MPHT-Promoted bromocyclization of of ortho-substituted arylalkynes: Application to the synthesis of 2-substituted 3-bromobenzofurans and -benzo[b]thiophenes

Article abstract of DOI:10.1002/ejoc.201000529

A convenient: and general approach to the synthesis of 2substituted 3-bromobenzofurans and -benzothiophenes was developed. The procedure is based, on the cyclization of orfho-substituted arylalkynes in the presence of N-methylpyrrolidin-2-one hydrotribromide (MPHT) as a soft and easy-tohandle electrophilic brominating reagent. Under mild reaction conditions, MPHT promoted the bromocyclization of various enynes and diynes as well as arylalkynes to give 2substituted 3-bromobenzofurans and -benzothiophenes in. high to excellent: yields. Subsequent: functionalization by palladium-catalyzed coupling reactions at the C-Br bond afforded general access to 2,3-disubstituted benzofurans and benzothiophenes of biological interest.

Full text of DOI:10.1002/ejoc.201000529

FULL PAPER
DOI: 10.1002/ejoc.201000529
MPHT-Promoted Bromocyclization of ortho-Substituted Arylalkynes:
Application to the Synthesis of 2-Substituted 3-Bromobenzofurans and
-Benzo[b]thiophenes
Maud Jacubert,[a] Abdellatif Tikad,[a] Olivier Provot,[a] Abdallah Hamze,[a]
Jean-Daniel Brion,[a] and Mouâd Alami*[a]
Keywords: Enynes / Alkynes / Oxygen heterocycles / Sulfur heterocycles / Cyclization
A convenient and general approach to the synthesis of 2-
substituted 3-bromobenzofurans and -benzothiophenes was
developed. The procedure is based on the cyclization of or-
various enynes and diynes as well as arylalkynes to give 2-
substituted 3-bromobenzofurans and -benzothiophenes in
high to excellent yields. Subsequent functionalization by pal-
tho-substituted arylalkynes in the presence of N-methylpyr- ladium-catalyzed coupling reactions at the C–Br bond af-
rolidin-2-one hydrotribromide (MPHT) as a soft and easy-to-
handle electrophilic brominating reagent. Under mild reac-
tion conditions, MPHT promoted the bromocyclization of
forded general access to 2,3-disubstituted benzofurans and
benzothiophenes of biological interest.
Introduction
As part of a program focusing on the functionalization
of arylalkynes,[1] we have recently reported their reactivity
with p-toluenesulfonic acid (PTSA) in EtOH.[2] There are
two main strands to this work, which consist of triple-bond
hydration[3] or cyclization reactions,[4] depending on the al-
kyne substrates. In the hydration process promoted by
PTSA, the reaction takes place rapidly in EtOH or water
and regioselectively affords in good yields a large variety of
ketones according to Markovnikov’s rules (Scheme 1,
Path A).
The second string of this program involves an intra-
molecular cyclization reaction, promoted by PTSA, of
ortho-substituted diarylalkynes. With substrates bearing an
ethoxycarbonyl or a carboxylic acid function (CO2Et,
COOH) at the ortho position, 3-substituted isocoumarins
were obtained in good to excellent yields (Scheme 1,
Path B).[4a] When applying this environmentally friendly,
metal-free procedure to ortho-(1-alkynyl)-anisole or -thio-
anisole derivatives, a series of 2-substituted benzofurans
and benzothiophenes was prepared in good to excellent
yields, respectively (Scheme 1, Path C).[4b] In these cycliza-
tion reactions,[5] PTSA activated the triple bond, and subse-
quent regioselective 5- or 6-endo-dig cyclization with the or-
tho substituent afforded the required 2-substituted hetero-
cycle. It should be noted that 2-substituted as well as 2,3-
disubstituted benzofurans and benzothiophenes are attract-
Scheme 1. Reaction of substituted arylalkynes with PTSA.
ive synthetic target molecules due to the wide spectrum of
their biological activities,[6] including antimitotic proper-
ties.[7]
In continuation of our studies concerning the design and
the preparation of anticancer agents,[1i,8] we were interested
in developing a novel access to this class of 2,3-disubsti-
tuted heterocycles. Generally, 2-substituted 3-halobenzofur-
ans and -benzo[b]thiophenes are prepared by electrophilic
cyclization of 2-alkynylphenol,[9] ether,[6e,6f,10] and sulfide
derivatives[10a,11] with a range of electrophiles (I2, ICl, etc.).
Alternative methods are based on treatment of 2-substi-
tuted benzothiophene derivatives with molecular Br2.[7c]
Our continuing interest in the electrophilic cyclization of
ortho-substituted arylalkynes encouraged us to further ex-
[a] Univ Paris-Sud, CNRS, BioCIS UMR 8076, Laboratoire de
Chimie Thérapeutique, Faculté de Pharmacie,
5 rue J.-B. Clément, Châtenay-Malabry, 92296, France
Fax: +33-1-46835828
E-mail: mouad.alami@u-psud.fr
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MPHT-Promoted Bromocyclization of ortho-Substituted Arylalkynes
amine the use of N-methylpyrrolidin-2-one hydrotribromide Table 1. MPHT-promoted bromocyclization of ortho-substituted
(MPHT), developed in our lab[12] as a mild electrophile, in
conjugated enynes 1.
the preparation of 2-substituted 3-bromobenzofurans and
-benzothiophenes. MPHT complex is a stable solid that
smoothly liberates bromine in organic solvents. It presents
several advantages over molecular bromine: (i) MPHT can
be stored for several months at room temperature with no
decrease in the free bromine titer. (ii) It is not corrosive or
necrosive, and therefore, it is easy to weigh and handle. Be-
cause MPHT is a mild reagent, we envisioned to use it in
the bromocyclization of highly unsaturated alkynes, includ-
ing 1,3-enynes and 1,3-diynes to provide 3-bromobenzo-
furans and -benzo[b]thiophenes having an alkenyl or an alk-
ynyl chain at the C-2 position, respectively. To the best of
our knowledge, only one example of the bromocyclization
of an enyne substrate is described in the literature. Larock
reported that 2-thiomethylarylenyne underwent bromocy-
clization in the presence of NBS over 2 d, whereas the bro-
mocyclization was unsuccessful with Br2 probably “because
Br2 addition to the carbon–carbon double bond is occurring
faster than cyclization”.[11b,11c] We report herein an easy and
versatile process for the synthesis of 2-substituted 3-bromo-
benzofurans and -benzothiophenes from the electrophilic
MPHT-promoted cyclization of 1,3-enynes and 1,3-diynes
as well as diarylalkynes. This method furnished heterocycles
bearing various substituents at the C-2 position and a bro-
mine atom at the C-3 position useful for further palladium-
catalyzed coupling reactions.
Results and Discussion
Required 1,3-enynes 1[13] and 1,3-diynes 3[14] were pre-
pared by Pd-catalyzed coupling reactions, according to lit-
erature procedures. Initially, 1,3-enyne substrates were
evaluated in the MPHT bromocyclization process, and the
results of this study are reported in Table 1. From these
results, we can see that all reactions work well in CH2Cl2 at
room temperature for 1 h. Enyne 1a bearing no substituent
on the styryl moiety reacted cleanly and rapidly with
MPHT (1.2 equiv.) to give expected (E)-2-styryl-3-bromo-
benzofuran (2a) in a good 81% yield (Table 1, Entry 1). It
is noteworthy that no product resulting from the bromina-
tion of the carbon–carbon double or triple bond of 1a was
1
[a] Isolated yield. [b] A complex mixture was obtained with Br2
detected in the crude mixture, as judged by H NMR spec-
(1.2 equiv.), and 35% of 2b was obtained by using NBS (1.2 equiv.)
instead of MPHT, but after 36 h at room temperature.
troscopy. When (E)- or (Z)-enynes 1b were employed as
substrates for the bromocyclization, a single (E)-styryl-
benzofuran 2b was obtained probably for thermodynamic
considerations (Table 1, Entries 2 and 3). Enynes 1 having
Next, 1,3-diynes 3a and 3b were evaluated in the presence
either electron-donating (Table 1, Entries 2–4 and 7) or elec- of 4.2 equiv. of MPHT (Table 2, Entries 1 and 2). We were
tron-withdrawing substituents (Table 1, Entries 5 and 6) on pleased to observe the quantitative formation of bis(3-bro-
the styryl moiety were evaluated and gave satisfactory yields mobenzofuran) 4a and bis(3-bromobenzothiophene) 4b,
in the corresponding (E)-2-substituted 3-bromobenzofurans which were used as starting materials for the synthesis of
2b–f. A thiophene nucleus was also tolerated on enyne 1g benzannulated phospholes,[15] dibenzothienopyrroles,[16] di-
and expected benzofuran 2g was obtained in a satisfactory thienosiloles,[17] and functionalized phenanthrenes[18] of
56% yield (Table 1, Entry 8). Finally, the reaction was suc- physical interest. Unsymmetrical diyne 3c reacted cleanly
cessfully achieved with enyne 1h bearing two methyl substit- with MPHT to afford expected heterocycle 4c, again with
uents on the double bond, thus demonstrating the general excellent yield (Table 2, Entry 3). Finally, the selectivity ob-
character of the method (Table 1, Entry 9).
served in the presence of conjugated diyne 3d must be espe-
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M. Jacubert, A. Tikad, O. Provot, A. Hamze, J.-D. Brion, M. Alami
FULL PAPER
cially underlined, as the bromocyclization reaction ef- The results of this study are summarized in Table 3. Under
ficiently occurred to provide 4d, with no addition of bro- the above reaction conditions, MPHT-promoted annu-
mine to the second carbon–carbon triple bond (Table 2, En- lations of 2-methoxydiarylalkynes 7a–f provided good
try 4).
Table 3. MPHT-promoted bromocyclization of ortho-substituted
diarylalkynes 7.
Table 2. MPHT-promoted bromocyclization of ortho-substituted
conjugated diynes 3.
[a] Isolated yield. [b] 1.5 equiv. of MPHT were used for 5 h.
Having demonstrated the efficiency of MPHT to pro-
mote the bromocyclization of conjugated enynes 1 and di-
ynes 3, we sought to extend the cyclization reaction with
highly conjugated (E)-enediyne 5.[19] Thus, after stirring
with MPHT (2.4 equiv.) at room temperature for 3 h, we
were pleased to observe the formation of 1,2-ethenyl
bis(benzofuran) 6, which was isolated in a moderate 21%
yield, despite the fact that the reaction conditions were un-
optimized (Scheme 2). Further cyclization of 6 (or its
benzothiophene analog) would provide a set of fused thi-
epins,[20] as well as 1-sila-, 1-germa-, 1-selenacyclohepta-
2,4,6-trienes[21] of biological interest.
Scheme 2. Bromocyclization of (E)-enediyne 5 with MPHT.
Having succeeded in developing an efficient bromocycli-
zation of conjugated enyne, diyne, and enediyne substrates,
we next examined the reaction with a range of ortho-substi-
tuted diarylalkynes 7, which were prepared by Pd-catalyzed
coupling reactions according to literature procedures.[22] [a] Isolated yield. [b] 3 h were required.
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MPHT-Promoted Bromocyclization of ortho-Substituted Arylalkynes
yields of the corresponding 2-aryl-3-bromobenzofurans 8a– tion of ortho-substituted alkynes at room temperature. Un-
f (Table 3, Entries 1–6). Similarly, 2-thioanisole derivative der these mild conditions, it was demonstrated that various
7g underwent rapid cyclization to give 2-aryl-3-bromo- conjugated enyne, diyne, enediyne, and arylalkyne sub-
benzothiophene 8g in nearly quantitative yield (97%; strates were successfully cyclized in good to excellent yields
Table 3, Entry 7). To determine the relative reactivity of to provide structurally interesting 2-substituted 3-bromo-
various substituents toward the bromocyclization, the benzofuran and -benzothiophene derivatives. By further
MPHT protocol was applied to unsymmetrically 2,2Ј-di- chemical manipulations, our synthetic approach should al-
substituted diarylalkynes 7h–k. Alkyne 7h with ortho-meth- low rapid access to a wide range of 2,3-disubstituted benzo-
oxy and orthoЈ-thiomethyl substituents underwent bromo- furans and benzothiophenes amenable for biological evalu-
cyclization at the sulfur atom to give selectively benzothio- ations.
phene 8h in good yield (Table 3, Entry 8). A similar selectiv-
ity was observed with diarylalkyne 7i having an ortho ester
function (Table 3, Entry 9). In this case, the 6-endo-dig cy-
clization proceeded selectively to provide exclusively isocou-
Experimental Section
marin 8i in an excellent 98% yield. We observed total hier-
archy of a OMe substituent versus a OTBDMS group
towards the bromocyclization, and the reaction gave 3-bro-
mobenzofuran 8j having a OTBDMS substituent at C-2Ј
(Table 3, Entry 10). Surprisingly, starting from o,oЈ,p-tri-
methoxyalkyne 7k, single cyclization product 8k was
formed, showing a significant difference in reactivity
between the two ortho-methoxy substituents of 7k (94%;
Table 3, Entry 11).
To increase the synthetic utility of these 2-substituted 3-
bromobenzofurans, the cyclization product (E)-2-(4-meth-
oxystyryl)-3-bromobenzofuran (2b) was converted into 2-
alkenyl-3-alkynylbenzofuran 9 and 2-alkenyl-3-arylbenzo-
furan 10 by Sonogashira and Suzuki cross-coupling reac-
tions with but-1-yn-4-ol and 3,4,5-trimethoxyphenylboronic
acid, respectively, in good yields (Scheme 3). One can note
that compound 10 may be regarded as a conformationally
restricted analog of vinylogous combretastatin A-4 of bio-
logical interest.[23]
General Comments: All glassware was oven-dried at 140 °C, and all
reactions were conducted under a nitrogen atmosphere. Solvents
were dried by standard methods and distilled before use. Piperidine
was dried and distilled from potassium hydroxide prior to use.
Pd(PPh3)4 was prepared following a literature procedure.[24] The
compounds were all identified by usual physical methods, that is,
1H NMR, 13C NMR, and IR spectroscopy, MS, and elemental
1
analysis. H and 13C NMR spectra were measured in CDCl3 with
1
a Bruker Avance 300 or Bruker ARX 400. H chemical shifts are
reported in ppm from the peak of residual chloroform (δ
=7.27 ppm) and coupling constants J were measured in Hz. The
following abbreviations are used: m (multiplet), s (singlet), d (doub-
let), t (triplet) dd (doublet of doublet), br. s (broad singlet). 13C
chemical shifts are reported in ppm from the central peak of de-
uteriochloroform (δ =77.14 ppm). IR spectra were measured with
a Bruker Vector 22 spectrophotometer as neat samples. Elemental
analyses (for all new cyclized products) were performed with a Per-
kin–Elmer 240 analyzer. Mass spectra were obtained by using a
Bruker Esquire electrospray ionization apparatus. Analytical TLC
was performed on Merck precoated silica gel 60F plates. Merck
silica gel 60 (230–400 mesh) was used for column chromatography.
Enynes 1a–c and 1e–g, enediynes 3a and 3b, and diarylalkynes 5a–
k were prepared according to literature procedures.
Experimental Procedures
(E)-1-Fluoro-4-[4-(2-methoxyphenyl)but-1-en-3-ynyl]benzene (1d):
To a mixture of (E)-1-(4-chlorobut-3-en-1-ynyl)-2-methoxyben-
zenechloroenyne (192 mg, 1 mmol) in toluene (4 mL) and EtOH
(2 mL) was successively added 4-fluorophenylboronic acid (168 mg,
1.2 mmol), K2CO3 (276 mg, 2 mmol), and Pd(PPh3)4 (58 mg,
0.05 mmol). The reaction mixture was heated at 100 °C under vig-
orous stirring and monitored by TLC until complete disappearance
of the starting material. The solvent was evaporated in vacuo and
water (10 mL) was added. After extraction with CH2Cl2
(3ϫ10 mL), the combined organic layer was dried with MgSO4,
and the solvent was removed under reduced pressure. The crude
material was purified by column chromatography to afford ex-
pected enyne 1d. Yield: 214 mg, 85%. 1H NMR (300 MHz,
CDCl3): δ = 3.91 (s, 3 H, OCH3), 6.37 (d, J = 16.2 Hz, 1 H, Hvinyl),
Scheme 3. Cross-coupling reactions of 2b under palladium cataly-
sis. Reagents and conditions: (i) CuI (10 mol-%), PdCl2(PPh3)2
(5 mol-%), but-1-yn-4-ol (1.6 equiv.), Et3N, 50 °C, 12 h; (ii) 3,4,5- 6.88–6.96 (m, 2 H, Harom), 7.00–7.06 (m, 3 H, H arom+vinyl), 7.30
trimethoxyphenylboronic acid (1.2 equiv.), Pd(PPh3)4 (5 mol-%),
K2CO3 (2 equiv.), toluene/H2O (2:1), 100 °C.
(dt, J = 7.9, 1.7 Hz, 1 H, Harom), 7.39 (dd, J = 8.8, 5.4 Hz, 2 H,
Harom), 7.45 (dd, J = 7.5, 1.7 Hz, 1 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 55.9 (CH3), 88.2 (Cq), 92.8 (Cq), 108.4 (CH), 110.7
(CH), 112.6 (Cq), 115.8 (JC,F = 21.8 Hz, 2 CH), 120.6 (CH), 128.0
(JC,F = 8.1 Hz, 2 CH), 129.9 (CH), 132.8 (JC,F = 3.1 Hz, Cq), 133.6
(CH), 139.7 (CH), 160.0 (Cq), 162.9 (JC,F = 248.6 Hz, Cq) ppm.
Conclusions
IR: ν = 1597, 1490, 1434, 1228, 1158, 1024, 954, 813, 750 cm–1.
In summary, we have shown that MPHT in CH2Cl2 is a
˜
soft and compatible reagent to promote the bromocycliza- MS (APCI+): m/z = 253.0 [M + H]+.
Eur. J. Org. Chem. 2010, 4492–4500
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FULL PAPER
1-Methoxy-2-(4-methylpent-3-en-1-ynyl)benzene (1h): To a solution
(E)-3-Bromo-2-styrylbenzofuran (2a): Yield: 242 mg, 81%. Rf = 0.57
of PdCl2(PPh3)2 (104 mg, 0.15 mmol), CuI (56.4 mg, 0.3 mmol), (cyclohexane/CH2Cl2, 95:5). 1H NMR (400 MHz, CDCl3): δ = 7.14
and bromo-1-methylpropene (400 mg, 3 mmol) in THF (10 mL)
and piperidine (1.2 mL, 11.9 mmol) was slowly added 2-methoxy-
phenylacetylene (461 µL, 2.4 mmol). The stirred reaction was
heated at reflux for 20 h and treated with a saturated NH4Cl solu-
tion (10 mL). The aqueous layer was extracted with EtOAc
(3ϫ10 mL), and the combined organic layer was dried with
MgSO4 and concentrated under vacuum. Purification by flash
chromatography afforded expected enyne 1h. Yield: 312 mg, 70%.
Rf = 0.41 (cyclohexane/CH2Cl2, 8:2). 1H NMR (300 MHz, CDCl3):
δ = 1.87 (s, 3 H, CH3), 2.01 (s, 3 H, CH3), 3.88 (s, 3 H, OCH3),
5.54 (br. s, 1 H, Hvinyl), 6.87 (d, J = 8.2 Hz, 1 H, Harom), 6.90 (t, J
= 7.5 Hz, 1 H, Harom), 7.25 (t, J = 7.9 Hz, 1 H, Harom), 7.40 (d, J
= 7.5 Hz, 1 H, Harom) ppm. 13C NMR (75 MHz, CDCl3): δ = 21.2
(CH3), 25.0 (CH3), 55.9 (OCH3), 87.8 (C), 92.1 (C), 105.7 (CH),
110.7 (CH), 113.4 (C), 120.5 (CH), 129.2 (CH), 133.2 (CH), 148.8
(d, J = 16.2 Hz, 1 H, Hvinyl), 7.28–7.43 (m, 5 H, Harom), 7.41 (d, J
= 16.2 Hz, 1 H, Hvinyl), 7.47 (d, J = 8.1 Hz, 1 H, Harom), 7.50 (d,
J = 7.6 Hz, 1 H, Harom), 7.59 (d, J = 7.6 Hz, 2 H, Harom) ppm. 13
C
NMR (100 MHz, CDCl3): δ = 97.0, 111.3, 113.8, 119.7, 123.6,
126.0, 127.1, 128.7, 128.9, 129.0, 132.0, 136.5, 151.5, 153.7 ppm.
IR: ν = 3058, 2924, 1446, 1013, 1001, 954, 741, 689 cm–1. MS
˜
(APCI+): m/z = 220.0 [M – Br + H]+. C16H11BrO (299.16): calcd.
C 64.24, H 3.71; found C 64.09, H 3.56.
(E)-2-(4-Methoxystyryl)-3-bromobenzofuran (2b): Yield: 191 mg,
1
58%. Beige solid. M.p. 85–86 °C. H NMR (300 MHz, CDCl3): δ
= 3.85 (s, 3 H, CH3), 6.93 (d, J = 8.6 Hz, 2 H, Harom), 6.99 (d, J
= 16.2 Hz, 1 H, Hvinyl), 7.28–7.39 (m, 3 H, Hvinyl+arom), 7.44–7.50
(m, 2 H, Harom), 7.53 (d, J = 8.6 Hz, 2 H, Harom) ppm. 13C NMR
(75 MHz, CDCl3): δ = 55.5 (CH3), 96.0 (C), 111.1 (CH), 111.6
(CH), 114.4 (2 CH), 119.5 (CH), 123.5 (CH), 125.6 (CH), 128.5 (2
CH), 129.1 (C), 129.2 (C), 131.6 (CH), 151.8 (Cq), 153.6 (C), 160.2
(C), 159.7 (C) ppm. IR: ν = 2908, 1593, 1434, 1268, 1240, 1119,
˜
1047, 749 cm–1. MS (APCI+): m/z = 373.0 [2M + H]+, 187.0 [M +
(C) ppm. IR: ν = 821, 953, 1014, 1173, 1243, 1450, 1505, 1599,
˜
H]+.
2926 cm–1. MS (APCI+): m/z = 329.0 [M + H]+ (79Br), 331.0 [M
+ H]+ (81Br), 250.0 [M – Br + H]+. C17H13BrO2 (329.19): calcd. C
62.03, H 3.98; found C 61.91, H 3.84.
Preparation of Unsymmetrical Diynes 3c and 3d: To a solution of
CuI (0.1 mmol) in pyrrolidine (10 mL) was added successively at
0 °C the iodoarylalkyne (1 mmol) and the terminal arylalkyne
(2 mmol). The stirred reaction was kept at room temperature for
one night and treated with a saturated NH4Cl solution (15 mL).
The aqueous layer was extracted with EtOAc (3ϫ10 mL), and the
combined organic layer was dried with MgSO4 and concentrated
under vacuum. Purification by flash chromatography afforded the
expected diynes.
(E)-5-[2-(3-Bromobenzofuran-2-yl)vinyl]benzo[1,3]dioxole
(2c):
Yield: 192 mg, 56%. Yellow solid. M.p. 122–123 °C. 1H NMR
(300 MHz, CDCl3): δ = 6.00 (s, 2 H, OCH2O), 6.83 (d, J = 8.0 Hz,
1 H, Harom), 6.94 (d, J = 16.1 Hz, 1 H, Hvinyl), 7.03 (dd, J = 8.0,
1.3 Hz, 1 H, Harom), 7.12 (d, J = 1.6 Hz, 1 H, Harom), 7.27–7.35
(m, 3 H, Hvinyl+arom), 7.43–7.49 (m, 2 H, Harom) ppm. 13C NMR
(75 MHz, CDCl3): δ = 96.4 (C), 101.5 (C), 105.9 (CH), 108.7 (CH),
111.2 (CH), 112.0 (CH), 119.5 (CH), 122.6 (CH), 123.6 (CH), 125.8
(CH), 129.0 (C), 131.0 (C), 131.6 (CH), 148.5 (C), 151.6 (C), 153.6
{2-[4-(2-Methoxyphenyl)buta-1,3-diynyl]phenyl}(methyl)
Sulfane
(3c):[25] Prepared from CuI (14.8 mg, 0.08 mmol), 1-(2-iodoethy-
nyl)-2-methoxybenzene (200 mg, 0.78 mmol), and 2-thiomethyl-
phenylacetylene. Yield: 152 mg, 70%. M.p. 82–83 °C. Rf = 0.22 (cy-
clohexane/EtOAc, 94:6). 1H NMR (400 MHz, CDCl3): δ = 2.51 (s,
3 H, SCH3), 3.91 (s, 3 H, OCH3), 6.89 (d, J = 8.7 Hz, 1 H, Harom),
6.92 (t, J = 7.5 Hz, 1 H, Harom), 7.09 (t, J = 7.5 Hz, 1 H, Harom),
7.17 (d, J = 7.9 Hz, 1 H, Harom), 7.29–7.36 (m, 2 H, Harom), 7.48–
7.51 (m, 2 H, Harom) ppm. 13C NMR (100 MHz, CDCl3): δ = 15.4
(SCH3), 56.0 (OCH3), 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 ppm.
(C) ppm. IR: ν = 746, 931, 1037, 1199, 1250, 1447, 1487, 2360 cm–1.
˜
MS (APCI+): m/z = 343.0 [M + H]+ (79Br), 345.0 [M + H]+ (81Br).
C17H11BrO3 (343.17): calcd. C 59.50, H 3.23; found C 59.41, H
3.16.
(E)-2-(4-Fluorostyryl)-3-bromobenzofuran (2d): Yield: 222 mg, 70%.
Yellow solid. M.p. 83–84 °C. 1H NMR (300 MHz, CDCl3): δ = 6.94
(d, J = 16.0 Hz, 1 H, Hvinyl), 7.01 (d, J = 8.6 Hz, 2 H, Harom), 7.17–
7.29 (m, 3 H, Harom), 7.36–7.48 (m, 4 H, Harom) ppm. 13C NMR
(75 MHz, CDCl3): δ = 97.0 (C), 111.2 (CH), 113.6 (JC,F = 1.5 Hz,
CH), 116.0 (JC,F = 21.9 Hz, 2 CH), 119.7 (CH), 123.7 (CH), 126.0
(CH), 128.7 (JC,F = 8.1 Hz, 2 CH), 129.0 (C), 130.7 (CH), 132.7
(JC,F = 3.0 Hz, Cq), 151.3 (C), 153.7 (C), 163.0 (JC,F = 249.1 Hz,
IR: ν = 2938, 1594, 1492, 1464, 1433, 1248, 1022, 733, 703 cm–1.
˜
MS (APCI+): m/z = 279.0 [M + H]+.
1-(2-Methoxyphenyl)-4-(4-methoxyphenyl)buta-1,3-diyne (3d): Pre-
pared from CuI (40.6 mg, 0.21 mmol), 1-(2-iodoethynyl)-2-meth-
oxybenzene (550 mg, 0.78 mmol), and 4-methoxyphenylacetylene.
Yield: 131 mg, 64%. M.p. 109–110 °C. Rf = 0.24 (cyclohexane/
acetone, 95:5). 1H NMR (300 MHz, CDCl3): δ = 3.82 (s, 3 H,
OCH3), 3.90 (s, 3 H, OCH3), 6.84–6.94 (m, 4 H, Harom), 7.32 (t, J
= 7.6 Hz, 1 H, Harom), 7.45–7.48 (m, 3 H, Harom) ppm. 13C NMR
(75 MHz, CDCl3): δ = 55.4 (OCH3), 55.9 (OCH3), 73.2, 77.7, 78.0,
82.5, 110.8, 111.3, 114.0, 114.2, 120.6, 130.6, 134.1, 134.4, 160.4,
C ) ppm. IR: ν = 740, 811, 847, 947, 1002, 1151, 1227, 1447, 1501,
˜
q
1592 cm–1. MS (APCI+): m/z = 317.0 [M + H]+ (79Br), 319.0 [M
+ H]+ (81Br). C16H10BrFO (317.15): calcd. C 60.59, H 3.18; found
C 60.47, H 3.01.
(E)-2-(4-Chlorostyryl)-3-bromobenzofuran (2e): Yield: 207 mg, 62%.
1
Yellow solid. M.p. 114–115 °C. H NMR (300 MHz, CDCl3): δ =
7.09 (d, J = 16.2 Hz, 1 H, Hvinyl), 7.29–7.38 (m, 5 H, Hvinyl+arom),
7.45–7.52 (m, 4 H, Harom) ppm. 13C NMR (75 MHz, CDCl3): δ =
97.5 (C), 111.3 (CH), 114.2 (CH), 119.8 (CH), 123.7 (CH), 126.2
(CH), 128.2 (2 CH), 128.9 (C), 129.2 (2 CH), 130.5 (CH), 134.3
161.5 ppm. IR: ν = 2936, 2837, 1601, 1508, 1489, 1247, 1171, 1024,
˜
750 cm–1. MS (APCI+): m/z = 263.0 [M + H]+.
(C), 135.0 (C), 151.2 (C), 153.8 (C) ppm. IR: ν = 812, 954, 1013,
˜
General Procedure for the Electrophilic Cyclization with MPHT: To
a solution of 1, 3, or 5 in CH2Cl2 (1 mmol) was added MPHT (for
quantity, see text), and the resulting solution was stirred at room
temperature until disappearance of the starting material (as judged
by TLC). The reaction mixture was next treated with a saturated
Na2S2O3 solution. The organic layer was washed with HCl 10%
(3ϫ10 mL) and dried with MgSO4. Removal of the solvent yielded
a crude product, which was purified by silica gel flash chromatog-
raphy to afford 2, 4, 6, or 8.
1091, 1192, 1252, 1448, 1489, 1592 cm–1. MS (APCI+): m/z = 333.0
[M + H]+ (79Br), 335.0 [M + H]+ (81Br). C16H10BrClO (333.61):
calcd. C 57.60, H 3.02; found C 333.48, H 2.94.
(E)-3-Bromo-2-[2-(naphthalen-2-yl)vinyl]benzofuran (2f): Yield:
175 mg, 50%. Yellow solid. M.p. 141–142 °C. 1H NMR (300 MHz,
CDCl3): δ = 7.22–7.39 (m, 3 H, Hvinyl+arom), 7.48–7.53 (m, 4 H,
Harom+naph), 7.57 (d, J = 16.2 Hz, 1 H, Hvinyl), 7.77–7.87 (m, 4 H,
Hnaph), 7.94 (s, 1 H, Hnaph) ppm. 13C NMR (75 MHz, CDCl3): δ
4496
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4492–4500

MPHT-Promoted Bromocyclization of ortho-Substituted Arylalkynes
= 97.1 (C), 111.3 (CH), 114.0 (CH), 119.7 (CH), 123.4 (CH), 123.7
(CH), 126.0 (CH), 126.6 (CH), 126.7 (CH), 127.9 (2 CH), 128.4
δ = 55.5 (OCH3), 77.0 (C), 99.5 (C), 102.9 (C), 111.6 (CH), 113.6
(C), 114.3 (2 CH), 120.0 (CH), 123.9 (CH), 126.6 (CH), 127.8 (C),
(CH), 128.7 (CH), 129.0 (C), 132.0 (CH), 133.6 (C), 133.8 (C), 133.6 (2 CH), 137.8 (C), 153.8 (C), 160.7 (C) ppm. IR: ν = 2208,
˜
134.0 (C), 151.6 (C), 153.8 (C) ppm. IR: ν = 804, 962, 1015, 1195,
1504, 1290, 1249, 1016, 905, 830, 725 cm–1. MS (APCI+): m/z =
˜
1258, 1446 cm–1. MS (APCI+): m/z = 349.0 [M + H]+ (79Br), 351.0 328.0 [M + H]+. C17H11BrO2 (327.17): calcd. C 62.41, H 3.39;
[M + H]+ (81Br). C20H13BrO (349.22): calcd. C 68.79, H 3.75; found
C 68.55, H 3.51
found C 62.13, H 3.10.
(E)-3-Bromo-2-[2-(3-bromobenzofuran-2-yl)vinyl]benzofuran
(6):
(E)-3-Bromo-2-[2-(thiophen-3-yl)vinyl]benzofuran
(2g):
Yield: Yield: 92 mg, 21%. Yellow solid. M.p. 232–233 °C. 1H NMR
171 mg, 56%. Gray solid. M.p. 65–66 °C. 1H NMR (300 MHz,
CDCl3): δ = 6.95 (d, J = 16.1 Hz, 1 H, Hvinyl), 7.29–7.34 (m, 2 H,
(300 MHz, CDCl3): δ = 7.26 (s, 2 H, Hvinyl), 7.40 (m, 2 H, Harom),
7.49 (m, 2 H, Harom), 7.56 (dd, J = 7.7, 0.8 Hz, 2 H, Harom), 7.73
(d, J = 8.2 Hz, 2 H, Harom) ppm. 13C NMR (75 MHz, CDCl3): δ
= 99.3 (CH), 115.5 (CH), 116.0 (CH), 120.0 (CH), 123.9 (CH),
Hvinyl+arom), 7.35–7.47 (m, 5 H, Harom), 7.48–7.51 (m, 1 H, Harom
)
ppm. 13C NMR (75 MHz, CDCl3): δ = 96.6 (C), 111.2 (CH), 113.7
(CH), 119.5 (CH), 123.6 (CH), 124.5 (CH), 125.0 (CH), 125.8
126.7 (CH), 129.0 (C), 150.9 (C), 154.1 (C) ppm. IR: ν = 738, 861,
˜
(CH), 126.0 (CH), 126.7 (CH), 129.0 (C), 139.4 (C), 151.4 (C), 943, 1017, 1106, 1202, 1259, 1343, 1447, 1612 cm–1. MS (APCI+):
153.6 (C) ppm. IR: ν = 738, 823, 853, 941, 1014, 1191, 1257, 1404, m/z = 441.0 [M + Na]+. C18H10Br2O2 (418.08): calcd. C 51.71, H
˜
1445, 1632 cm–1. MS (APCI+): m/z = 305.0 [M + H]+ (79Br), 307.0 2.41; found C 51.50, H 2.28.
[M + H]+ (81Br). C14H9BrOS (305.19): calcd. C 55.10, H 2.97;
3-Bromo-2-(4-methoxyphenyl)benzofuran (8a):[28] Yield: 297 mg,
found C 55.19, H 3.06.
98%. Yellow solid. M.p. 66–67 °C. Rf = 0.51 (cyclohexane/ CH2Cl2,
1
3-Bromo-2-(2-methylprop-1-enyl)benzofuran (2h): Yield: 128 mg, 8:2). H NMR (400 MHz, CDCl3): δ = 3.88 (d, J = 0.9 Hz, 3 H,
1
51%. Rf = 0.62 (cyclohexane/CH2Cl2, 95:5). H NMR (300 MHz,
CDCl3): δ = 2.01 (s, 3 H, CH3), 2.22 (d, J = 1.3 Hz, 3 H, CH3),
OCH3), 7.02 (d, J = 7.9 Hz, 2 H, Harom), 7.32 (m, 2 H, Harom),
7.50 (m, 2 H, Harom), 8.12 (d, J = 7.9 Hz, 2 H, Harom) ppm. 13C
6.25 (q, J = 1.3 Hz, 1 H, Hvinyl), 7.26–7.33 (m, 2 H, Harom), 741– NMR (100 MHz, CDCl3): δ = 55.5 (OCH3), 92.3, 111.3, 114.2 (2
7.50 (m, 2 H, Harom) ppm. 13C NMR (75 MHz, CDCl3): δ = 20.8
C), 119.7, 122.4, 123.5, 125.3, 128.5 (2 C), 129.9, 150.7, 153.1,
(CH3), 27.8 (CH3), 95.0 (C), 111.2, 111.5 (CH), 119.3 (CH), 123.4 160.4 ppm. IR: ν = 2959, 1609, 1450, 1251, 1117, 1072, 1030, 985,
˜
(CH), 124.9 (CH), 128.3 (C), 141.8 (C), 152.1 (C), 153.4 ppm. IR: 830, 783 cm–1. MS (APCI+): m/z = 224 [M – Br + H]+.
ν = 2930, 1450, 1259, 1197, 1011, 738 cm–1. MS (APCI+): m/z =
˜
3-Bromo-2-(2-methoxyphenyl)benzofuran (8b):[9b] Yield: 239 mg,
79%. Rf = 0.38 (cyclohexane/ CH2Cl2, 8:2). H NMR (300 MHz,
CDCl3): δ = 3.89 (s, 3 H, OCH3), 7.05 (d, J = 8.1 Hz, 1 H, Harom),
7.09 (td, J = 7.5, J = 1.0 Hz, 1 H, Harom), 7.35 (m, 2 H, Harom),
7.49 (m, 2 H, Harom), 7.60 (m, 2 H, Harom) ppm. 13C NMR
252.0 [M + H]+. C12H11BrO (251.12): calcd. C 57.39, H 4.42; found
C 57.33, H 4.37.
1
3-Bromo-2-(3-bromobenzofuran-2-yl)benzofuran (4a):[26] Yield:
376 mg, 96%. White solid. M.p. 224–225 °C. Rf = 0.43 (cyclohex-
1
ane/ CH2Cl2, 96:4). H NMR (400 MHz, CDCl3): δ = 7.38 (t, J = (75 MHz, CDCl3): δ = 55.8 (OCH3), 96.8 (C), 111.6 (CH), 111.7
7.4 Hz, 2 H, Harom), 7.45 (t, J = 7.4 Hz, 2 H, Harom), 7.59 (d, J =
(CH), 118.4 (C), 119.9 (CH), 120.6 (CH), 123.3 (CH), 125.3 (CH),
129.1 (CH), 131.5 (CH), 131.8 (CH), 150.6 (C), 154.0 (C), 157.8
8.2 Hz, 2 H, Harom), 7.64 (d, J = 7.7 Hz, 2 H, Harom) ppm. 13C
NMR (100 MHz, CDCl3): δ = 98.3 (2 C), 111.9 (2 C), 120.5 (2 C), (C) ppm. IR: ν = 2933, 1486, 1447, 1255, 1058, 1044, 1024,
˜
124.1 (2 C), 126.9 (2 C), 128.7 (2 C), 142.8 (2 C), 154.7 (2 C) ppm.
740 cm–1. MS (ESI+): m/z = 224.0 [M – Br + H]+. C15H11BrO2
(303.15): calcd. C 59.43, H 3.66; found C 59.19, H 3.76.
IR: ν = 2923, 1437, 1260, 1211, 1122, 743 cm–1. MS (APCI+): m/z
˜
= 312.0 [M – 81Br+H]+, 314.0 [M – 79Br + H]+.
3-Bromo-2-p-tolylbenzofuran (8c): Yield: 229 mg, 80%. Yellow so-
lid. M.p. 70–72 °C. Rf = 0.65 (cyclohexane/ CH2Cl2, 9:1). 1H NMR
(400 MHz, CDCl3): δ = 2.43 (s, 3 H, CH3), 7.32 (m, 4 H, Harom),
7.53 (m, 2 H, Harom), 8.07 (d, J = 8.3 Hz, 2 H, Harom) ppm. 13C
3-Bromo-2-(3-bromobenzo[b]thiophen-2-yl)benzo[b]thiophene
(4b):[27] Yield: 395 mg, 97%. Yellow solid. Rf = 0.67 (cyclohexane/
CH2Cl2, 9:1). 1H NMR (300 MHz, CDCl3): δ = 7.50 (m, 4 H,
Harom), 7.85 (d, J = 7.6 Hz, 2 H, Harom), 7.93 (d, J = 7.7 Hz, 2 H, NMR (100 MHz, CDCl3): δ = 21.6 (CH3), 93.3, 111.3, 119.9, 123.5,
Harom) ppm. 13C NMR (75 MHz, CDCl3): δ = 111.0 (2 C), 122.4
125.5, 126.9 (3 C), 129.4 (2 C), 129.8, 139.4, 150.8, 153.2 ppm. IR:
(2 C), 124.2 (2 C), 125.6 (2 C), 126.5 (2 C), 129.5 (2 C), 138.2 (2 ν = 2919, 1503, 1450, 1253, 1204, 1072, 1020, 817, 741 cm–1. MS
˜
C), 139.3 (2 C) ppm.
(APCI+): m/z = 208 [M – Br + H]+.
3-Bromo-2-(3-bromobenzothiophen-2-yl)benzofuran (4c): Yield:
4-(3-Bromobenzofuran-2-yl)-N,N-dimethylbenzenamine (8d): Yield:
99%. Yellow solid. M.p. 113–118 °C. Rf = 0.59 (cyclohexane/ 221 mg, 74%. Rf = 0.57 (cyclohexane/ CH2Cl2, 8:2). 1H NMR
EtOAc, 96:4). 1H NMR (300 MHz, CDCl3): δ = 7.35–7.64 (m, 6
(300 MHz, CDCl3): δ = 3.04 (s, 6 H, N-CH3), 6.80 (d, J = 8.9 Hz,
H, Harom), 7.86 (d, J = 7.5 Hz, 1 H, Harom), 7.96 (d, J = 8.4 Hz, 1 2 H), 7.29 (m, 2 H, Harom), 7.50 (m, 2 H, Harom), 8.08 (d, J =
H, Harom) ppm. 13C NMR (75 MHz, CDCl3): δ = 99.3 (C), 109.9 8.7 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 40.3 (2 CH3),
(C), 111.8 (CH), 120.4 (CH), 122.4 (CH), 124.0 (CH), 124.3 (CH), 90.6, 111.0 (CH), 111.9 (2 C), 117.4 (C), 119.3 (CH), 123.3 (CH),
125.6 (CH), 126.7 (2 CH), 128.7 (C), 138.3 (C), 138.8 (C), 145.4 124.6 (CH), 128.1 (2 C), 130.2 (C), 150.8 (C), 151.6 (C), 153.0 (C)
(C), 148.4 (C), 154.2 (C) ppm. IR: ν = 2923, 1454, 1257, 1241, ppm. IR: ν = 2889, 1607, 1510, 1450, 1361, 1194, 816, 742 cm–1.
˜
˜
1040, 978, 737, 720 cm–1. MS (APCI +): m/z = 409.0 [M + H]+.
C16H8Br2OS (408.11): calcd. C 47.09, H 1.98; found C 46.89, H
1.89.
MS (APCI+): m/z = 316 [M(79Br) + H]+, 318 [M(81Br) + H]+.
C16H14BrNO (316.20): calcd. C 60.78, H 4.46, N 4.43; found C
60.54, H 4.29, N 4.23.
3-Bromo-2-[2-(4-methoxyphenyl)ethynyl]benzofuran (4d): Yield:
288 mg, 88%. Yellow solid. M.p. 82–83 °C. Rf = 0.23 (cyclohexane/
CH2Cl2, 9:1). 1H NMR (300 MHz, CDCl3): δ = 3.83 (s, 3 H,
3-Bromo-2-(naphthalen-1-yl)benzofuran (8e): Yield: 242 mg, 75%.
White solid. M.p. 107–109 °C. Rf = 0.65 (cyclohexane/ CH2Cl2,
9:1). H NMR (300 MHz, CDCl3): δ = 7.43 (m, 2 H), 7.62 (m, 5
1
OCH3), 6.90 (d, J = 7.6 Hz, 2 H, Harom), 7.29–7.41 (m, 2 H, Harom), H), 7.87 (d, J = 8.7 Hz, 1 H, Hnaph), 8.00 (m, 3 H) ppm. 13C NMR
7.45 (d, J = 8.3 Hz, 1 H, Harom), 7.50 (d, J = 7.4 Hz, 1 H, Harom), (75 MHz, CDCl3): δ = 97.3, 111.7, (CH), 120.1 (CH), 123.7 (CH),
7.56 (d, J = 7.6 Hz, 2 H, Harom) ppm. 13C NMR (75 MHz, CDCl3):
125.1 (C), 125.7 (CH), 126.1 (CH), 126.4 (CH), 126.5 (C), 127.0
Eur. J. Org. Chem. 2010, 4492–4500
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4497

M. Jacubert, A. Tikad, O. Provot, A. Hamze, J.-D. Brion, M. Alami
(CH), 128.6, (CH), 128.9 (C), 129.7 (CH), 130.6 (CH), 131.6 (C), C20H23BrO2Si (402.07): calcd. C 59.55, H 5.75; found C 59.38, H
FULL PAPER
133.9 (C), 152.2 (C), 154.1 (C) ppm. IR: ν = 3053, 1449, 1259, 5.61.
˜
1029, 1014, 968, 800, 772, 743 cm–1. MS (APCI+): m/z = 244.0
3-Bromo-2-(2,4-dimethoxyphenyl)benzofuran (8k): Yield: 310 mg,
[M – Br + H]+. C18H11BrO (323.18): calcd. C 66.89, H 3.43; found
93%. Yellow solid. M.p. 59–61 °C. Rf = 0.26 (cyclohexane/ EtOAc,
C 66.78, H 3.36.
1
9:1). H NMR (400 MHz, CDCl3): δ = 3.87 (s, 3 H, OCH3), 3.88
3-Bromo-2-(naphthalen-2-yl)benzofuran (8f): Yield: 197 mg, 61%.
Yellow solid. M.p. 98–102 °C. Rf = 0.56 (cyclohexane/ CH2Cl2,
(s, 3 H, OCH3), 5.61 (m, 2 H, Harom), 7.33 (m, 1 H, Harom), 7.34
(m, 1 H, Harom), 7.51 (m, 1 H, Harom), 7.53 (m, 1 H, Harom), 7.57
(m, 1 H, Harom) ppm. 13C NMR (100 MHz, CDCl3): δ = 55.6
(OCH3), 55.8 (OCH3), 96.2, 99.2, 104.9, 111.2, 111.5, 119.7, 123.2,
1
9:1). H NMR (300 MHz, CDCl3): δ = 7.38 (m, 2 H), 7.57 (m, 4
H), 7.87 (m, 4 H), 7.96 (m, 2 H), 8.30 (d, J = 8.7 Hz, 1 H, Hnaph),
8.68 (s, 1 H, Hnaph) ppm. 13C NMR (75 MHz, CDCl3): δ = 94.4
(C), 110.1 (C), 111.4 (CH), 120.1 (CH), 123.7 (CH), 124.0 (CH),
125.8 (CH), 126.6 (CH), 126.8 (CH), 127.1 (CH), 127.9 (CH), 128.4
(CH), 128.8 (CH), 129.8 (C), 133.2 (C), 133.4 (C), 150.5 (C), 153.4
125.0, 129.1, 132.6, 150.8, 153.8, 159.1, 162.6 ppm. IR: ν = 2938,
˜
1616, 1499, 1449, 1209, 1161, 1033, 986, 745 cm–1. MS (APCI+):
m/z = 254.0 [M – Br + H]+. C16H13BrO3 (333.18): calcd. C 57.68,
H 3.93; found C 57.55, H 3.66.
(C) ppm. IR: ν = 3058, 1450, 1259, 1065, 994, 857, 815, 742 cm–1.
˜
MS (APCI+): m/z = 244.0 [M – Br + H]+. C18H11BrO (323.18):
(E)-4-[2-(4-Methoxystyryl)benzofuran-3-yl]but-3-yn-1-ol (9):
A
solution of PdCl2(PPh3)2 (5 mol-%), CuI (10 mol-%), 2b (329 mg,
1 mmol), and butyn-4-ol (112 mg, 1.6 mmol) in TEA (10 mL) was
stirred at 50 °C for 12 h. The stirred reaction was next treated with
saturated NH4Cl solution (25 mL). The aqueous layer was ex-
tracted with ethyl ether (3ϫ20 mL), the combined organic layer
was washed successively with aqueous HCl (0.2 , 15 mL),
NaHCO3 (10 mL), and H2O (2ϫ25 mL), dried with MgSO4, and
concentrated under vacuum. Yield: 254 mg, 80%. Brown oil. Rf =
calcd. C 66.89, H 3.43; found C 67.01, H 3.60.
3-Bromo-2-(4-methoxyphenyl)benzo[b]thiophene (8g):[29] Yield:
309 mg, 97%. Yellow solid. M.p. 83 °C. Rf = 0.41 (cyclohexane/
CH2Cl2, 8:2). 1H NMR (300 MHz, CDCl3): δ = 3.88 (s, 3 H,
OCH3), 7.02 (d, J = 8.5 Hz, 2 H, Harom), 7.39 (t, J = 7.5 Hz, 1 H,
H
arom), 7.47 (t, J = 7.6 Hz, 1 H, Harom), 7.71 (d, J = 8.4 Hz, 2 H,
Harom), 7.80 (d, J = 7.8 Hz, 1 H, Harom), 7.85 (d, J = 8.0 Hz, 1 H,
arom) ppm. 13C NMR (75 MHz, CDCl3): δ = 55.5 (OCH3), 104.4
H
1
0.50 (cyclohexane/ EtOAc, 5:5). H NMR (300 MHz, CDCl3): δ =
(C), 114.2 (2 C), 122.2 (CH), 123.6 (CH), 125.3 (CH), 125.4 (CH),
125.5 (C), 131.1 (2 C), 137.6 (C), 138.3 (C), 139.4 (C), 160.2 (C)
2.86 (t, J = 6.3 Hz, 2 H, CH2-C), 3.84 (s, 3 H, OMe), 3.92 (t, J =
6.3 Hz, 2 H, CH2O), 6.93 (dd, J = 9.0, 2.4 Hz, 2 H, Harom), 7.06
(d, J = 16.2 Hz, 1 H, Hvinyl), 7.63–7.20 (m, 7 H, Harom+vinyl) ppm.
13C NMR (100 MHz, CDCl3): δ = 24.5 (CH2), 55.5 (CH3), 61.5
(CH2), 73.1 (C), 94.1 (C), 112.7 (CH), 114.4 (CH), 120.1 (2 CH),
123.3 (CH), 125.3 (CH), 128.5 (CH), 129.6 (2 CH), 131.3 (CH),
ppm. IR: ν = 2922, 1606, 1494, 1433, 1248, 1177, 1032, 831, 802,
˜
749 cm–1. MS (APCI+): m/z = 240 [M – Br + H]+.
3-Bromo-2-(2-methoxyphenyl)benzo[b]thiophene (8h): Yield: 258 mg,
81%. Beige solid. M.p. 85–87 °C. Rf = 0.27 (cyclohexane). 1H
NMR (300 MHz, CDCl3): δ = 3.86 (s, 3 H, OCH3), 7.06 (m, 2 H,
Harom), 7.45 (m, 4 H, Harom), 7.82 (d, J = 7.7 Hz, 1 H, Harom), 7.87
(d, J = 8.0 Hz, 1 H, Harom) ppm. 13C NMR (75 MHz, CDCl3): δ
= 55.8 (OCH3), 107.8 (C), 111.6 (CH), 120.6 (CH), 121.9 (C), 122.3
(CH), 123.5 (CH), 125.0 (CH), 125.3 (CH), 130.8 (CH), 132.5 (C),
153.9 (C), 157.8 (C), 160.2 (C) ppm. IR: ν = 3448, 2935, 1734,
˜
1602, 1577, 1508, 1452, 1423, 1373, 1245, 1034, 959, 932, 746 cm–1.
C21H18O3 (318.37): calcd. C 79.22, H 5.70; found C 79.00, H 5.36.
(E)-2-(4-Methoxystyryl)-3-(3,4,5-trimethoxy-phenyl)benzofuran
(10): To a solution of 2b (1 mmol) in toluene (4 mL) and EtOH
(2 mL) was successively added 3,4,5-trimethoxyphenyl boronic acid
(254 mg, 1.2 mmol), K2CO3 (2 mmol), and Pd(PPh3)4 (0.05 mmol).
The reaction mixture was heated at 100 °C under vigorous stirring
and monitored by TLC until complete disappearance of the start-
ing material. The solvent was evaporated in vacuo, and water
(10 mL) was added. After extraction with CH2Cl2 (3ϫ10 mL), the
combined organic layer was dried with MgSO4, and the solvent
was removed under reduced pressure. The crude material was puri-
fied by column chromatography to afford 10. Yield: 374 mg, 90%.
135.4 (C), 138.5 (C), 138.7 (C), 157.4 (C) ppm. IR: ν = 2938, 1482,
˜
1459, 1432, 1248, 1115, 1024, 889, 748, 725 cm–1. MS (APCI+):
m/z = 240 [M – Br + H]+. C15H11BrOS (319.22): calcd. C 56.44, H
3.47; found C 56.29, H 3.36.
4-Bromo-3-(2-methoxyphenyl)-1H-isochromen-1-one (8i): Yield:
324 mg, 98%. White solid. M.p. 129–131 °C. Rf = 0.37 (cyclohex-
1
ane/ CH2Cl2, 8:2). NMR H (300 MHz, CDCl3): δ = 3.85 (s, 3 H,
OCH3), 7.00 (d, J = 8.4 Hz, 1 H, Harom), 7.05 (td, J = 7.5, 0.9 Hz,
1 H, Harom), 7.40–7.49 (m, 2 H, Harom), 7.60 (td, J = 7.5, 1.2 Hz,
1 H, Harom), 7.84 (td, J = 7.6, 1.3 Hz, 1 H, Harom), 7.92 (d, J =
8.1 Hz, 1 H, Harom), 8.35 (dd, J = 7.9, 0.8 Hz, 1 H, Harom) ppm.
13C NMR (75 MHz, CDCl3): δ = 55.8 (OCH3), 103.9 (C), 111.5
(CH), 120.4 (CH), 121.0 (C), 122.5 (C), 126.5 (CH), 129.2 (CH),
130.0 (CH), 131.3 (CH), 131.9 (CH), 135.4 (CH), 136.6 (C), 150.8
Yellow oil. Rf
=
0.25 (cyclohexane/EtOAc, 8:2). 1H NMR
(300 MHz, CDCl3): δ = 3.72 (s, 3 H, OCH3), 3.82 (s, 6 H, OCH3),
3.90 (s, 3 H, OCH3), 6.71 (s, 2 H, Harom), 6.80 (d, J = 7.8 Hz, 2 H,
Harom), 6.98 (d, J = 16.2 Hz, 1 H, Hvinyl), 7.15–7.7.30 (m, 2 H,
Harom), 7.35 (d, J = 16.2 Hz, 1 H, Hvinyl), 7.42 (d, J = 7.8 Hz, 2 H,
Harom), 7.36–7.60 (m, 2 H, Harom) ppm. 13C NMR (100 MHz,
CDCl3): δ = 55.3 (CH3), 56.3 (2 CH3), 61.0 (CH3), 106.6 (2 CH),
110.9 (CH), 112.9 (CH), 114.3 (2 CH), 118.8 (C), 119.7 (CH), 123.0
(C), 157.5 (C), 161.7 (C) ppm. IR: ν = 2952, 1732, 1279, 1072,
˜
1020, 753 cm–1. MS (ESI+): m/z = 354 [M + Na]+. C16H11BrO3
(329.99): calcd. C 58.03, H 3.35; found C 57.88, H 3.20.
[2-(3-Bromobenzofuran-2-yl)phenoxy](tert-butyl)dimethylsilane (8j): (CH), 124.9 (CH), 127.9 (C), 128.0 (2 CH), 129.1 (C), 129.5 (C),
Yield: 375 mg, 93%. Rf = 0.76 (cyclohexane/ CH2Cl2, 9:1). 1H 130.5 (CH), 137.5 (C), 151.1 (C), 153.6 (C), 154.2 (C), 159.8 (C)
NMR (300 MHz, CDCl3): δ = 0.06 (s, 6 H, CH3Si), 0.84 (s, 9 H, ppm. IR: ν = 2932, 2249, 2068, 1602, 1580, 1509, 1452, 1414, 1389,
˜
CH3C), 6.99 (d, J = 8.2 Hz, 1 H, Harom), 7.09 (td, J = 7.5, 1.0 Hz, 1307, 1243, 1173, 1125, 1032, 1005, 961, 907, 843, 819 cm–1.
1 H, Harom), 7.36 (m, 3 H, Harom), 7.48 (m, 1 H, Harom), 7.59 (m, C26H24O5 (416.47): calcd. C 74.98, H 5.81; found C 74.89, H 5.66.
2 H, Harom) ppm. 13C NMR (100 MHz, CDCl3): δ = –4.5 (2 CH3),
18.2 (C), 25.6 (3 CH3), 96.3 (C), 111.5 (CH), 119.8 (CH), 120.8
(CH), 121.3 (CH), 123.3 (CH), 125.3 (CH), 128.8 (2 C), 131.3
Acknowledgments
(CH), 132.0 (CH), 151.2 (C), 153.8 (C), 154.4 (C) ppm. IR: ν =
˜
2930, 1483, 1449, 1281, 1258, 916, 887, 826, 780, 743 cm–1. MS
The Centre National de la Recherche Scientifique (CNRS) is grate-
fully acknowledged for financial support of this research, and the
(APCI+): m/z = 403 [M(79Br) + H]+, 405 [M(81Br) + H]+.
4498
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Eur. J. Org. Chem. 2010, 4492–4500

MPHT-Promoted Bromocyclization of ortho-Substituted Arylalkynes
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is acknowledged for a doctoral fellowship to M.J. Thanks also to
the Association de Recherche sur le Cancer (ARC) for a postdoc-
toral grant to. A.T. and for financial support. Thanks also to E.
Morvan for her help in the NMR spectroscopic experiments.
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M. Jacubert, A. Tikad, O. Provot, A. Hamze, J.-D. Brion, M. Alami
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Published Online: June 23, 2010
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