Synthesis of sulfur-containing aryl and heteroaryl vinyls via Suzuki-Miyaura cross-coupling for the preparation of SERS-active polymers

Article abstract of DOI:10.1016/j.tetlet.2009.07.061

The preparation of sulfur-containing aryl and heteroaryl vinyl co-monomers via Suzuki-Miyaura cross-coupling between the corresponding mercaptomethyl arylboronates and in situ-generated vinyl bromides is described. Surface-enhanced Raman scattering (SERS) studies of the target compounds on gold nanoparticles confirmed their potential as spectroscopic tags in the fabrication of SERS-encoded polymers for combinatorial screening and biomedical diagnostics.

Full text of DOI:10.1016/j.tetlet.2009.07.061

Tetrahedron Letters 50 (2009) 5467–5469
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of sulfur-containing aryl and heteroaryl vinyls via Suzuki–Miyaura
cross-coupling for the preparation of SERS-active polymers
Rolando Perez-Pineiro a,b, Sheng Dai a, Ramon Alvarez-Puebla a, James Wigginton a,
Baker Jawabrah Al-Hourani a,b, Hicham Fenniri a,b,
*
a National Institute for Nanotechnology, National Research Council, University of Alberta, 11421 Saskatchewan Drive, Edmonton, AB, Canada T6G 2M9
b Department of Chemistry, University of Alberta, 11421 Saskatchewan Drive, Edmonton, AB, Canada T6G 2M9
a r t i c l e i n f o
a b s t r a c t
Article history:
The preparation of sulfur-containing aryl and heteroaryl vinyl co-monomers via Suzuki–Miyaura cross-
coupling between the corresponding mercaptomethyl arylboronates and in situ-generated vinyl bro-
mides is described. Surface-enhanced Raman scattering (SERS) studies of the target compounds on gold
nanoparticles confirmed their potential as spectroscopic tags in the fabrication of SERS-encoded poly-
mers for combinatorial screening and biomedical diagnostics.
Received 29 April 2009
Revised 7 July 2009
Accepted 9 July 2009
Available online 17 July 2009
Ó 2009 Elsevier Ltd. All rights reserved.
The bar-coded resins (BCRs) were recently introduced for appli-
cations in combinatorial synthesis and screening,1 and for biomed-
ical diagnostics.2 The defining characteristic of the BCRs is their
preparation from spectroscopically active styrene co-monomers
displaying unique IR and Raman vibrational fingerprints. Using
the styrene co-monomers’ substitution pattern as the source of
spectral diversity, over 600 BCRs were generated from a small set
of unique styrene co-monomers.3 The BCRs can be identified using
hyperspectral4 and/or time-of-flight secondary ion mass spectrom-
etry5 imaging/mapping.
of a second.8 To take advantage of the SERS effect, the encoded
polymer must be chemically or physically adsorbed on the surface
of a SERS-active nanoparticle (silver or gold).9 A key step toward
this goal requires the synthesis of a new family of methylthio sty-
rene derivatives that we describe in this report along with their
characterization by Raman and SERS spectroscopies. Because of
their high affinity for metallic surfaces, we reasoned that the thio-
ether groups would adsorb on the nanoparticle surface to generate
a self-assembled monolayer, which can then be copolymerized
with a styrene co-monomer in a suspension polymerization set-
up1 to generate SERS-active BCRs.
A potentially important application for the BCRs is in Dual
REcursive Deconvolution (DRED), a strategy devised for the rapid
screening of resin-supported combinatorial libraries.6 DRED oper-
ates through the iterative identification of the first and last ran-
domized positions of active members in a combinatorial library
generated through split synthesis. The last building block can be
readily obtained from pool screening after the last step of library
generation while identification of the first randomized position
could be determined from the BCR’s vibrational fingerprint. To this
end we developed a rapid bead-identification strategy based on Ra-
man spectroscopy.4 Although this method is limited by low signal-
to-noise ratio, we have been able to record reliable spectra of the
BCRs in 10 ms using state-of-the-art instrumentation,4 which
translates into a screening speed of 10–100 beads/s. To further
push this limit and reduce the cost associated with the Raman
detection set-up, we opted to design a new family of metal nano-
particle–BCR (NP–BCR) composites that can be detected with very
high sensitivity using surface-enhanced Raman scattering (SERS).7
With enhancement factors reaching 1011 relative to Raman scatter-
ing, thousands of beads could in principle be classified in a fraction
Chart 1 shows sulfide-containing aryl and heteroaryl vinyl com-
pounds obtained via Pd-catalyzed Suzuki cross-coupling between
* Corresponding author. Tel.: +1 780 641 1750; fax: +1 780 641 1601.
E-mail address: hicham.fenniri@ualberta.ca (H. Fenniri).
Chart 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.061

5468
R. Perez-Pineiro et al. / Tetrahedron Letters 50 (2009) 5467–5469
vinyl bromide generated in situ and the corresponding aryl/hetero-
aryl boronic acids. This strategy differs from our previously re-
ported method10 for thioacetyl styrene derivatives not only from
the synthetic point of view but also from a practical perspective.
The thioethers prepared here are anticipated to be chemically
more stable, thus preventing undesired cross-linking, known to
dramatically affect the physical properties of the beads such as
swelling, porosity, and on-bead reactivity.1b
phines was recently reported.21 Finally, the cross-coupling reaction
of 6-(mercaptomethyl)pyridin-3-ylboronic acid was also tested
and the corresponding vinyl derivative 1e was obtained in low
yields. In this case the major reaction product identified was the
2-(methylthio)pyridine resulting from a thermal protodeborona-
tion process upon prolonged heating.
To test the potential of compounds 1a–e in the preparation of
SERS-active BCRs, the Raman spectra of co-monomers 1a–e were
recorded and compared with the corresponding predicted spectra.
Furthermore the SERS spectra were recorded in the presence of a
Au(0) nanoparticle (Au–NP) solution22 (Fig. 1). In all cases, the
predicted spectra for the pure compounds correlated well with
the experimental Raman and SERS spectra. While the Raman
experiments were carried out on the bulk material, the SERS
spectra were recorded using dilute solutions of each co-monomer
(ꢀ10À5 M), thus confirming the coordination of the mercaptom-
ethyl moiety onto the Au–NP. The significant enhancement of
the C–S stretching vibrational mode is further evidence of the
coordination to the Au–NP surface. Table S1 summarizes the
assignment of the most characteristic Raman and SERS bands
for each co-monomer. From these data, it is clear that each co-
monomer features a unique vibrational spectrum, which is a
key requisite for their utilization in the preparation of a library
of SERS-active BCRs.1
Mercaptomethyl styrenes have previously been obtained
either by dehydration of (methylthiophenyl) methanol in the
11
presence of Al2O3 or by reaction of Grignard reagents from
halo-(alkyl)styrenes with dimethyl disulfide.12 Palladium-cata-
lyzed cross-coupling reactions are efficient to introduce a vinyl
group onto aromatic rings. Examples covering the use of potas-
sium vinyl-trifluorborate,13 vinyl-tributyltin,14 trivinyl-indium,15
vinyl-magnesium,16 vinyl-polysiloxane,17 and vinyl-triethylsi-
lane18 have been extensively reviewed in the recent literature.
However, the use of sulfur-containing substrates in vinylation
reactions has not received as much attention.19,20 Recently Lando
et al. reported a simple and efficient protocol for the synthesis of
several functionalized styrenes via Pd-catalyzed Suzuki cross-cou-
pling between arylboronic acids and vinyl bromide generated
in situ from 1,2-dibromo ethane.20 Taking into account the sim-
plicity of this experimental procedure, the use of mild reaction
conditions, and its functional group tolerance, we decided to ex-
tend its scope to the preparation of sulfur-containing aryl and
heteroaryl vinyl co-monomers.
Monitoring of the reaction progress by GC–MS confirmed the
formation of the desired compounds. After final work-up and puri-
fication by flash chromatography, the three mercaptomethyl sty-
rene isomers, Table 1 (entry a–c), were isolated in moderate
yields as the main reaction products. Interestingly, the most steri-
cally hindered ortho-mercaptomethyl styrene derivative 1c was
obtained in higher yield. A possible explanation for this result
could lie in the co-existence of a parallel competing homocoupling
reaction inferred from the concomitant formation of the
corresponding bis-mercaptomethyl-biphenyls 2a–c (Chart 1). We
then explored the synthesis of vinyl heterocyclic compounds. The
3-vinylthiophene co-monomer (1d) was previously obtained via
Pd-catalyzed cross-coupling of 3-bromo thiophene with potassium
vinyltrifluorborate13 or triethyl vinylsilanes.18 However, these pro-
cedures tend to have long reaction times and/or poor yields, com-
monly associated with an inefficient oxidative addition step of the
thiophene ring to the Pd(0) complex. In this context we have found
that involvement of this heterocycle in the transmetalation step to
the Pd(II) center, as a thiophene-3-ylboronic acid derivative,
greatly improves the synthetic outcome of co-monomer 1d. Con-
sistent with this result, a successful catalytic coupling reaction
between thiophene boronic acid with heteroaryl bromides or acti-
vated heteroaryl chlorides in the presence of Pd(II) and monophos-
Table 1
Results of the Pd-catalyzed cross-coupling reaction between 1,2-dibromoethane and
the corresponding aryl or heteroaryl boronic acids
KOH/THF
100°C, 1h
R1B(OH)2
Br
R1
R1 R1
Br
Br
Pd(OAc)2/PPh3
MeOH, 100°C, 1h
1
2
Entry
Product 1
Yielda (%) 1:2
a
b
c
d
e
1a
1b
1c
1d
1e
41:4.8
33:12
51:2.5
60:2.8
17:0
a
Isolated yields for cross-coupling product. All compounds were characterized
by 1H/13C NMR, Raman, SERS, GC/MS, and MS.
Figure 1. Calculated, Raman, and SERS spectra for compounds 1a–e.

R. Perez-Pineiro et al. / Tetrahedron Letters 50 (2009) 5467–5469
5469
7. (a) Farah, A. A.; Alvarez-Puebla, R. A.; Fenniri, H. J. Coll. Interf. Sci. 2008, 319,
572–576; (b) Farah, A. A.; Bravo-Vasquez, J.-P.; Alvarez-Puebla, R. A.; Cho, J.-Y.;
Fenniri, H. Small 2009. doi:10.1002/smll.200801398.
8. (a) Camden, J. P.; Dieringer, J. A.; Van Duyne, R. P. Acc. Chem. Res. 2008, 41,
1662–1673; (b) Kneipp, K.; Kneipp, H. Acc. Chem. Res. 2006, 39, 443–450; (c)
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Acknowledgments
We thank NRC—Canada, NSERC—Canada, and the US National
Institutes of Health (NIH EB03824) for supporting this program.
Supplementary data
9. (a) Zhang, J.; Gao, Y.; Alvarez-Puebla, R.; Fenniri, H.; Buriak, J. M. Adv. Mat. 2006,
18, 3233–3237; (b) Alvarez-Puebla, R. A.; Cui, B.; Bravo-Vasquez, J.-P.; Veres, T.;
Fenniri, H. J. Phys. Chem. C 2007, 1, 6720–6723; (c) Alvarez-Puebla, R. A.; Bravo-
Vasquez, J.-P.; Cui, B.; Veres, T.; Fenniri, H. ChemMedChem 2007, 2, 1165–1167;
(d) Alvarez-Puebla, R.; Bravo-Vasquez, J.-P.; Cheben, P.; Xu, D.-X.; Waldron, P.;
Fenniri, H. J. Coll. Interf. Sci. 2009, 333, 237–241.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.07.061.
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