An improved sonogashira coupling procedure for the construction of rigid aromatic multifunctional monomers bearing 1,3-substituted acetylenic units

Article abstract of DOI:10.1055/s-2002-19768

The efficient synthesis of rigid multifunctional vinylic monomers 1 and 2 from 3,5-dibromobenzene derivatives and propargyl alcohol via the Sonogashira reaction is reported. For example, a series of 3,5-bis(3-hydroxyprop-1-ynl)benzoate ester derivatives have been prepared efficiently using an improved palladium catalyst system. Subsequent hydrolysis and reaction with 4-vinylaniline afforded a new monomer 2 for use in functional macroporous polymer systems. In addition, Sonogashira and Wittig methodologies have been optimised in order to construct successfully an alternative rigid monomer 1 from 3,5-dibromobenzaldehyde.

Full text of DOI:10.1055/s-2002-19768

LETTER
251
An Improved Sonogashira Coupling Procedure for the Construction of Rigid
Aromatic Multifunctional Monomers Bearing 1,3-Substituted Acetylenic
Units
An
Improved
S
o
o
nogashira
C
u
oupling Proc
i
edure se Davidson,a Keith W. Freebairn,b Andrew T. Russell,a Harish S. Trivedi,b Wayne Hayes*a
a
Department of Chemistry, The University of Reading, Whiteknights, Reading, Berkshire, RG6 6AD, UK
b
GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK
Fax +44(118)9316331; E-mail: w.c.hayes@reading.ac.uk
Received 4 November 2001
The synthesis of monomer 1 employed the conditions
reported4 by Brown et al. for the synthesis of 3,5-dibro-
mobenzaldehyde from 3,5-dibromobenzoic acid via a two
step reduction/selective oxidation process (Scheme 1).
Abstract: The efficient synthesis of rigid multifunctional vinylic
monomers 1 and 2 from 3,5-dibromobenzene derivatives and prop-
argyl alcohol via the Sonogashira reaction is reported. For example,
a series of 3,5-bis(3-hydroxyprop-1-ynl)benzoate ester derivatives
have been prepared efficiently using an improved palladium cata- Employing the original reaction conditions described1 by
lyst system. Subsequent hydrolysis and reaction with 4-vinylaniline
afforded a new monomer 2 for use in functional macroporous poly-
Sonogashira and co-workers (0.4 mol% Pd (PPh3)2Cl2, 0.8
mol% CuI, triethylamine, THF) in conjunction with 3,5-
mer systems. In addition, Sonogashira and Wittig methodologies
dibromobenzaldehyde and propargyl alcohol, the key in-
have been optimised in order to construct successfully an alternative
termediate 3,5-bis(3-hydroxyprop-1-yl)benzaldehyde 3
rigid monomer 1 from 3,5-dibromobenzaldehyde.
was constructed in good yield (Table, entry 1). The hy-
Key words: Sonogashira reaction, palladium, cross-coupling, or-
droxyl moieties of 3 were then protected in the form of
ganometallic reagents, tri-2-furylphosphine
their corresponding tert-butyldimethylsilyl (TBDMS)
ethers. Subsequent conversion of the aldehyde group of
the protected diol 4 to the corresponding olefin 5 employ-
The palladium(0)/copper(I) halide catalysed coupling of
ing standard Wittig conditions5 followed by deprotection
terminal alkynes with aryl or alkenyl halides, first
of the TBDMS groups afforded the desired monomer 1 in
reported1 by Sonogashira and co-workers, is a widely
96% yield.
used method for the synthesis of arylalkynes and conju-
gated enynes.2 As part of our research towards the synthe-
sis of novel rigid vinylic monomers 1 and 2 (Figure) for
use in imprinted polymer systems,3 an efficient and robust
procedure for the coupling of propargyl alcohol to a range
of 3,5-dibromobenzene derivatives was required. Conse-
quently, use of Sonogashira coupling methodologies was
investigated and the results of these studies are reported
herein.
In addition to monomer 1, novel rigid monomers such as
2 (Figure), comprised of 3,5-bis-acetylenated aromatic
units tethered to a polymerisable vinylic group, were also
targeted to enable structure-property relationships of the
resultant imprinted polymers to be studied. The approach
used to obtain monomers such as 2 also involved use of
the palladium mediated cross-couplings of propargyl al-
cohol to 3,5-dibromobenzoic acid ethyl ester (Scheme 2).
However, in stark contrast to monomer 1, the synthesis of
monomer 2 required significant modification of the Sono-
gashira-based methodologies.
Under the original coupling conditions (Table, entry 2),
the desired bis-acetylenic product 6a was not isolated,
only a moderate yield of mono-substituted product 7a was
obtained. This effect has also been observed6 by Krause
and co-workers in the coupling of trimethylsilylacetylene
to methyl bromobenzoate derivatives and higher catalyst
loadings were found to increase cross-coupling yields.6
However, in the case of 6a, this approach proved ineffec-
tive (Table, entry 3). In light of these initial disappointing
results, a range of different palladium catalyst and ligand
combinations were screened in order to optimise the coup-
ling of propargyl alcohol to 3,5-dibromobenzoic acid eth-
yl ester (see Table). The catalytic system PdCl2/PPh3 re-
ported by Philp et al.7 (Table, entry 4) for the successful
coupling of propargyl alcohol to 3,5-substituted halo-
genobenzenes unfortunately failed to yield the desired
product 6a. Several reports have detailed the use of
N
O
H
OH
OH
1
OH
OH
2
Figure
Synlett 2002, No. 2, 01 02 2002. Article Identifier:
1437-2096,E;2002,0,02,0251,0254,ftx,en;G32401ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

252
L. Davidson et al.
LETTER
dium salts such as Pd(OAc)2 in the presence of Ph4PX
(where X = Cl, Br, I) in Heck type arylations of unreactive
aryl halides. This catalyst combination proved almost in-
active for the Sonogashira coupling of propargyl alcohol
to 3,5-dibromobenzoic acid ethyl ester, (Table, entry 6)
with only a low yield of the mono-acetylenic ester 7a ob-
tained. Subsequent combination of the catalyst Pd(dba)2
with Ph4PCl also proved unsuccessful (Table, entry 7).
O
OH
O
i. H3B:S(CH3)2, THF, 70 °C
ii. PCC, CH2Cl2, 40 °C
95%
Br
Br
Br
Br
Pd(PPh3)2Cl2
CuI, Et3N, THF
70 °C
OH
The prolonged reaction times of the procedures described
above in conjunction with inefficient cross-couplings led
to the consideration of the use of the tri-2-
furylphosphine12 (TFP) ligand. Farina and co-workers13
first reported use of the TFP ligand in Stille cross-cou-
pling reactions, demonstrating an increased rate of reac-
tion that was attributed to the low electron donating ability
of the TFP ligand. In addition, Vasella and co-workers
have observed14 that palladium catalysts incorporating the
TFP ligand are the most effective systems for the cross-
coupling of THP protected propargyl alcohol with iodo-
alkynes. Therefore, in light of these reports, the efficiency
of the TFP ligand was tested in the Sonogashira coupling
of propargyl alcohol to 3,5-dibromobenzoic acid ethyl es-
ter. Initial use of the TFP ligand in combination with the
Pd2(dba)3 catalyst (Table, entry 8) was disappointing and
afforded poor results. None of the bis-acetylenic ethyl es-
ter 6a was isolated, and a high yield of a by-product incor-
porating the furyl unit was isolated. Buchwald et al. have
reported15 the successful use of the catalyst system Pd(Ph-
CN)2Cl2 in the Sonogashira coupling of aryl bromides at
room temperature. Consequently, the TFP ligand was uti-
lised in combination with the Pd(PhCN)2Cl2 species (Ta-
ble, entry 9) and delivered an acceptable yield16 of the
desired 3,5-bis(3-hydroxyprop-1-ynl)benzoic acid ethyl
ester 6a in a significantly shorter reaction time and a dra-
matic increase in the yield per coupling (up to 65%). Sub-
sequent hydrolysis of the ethyl ester functionality to the
corresponding carboxylic acid, followed by protection of
the hydroxyl groups as their corresponding TBDMS
72%
O
O
TBDMSCl
Imidazole
DMF
r.t.
74%
OTBDMS
OTBDMS
OH
OH
4
3
i. NaH, Ph3PCH3Br, THF, 70 °C: 4
5
ii. TBAF , THF, AcOH
96%
OH
OH
1
Scheme 1
Pd2(dba)3 or Pd(dba)2 in the presence of phosphine
ligands as effective catalysts in the Sonogashira reac-
tion.8–10 However, in the case of 6a, this catalytic system
required extensive heating in order to afford the desired
product in moderate yield (Table, entry 5). Reetz et al.11
have reported high catalytic activity from the use of palla-
R
R
R
OH
+
Br
Pd(0)
Br
Br
CuI, Ligand,
THF,∆
OH
OH
OH
7a-d
6a-d
R
i. LiOH, H2O
ii. TBDMSCl, Imidazole, DMF
CO2Et
a
b
c
d
CO2Me
N
O
i
i. EDCI, HOBt.H2O
CO2 Pr
CO2H
H
t
CO2 Bu
NH2
ii. TBAF, THF, AcOH
OTBDMS
OH
OTBDMS
OH
8
2
Scheme 2
Synlett 2002, No. 2, 251–254 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
An Improved Sonogashira Coupling Procedure
253
Table Cross-coupling of Propargyl Alcohol to 3,5-Dibromo-benzene Derivatives
Entrya
R
Pd catalyst (mol%)
Ligand (mol%)
CuI (mol%)
Yieldb (%)
6
7
1
2
CHO
Pd(PPh3)2Cl2 (0.4)
Pd (PPh3)2Cl2 (0.4)
Pd (PPh3)2Cl2 (1.1)c
PdCl2 (0.5)
n/a
0.8
0.8
4.3
0.5
0.4
8
72
0
21
54
42
35
62
10
2
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Me
CO2-i-Pr
CO2-t-Bu
n/a
3
n/a
0
4
PPh3 (1)
PPh3 (2)
Ph4PCl (2.4)
Ph4PCl (1)
TFPd (1.3)
TFP (1.3)
AsPh3 (1.3)
TFP (1.3)
TFP (1.3)
TFP (1.3)
0
5
Pd(dba)2 (0.4)
34
0
6
Pd(OAc)2 (4)
7
Pd(dba)2 (0.05)
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0
8
Pd2(dba)3 (0.6)
0
33
47
61
44
61
52
9
Pd(PhCN)2Cl2 (0.6)
Pd(PhCN)2Cl2 (0.6)
Pd(PhCN)2Cl2 (0.6)
Pd(PhCN)2Cl2 (0.6)
Pd(PhCN)2Cl2 (0.6)
42
0
10
11
12
13
10
22
21
a In all cases, reactions were performed in refluxing THF with addition of 2.5 equiv triethylamine (distilled from calcium sulfate).
b Yields refer to compounds isolated by column chromatography on silica gel. All compounds were characterised completely, and were in full
agreement with structures.
c With addition of 2.7 equiv DBU.
d TFP = tri-2-furylphosphine.
ethers afforded intermediate 8. EDCI mediated amidation the yield whichever ester was substituted for the original
with 4-vinylaniline and subsequent deprotection of the ethyl moiety. In the case of all the 3,5-dibrominated aro-
TBDMS groups afforded the required vinylic monomer 2 matic esters examined, moderate yields of the required
in an acceptable yield of 72%.
bis-acetylenic esters 6b–d were obtained (Table, entries
11–13). Only in the case of 3,5-dibromobenzoic acid me-
thyl ester was a low yield of the bis-acetylenic product 6b
observed.
In addition to the TFP ligand, Farina and co-workers have
studied the use of other ligands of low donor ability in the
Stille reaction, such as the triphenylarsine ligand.17 Subse-
quent mixing of this ligand with sources of palladium(0) In summary, an improved method for the Sonogashira
afforded catalysts that afforded fast coupling rates, but coupling of acetylenic systems to a range of 3,5-dibro-
that were relatively unstable during the course of the reac- mobenzoate ester derivatives has been developed en-
tion in comparison to the TFP derived systems. Compara- abling the synthesis of several new rigid functional vinylic
ble results were obtained in this study upon examination monomer systems. The catalyst Pd(PhCN)2Cl2 in con-
of the Pd(PhCN)2Cl2/triphenylarsine and Pd(PhCN)2Cl2/ junction with tri-2-furylphosphine afforded successfully
TFP systems. Therefore, although the triphenylarsine the desired 3,5-bis(3-hydroxyprop-1-ynl)benzoic acid
ligand did increase the rate of formation of the mono-acet- ethyl ester 6a from the cross-coupling of propargyl alco-
ylenic product 7a, the catalyst appeared to decompose be- hol to the 3,5-dibromobenzoic acid ethyl ester substrate in
fore the desired bis-acetylenic product 6a could be acceptable yields with concomitant short reaction times.
formed, and thus only product 7a was isolated (Table, en- This catalytic combination also proved to be active for the
try 10).
cross coupling of propargyl alcohol to other ester deriva-
tives of 3,5-dibromobenzoic acid.
Having uncovered that the enhanced reactivity of the
Pd(PhCN)2Cl2/TFP catalyst allows formation of the bis-
acetylenated derivative 6a, presumably via the intermedi-
acy of the bromide 7a, we then examined the effect of
variations of the ester functionality in the starting material
upon the efficiency of this process (Scheme 2). This study
proved surprisingly important with a noticeable change in
Acknowledgement
LD would like to thank BBSRC and GlaxoSmithKline for funding.
In addition, the authors would like to thank Mr Neil Carter for hel-
pful suggestions at the outset of this work.
Synlett 2002, No. 2, 251–254 ISSN 0936-5214 © Thieme Stuttgart · New York

254
L. Davidson et al.
LETTER
(15) Hundertmark, T.; Littke, A. F.; Buchwald, S. L.; Fu, G. C.
Org. Lett. 2000, 2, 1729.
References
(1) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron
Lett. 1975, 4467. (b) Sonogashira, K. In Comprehensive
Organic Synthesis, Vol. 3; Trost, B. M.; Fleming, I., Eds.;
Pergamon Press: New York, 1991, 521.
(2) (a) Nicolaou, K. C.; Hwang, C.-K.; Smith, A. L.;
Wendeborn, S. V. J. Am. Chem. Soc. 1990, 112, 7416.
(b) Nicolaou, K. C.; Smith, A. L.; Wenderborn, S. V.;
Hwang, C.-K. J. Am. Chem. Soc. 1991, 113, 3106.
(3) For excellent reviews of molecular imprinted polymers, see:
(a) Wulff, G. Angew. Chem., Int. Ed. Engl. 1995, 34, 1812.
(b) Whitcombe, M. J.; Vulfson, E. N. Adv. Mater. 2001, 13,
467.
(4) Brown, H. C.; Gundu Rao, C.; Kulkarni, S. V. Synthesis
1979, 704.
(5) Clark, R. D.; Jahinger, J. Org. Chem. 1989, 54, 1174.
(6) Thorand, S.; Krause, N. J. Org. Chem. 1998, 63, 8551.
(7) Robinson, J. M. A.; Kariuki, B. M.; Harris, D. M.; Philp, D.
J. Chem. Soc., Perkin Trans. 2 1998, 2459.
(16) Typical Procedure for the Preparation of 6a:
Bisbenzonitriledichloropalladium (75 mg, 0.20 mmol) and
copper iodide (25 mg, 0.10 mmol) were added to a dry round
bottomed flask which was purged with argon and filled with
dry THF (10 mL). Tri-2-furylphoshine (94 mg, 0.40 mmol)
and triethylamine (1.1 mL, 7.80 mmol) were added,
followed by 3,5-dibromobenzoic acid ethyl ester (1.01 g,
3.30 mmol). The reaction was stirred at r.t. for 20 min.
Propargyl alcohol (0.55 g, 9.80 mmol) was added gradually
over 20 min, and the reaction was refluxed under argon for
10 h. The residue of palladium salts was filtered and washed
with THF. The combined filtrate and washings were
evaporated under reduced pressure. The residue was taken
up in chloroform (50 mL) and washed with 1 M hydrochloric
acid (20 mL) followed by brine (2 20 mL). The combined
organic layers were dried over sodium sulfate, filtered at the
pump and concentrated in vacuo to yield a brown oil.
Subsequent purification using column chromatography
(SiO2, 6:4 CH2Cl2:EtOAc) afforded a white solid (mp 163–
164 °C, 0.351 g, 42%).
(8) Böhm, V. P. W.; Hermann, W. A. Eur. J. Org. Chem. 2000,
3679.
1H NMR (250 MHz, CDCl3): = 1.17 (t, 3 H, J = 7.1 Hz,
CH3), 4.22 (q, 2 H, J = 7.1 Hz, CH2), 4.42 (s, 4 H, 2 CH2),
7.43 (t, 1 H, J = 1.6 Hz, ArH), 7.86 (d, 2 H, J = 1.6 Hz, ArH).
13C NMR (67.5 MHz, CDCl3): = 13.2 (CH3), 50.2 (2 CH2),
60.6 (CH2), 82.5 (2 C C), 88.1 (2 C C), 122.3
(2 ArCH), 129.7 (ArCH), 131.3 (2 ArC-C), 137.3 (ArC-
COOEt), 164.4 (C=O); IR: max 666, 723, 1414, 1462, 1585,
1735, 2354, 2856, 2923 cm–1; m/z (TOF MS ES+) mobile
phase 70:30 CH3CN:0.05 M NH4OAc(aq), flow injection:
calculated for C15H14O4 258.2732, found 792.3010 [3 M +
NH4]+, 534.2120 [2 M + NH4]+, 517.1837 [2 M + H]+,
481.1641 [2 M + H – 2 H2O]+, 300.1233 [MH + CH3CN]+,
259.0965 [MH+].
(9) Shen, W.; Thomas, S. A. Org. Lett. 2000, 2, 2857.
(10) Mori, A.; Kawashima, J.; Shimada, T.; Suguro, M.;
Hirabayashi, K.; Nishihara, Y. Org. Lett. 2000, 2, 2935.
(11) (a) Reetz, M. T.; Lohmer, G.; Schwickardi, R. Angew.
Chem. Int. Ed. 1998, 37, 481. (b) Reetz, M. T.;
Wetsermann, E.; Lohmer, R.; Lohmer, G. Tetrahedron Lett.
1998, 39, 8449.
(12) For a comprehensive review of the use of 2-furylphosphines
as ligands in palladium mediated reactions see: Andersen, N.
G.; Keay, B. A. Chem. Rev. 2001, 101, 997.
(13) Farina, V.; Baker, S. R.; Benigni, D. A.; Sapino, C.
Tetrahedron Lett. 1988, 29, 5739.
(14) Cai, C.; Vasella, A. Helv. Chem. Acta 1995, 78, 2053.
(17) Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585.
Synlett 2002, No. 2, 251–254 ISSN 0936-5214 © Thieme Stuttgart · New York