Synthesis of 3,5-disubstituted 4-hydroxybenzoates by aryl-aryl and alkynyl-aryl coupling

Full text of DOI:10.1021/jo991907m

J . Org. Chem. 2000, 65, 2837-2842
2837
Sch em e 1a
Syn th esis of 3,5-Disu bstitu ted
4-Hyd r oxyben zoa tes by Ar yl-Ar yl a n d
Alk yn yl-Ar yl Cou p lin g
Adelheid Godt,* O¨ mer U¨ nsal, and Mark Roos
Max-Planck-Institut fu¨r Polymerforschung, Ackermannweg
10, D-55128 Mainz, Germany
Received December 14, 1999
Angled molecules such as 1,3-diarylbenzene,1 1,3-di-
(arylethynyl)benzene,2 and 1,3-di(arylbutadiynyl)ben-
zene3 have been used as building blocks for macrocycles
and polymers. Frequently, these building blocks carry
functional groups either in the 2- or 5-position and are,
therefore, interesting ligands for transition metals4 or key
building blocks for functionalized nanoscopic objects.1-3
1,3-Diarylbenzene, 1,3-di(arylethynyl)benzene, and 1,3-
di(arylbutadiynyl)benzene with a functional group in the
2-position and additionally a second, selectively addres-
sable, functional group in the 5-position are rare,3,5
though even more versatile building blocks for the above-
mentioned applications. We were interested in a general
approach to such compounds with functional groups that
can be easily derivatized. The latter requirement will
allow for a fine-tuning of the final functional groups at a
late step in the synthesis. As the target structures, we
choose 4-hydroxybenzoate with aryl-, arylethynyl-, and
arylbutadiynyl substituents in the 3- and 5-positions.
Here, we report on the synthesis of the angled compounds
3, 4, 8, and 12 by aryl-aryl6 or aryl-alkynyl7 coupling
starting from readily available ethyl 3,5-diiodo-4-hy-
droxybenzoate (1a ).8
Resu lts a n d Discu ssion
E t h yl 3,5-Dia r yl-4-h yd r oxyb en zoa t es 3 a n d
4
(Sch em e 1). The terphenylenes 3a ,b were obtained by
Suzuki coupling6 of diiodo hydroxybenzoate 1a with aryl
a
Key: (a) Pd2(dba)3, K2CO3 (for 3a ,b) or Cs2CO3 (for 3c),
* To whom correspondence should be addressed. E-mail: godt@
mpip-mainz.mpg.de.
(1) (a) Hensel, V.; Lu¨tzow, K.; J acob, J .; Gessler K.; Saenger, W.;
Schlu¨ter, A. D. Angew. Chem. 1997, 109, 2768; Angew. Chem., Int. Ed.
Engl. 1997, 36, 2654. (b) Kannan, A.; Rajakumar, P.; Kabaleeswaran,
V.; Rajan, S. S. J . Org. Chem. 1996, 61, 5090.
acetone, water, reflux (3a : 70%; 3b: 88%; 3c: 81%); (b) n-Bu4NF,
THF, rt (3d : 99%); (c) 1-ethoxy-4-iodobenzene, Pd(PPh3)2Cl2, CuI,
piperidine, rt (4a : 81%); (d) 1-iodo-4-nitrobenzene, Pd(PPh3)2Cl2,
CuI, Et3N, THF, rt (4b: 80%).
(2) E.g.: (a) Moore, J . S. Acc. Chem. Res. 1997, 30, 402 and literature
cited therein. (b) Ho¨ger, S.; Meckenstock, A.-D.; Pellen, H. J . Org.
Chem. 1997, 62, 4556. (c) Mongin, O.; Papamicae¨l, C.; Hoyler, N.;
Gossauer, A. J . Org. Chem. 1998, 63, 5568. (d) Iyer, V. S.; Wehmeier,
M.; Brand, J . D.; Keegstra, M. A.; Mu¨llen, K. Angew. Chem. 1997, 109,
1676; Angew. Chem., Int. Ed. Engl. 1997, 36, 1604. (e) Weiss, K.;
Michel, A.; Auth, E.-M.; Bunz, U. H. F.; Mangel, T.; Mu¨llen, K. Angew.
Chem. 1997, 109, 522; Angew. Chem., Int. Ed. Engl. 1997, 36, 506.
(3) Tobe, Y.; Utsumi, N.; Nagano, A.; Naemura, K. Angew. Chem.
1998, 110, 1347; Angew. Chem., Int. Ed. Engl. 1998, 37, 1285.
(4) E. g.: Balaich, G. J .; Hill, J . E.; Waratuke, S. A.; Fanwick, P.
E.; Rothwell, I. P. Organometallics 1995, 14, 656.
(5) (a) Prince, R. R.; Okada, T.; Moore J . S. Angew. Chem., Int. Ed.
1999, 38, 233. (b) Yang, H.; Hay, A. S. Synthesis 1992, 467.
(6) (a) Knight, D. W. In Comprehensive Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 3, p 481.
(b) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457. (c) Martin, A.
R.; Yang, Y. Acta Chem. Scand. 1993, 47, 221.
boronic acids 2a ,b, catalyzed by Pd2(dba)3 in acetone/
water with potassium carbonate as the base.9 Careful
degassing of the reaction mixture was essential to give
a very high conversion of 1a .10
The same approach should be suitable for the prepara-
tion of larger building blocks such as 4 with the corre-
sponding boronic acids as coupling partners. Alterna-
tively, one can prepare a terphenylene unit with funtional
groups at the phenyl substituents which allows, in a
second step, for the enlargement of these phenyl substit-
uents. The latter strategy was realized by the coupling
of boronic acid 2c with diiodo hydroxybenzoate 1a to give
(7) (a) Takahashi, S.; Kuroyama, Y.; Sonogashira, K.; Hagihara, N.
Synthesis 1980, 627. (b) Sonogashira, K. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford,
1991; Vol. 3, p 521.
(8) Sheahan, M. M.; Wilkinson, J . H.; MacLagan, N. F. Biochem. J .
1951, 48, 188.
(9) Procedure analogous to: Wallow, T. I.; Novak, B. M. J . Org.
Chem. 1994, 59, 5034.
(10) The importance of degassing has also been pointed out by
Campi, E. M.; J ackson, W. R.; Marcuccio, S. M.; Naeslund, C. G. M. J .
Chem. Soc., Chem. Commun. 1994, 2395.
10.1021/jo991907m CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/06/2000

2838 J . Org. Chem., Vol. 65, No. 9, 2000
Notes
Sch em e 2a
the terphenylene 3c. Desilylation of 3c with n-Bu4NF
gave 3d , which coupled cleanly and quantitatively with
iodobenzene derivatives giving the extended, angular
molecules 4. Whereas the terphenylenes 3a ,b were
obtained in satisfying yields (70-88%), the yield of 3c
was rather low (50%) when prepared under the same
conditions. Replacing potassium carbonate with cesium
carbonate increased the yield of 3c significantly (81%).11
The boronic acid 2c was prepared in two steps: (1)
coupling of 1-bromo-4-iodobenzene with triisopropylsi-
lylethyne (85%) and (2) halogen metal exchange and
workup with triisopropyl borate (90%).12 The boronic acid
2c can be prepared easily in multigram amounts and is
therefore a convenient building block for a sequence of
coupling reactions involving first the boronic acid and
then the alkyne functionality as demonstrated by the
synthesis of compounds 4 via 3c.
Eth yl 3,5-Di(2-a r yleth yn yl)-4-h yd r oxyben zoa tes 8
(Sch em e 2). In contrast to the coupling of 1a with
arylboronic acids, a direct coupling of 1a with phenyl-
ethyne (5a ) in the presence of Pd(PPh3)2Cl2 and CuI in
piperidine7 at room temperature did not give 8a but, in
addition to some starting material, the benzofuran 9a .13
A similar reaction, the Pd/Cu-catalyzed reaction of 2,4,6-
triiodophenol with phenylethyne in triethylamine, has
been reported to give the nonisomerized coupling product
in good yield.14 However, the formation of benzofuran
during such coupling reactions has also been described.15
Consequently, the OH group was protected prior to the
aryl-alkynyl coupling step. Attempts to synthesize the
THP-ether 1b failed.16 The TBDMS ether 1c,17 MEM-
ether 1d , and p-methoxybenzyl (PMB) ether 1e18 were
easily prepared. These compounds showed a varying
suitability for alkynyl-aryl coupling. The coupling of
TBDMS ether 1c with p-tolylethyne (5c) in piperidine
or triethylamine/THF in the presence of Pd(PPh3)2Cl2 and
CuI gave product mixtures consisting mainly of benzo-
furan 9c or containing significant amounts of benzofuran
9c, respectively. Coupling of MEM-ether 1d with aryl-
ethynes 5c,d resulted in formation of 6c,d accompanied
by ca. 10% or more of benzofurans 9c,d . The formation
of benzofuran was easily understood after discovering
that the MEM group of 1d is cleaved in piperidine at
room temperature. The best results were obtained using
the PMB-ether 1e. The coupling reaction of 1e with 5b-d
in piperidine in the presence of Pd(PPh3)2Cl2 and CuI
proceeded fast and quantitatively to give the products
7b-d accompanied by small, varying amounts of corre-
a
Key: (a) Pd(PPh3)2Cl2, CuI, piperidine, rt (7b: 54%); (b)
Pd(PPh3)2Cl2, CuI, THF, Et3N, rt (7c: 80%; 7d : 78%); (c) concd
HCl, EtOH, CH2Cl2, reflux (8d : 92%); (d) TMSCl, SnCl2, anisole,
CH2Cl2, rt (8c: 62%; 8d : 63%). THP ) tetrahydropyran-2-yl;
TBDMS ) tert.butyl-dimethylsilyl; MEM ) methoxyethoxymethyl;
PMB ) 4-methoxybenzyl.
1
sponding benzofurans 9b-d (0-6%; determined by H
NMR spectroscopy19). The formation of benzofurans
indicated that even the PMB-group is labile under the
reaction conditions. Indeed, we found that the PMB-
group is cleaved off slowly when 1e (quantitative cleavage
after a maximum of 15 h) or the coupling products 7b,c
(60-80% cleavage after 22.5 h) are heated to 60 °C in
piperidine. This suggested that control of temperature
and reaction time during the slightly exothermic coupling
reaction is important in order to minimize the extent of
benzofuran formation. Using a base with a lower nucleo-
philicity than that of piperidine may also avoid depro-
tection and consequently benzofuran formation. To test
this hypothesis, a mixture of triethylamine and THF was
used instead of piperidine as the base and solvent for the
coupling reaction of 1e with 5c,d . A quantitative and
(11) Cs2CO3 as the base in Suzuki coupling reactions has been used
occasionally: Littke, A. F.; Fu, G. C. Angew. Chem. 1998, 110, 3586;
Angew. Chem., Int. Ed. Engl. 1998, 37, 3387 and literature therein.
(12) Brown, H. C.; Cole, T. E. Organometallics 1983, 2, 1316.
(13) Benzofurans
9 and 13 have not been isolated from these
experiments. They have been prepared separately from phenols 8 or
12 (Godt, A. Manuscript in preparation). With the help of the known
NMR data of benzofurans 9 and 13, the side product of the deprotection
step could be easily identified as the benzofuran. Characteristic signals
are the doublets of the two protons in ortho position to the ester group
above 8 ppm and the singlet at ca. 7.0 ppm caused by the proton at
the furan ring. Representatively, the analytical data of 9c and 13c
are given in the Supporting Information.
(14) Tao, W.; Nesbitt, S.; Heck, R. F. J . Org. Chem. 1990, 55, 63.
(15) E. g.: (a) Arcadi, A.; Marinelli, F.; Cacchi, S. Synthesis 1986,
749. (b) Kundu, N. G.; Pal, M.; Mahanty, J . S.; De, M. J . Chem. Soc.,
Perkin Trans. 1 1997, 2815.
(16) 3,4-Dihydro-2H-pyran, TsOH monohydrate or pyridinium to-
sylate, diethyl ether, rt or 0 °C.
(17) Preparation according to Corey, E. J .; Venkateswarlu, A. J . Am.
Chem. Soc. 1972, 94, 6190.
(18) Godt, A. J . Org. Chem. 1997, 62, 7471.
(19) Very small amounts of benzofuran 9 were estimated with the
help of the 13C satellites of the singlet corresponding to the protons of
the 4-hydroxybenzoate unit of compounds 7 or 8.

Notes
J . Org. Chem., Vol. 65, No. 9, 2000 2839
Sch em e 3a
clean reaction of 5c (one experiment) and 5d (two
experiments) with 1e resulted. No benzofuran was
detected by 1H NMR spectroscopy. The coupling reaction
in Et3N/THF was extremely slow compared to that in
piperidine: e.g., the degree of conversion of the coupling
of 1e with 5d in Et3N/THF was 23% after 3.5 h and the
reaction was still incomplete after 22 h at room temper-
ature, while the reaction in piperidine was quantitative
after 2.3 h at room temperature.20 Nevertheless, the
reaction in Et3N/THF was quantitative after ca. 44 h.
The final step to form the title compounds 8 was the
deprotection of the phenolic OH-group. Cleavage of the
PMB-ether with ceric ammonium nitrate21 or with DDQ22
was very slow and gave side products. A clean and
quantitative removal of the PMB-group of 7d was achieved
by heating (60 °C, 5.3 h) 7d in CH2Cl2/EtOH in the
presence of concentrated HCl. Applying this procedure
(80 °C, 6.5 h) to 7c gave the hydroxybenzoate 8c
contaminated with ca. 8% of the benzofuran 9c.23 Even
with the milder procedure described by Akiyama et al.24
with SnCl2, TMSCl, and anisole as reagents, the forma-
tion of the hydroxybenzoate 8c was accompanied by
formation of the benzofuran 9c. The amount of 9c
depended on the reaction time: After 2, 3.6, and 6 h at
room temperature 1%, 3%, and 9% of 9c were found in
the crude products.19 Chromatography followed by re-
crystallization gave 8c with less than 1% of the benzo-
furan 9c. Experiments to synthesize the hydroxybenzoate
8b starting from 7b proceeded unsatisfactorily by either
procedure. Heating 7b in CH2Cl2/EtOH in the presence
of concentrated HCl for 2.3 h at 40 °C gave a 4:6 mixture
of the hydroxybenzoate 8b and the benzofuran 9b. The
product obtained from 7b using SnCl2, TMSCl, and
anisole (rt, 45 min) contained, in addition to 8b, about
15% of 9b and ca. 8% of an unidentified side product.
We did not attempt to isolate the hydroxybenzoate 8b
from these mixtures.
Eth yl 3,5-Di(4-ar ylbu tadiyn yl)-4-h ydr oxyben zoates
12 (Sch em e 3). In analogy to the synthesis of the
hydroxybenzoates 8 via the PMB-protected hydroxyben-
zoates 7, the butadiynylic hydroxybenzoates 12 were
synthesized via the PMB-protected hydroxybenzoates 11.
Compounds 11b-d were obtained by coupling the diiodo
compound 1e with 1-aryl-2-(trimethylstannyl)butadiynes
10 in the presence of Pd2(dba)3 and AsPh3 in refluxing
THF.18 Using the O-unprotected diiodo compound 1a
under the same coupling conditions led to only 30%
conversion of 1a , whereas all the stannylbutadiyne 10b
was used up.
A comparison of the results on PMB-removal from
compounds 7b-d shows that compound 7b, carrying
ethoxy substituents, forms benzofuran most easily, while
compound 7d , carrying bromo substituents, resists ben-
zofuran formation under the reaction conditions used for
deprotection. Obviously, an increase in electron density
a
Key: (a) Pd2(dba)3, AsPh3, THF, 60 °C (70-88%); (b) concd
HCl, EtOH, CH2Cl2, reflux; (12c: 81%; 12d : 90%) (c) TMSCl,
SnCl2, anisole, CH2Cl2, rt (12b: 62%; 12c: 62%; 12d : 71%).
in the CC triple bond increases the amount of benzofuran
formed. This suggests that the rate-determining step for
benzofuran formation is an electrophilic attack at the
triple bond. Therefore, because of the lower nucleophi-
licity of a butadiyne moiety compared to an ethyne
moiety, deprotection of the compounds 11b-d was ex-
pected to be less troublesome. Indeed, transformation of
11c,d into hydroxybenzoates 12c,d through heating in
CH2Cl2/EtOH/HCl proceeded cleanly and quantitatively.
The same result was obtained using TMSCl/SnCl2/anisole
in CH2Cl2.24 However the latter procedure gave consider-
ably lower yields (60-70% compared to 80-90% for the
former procedure) due to higher loss of 12c,d upon
removing the accompanying product, di(methoxyphenyl)-
methane, which formed in the reaction of the PMB-
moiety with anisole. Reaction of the donor substituted
compound 11b in refluxing CH2Cl2/EtOH/HCl for 18.5 h
gave a mixture of the hydroxybenzoate 12b and the
(20) Large differences in the reaction rate of alkynyl-aryl-coupling
upon varying the amine have been reported: Alami, M.; Ferri, F.;
Linstrumelle, G. Tetrahedron Lett. 1993, 34, 6403.
(21) E.g.: (a) J ohansson, R.; Samuelsson J ., J . Chem. Soc., Perkin
Trans. 1 1984, 2371. (b) Classon, B.; Garegg, P. J .; Samuelsson, B.
Acta Chem. Scand. 1984, B38, 419.
(22) E.g.: Horita, K.; Yoshioka, T.; Tanaka, T.; Oikawa, Y.; Yone-
mitsu, O. Tetrahedron 1986, 42, 3021.
(23) Formation of benzofuran as a side product upon cleavage of an
o-alkynylphenyl acetate under acidic conditions was described: Arcadi,
A.; Cacchi, S.; Rosario, M. D.; Fabrizi, G.; Marinelli, F. J . Org. Chem.
1996, 61, 9280.
(24) Akiyama, T.; Shima, H.; Ozaki, S. Synlett 1992, 415.

2840 J . Org. Chem., Vol. 65, No. 9, 2000
Notes
7.32 (half of AA′XX′, 2 H, H-3, -5), 1.12 (s, 21 H, CH(CH3)2). 13C
NMR: δ ) 133.4 (C-3,-5), 131.4 (C-2,-6), 122.5 (C-1,-4), 105.9,
92.0 (CtC), 18.6 (CH3), 11.3 (CH). FD-MS: m/z ) 336.5 (100).
Anal. Calcd for C17H25BrSi (337.383): C, 60.52, H 7.47, Br 23.68;
found C 61.40, H 6.94, Br 23.53;
benzofuran 13b (ca. 6%).13 The formation of 13b could
be avoided by applying the alternative reagents TMSCl/
SnCl2/anisole.
Con clu sion
4-(Tr iisop r op ylsilyleth yn yl)p h en ylbor on ic Acid (2c). To
a solution of 1-bromo-4-(triisopropylsilylethynyl)benzene (12.5
g, 37.0 mmol) in THF (250 mL) at -78 °C was added 1.6 M
n-BuLi in hexane (30 mL, 48 mmol). After 30 min at -78 °C,
this cold solution was added via a transfer needle to triisopro-
pylborate (25.4 mL, 110 mmol), which was cooled to -45 °C.12
After complete addition of the aryllithium, the reaction mixture
was allowed to reach room temperature and the reaction mixture
was stirred at room temperature overnight. The reaction mixture
was quenched with 2 N HCl. After the mixture was stirred for
1 h at room temperature, the organic phase was separated and
washed with brine. The combined aqueous phases were extracted
with diethyl ether. The combined organic phases were dried
(MgSO4), and the solvent was removed in vacuo. Flash chroma-
tography (petroleum ether/diethyl ether 1:2 v/v f diethyl ether;
Rf (Et2O) ) 0.76) gave 2c (10 g, 90%) as a colorless solid. In
most cases, the crude product was used for the reaction with
We have developed syntheses for 3,5-diaryl-, 3,5-di-
(arylethynyl)-, and 3,5-di(arylbutadiynyl)-4-hydroxyben-
zoates 3, 4, 8, and 12. The m-terphenylene compounds 3
were obtained by starting with the diiodo compound 1a
and arylboronic acids. Compound 3c is of special interest
because it allows for an extension of the m-terphenylene
unit by alkynyl-aryl coupling as shown by the prepara-
tion of compounds 4.
The reaction of 1a with arylethynes gave primarily
benzofuran 9. The reaction of 1a with 1-aryl-2-(trimeth-
ylstannyl)butadiynes resulted in very low conversion of
1a . Therefore, to synthesize the acetylenic compounds 8
and 12, the OH-group of 1a was protected. PMB was
found to be the most suitable protecting group. Removal
of the PMB-group from the coupling products 7 and 11
was only achieved under acidic conditions. Depending on
the substituents R2 of the compounds 7 and 11 and on
the reaction conditions, this deprotection was accompa-
nied by formation of the benzofurans 9 or 13.
1
1a . H NMR (DMSO): δ ) 8.16 (s, 2 H,OH), 7.77, 7.40 (AA′XX′,
2 H each, ArH), 1.08 (s, 21 H, CH(CH3)2). 13C NMR (DMSO):
δ ) 134.2, 130.5 (C-2,-6, C-3,-5), 123.7 (C-4), 107.4 and 90.6
(CtC), 18.4 (CH3), 10.7 (CH).
E t h yl 3,5-Di[4-(t r iisop r op ylsilylet h yn yl)p h en yl]-4-h y-
d r oxyben zoa te (3c). To the carefully degassed, biphasic mix-
ture of 1a (2.62 g, 6.28 mmol), 4-(triisopropylsilylethynyl)-
phenylboronic acid (2c) (5.70 g, 18.9 mmol), and Cs2CO3 (8.20
g, 25.2 mmol) in acetone (60 mL) and water (20 mL) was added
Pd2(dba)3 (173 mg, 0.19 mmol). The dark mixture was kept at
65 °C for 18 h. After the mixture was cooled to room tempera-
ture, diethyl ether was added. The organic phase was washed
with 2 N HCl, dried (MgSO4), and concentrated in vacuo. Flash
chromatography (petroleum ether/CH2Cl2 4:1 v/v; Rf ) 0.24) gave
3c (3.5 g, 81%) as a colorless solid. Mp: 88 °C dec. 1H NMR: δ
) 7.95 (s, 2 H, HR), 7.58, 7.48 (AA′XX′, 4 H each, Hâ), 5.68 (s, 1
H, OH), 4.35 (q, J ) 7 Hz, 2 H, CH2), 1.36 (t, J ) 7 Hz, 3 H,
CH3), 1.13 (s, 42 H, CH(CH3)2). 13C NMR: δ ) 166.1 (CO2), 153.1
(CR-4), 136.4 (Câ-1), 132.6 (Câ-3, -5), 131.6 (CR-2, -6), 129.2
(Câ-2, -6), 128.3 (CR-3,-5), 123.5, 123.3 (CR-1, Câ-4), 106.6, 91.9
(CtC), 60.9 (CH2), 18.7 (CH(CH3)2), 14.4 (CH2CH3), 11.3 (SiCH).
Exp er im en ta l Section
Gen er a l Meth od s. All reactions were performed under
argon. Solutions were degassed, if necessary, through several
freeze-pump-thaw cycles. THF was distilled from sodium/
benzophenone. Piperidine and triethylamine were dried over
CaH2. Pd(PPh3)2Cl2 was synthesized according to the literature,25
with 2.1 times the amount of methanol, however. Ethyl 3,5-
diiodo-4-hydroxybenzoate 1a ,8 ethyl 3,5-diiodo-4-(4-methoxyben-
zyloxy)benzoate 1e,18 arylethynes 5,18 1-ethoxy-4-iodobenzene,18
and compounds 1118 were synthesized as described. The petro-
leum ether used had a boiling range of 30-40 °C. For flash
chromatography, Merck silica gel (40-63 µm) was used. TLC
was carried out on silica gel coated aluminum foils (Merck
alumina foils 60F254). Unless otherwise specified, NMR spectra
were recorded in CDCl3 as solvent and internal standard on a
300 MHz spectrometer at room temperature. For signal assign-
ment, the carbon multiplicity was determined by a DEPT
experiment. The subscripts R, â, γ, and δ refer to the aromatic
rings.The hydroxybenzoate moiety is named with R. The benzene
unit of the PMB protecting group is named δ. The benzene unit
closest to the hydroxybenzoate moiety is named â and the
residual benzene unit is named γ. For the numbering of the
positions, the ethyl 4-hydroxybenzoate is considered as the
substituted parent compound. The melting points were deter-
mined in open capillaries or with a melting table microscope.
1-Br om o-4-(tr iisop r op ylsilyleth yn yl)ben zen e. To a de-
gassed, cold (ca. 0 °C) solution of 1-bromo-4-iodobenzene (73.84
g, 261 mmol) and triisopropylsilylacetylene (60.9 mL, 272 mmol)
in piperidine (300 mL) were added Pd(PPh3)2Cl2 (1.83 g, 2.61
mmol) and CuI (994 mg, 5.22 mmol). After the reaction mixture
was stirred for 2 h at 0 °C (ice bath) and for a further 15 h at
room temperature, diethyl ether and 2 N HCl (exothermic!) were
added. The organic phase was washed twice with 2 N HCl, and
the combined aqueous phases were extracted with diethyl ether.
The combined organic phases were dried (MgSO4), and the
solvent was removed in vacuo. Distillation (140-145 °C/0.6
mbar) gave 1-bromo-4-(triisopropylsilylethynyl)benzene (75 g,
85%) as a slightly yellow liquid. The material contained most
probably TIPS-CtC-CtC-TIPS (3 mol %; 1H NMR: δ ) 1.09).
Piperidine can be substituted by a 1:1 mixture of THF/piperidine.
In several experiments, the addition of further triisopropylsilyl-
acetylene (0.1-0.3 equiv) was necessary to drive the reaction to
completion. 1H NMR: δ ) 7.42 (half of AA′XX′, 2H, H-2, -6),
Anal. Calcd for
C43H58O3Si2 (679.106): C, 76.05; H, 8.61.
Found: C, 75.95; H, 8.58.
Eth yl 3,5-Di(4-eth yn ylp h en yl)-4-h yd r oxyben zoa te (3d ).
To a solution of 3c (3.40 g, 5.00 mmol) in THF (10 mL) was added
1 M n-Bu4NF in THF (10 mL, 10 mmol) at room temperature.
A yellow precipitate formed slowly. After 2 h at room tempera-
ture, 2 N HCl was added, and the aqueous phase was extracted
with diethyl ether. The combined organic phases were dried
(MgSO4), and the solvent was removed in vacuo. Flash chroma-
tography (petroleum ether/diethyl ether 4:1 v/v; Rf ) 0.58) gave
3d (1.8 g, 99%) as a colorless solid. Mp: 151.4-153.7 °C. 1H
NMR: δ ) 7.95 (s, 2 H, HR), 7.60, 7.50 (AA′XX′, 4 H each, Hâ),
5.74 (s, 1 H, OH), 4.34 (q, J ) 7 Hz, 2 H, CH2), 3.13 (s, 2 H,
CtCH), 1.36 (t, J ) 7 Hz, 3 H, CH3). 13C NMR: δ ) 166.0 (CO2),
153.1 (CR-4), 136.9 (Câ-1), 132.7 (Câ-3, -5), 131.7 (CR-2, -6), 129.3
(Câ-2, -6), 128.2 (CR-3, -5), 123.4 (CR-1), 122.0 (Câ-4), 83.2, 78.2
(CtCH) (both signals appear in the DEPT-135 spectrum with
very low intensity), 61.0 (CH2), 14.4 (CH3). Anal. Calcd for
C25H18O3 (366.416): C, 81.95; H, 4.95. Found: C, 81.92; H, 4.98.
Gen er a l Com m en t on th e Alk yn yl-Ar yl Cou p lin g Usin g
P d (P P h 3)2Cl2, Cu I, a n d Ba se. The reaction is slightly exo-
thermic. Therefore, in the case that larger amounts of starting
materials and/or smaller amounts of solvent are used, cooling
with an ice bath is recommended before the addition of the
catalysts.
E t h yl 3,5-Di[4-(4-et h oxyp h en ylet h yn yl)p h en yl]-4-h y-
d r oxyben zoa te (4a ). To a degassed solution of 3d (1.50 g, 4.09
mmol) and 1-ethoxy-4-iodobenzene (2.44 g, 9.83 mmol) in pip-
eridine (40 mL) were added Pd(PPh3)2Cl2 (69 mg, 0.098 mmol)
and CuI (38 mg, 0.199 mmol). A bright yellow precipitate formed.
After 16 h at room temperature, the reaction mixture was diluted
with CH2Cl2, whereupon the precipitate dissolved. The reaction
mixture was washed with 2 N HCl (exothermic!), and the
combined aqueous phases were extracted with CH2Cl2. The
(25) Heck, R. F. Palladium Reagents in Organic Syntheses; Academic
Press: 1985; p 18.

Notes
J . Org. Chem., Vol. 65, No. 9, 2000 2841
combined organic phases were dried (MgSO4) and concentrated
in vacuo. Flash chromatography (petroleum ether/CH2Cl2 1:1 v/v;
Rf ) 0.35) gave 4a (2.0 g, 81%) as a colorless solid. Mp: 200.3-
0.21 mmol) at room temperature. Soon the solution color turned
dark-yellow to orange. The reaction mixture was stirred at room
temperature for 3.7 h, whereupon water was added. The aqueous
phase was extracted with CH2Cl2, the combined organic phases
were washed with water and dried (Na2SO4), and the solvent
was removed in vacuo. Flash chromatography (petroleum ether/
CH2Cl2 1:1.5 v/v, Rf ) 0.45) gave 5c (624 mg) accompanied by
reaction products of the protecting group and traces of benzo-
furan 9c. Subsequent recrystallization from ethanol (14 mL)
gave 8c (510 mg, 62%), contaminated with less than 1% of
benzofuran 9c, as very fine, colorless needles. Mp: 129.8-130.1
°C. 1H NMR: δ ) 8.10 (s, 2 H, HR), 7.45, 7.17 (AA′XX′, 4 H each,
Hâ), 6.61 (s, 1 H, OH), 4.36 (q, J ) 7 Hz, 2 H, CH2), 2.37 (s, 6 H,
ArCH3), 1.39 (t, J ) 7 Hz, 3 H, CH2CH3). 13C NMR: δ ) 165.1
(CO2Et), 160.0 (CR-4), 139.2 (Câ-4), 133.9 (CR-2,-6), 131.6 (Câ-2,
-6), 129.2 (Câ-3, -5), 123.1 (CR-1), 119.2 (Câ-1), 110.6 (CR-3, -5),
96.3, 81.9 (CtC), 61.1 (CH2), 21.5 (ArCH3), 14.3 (CH2CH3). Anal.
Calcd for C27H22O3 (394.470): C, 82.21; H, 5.62. Found: C, 82.22;
H, 5.73.
Eth yl 3,5-Di[2-(4-br om op h en yl)eth yn yl]-4-h yd r oxyben -
zoa te (8d ). A solution of 7d (1.00 g, 1.55 mmol) in CH2Cl2 (20
mL), ethanol (5 mL), and concentrated HCl (0.9 mL) was stirred
at 60 °C for 5.7 h. After the solution was cooled to room
temperature, water was added, and the organic phase was
washed with water, dried (MgSO4), and concentrated in vacuo.
From the thus-obtained solid, 4-methoxybenzyl alcohol and
4-methoxybenzylethyl ether were distilled off (40-45 °C bath
temperature/0.001 mbar) to give 8d (752 mg, 92%) as an off-
white residue. Mp: 167-168 °C. Anal. Calcd for C25H16Br2O3
(524.220): C, 57.28; H, 3.08. Found: C, 57.27; H, 3.00. For NMR
data see the Supporting Information.
1
202.2 °C. H NMR: δ ) 7.98 (s, 2 H, HR), 7.61, 7.53 (AA′XX′, 4
H each, Hâ), 7.46 (half of AA′XX′, 4 H, Hγ-2,-6), 6.86 (half of
AA′XX′, 4 H, Hγ-3, -5), 5.77 (br s, 1 H, OH), 4.36 (q, J ) 7 Hz, 2
H, CO2CH2), 4.04 (q, J ) 7 Hz, 4 H, ArOCH2), 1.41 (t, J ) 7 Hz,
6 H, ArOCH2CH3), 1.37 (t, J ) 7 Hz, 3 H, CO2CH2CH3). 13C
NMR: δ ) 166.1 (CO2), 159.2 (Cγ-4), 153.2 (CR-4), 135.9 (Câ-1),
133.1 (Cγ-2, -6), 132.0 (Câ-3, -5), 131.6 (CR-2, -6), 129.3 (Câ-2, -6),
128.3 (CR-3, -5), 123.6, 123.3 (CR-1, Câ-4), 115.0 (Cγ-1), 114.6
(Cγ-3, -5), 90.6 (CtCArγ), 87.6 (CtCArγ), 63.5 (ArOCH2), 60.9
(CO2CH2), 14.7 (ArOCH2CH3), 14.4 (CO2CH2CH3). Anal. Calcd
for C41H34O5 (606.718): C, 81.17; H, 5.65. Found: C, 81.02; H,
5.71.
Eth yl 3,5-Di[4-(4-n itr oph en yleth yn yl)ph en yl]-4-h ydr oxy-
ben zoa te (4b). To a degassed solution of 3d (600 mg, 1.64 mmol)
and 1-iodo-4-nitrobenzene (1.10 g, 4.42 mmol) in THF (15 mL)
and triethylamine26 (20 mL) were added Pd(PPh3)2Cl2 (28 mg,
0.04 mmol) and CuI (15 mg, 0.08 mmol). After 16 h at room
temperature, the reaction was worked up as described for 4a .
Flash chromatography (petroleum ether/CH2Cl2 1:3 v/v; Rf )
0.62) gave 4b (880 mg, 80%) as a yellow solid. Mp: 274.6-277.2
°C dec. Anal. Calcd for C37H24N2O7 (608.606): C, 73.02; H, 3.97;
N, 4.60. Found: C, 72.91; H, 4.06; N, 4.45. For NMR data see
the Supporting Information.
Eth yl 3,5-Di[2-(4-eth oxyp h en yl)eth yn yl]-4-(4-m eth oxy-
ben zyloxy)ben zoa te (7b). To a degassed solution of 1e (2.00
g, 3.72 mmol) and (4-ethoxyphenyl)ethyne (5b) (1.20 g, 8.21
mmol) in piperidine (20 mL) were added Pd(PPh3)2Cl2 (26 mg,
0.037 mmol) and CuI (14 mg, 0.074 mmol). The reaction heat
was counterbalanced by cooling with an ice bath for a short time.
After 3 h of stirring at room temperature, the reaction mixture
was cooled with an ice bath and water was added. The product
was extracted into diethyl ether/THF, and the combined organic
phases were washed with saturated aqueous NH4Cl, dried
(MgSO4), and concentrated in vacuo. Filtration through silica
gel (petroleum ether/diethyl ether 1:1 v/v; Rf ) 0.44) followed
by recrystallization from ethanol gave 7b (1.2 g, 54%) as an off-
white solid, free of benzofuran 9b (according to 1H NMR
Alternatively, the deprotection of 8d (1.10 g, 1.71 mmol) was
achieved as described for 8c with TMSCl, SnCl2, and anisole.
The crude product was suspended in diethyl ether to give 8d
(563 mg, 63%) as a colorless solid.
Eth yl 3,5-Di[4-(4-eth oxyp h en yl)bu ta d iyn yl]-4-h yd r oxy-
ben zoa te (12b). To a solution of 11b (620 mg, 1.00 mmol) in
CH2Cl2 (12 mL) were added successively anisole (0.4 mL, 3.7
mmol), trimethylsilyl chloride (0.4 mL, 3.5 mmol), and SnCl2
(19 mg, 0.1 mmol) at room temperature. Soon the solution turned
dark-yellow to orange colored. The reaction mixture was stirred
at room temperature for 2 h, whereupon water was added. The
aqueous phase was saturated with NaCl and then extracted with
THF. The combined organic phases were washed with brine and
dried (Na2SO4), and the solvent was removed in vacuo. The solid
residue was suspended in diethyl ether (7 mL) to give 12b (442
mg) accompanied by traces of products resulting from the pro-
tecting group. Subsequent recrystallization from ethanol con-
taining some acetone gave 12b (326 mg, 62%; the yield was
calculated by taking into account the amount of residual solvent
determined by 1H NMR spectroscopy) as a yellow powder con-
taining ethanol (ca. 4%). Ethanol could be exchanged against
THF by dissolving the product in THF and removing the solvent
in vacuo. Attempts to remove residual THF at room temperature
1
spectroscopy). Mp: 144.8-146.4 °C. H NMR: δ ) 8.10 (s, 2 H,
HR), 7.48, 6.84 (AA′XX′, 2 H each, Hδ), 7.42, 6.87 (AA′XX′, 4 H
each, Hâ), 5.37 (s, 2 H, OCH2Ar), 4.37 (q, J ) 7 Hz, 2 H, CO2CH2),
4.06 (q, J ) 7 Hz, 4 H, ArOCH2), 3.78 (s, 3 H, OCH3), 1.43 (t, J
) 7 Hz, 6 H, ArOCH2CH3), 1.41 (t, J ) 7 Hz, 3 H, CO2CH2CH3).
13C NMR: δ ) 165.2 (CO2Et), 163.3 (CR-4), 159.6 (Cδ-4), 159.3
(Câ-4), 134.1 (CR-2, -6), 133.1 (Câ-2, -6), 130.1 (Cδ-2, -6), 129.2
(Cδ-1), 125.9 (CR-1), 118.4 (CR-3, -5), 114.9 (Câ-1), 114.6 (Câ-3,
-5), 113.7 (Cδ-3, -5), 94.8 and 83.7 (CtC), 75.3 (OCH2Ar), 63.5
(ArOCH2CH3), 61.2 (CO2CH2), 55.2 (OCH3), 14.7 (ArOCH2CH3),
14.3 (CO2CH2CH3). Anal. Calcd for C37H34O6 (574.673): C, 77.33;
H, 5.96. Found: C, 77.30; H, 5.88.
Eth yl 3,5-Di[2-(4-m eth ylp h en yl)eth yn yl]-4-(4-m eth oxy-
ben zyloxy)ben zoa te (7c). To a degassed solution of 1e (2.00
g, 3.72 mmol) and p-tolylethyne (5c) (958 mg, 8.25 mmol) in THF
(15 mL) and Et3N (3 mL, 22 mmol) were added PdCl2(PPh3)2
(52 mg, 0.074 mmol) and CuI (28 mg, 0.15 mmol), whereupon
the reaction mixture turned immediately black. After 44 h of
stirring at room temperature, the reaction mixture was cooled
with an ice bath, and 2 N HCl was added. The aqueous phase
was extracted with diethyl ether. The combined organic phases
were washed with 2 N HCl, which was saturated with NaCl,
dried (MgSO4), and concentrated in vacuo. Flash chromatogra-
phy (petroleum ether/diethyl ether 2:1 v/v; Rf ) 0.37) gave 1.9 g
of a light brown solid that was recrystallized from ethanol (100
mL) to yield 7c (1.53 g, 80%) as a powdery, slightly beige solid.
Mp: 126.6-127.2 °C. Anal. Calcd for C35H30O4 (514.621): C,
81.69; H, 5.88. Found: C, 81.77; H, 5.93. For NMR data see the
Supporting Information.
failed. In one experiment, THF was removed by keeping the
-2
compound at 70 °C/10
mbar for several hours. However,
because 12b occasionally isomerized on heating, it is advisable,
if possible, to use the compound containing residual solvent.
1H NMR: δ ) 8.10 (s, 2 H, HR), 7.46, 6.85 (AA′XX′, 4 H each,
Hâ), 6.52 (s, 1 H, OH), 4.34 (q, J ) 7 Hz, 2 H, CO2CH2), 4.04 (q,
J ) 7 Hz, 4 H, ArOCH2), 1.42 (t, J ) 7 Hz, 6 H, ArOCH2CH3),
1.37 (t, J ) 7 Hz, 3H, CO2CH2CH3). 13C NMR: δ ) 164.6
(CO2Et), 162.6 (CR-4), 160.2 (Câ-4), 135.5 (CR-2, -6), 134.3 (Câ-2,
-6), 123.5 (CR-1), 114.8 (Câ-3, -5), 112.9 (Câ-1), 109.7 (CR-3, -5),
84.2, 81.0 (CtC-CtC), 73.9, 72.1 (CtC-CtC), 63.7 (ArOCH2),
61.3 (CO2CH2), 14.7 (ArOCH2CH3), 14.3 (CO2CH2CH3).
FD-MS: C33H26O5 (502.566) m/z ) 502.7 (100).
Eth yl 3,5-Di[4-(4-m eth ylp h en yl)bu ta d iyn yl]-4-h yd r oxy-
ben zoa te (12c). A solution of 11c (347 mg, 0.62 mmol) in CH2-
Cl2 (20 mL), ethanol (5 mL), and concentrated HCl (0.9 mL) was
refluxed for 17 h. After the solution was cooled to room
temperature, water was added, the aqueous phase was extracted
with THF, and the combined organic phases were washed with
brine and finally dried (Na2SO4). Removal of solvent in vacuo
was followed by recrystallization in ethanol (ca. 70 mL) to give
12c (220 mg, 81%) containing ethanol. Ethanol could be ex-
changed against THF by dissolving the product in THF and
Eth yl 3,5-Di[2-(4-m eth ylp h en yl)eth yn yl]-4-h yd r oxyben -
zoa te (8c). To a solution of 7c (1.07 g, 2.08 mmol) in CH2Cl2
(23 mL) were added successively anisole (0.7 mL, 6.4 mmol),
trimethylsilyl chloride (0.8 mL, 6.3 mmol), and SnCl2 (39 mg,
(26) Use of piperidine instead of triethylamine resulted in addi-
tion of piperidine onto the triple bond of the coupling product 4b.

2842 J . Org. Chem., Vol. 65, No. 9, 2000
Notes
removing the solvent in vacuo. However, then THF (13%) was
tightly included: Even after heating the product to 60 °C/0.01
mbar for 7h, the powder contained THF. FD-MS: C31H22O3
(442.514) m/z ) 221.2 (3), 442.5 (100), 885.8 (5). For NMR data
see the Supporting Information.
Alternatively, the deprotection of 11c (1.95 g, 3.46 mmol) was
achieved as described for 12b with TMSCl, SnCl2, and anisole.
The crude product was suspended in diethyl ether. The precipi-
tate was isolated from the cold (-78 °C) suspension and
recrystallized from ethanol (150 mL)/acetone (50 mL) to give 12c
(1.1 g, 62%) as a pale yellow powder.
Ack n ow led gm en t. We thank J . Thiel for assistance
in the laboratory.
Su p p or tin g In for m a tion Ava ila ble: Detailed experi-
mental procedures and full characterization of the compounds
1d , 3a ,b, 7d , and 12d , NMR data of 4b, 7c, 8d , and 12c, as
well as analytical data of the benzofurans 9c and 13c are
given. This material is available free of charge via the Internet
at http://pubs.acs.org.
J O991907M