, 31.5, 38.1, 55.3, 113.5 (2),
130.2 (3), 163.2, 199.0. MS (EI) m/z¼206 [M]þ.
4.4.1. 1-(3-Methoxyphenyl)-hexan-1-one 2r. Yield: 60%. IR (cmꢁ1
2954, 2932, 1684, 1596, 1260. 1H NMR (CDCl3, 300 MHz, 298 K):
)
4.3.14. 1-(4-Aminophenyl)-6-hydroxyhexan-1-one
2m15. Yield:
d
ppm 0.89 (t, 3H, J¼7.6 Hz), 1,27–1.40 (m, 4H), 1.70 (m, 2H),
72%; yellow solid; mp 114 ꢀC. 1H NMR (CD3OD, 300 MHz, 298 K):
2.92 (t, 2H, J¼7.6 Hz), 3.81 (s, 3H), 7.07 (ddd, 1H, J¼8.1 Hz,
J¼2.8 Hz, J¼0.9 Hz), 7.35 (dd, 1H, J¼8.1 Hz, J¼8.1 Hz), 7.46 (dd,
1H, J¼2.8 Hz, J¼1.7 Hz), 7.51 (ddd, 1H, J¼8.1 Hz, J¼1.7 Hz,
d
ppm 1.20–1.80 (m, 6H), 2.87 (t, 2H, J¼7.6 Hz), 3.55 (t, 2H,
J¼6.4 Hz), 6.63 (d, 2H, J¼8.8 Hz), 7.75 (d, 2H, J¼8.8 Hz). 13C NMR
(CD3OD, 75 MHz, 298 K):
d
ppm 26.1, 26.7, 33.5, 38.6, 62.3, 114.3 (2),
J¼0.9 Hz). 13C NMR (CDCl3, 75 MHz, 298 K):
d ppm 14.0, 22.6,
126.8, 132.1(2), 153.6, 201.5. MS (ESI) m/z¼230 [MþNa]þ.
24.2, 31.6, 38.7, 55.4, 112.3, 119.2, 120.6, 129.4, 138.4, 159.7, 202.2.
Anal. Calcd for C13H18O2: C, 75.69; H, 8.80. Found C, 75.35;
H, 8.54.
4.3.15. 3-Hydroxy-1-(4-hydroxyphenyl)propan-1-one 2n30. Yield:
79%; white solid; mp 140 ꢀC. IR (cmꢁ1) 3462, 3114, 1643, 1596. 1H
NMR (CD3OD, 300 MHz, 298 K):
d
ppm 3.14 (t, 2H, J¼6.2 Hz), 3.93 (t,
4.4.2. 1-Phenylhexan-1-one 2s30. Yield: 89%; colorless oil. IR
2H, J¼6.2 Hz), 6.84 (d, 2H, J¼8.9 Hz), 7.89 (d, 2H, J¼8.9 Hz). 13C NMR
(cmꢁ1) 2930, 1683, 1597, 1448, 745. 1H NMR (CDCl3, 300 MHz,
(CD3OD, 75 MHz, 298 K):
d
ppm 41.7, 58.9, 116.2, 130.2, 131.8, 163.8,
298 K):
d
ppm 0.91 (t, 3H, J¼7.2 Hz), 1.34–1.44 (m, 4H), 1.75
199.7. MS (ESI) m/z¼167 [MþH]þ.
(quint, 2H, J¼7.2 Hz), 2.96 (t, 2H, J¼7.2 Hz), 7.40–7.59 (m, 3H),
7.93–7.98 (dt, 2H, J¼5.8 Hz, J¼1.4 Hz). 13C NMR (CDCl3, 75 MHz,
4.3.16. 3-Hydroxy-1-(2-hydroxyphenyl)propan-1-one
2o. Yield:
298 K): d ppm 13.9, 22.5, 24.1, 31.5, 38.6, 128.0 (2), 128.5 (2),
73%. 1H NMR (CD3COCD3, 300 MHz, 298 K):
d
ppm 2.80 (br s, 1H),
132.8, 137.2, 200.5.
3.31 (t, 2H, J¼8.8 Hz), 4.01 (m, 2H), 6.87–7.01 (m, 2H), 7.55 (td, 1H,
J¼7.9 Hz, J¼1.3 Hz), 7.98 (dd,1H, J¼7.9 Hz, J¼1.3 Hz),12.40 (br s,1H).
4.4.3. 4-Ethoxy-4-(4-isopropylphenyl)-1-(4-methoxyphenyl)-butan-
13C NMR (CD3COCD3, 75 MHz, 298 K):
d
ppm 41.0, 57.3, 117.7, 118.8,
1-one 2u. Yield: 69%. IR (cmꢁ1) 2960, 1672, 1596, 1509, 1261, 1165,
120.1, 130.7, 136.2, 205.1. Anal. Calcd for C9H10O3: C, 65.05; H, 6.07.
Found C, 64.87; H, 5.90.
987, 828. 1H NMR (CDCl3, 300 MHz, 298 K):
d ppm 1.15 (t, 3H,
J¼6.9 Hz), 1.24 (d, 6H, J¼6.6 Hz), 2.08–2.17 (m, 2H), 2.90 (q, 1H,
J¼6.9 Hz), 3.01 (td, 2H, J¼7.2 Hz, J¼1.8 Hz), 3.26 (m, 2H), 3.86 (s,
3H), 4.31 (t, 1H, J¼6.3 Hz), 6.92 (d, 2H, J¼8.8 Hz), 7.12–7.25 (m, 4H),
4.3.17. 3-Ethoxy-1-(2-methoxyphenyl)propan-1-one 2p. Yield: 73%;
yellow oil. IR (cmꢁ1) 2974, 2868, 1672, 1597. 1H NMR (CDCl3,
7.92 (d, 2H, J¼8.8 Hz). 13C NMR (CDCl3, 75 MHz, 298 K):
d ppm 15.3,
300 MHz, 298 K):
d
ppm 1.13 (t, 3H, J¼7.0 Hz), 3.23 (t, 2H, J¼6.8 Hz),
24.0 (2), 32.9, 33.8, 34.4, 55.4, 64.1, 80.8, 113.6 (2), 126.4 (4), 130.3
(3), 139.9, 148.0, 163.3, 198.8. Anal. Calcd for C22H28O3: C, 77.61; H,
8.29. Found C, 77.62; H, 8.36.
3.45 (q, 2H, J¼7.0 Hz), 3.76 (t, 2H, J¼6.7 Hz), 3.83 (s, 3H), 6.85–7.00
(m, 2H), 7.35–7.45 (m, 1H), 7.65 (dd, 1H, J¼7.8 Hz, J¼1.8 Hz). 13C
NMR (CDCl3, 75 MHz, 298 K):
d ppm 14.9, 43.9, 55.2, 65.6, 66.0,
111.3, 120.3, 127.9, 130.0, 133.2, 158.4, 200.0. MS (EI) m/z¼208 [M]þ.
4.4.4. Ethyl 4-(4-methoxyphenyl)-4-oxobutanoate 2v30. Yield: 51%.
Anal. Calcd for C12H16O3: C, 69.21; H, 7.74. Found C, 69.00; H, 7.52.
IR (cmꢁ1) 2980, 2841, 1730, 1599, 1576, 1510, 1249, 1217, 1163, 1023,
833, 799. 1H NMR (CDCl3, 300 MHz, 298 K):
d ppm 1.25 (t, 3H,
4.3.18. 1-(2-Methoxyphenyl)hexan-1-one 2q31. Yield: 80%; colorless
J¼7.1 Hz), 2.72 (t, 2H, J¼6.7 Hz), 3.25 (t, 2H, J¼6.7 Hz), 3.85 (s, 3H),
oil. IR (cmꢁ1) 2928, 2858, 1674, 1597. 1H NMR (CDCl3, 300 MHz,
4.10 (q, 2H, J¼7.1 Hz), 6.90 (d, 2H, J¼9.0 Hz), 7.95 (d, 2H, J¼9.0 Hz).
298 K):
d
ppm 0.87 (t, 3H, J¼6.9 Hz), 1.25–1.35 (m, 4H), 1.55–1.75
13C NMR (CDCl3, 75 MHz, 298 K):
d ppm 14.1, 28.4, 33.0, 55.4, 60.5,
(m, 2H), 2.92 (t, 2H, J¼7.5 Hz), 3.84 (s, 3H), 6.85–7.00 (m, 2H), 7.30–
113.7 (2), 129.7 (2), 130.2, 163.5, 173.0, 196.6.
7.45 (m, 1H), 7.61 (dd, 1H, J¼7.6 Hz, J¼1.8 Hz). 13C NMR (CDCl3,
75 MHz, 298 K):
d
ppm 13.7, 22.3, 23.9, 31.4, 43.5, 55.2, 111.4, 120.4,
4.4.5. 1-(4-Methoxyphenyl)-ethanone 2w30. Yield: 77%. IR (cmꢁ1
)
128.7, 129.9, 132.8, 158.1, 202.9. MS (EI) m/z¼206 [M]þ.
1672, 1600, 1312, 1205. 1H NMR (CDCl3, 300 MHz, 298 K):
d ppm
2.55 (s, 3H), 3.87 (s, 3H), 6.92 (d, 2H, J¼8.9 Hz), 7.95 (d, 2H,
4.3.19. 3-Ethoxy-1-(4-(3-phenylprop-2-ynyloxy)phenyl)propan-1-
J¼8.9 Hz). 13C NMR (CDCl3, 75 MHz, 298 K):
d ppm 26.7, 55.9, 114.1
one 2t. Yield: 76%; yellow solid; mp 61 ꢀC. IR (cmꢁ1) 2939, 2803,
(2), 130.7, 131.0 (2), 163.9, 197.2.
1669, 1595. 1H NMR (CDCl3, 300 MHz, 298 K):
d ppm 1.18 (t, 3H,
J¼7.0 Hz), 3.20 (t, 2H, J¼6.7 Hz), 3.52 (q, 2H, J¼7.0 Hz), 3.84 (t, 2H,
J¼6.7 Hz), 4.96 (s, 2H), 7.06 (d, 2H, J¼9.0 Hz), 7.30–7.40 (m, 3H),
7.40–7.50 (m, 2H), 7.97 (d, 2H, J¼9.0 Hz). 13C NMR (CDCl3, 75 MHz,
4.4.6. 1-(4-Aminophenyl)-hexan-1-one 2x30. Yield: 91%. IR (cmꢁ1
3462, 3355, 2933, 1627, 1587, 1560, 1318, 1258, 1210, 1176, 818. 1H
NMR (CDCl3, 300 MHz, 298 K):
)
d
ppm 0.90 (t, 3H, J¼6.6 Hz),1.36 (m,
298 K):
d
ppm 15.0, 38.6, 56.6, 65.8, 66.4, 83.0, 87.7, 114.6 (2), 121.9,
4H),1.73 (q, 2H, J¼7.3 Hz), 2.85 (t, 2H, J¼7.3 Hz), 4.06 (br s, 2H, NH2),
128.2 (2), 128.8, 130.3 (2), 130.7, 131.7 (2), 161.5, 196.9. MS (ESI)
m/z¼309 [MþH]þ. Anal. Calcd for C20H20O3: C, 77.90; H, 6.54. Found
C, 77.54; H, 6.23.
6.64 (d, 2H, J¼8.5 Hz), 7.81 (d, 2H, J¼8.5 Hz). 13C NMR (CDCl3,
75 MHz, 298 K):
d ppm 13.8, 22.4, 24.5, 31.5, 37.8, 113.5 (2), 127.2,
130.3 (2), 151.2, 198.8.
4.4. Typical procedure for the synthesis of ketones under
microwaves irradiation
4.4.7. 1-(4-Methoxyphenyl)-2-p-tolyl-ethanone 5a19i. Yield: 97%.
IR (cmꢁ1) 3005, 2901, 1678, 1596, 1501, 1321, 1254, 1177, 1027,
995, 829, 774. 1H NMR (CDCl3, 300 MHz, 298 K):
d ppm 2.32
To an Emrys Optimizer 0.5–2 mL Pyrex reaction vessel were
added alkyne (1 mmol) and PTSA (see tables for quantity) in EtOH
(s, 3H), 3.86 (s, 3H), 4.19 (s, 2H), 6.92 (d, 2H, J¼8.7 Hz), 7.12
(d, 2H, J¼8.1 Hz), 7.16 (d, 2H, J¼8.1 Hz), 7.98 (d, 2H, J¼8.7 Hz).

M. Jacubert et al. / Tetrahedron 66 (2010) 3775–3787
3785
13C NMR (CDCl3, 75 MHz, 298 K):
d
ppm 21.0, 44.9, 55.4, 113.7
(m, 3H), 8.50 (d, 1H). 13C NMR (CDCl3, 75 MHz, 298 K):
d
ppm
(2), 129.2 (2), 129.3 (2), 129.7, 130.9 (2), 131.8, 136.3, 163.4,
196.4.
106.1, 111.4, 121.1, 123.1, 124.5, 125.4, 125.7, 126.3, 127.0, 127.5,
128.4, 128.8, 129.2, 129.7, 130.9, 134.1, 155.1, 155.8. MS (APCI)
m/z¼245 (MþH)þ.
4.4.8. 1-(4-Methoxyphenyl)-2-(4-bromophenyl)-ethanone
5b19i. Yield: 98%. IR (cmꢁ1) 33017, 1675, 1598, 1573, 1257, 1177.
4.4.16. 2-(Benzofuran-2-yl)phenol 7d33. Yield: 61%; colorless solid;
1H NMR (CDCl3, 300 MHz, 298 K):
d
ppm 3.89 (s, 3H), 4.18 (s,
mp 97 ꢀC. IR (cmꢁ1) 3451, 3352, 1590, 1446, 1212, 1017, 743. 1H NMR
2H), 6.93 (dd, 2H, J¼6.6 Hz, J¼1.8 Hz), 7.14 (dd, 2H, J¼7.5 Hz,
(CDCl3, 300 MHz, 298 K):
(s, 1H), 6.99–7.09 (m, 3H), 7.28 (m, 1H), 7.35 (m, 1H), 7.46 (m, 1H).
13C NMR (CDCl3, 75 MHz, 298 K):
ppm 103.5, 111.2, 116.2, 117.5,
d ppm 6.72–6.78 (m, 2H), 6.84 (s,1H), 6.91
J¼2.2 Hz), 7.44 (dd, 2H, J¼6.6 Hz, J¼1.8 Hz), 7.97 (dd, 2H,
J¼7.5 Hz, J¼2.2 Hz). 13C NMR (CDCl3, 75 MHz, 298 K):
d
ppm
d
44.5, 55.5, 113.9 (2), 120.8, 128.5, 130.8 (2), 131.2 (2), 131.7 (2),
134.0, 163.7, 195.5.
120.9, 121.1, 123.6, 124.6, 127.3, 128.6, 130.4, 153.5, 154.1, 154.4. MS
(APCIþ) m/z¼211 [MþH]þ.
4.4.9. 2-Phenyl-1-p-tolyl-ethanone 5c19i. Yield: 80%. IR (cmꢁ1
)
4.4.17. 2-(2,4-Dimethoxyphenyl)benzofuran 7e. Yield: 65%; color-
less solid; mp 49–52 ꢀC. IR (cmꢁ1) 2937, 2836, 1610, 1502,
1252, 1208, 1158, 1029, 796, 740. 1H NMR (CDCl3, 300 MHz,
1680, 1603, 1334, 1222, 1198, 1172, 814, 729. 1H NMR (CDCl3,
300 MHz, 298 K): 2.42 (s, 3H), 4.29 (s, 2H), 7.25–7.44 (m, 7H), 7.95
(d, 2H, J¼8.1 Hz). 13C NMR (CDCl3, 75 MHz, 298 K):
d
ppm 21.6, 45.3,
298 K): d ppm d 3.90 (s, 3H), 4.01 (s, 3H), 6.61–6.68 (m, 2H),
126.7, 128.6 (2), 128.7 (2), 129.2 (2), 129.4 (2), 134.0, 134.7, 143.9,
197.3.
7.22–7.32 (m, 3H), 7.54 (dt, 1H, J¼6.6 Hz, J¼1.1 Hz), 7.62 (m,
1H), 8.03 (d, 1H, J¼8.6 Hz). 13C NMR (CDCl3, 75 MHz, 298 K):
d
ppm 55.6 (2), 98.9, 104.4, 105.0, 110.7, 112.9, 120.8, 122.7,
4.4.10. 1-(4-Aminophenyl)-2-p-tolyl-ethanone 5d19i. Yield: 79%. IR
123.7, 128.1, 130.2, 152.6, 153.8, 157.9, 161.1. MS (APCIþ)
m/z¼255.0 (MþH)þ. Anal. Calcd for C16H14O3: C, 75.57; H, 5.55.
Found C, 75.39; H, 5.41.
(cmꢁ1) 3472, 3356, 1656, 1630, 1587, 1567, 1335, 1316, 1232, 1174,
814. 1H NMR (CDCl3, 300 MHz, 298 K):
d ppm 2.31 (s, 3H), 4.14 (m,
4H), 6.62 (d, 2H, J¼8.7 Hz), 7.11 (d, 2H, J¼7.8 Hz), 7.16 (d, 2H,
J¼7.8 Hz), 7.86 (d, 2H, J¼8.7 Hz). 13C NMR (CDCl3, 75 MHz, 298 K):
4.4.18. 2-(4-Methoxyphenyl)benzo[b]thiophene 7f30. Yield: 94%;
d
ppm 21.0, 44.6, 113.7 (2), 127.1, 129.1 (2), 129.2 (2), 131.1 (2), 132.3,
colorless solid; mp 199–201 ꢀC. IR (cmꢁ1) 2357, 1604, 1497, 1434,
136.1, 151.1, 196.0.
1244, 1077, 1030, 820, 746. 1H NMR (CDCl3, 300 MHz, 298 K):
d ppm
3.86 (s, 3H), 6.96 (d, 2H, J¼8.8 Hz), 7.28–7.37 (m, 2H), 7.43 (s, 1H),
4.4.11. 2-Phenyl-1-(3,4,5-trimethoxyphenyl)-ethanone 5e19i. Yield:
7.65 (d, 2H, J¼8.7 Hz), 7.74 (d, 1H, J¼7.2 Hz), 7.81 (d, 1H, J¼7.7 Hz).
68%. IR (cmꢁ1) 2940, 2360, 1676, 1582, 1504, 1453, 1411, 1331, 1152,
13C NMR (CDCl3, 75 MHz, 298 K):
d ppm 55.4, 114.3 (2), 118.2, 122.2,
1000, 697. 1H NMR (CDCl3, 300 MHz, 298 K):
d
ppm 3.85 (s, 6H),
3.87 (s, 3H), 4.22 (s, 2H), 7.23–7.33 (m, 7H). 13C NMR (CDCl3,
75 MHz, 298 K): ppm 45.6, 56.2 (2), 60.9, 106.3 (2), 126.9, 128.7
123.2, 123.9, 124.4, 127.0, 127.7 (2), 139.2, 140.9, 144.1, 159.8. MS
(APCI) m/z¼241 (MþH)þ.
d
(2), 129.2 (2), 131.7, 134.8, 141.6, 153.0 (2), 196.4.
4.4.19. 2-(Naphthalen-1-yl)benzo[b]thiophene 7g34. Yield: 94%;
beige solid; mp 106–108 ꢀC. IR (cmꢁ1) 3051, 1456, 1435, 1390, 1155,
4.4.12. 1-(4-Methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-ethanone
799, 772, 743, 725. 1H NMR (CDCl3, 300 MHz, 298 K):
d ppm 7.38–
5f19e. Yield: 55%. IR (cmꢁ1) 2935, 2834, 1675, 1596, 1509, 1122. 1H
7.48 (m, 2H), 7.49 (s, 1H), 7.53–7.58 (m, 3H), 7,69 (d, 1H, J¼7,0 Hz),
NMR (CDCl3, 300 MHz, 298 K):
d
ppm 3.81 (s, 3H), 3.83 (s, 6H), 3.86
7.87–7.96 (m, 4H), 8.32–8.35 (m, 1H). 13C NMR (CDCl3, 75 MHz,
(s, 3H), 4.15 (s, 2H), 6.46 (s, 2H), 6.93 (d, 2H, J¼8.9 Hz), 7.98 (d, 2H,
298 K): d ppm 122.2, 123.7, 124.2, 124.4, 124.6, 125.3, 125.9, 126.3,
J¼8.9 Hz). 13C NMR (CDCl3, 75 MHz, 298 K):
d
ppm 45.4, 55.4, 56.1
126.8, 128.5, 128.6, 129.0, 131.9, 132.5, 133.9, 140.3, 140.4, 142.3. MS
(2), 60.8, 106.4 (2), 113.8 (2), 129.6, 130.5 (2), 130.9, 136.8, 153.3 (2),
163.6, 196.1.
(APCI) m/z¼261 (MþH)þ.
4.4.20. 2-(Benzo[b]thiophen-2-yl)phenol 7h. Yield: 88%; colorless
4.4.13. 2-(4-Methoxyphenyl)benzofuran 7a32. Yield: 79%; colorless
solid; mp 91–94 ꢀC. IR (cmꢁ1) 3511, 3054, 1481, 1449, 1432, 1333,
solid; mp 148–150 ꢀC. IR (cmꢁ1) 2960, 2837, 1606, 1502, 1451, 1241,
1290, 1173, 747. 1H NMR (CDCl3, 300 MHz, 298 K):
d ppm 5.63 (s,
1022, 835, 818, 700. 1H NMR (CDCl3, 300 MHz, 298 K):
d
ppm 3.87
1H), 6.99–7.05 (m, 2H), 7.27–7.43 (m, 3H), 7.40 (dd, 1H, J¼7.6 Hz,
(s, 3H), 6.89 (d, 1H, J¼0.9 Hz), 6.99 (d, 2H, J¼9.0 Hz), 7.19–7,29 (m,
J¼1.6 Hz), 7.56 (s, 1H), 7.81–7.89 (m, 2H). 13C NMR (CDCl3, 75 MHz,
2H), 7.50–7.58 (m, 2H), 7.81 (d, 2H, J¼9.0 Hz). 13C NMR (CDCl3,
298 K):
d ppm 116.5, 121.0, 121.2, 122.3, 123.0, 123.8, 124.7, 124.8,
75 MHz, 298 K):
d
ppm 55.3, 99.7,111.0, 114.2 (2),120.5, 122.8, 123.3,
130.0, 130.4, 139.4, 140.0, 140.4, 152.9. MS (APCIþ) m/z¼227.0
(MþH)þ. Anal. Calcd for C14H10OS: C, 74.31; H, 4.45. Found C, 74.01;
H, 4.22.
123.7, 126.4 (2), 129.5, 154.7, 156.0, 159.9. MS (APCI) m/z¼225
(MþH)þ.
4.4.14. 2-(2-Methoxyphenyl)benzofuran 7b32. Yield: 83%; colorless
4.4.21. 3-(2-Methoxyphenyl)-1H-isochromen-1-one 7i23. Yield:95%;
solid; mp 78–80 ꢀC. IR (cmꢁ1) 2939, 1492, 1446, 1282, 1247,
white solid; mp 122–124 ꢀC. IR (cmꢁ1) 1724, 1625, 1493, 1225, 1021,
1015, 742. 1H NMR (CDCl3, 300 MHz, 298 K):
d
ppm 3.89 (s,
754.1H NMR (CDCl3, 300 MHz, 298 K):
d ppm 3.96 (s, 3H), 7.00 (d,1H,
3H), 6.90 (d, 1H, J¼8.3 Hz), 6.98 (td, 1H, J¼7.6 Hz, J¼1.0 Hz),
7.09–7.26 (m, 4H), 7.40–7.43 (m, 1H), 7.48–7.51 (m, 1H), 7.98
(dd, 1H, J¼7.8 Hz, J¼1.7 Hz). 13C NMR (CDCl3, 75 MHz, 298 K):
J¼8.3 Hz), 7.07 (t,1H, J¼8.0 Hz), 7.36–7.40 (m, 2H), 7.45–7.51 (m, 2H),
7.70 (t, 1H, J¼8.3 Hz), 7.97 (dd, 1H, J¼7.9, J¼1.7 Hz), 8.30 (d, 1H,
J¼7.9 Hz). 13C NMR (CDCl3, 75 MHz, 298 K):
d ppm 55.8, 107.1, 111.5,
120.8, 120.9, 121.0, 126.4, 128.1, 129.0, 129.5, 130.9, 134.8, 138.2, 150.6,
d
ppm 55.6, 106.5, 111.0, 111.2, 119.5, 120.9, 121.2, 122.8, 124.2,
127.2, 129.4, 129.9, 152.3, 154.0, 166.7. MS (APCI) m/z¼225
157.4, 162.8. MS (APCI) m/z¼253 (MþH)þ.
(MþH)þ.
4.4.22. 2-(2-Methylprop-1-enyl)benzofuran
colorless solid; mp 44–48 ꢀC. IR (cmꢁ1) 2929, 1453, 1196, 1055, 847,
790, 748. 1H NMR (CDCl3, 300 MHz, 298 K):
ppm 1.98 (s, 3H), 2.13
10a35. Yield:
72%;
4.4.15. 2-(Naphthalen-1-yl)benzofuran 7c32. Yield: 93%; yellow
solid; mp 161–162 ꢀC. IR (cmꢁ1) 3055, 1452, 1257, 979, 793, 771,
d
737. 1H NMR (CDCl3, 300 MHz, 298 K):
d
ppm 7.11 (s, 1H), 7.29–
(s, 3H), 6.20 (s, 1H), 6.51 (s, 1H), 7.17–7.25 (m, 2H), 7.43 (d, 1H,
7.40 (m, 2H), 7.55–7.64 (m, 4H), 7.69 (d, 1H, J¼7.8 Hz), 7.91–7.95
J¼7.5 Hz), 7.43 (d, 1H, J¼7.5 Hz). 13C NMR (CDCl3, 75 MHz, 298 K):

3786
M. Jacubert et al. / Tetrahedron 66 (2010) 3775–3787
d
ppm 20.7, 27.5, 103.8, 110.9, 114.7, 120.5, 122.7, 123.7, 129.2, 139.7,
906, 819, 739. 1H NMR (CDCl3, 300 MHz, 298 K):
d ppm 7.07 (d, 1H,
154.2, 155.8. MS (APCIþ) m/z¼173.0 (MþH)þ.
J¼0.7 Hz), 7.27–7.32 (m, 1H), 7.38 (m, 1H), 7.51–7.57 (m, 3H), 7.60–
7.66 (m, 2H), 7.85–7.88 (m, 3H), 8.15 (s, 1H). 13C NMR (CDCl3,
4.4.23. (E)-2-(Hex-1-enyl)benzofuran 10b. Yield: 47%. 1H NMR
75 MHz, 298 K): d ppm 80.2, 95.7, 111.4, 111.8, 119.3, 121.4, 123.5,
(CDCl3, 300 MHz, 298 K):
d
ppm 0.93–0.98 (m, 3H), 1.37–1.53 (m,
125.8, 126.9, 127.3, 128.0, 128.1, 128.4, 132.1, 133.1, 133.3, 139.0,
150.5, 155.1. MS (APCIþ) m/z¼269.0 (MþH)þ. Anal. Calcd for
C20H12O: C, 89.53; H, 4.51. Found C, 89.11; H, 4.32.
4H), 2.27 (q, 2H, J¼6.8 Hz), 6.33 (d, 1H, J¼16.0 Hz), 6.47–6.60 (m,
2H), 7.15–7.26 (m, 2H), 7.41–7.50 (m, 2H). 13C NMR (CDCl3, 75 MHz,
298 K):
d ppm 14.1, 22.4, 31.3, 32.8, 102.7, 110.9, 118.7, 120.7, 122.8,
124.1, 129.3, 134.1, 154.7, 155.4. Anal. Calcd for C14H16O: C, 83.96; H,
8.05. Found C, 83.66; H, 7.82.
References and notes
1. For an excellent review, see: Hintermann, L.; Labonne, A. Synthesis 2007, 1121.
2. Kucherov, M. Chem. Ber. 1881, 14, 1540.
3. (a) Marion, N.; Ramo´ n, R. S.; Nolan, S. P. J. Am. Chem. Soc. 2009, 131, 448; (b)
Mizushima, E.; Sato, K.; Hayashi, T.; Takana, M. Angew. Chem., Int. Ed. 2002, 41,
4563; (c) Casado, R.; Contel, M.; Laguna, M.; Romero, P.; Sanz, S. J. Am. Chem.
Soc. 2003, 125, 11925.
4.4.24. (E)-2-Styrylbenzofuran 10c30. Yield: 73%; colorless solid;
124–126mp ꢀC. IR (cmꢁ1) 3057, 1450, 1256, 958, 907, 804, 738, 691.
1H NMR (CDCl3, 300 MHz, 298 K):
d ppm 6.70 (s, 1H), 7.03 (d, 1H,
J¼16.2 Hz), 7.20–7.42 (m, 6H), 7.50 (d, 1H, J¼8.0 Hz), 7.55 (d, 3H,
J¼7.4 Hz). 13C NMR (CDCl3, 75 MHz, 298 K):
d ppm 105.3, 111.0,
116.6, 121.0, 123.0, 124.8, 126.8 (2), 128.3, 128.9, 129.3, 130.4, 136.7,
4. (a) Tokunaga, M.; Wakatsuki, Y. Angew. Chem., Int. Ed. 1998, 37, 2867; (b) Chen,
Y.; Valentini, M.; Pregosin, P. S.; Albinati, A. Inorg. Chim. Acta 2002, 327, 4; (c)
´
Alvarez, P.; Gimeno, J.; Lastra, E.; Garcıa-Granda, S.; Van der Maelen, J. F.;
155.0, 155.2. MS (APCIþ) m/z¼221.0 (MþH)þ.
Bassetti, M. Organometallics 2001, 20, 3762.
5. (a) Hirabayashi, T.; Okimoto, Y.; Saito, A.; Morita, M.; Sakaguchi, S.; Ishii, Y.
Tetrahedron Lett. 2006, 62, 2231; (b) Chin, C. S.; Chang, W.-T.; Yang, S.; Joo, K.-S.
Bull. Korean Chem. Soc. 1997, 18, 324; (c) Kanemitsu, H.; Uehara, K.; Fukuzumi,
S.; Ogo, S. J. Am. Chem. Soc. 2008, 130, 17141.
6. (a) James, B. R.; Rempel, G. L. J. Am. Chem. Soc. 1969, 91, 863; (b) Blum, J.;
Huminer, H.; Alper, H. J. Mol. Catal. 1992, 75, 153.
7. (a) Baidossi, W.; Lahav, M.; Blum, J. J. Org. Chem. 1997, 62, 669; (b) Israelsohn, O.;
Vollhardt, K. P. C.; Blum, J. J. Mol. Catal. 2002, 184, 1; (c) Hartman, J. W.; Sperry, L.
Tetrahedron Lett. 2004, 45, 3787.
4.4.25. (E)-2-(4-Methoxystyryl)benzofuran 10d. Yield: 75%; color-
less solid; mp 143 ꢀC. IR (cmꢁ1) 2996, 1600, 1506, 1450, 1238, 1176,
1025, 965, 944, 826, 816, 743. 1H NMR (CDCl3, 300 MHz, 298 K):
d
ppm 3.85 (s, 3H), 6.63 (s, 1H), 6.86–6.94 (m, 3H), 7.18–7.32 (m,
3H), 7.47–7.54 (m, 4H). 13C NMR (CDCl3, 75 MHz, 298 K):
d
ppm
55.5,104.4,110.9,114.4 (2),114.5,120.8,122.9,124.4,128.2 (2),129.4,
129.5, 130.1, 154.9, 155.6, 159.9. MS (APCIþ) m/z¼251.0 (MþH)þ.
Anal. Calcd for C17H14O2: C, 81.58; H, 5.64. Found C, 81.44; H, 5.52.
8. Liu, B.; De Brabander, J. K. Org. Lett. 2006, 8, 4907.
9. (a) Boll, M.; Schink, B.; Messerschmidt, A.; Kroneck, P. M. H. Biol. Chem. 2005,
386, 999; (b) Alipui, O. D.; Zhang, D.; Schulz, H. Biochem. Biophys. Res. Commun.
2002, 292, 1171; (c) Wang, S. C.; Person, M. D.; Johnson, W. H.; Whitman, C. P.
Biochemistry 2003, 42, 8762.
10. Tsuchimoto, T.; Joya, T.; Shirakawa, E.; Kawakami, Y. Synlett 2000, 1777.
11. Allen, A. D.; Chiang, Y.; Kresge, A. J.; Tidwell, T. T. J. Org. Chem. 1982, 47, 775 and
references cited therein.
4.4.26. (E)-2-Styrylbenzo[b]thiophene 10e36. Yield: 78%; beige
solid; mp 198 ꢀC. IR (cmꢁ1) 2926,1447,1432, 947, 818, 739, 725, 690.
1H NMR (CDCl3, 300 MHz, 298 K):
d
ppm 7.01 (d, 1H, J¼16.0 Hz),
7.26–7.40 (m, 7H), 7.52 (d, 2H, J¼7.4 Hz), 7.70 (m, 1H), 7.78 (m, 1H).
13C NMR (CDCl3, 75 MHz, 298 K):
ppm 122.4, 122.5, 123.4, 123.6,
12. Menash, N.; Shvo, Y. J. Org. Chem. 1993, 58, 7434.
13. (a) Alami, M.; Ferri, F. Synlett 1996, 755; (b) Liron, F.; Le Garrec, P.; Alami, M.
Synlett 1999, 246; (c) Alami, M.; Liron, F.; Gervais, M.; Peyrat, J.-F.; Brion, J.-D.
Angew. Chem., Int. Ed. 2002, 41, 1578; (d) Hamze, A.; Provot, O.; Alami, M.; Brion,
J.-D. Org. Lett. 2005, 7, 5625; (e) Hamze, A.; Provot, O.; Brion, J.-D.; Alami, M.
Synthesis 2007, 2025; (f) Hamze, A.; Provot, O.; Brion, J.-D.; Alami, M. J. Org.
Chem. 2007, 72, 3868; (g) Giraud, A.; Provot, O.; Hamze, A.; Brion, J.-D.; Alami,
M. Tetrahedron Lett. 2008, 49, 1107.
14. Kwatra, M. M.; Simon, D. Z.; Salvador, R. L.; Cooper, P. D. J. Med. Chem.1978, 21, 253.
15. Olivi, N.; Thomas, E.; Peyrat, J.-F.; Alami, M.; Brion, J.-D. Synlett 2004, 2175.
16. (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 4467; (b)
Alami, M.; Ferri, F.; Linstrumelle, G. Tetrahedron Lett. 1993, 34, 6403.
17. For a review see: Swaminathan, S.; Narayanan, K. V. Chem. Rev. 1971, 71, 429.
18. (a) Tzalis, D.; Koradin, C.; Knochel, P. Tetrahedron Lett. 1999, 40, 6193; (b) For
a review, see: Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. Rev. 2004, 104, 3079.
d
124.7, 124.9, 126.7 (2), 128.2, 128.9 (2), 131.0, 136.8, 139.1, 140.4,
143.1. MS (APCIþ) m/z¼237.0 (MþH)þ.
4.4.27. 2,20-Bibenzofuran 11a. Yield: 58%; colorless solid; mp 177–
178 ꢀC. IR (cmꢁ1) 1439, 1255, 1172, 1048, 875, 814, 748, 611. 1H NMR
(CDCl3, 300 MHz, 298 K):
d ppm 6.92–6.96 (m, 2H), 7.03 (m, 1H),
7.07 (m, 1H), 7.18–7.27 (m, 3H), 7.46 (m, 1H), 7.54 (m, 1H), 7.65 (m,
1H). 13C NMR (CDCl3, 75 MHz, 298 K):
d ppm 103.8, 111.4, 121.5,
123.5, 125.2, 128.7, 147.8, 155.2. MS (APCIþ) m/z¼235.0 (MþH)þ.
Anal. Calcd for C16H10O2: C, 82.04; H, 4.30. Found C, 81.77; H, 4.12.
19. (a) Thierney, J. P.; Lidstrom, P. Microwave Assisted Organic Synthesis; Blackwell
Publishing Ldt: Oxford, 2005; (b) Caddick, S. Tetrahedron 1995, 51, 10403; (c)
Perreux, L.; Loupy, A. Tetrahedron 2001, 57, 9199; (d) Lisstro¨m, P.; Thierney, J.;
Wathey, B.; Westman, J. Tetrahedron 2001, 57, 9225; (e) Bekaert, A.; Provot, O.;
Rasolojaona, O.; Peyrat, J.-F.; Alami, M.; Brion, J.-D. Tetrahedron Lett. 2005, 46,
4187; (f) Le Bras, G.; Provot, O.; Bekaert, A.; Peyrat, J.-F.; Alami, M.; Brion, J.-D.
Synthesis 2006, 1537; (g) L’Hermite, N.; Giraud, A.; Provot, O.; Peyrat, J.-F.;
Alami, M.; Brion, J.-D. Tetrahedron 2006, 62, 11994; (h) Giraud, A.; Provot, O.;
Peyrat, J.-F.; Alami, M.; Brion, J.-D. Tetrahedron 2006, 62, 7667; (i) Le Bras, G.;
Provot, O.; Peyrat, J.-F.; Alami, M.; Brion, J.-D. Tetrahedron Lett. 2006, 47, 5497;
(j) Le Bras, G.; Radanyi, C.; Peyrat, J.-F.; Brion, J.-D.; Alami, M.; Marsaud, V.;
Stella, B.; Renoir, J.-M. J. Med. Chem. 2007, 50, 6189.
¨
4.4.28. 2-(Benzo[b]thiophen-2-yl)benzofuran
11b. Yield:
76%;
colorless solid; mp 207–209 ꢀC. IR (cmꢁ1) 3055, 1426, 1202, 988,
932, 878, 827, 799, 737, 625. 1H NMR (CDCl3, 300 MHz, 298 K):
d
ppm 7.03 (s, 1H), 7.29–7.44 (m, 4H), 7.57 (d, 1H, J¼8.0 Hz), 7.62 (d,
1H, J¼7.4 Hz), 7.76 (s, 1H), 7.85 (m, 2H). 13C NMR (CDCl3, 75 MHz,
298 K):
d ppm 103.4, 111.3, 121.1, 121.2, 122.4, 123.4, 124.1, 124.9,
125.0, 125.1, 129.0, 133.0, 139.7, 140.2, 151.1, 155.5. MS (APCIþ)
m/z¼251.0 (MþH)þ. Anal. Calcd for C16H10OS: C, 76.77; H, 4.03.
Found C, 76.44; H, 3.80.
20. (a) Pettit, G. R.; Singh, S. B.; Niven, M. L.; Hamel, E.; Schmidt, J. M. J. Nat. Prod.
1987, 50, 119; (b) Provot, O.; Giraud, A.; Peyrat, J.-F.; Alami, M.; Brion, J.-D.
Tetrahedron Lett. 2005, 46, 8547; (c) Mousset, C.; Giraud, A.; Provot, O.; Hamze,
A.; Bignon, J.; Liu, J.-M.; Thoret, S.; Dubois, J.; Brion, J.-D.; Alami, M. Bioorg. Med.
Chem. Lett. 2008, 18, 3266; (d) Hamze, A.; Giraud, A.; Messaoudi, M.; Provot, O.;
Peyrat, J.-F.; Bignon, J.; Liu, J.-M.; Wdzieczak-Bakala, J.; Thoret, S.; Dubois, J.;
Brion, J.-D.; Alami, M. ChemMedChem 2009, 4, 1912; (e) Messaoudi, S.; Tre´guier,
B.; Hamze, A.; Provot, O.; Peyrat, J.-F.; Rodrigo De Losada, J.; Liu, J.-M.; Bignon,
J.; Wdzieczak-Bakala, J.; Thoret, S.; Dubois, J.; Brion, J.-D.; Alami, M. J. Med.
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4.4.29. 2-(Benzofuran-2-yl)-1-(4-methoxyphenyl)ethanone
11c. Yield: 94%; colorless solid; mp 104–106 ꢀC. IR (cmꢁ1) 2936,
1678, 1454, 1251, 1219, 1170, 751. 1H NMR (CDCl3, 300 MHz, 298 K):
d
ppm 3.87 (s, 3H), 4.40 (s, 2H), 6.62 (s, 1H), 6.95 (d, 2H, J¼8.7 Hz),
7.16–7.26 (m, 2H), 7.43 (d, 1H), 7.50 (d, 1H), 8.04 (d, 2H, J¼8.7 Hz).
13C NMR (CDCl3, 75 MHz, 298 K):
ppm 38.8, 55.7,105.3,111.2,114.1
21. Jacubert, M.; Hamze, A.; Provot, O.; Peyrat, J.-F.; Brion, J.-D.; Alami, M. Tetra-
hedron Lett. 2009, 50, 3588.
d
(2), 120.8, 122.8, 123.9, 128.8, 129.3, 131.2 (2), 152.0, 155.1, 164.0,
193.1. MS (APCIþ) m/z¼289.0 (MþNa)þ. Anal. Calcd for C17H14O3: C,
76.68; H, 5.30. Found C, 76.39; H, 4.99.
22. For benzofuran derivatives, see for example: (a) Donnelly, D. M. X.; Meegan, M.
J. In Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Ed.; Pergamon: New
York, NY, 1984; Vol. 4; (b) Bakunov, S.; Bakunova, S.; Wenzler, T.; Barszcz, T.;
Werbovetz, K.; Brun, R.; Tidwell, R. J. Med. Chem. 2008, 51, 6927; (c) McCallion,
G. D. Curr. Org. Chem. 1999, 3, 67 For benzothiphene derivatives see for example:
(d) Palkowitz, A. D.; Glasebrook, A. L.; Thrascher, K. J.; Hauser, K. L.; Short, L. L.;
Phillips, D. L.;Muehl, B. S.;Sato,M.; Shetler, P. K.; Cullinan,G. J.; Pell, T. R.;Bryant, H. U.
4.4.30. 2-(Naphthalen-2-ylethynyl)benzofuran 11d. Yield: 28%;
beige solid; mp 136–137 ꢀC. IR (cmꢁ1) 3058, 2934, 1448, 1258, 1165,

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