Immobilized boronic acid for Suzuki-Miyaura coupling: Application to the generation of pharmacologically relevant molecules

Article abstract of DOI:10.1039/c7ra06662g

An synthetic strategy for the generation of a variety of biaryl and related derivatives, based on Suzuki-Miyaura coupling using immobilized boronic acid, is described. The importance of the methodology was demonstrated by its further application to biologically interesting compounds such as 4-biaryl-β-lactams, descripted as cholesterol absorption inhibitors and anti-MRSA active agents, neoflavonoids, imidazoles, isoxazolines, among others.

Full text of DOI:10.1039/c7ra06662g

RSC Advances
View Article Online
View Journal | View Issue
PAPER
Immobilized boronic acid for Suzuki–Miyaura
coupling: application to the generation of
pharmacologically relevant molecules†
Cite this: RSC Adv., 2017, 7, 34994
*
M. Martinez-Amezaga, C. M. L. Delpiccolo and E. G. Mata
An synthetic strategy for the generation of a variety of biaryl and related derivatives, based on Suzuki–
Miyaura coupling using immobilized boronic acid, is described. The importance of the methodology was
demonstrated by its further application to biologically interesting compounds such as 4-biaryl-b-
lactams, descripted as cholesterol absorption inhibitors and anti-MRSA active agents, neoflavonoids,
imidazoles, isoxazolines, among others.
Received 14th June 2017
Accepted 5th July 2017
DOI: 10.1039/c7ra06662g
rsc.li/rsc-advances
Introduction
Small organic molecules are of particular interest for medicinal
chemistry and drug discovery not only because they constitute
most of the medicines marketed today, but also because they
are useful as probes to dissect biological systems providing
information which eventually leads to the discovery of new drug
targets.1 Through recent decades, solid-phase organic synthesis
(SPOS) has become an important tool for the generation of
structurally diverse small organic molecules including appli-
cation to a series of very creative strategies such as diversity-
oriented synthesis (DOS).2 Apart from the well-known advan-
tages, like the fast isolation of resin-bound intermediates/
products by ltering the resin beads, the use of high-boiling
solvents and the easy manipulation,3 solid-phase organic
synthesis has raised interest in metal-catalyzed cross-coupling
reactions since undesirable soluble homodimers can be
removed by ltration providing chemoselectivity, while
anchoring one of the substrates makes its homodimerization
a discouraging process due to the site isolation.4 An extra
benet can be considered within the principles of green
chemistry: SPOS signicantly reduces solvent waste by avoiding
many chromatographic purications (Scheme 1).5
Scheme 1 Cross-coupling reaction on solid-phase synthesis.
are among the most remarkable features of this transformation,
together with the fact that the non-toxic organoboron reagents
can be easily synthesized by different procedures and exhibit
high stability to air and moisture.6 One of the main drawbacks
of Suzuki–Miyaura cross-coupling reaction is the formation of
undesirable boronic acid homocoupling by-products.7 This
problem can be avoided by a rigorous exclusion of oxygen
giving, however, less support to the claim that Suzuki–Miyaura
coupling is an “easy to handle” reaction. Site segregation in the
solid-supported version of this reaction, makes self-coupling
between immobilized boronic acid moieties a less favorable
process. Many examples of this transformation on solid phase
have been reported in the literature,8 however, very few are
based on immobilized boronic acids.9
The Suzuki–Miyaura coupling is, arguably, one of the most
versatile and successful synthetic tool for formation of carbon–
carbon bonds. The Suzuki–Miyaura reaction is basically the
reaction of arylboronic acids with aryl halides or pseudo halides
under palladium catalyst to obtain biaryl fragments, which are
present in many biologically relevant molecules. The mild
reaction conditions and the broad functional groups tolerance
Results and discussion
For some years, our research group has been focused on the
mentioned advantage of the combination of solid-phase
synthesis and metal-catalyzed chemistry to build libraries of
pharmacologically relevant molecules.10 In the search for
alternative source of immobilized biaryl-containing b-lactam
derivatives we decided to study the underdeveloped but prom-
ising solid-phase Suzuki–Miyaura reaction with a boronic acid
´
´
Instituto de Quımica Rosario (CONICET-UNR), Facultad de Ciencias Bioquımicas y
´
Farmaceuticas, Universidad Nacional de Rosario, Suipacha 531, 2000 Rosario,
Argentina. E-mail: mata@iquir-conicet.gov.ar; Fax: +54 341 4370477
† Electronic supplementary information (ESI) available: Experimental details,
spectroscopic data: 1H NMR and 13C NMR spectra. See DOI: 10.1039/c7ra06662g
34994 | RSC Adv., 2017, 7, 34994–35003
This journal is © The Royal Society of Chemistry 2017

View Article Online
Paper
RSC Advances
Table 1 Optimization of conditions for the solid-phase version of Suzuki–Miyaura coupling with immobilized boronic acids
Entry
Equiv. of iodide 2a
Pd catalyst (mol%)
Base (equiv.)
Solvent
Conditionsa
Yieldb (%)
1
2
3
4
5
6
7
8
9
1
1
4
1
4
4
4
4
4
Pd(OAc)2 (5)
PdCl2dppf (5)
Pd(PPh3)4 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
K2CO3 (1.2)
K2CO3 (1.2)
Cs2CO3 (1.2)
K2CO3 (1.2)
K2CO3 (2.4)
K2CO3 (2.4)
K2CO3 0.5 M (2.4)
K2CO3 0.5 M (2.4)
K2CO3 0.5 M (2.4)
MeCN
DMF
75 ꢀC, 4 h
30 (60)
22 (40)
37c
75 ꢀC, 4 h
Diglyme
MeCN
MeCN
MeCN
MeCN
Diglyme
MeCN
150 ꢀC, 3 h
75 ꢀC, 7 h
32 (63)
d
MW, 100, 100 ꢀ
100 ꢀC, 5 h
100 ꢀC, 5 h
150 ꢀC, 3 h
Reux, 5 he
C
40 (76)
96
50
88
a
Except noted otherwise, all reactions were carried in a sealed tube. b Yields were determined by 1H NMR using an internal standard (mesitylene).
Conversion by 1H NMR in brackets. No starting material detected by 1H NMR. Mixture of products, mostly starting material. Open system,
c
d
e
reux conditions.
as the immobilized substrate9 and apply the metholodogy to the phenylboronic acid (1a) was treated with the iodide 2a,
generation of biaryl derivatives of privileged structures such as Pd(PPh3)4 (5 mol%) and Cs2CO3 (1,2 equiv.) in diglyme at 150 ꢀC
b-lactams, neoavonoids, imidazoles, isoxazolines, etc.
for 3 h,12 giving the expected biaryl 3aa in 37% yield but no
In order to nd the optimal conditions, we rst synthesized starting material was detected by 1H NMR (entry 3). Aerwards,
the immobilized 4-carboxyphenylboronic acid 1a from 4-for- we used the combination of a ligandless catalyst such as
mylphenylboronic acid by oxidation with sodium permanga- Pd2(dba)3 and a hindered phosphine ligands [P(o-tolyl)3]13 in
nate and anchoring to Wang resin by standard procedure. We order to increase Pd catalytic activity, but a small amount of the
then analyzed the reaction of 1a with 4-iodoacetophenone (2a) required biaryl derivative was obtained together with an
(Table 1 and Fig. 1).
intractable mixture of products. Taking as reference the
When the immobilized boronic acid (1a) was treated with 1 conditions of entry 1, we proceeded to increase the reaction
equiv. of 4-iodoacetophenone (2a), 1.2 equiv. of K2CO3, under time, but conversion and yield were hardly affected (entry 4).
“ligand-free” conditions [Pd(OAc)2 (5 mol%)], in anhydrous Although is clear that heating effects in microwave irradiation
acetonitrile for 4 h at 75 ꢀC,9b an incomplete conversion was are just thermal,14 it is still an interesting alternative as a rapid
observed, and the expected product 3aa was obtained in 30% way to reach high reaction temperatures15 in order to improve
yield, aer cleavage with TFA and methylation with diazo- yields. However, in our case, low conversion together with
methane (entry 1). In the case of using PdCl2dppf11 (5 mol%) as a mixture of unidentied compounds was obtained under
catalyst, a similar result was obtained, albeit conversion and microwave irradiation (entry 5). Going back to conventional
yield were lower (entry 2). Other conditions reported in litera- heating, we increased the equivalents of the iodide, reagents
ture were also attempted, thus, Wang resin-bound and temperature, having a slightly better yield (40%, entry 6).
Fig. 1 Structures and numbering of building blocks.
This journal is © The Royal Society of Chemistry 2017
RSC Adv., 2017, 7, 34994–35003 | 34995

View Article Online
RSC Advances
Paper
Table 2 Solid-phase Suzuki–Miyaura reaction between organic halides and immobilized boronic acida
Entry
1
Halides/pseudohalides
Product
Yieldb (%)
96
2
99
3
4
96
99
5
6
7
99
87
81 (78)
8
77
9
52
37
10
11
20
12
13
8
15
14
15
79 (76)
65 (60)
34996 | RSC Adv., 2017, 7, 34994–35003
This journal is © The Royal Society of Chemistry 2017

View Article Online
Paper
RSC Advances
Table 2 (Contd.)
Entry
Halides/pseudohalides
Product
Yieldb (%)
16
NDc (90)
17
83 (86)
18
NDc (48)
a
Conditions: halide or pseudo-halide (4 equiv.), Pd(OAc)2 (10 mol%), K2CO3 (2.4 equiv.) in H2O (0.2 mL), MeCN, 100 ꢀC, 5 h, in a sealed tube.
b
c
Determined by 1H NMR vs. internal standard (mesitylene), isolated yields aer column chromatography are reported in brackets. ND ¼ not
determined.
Finally, in our initial attempts we have noticed the difficulty of donating substituents on the aryl halides, Suzuki coupling
solubilising the carbonate and, since the addition of a base is proved to be less efficient, again with little inuence from the
considered to be crucial for the success of the reaction,16 we halide used (entries 8–12). As expected, 2-iodothiophene gave
decided to study the addition of an small amount of water to the corresponding heterobiaryl derivative in low yield probably
increase dissolution, hoping that would not affect in any due to the poisoning of the catalyst (entry 13).17 In order to apply
signicant way the polymer support swelling. Thus, we dis- the methodology to structures of greater complexity and
solved the K2CO3 (2.4 equiv.) in a small amount of water and interest, biaryl-containing b-lactam derivatives were synthe-
added to the suspension of resin 1a, 4-iodoacetophenone (2a) (4 sized using the optimized conditions. b-Lactam unit is a well-
equiv.) and 10 mol% of Pd(OAc)2 in acetonitrile. To our delight, known privileged structure present in numerous bioactive
aer 5 h at 100 ꢀC in a sealed tube, followed by cleaving from the compounds. Aside from their antibacterial properties,18 b-lac-
resin and methylation with diazomethane, the expected product tams also show other biological activities, most signicantly
was achieved in 96% yield (entry 7). At the same time, a varia- inhibition of cholesterol absorption, that include the commer-
tion using more harsh conditions such as heating in diglyme at cial drug ezetimibe,19 which is one of the most prescribed
150 ꢀC for 5 h, was analyzed giving lower yield, probably due to medicine in US.
starting material/product decomposition (entry 8). Good results
were obtained using an open system (entry 9), although yield of cholesterol absorption inhibitors20 and antibacterial activity
entry 7 was still the optimum.
against methicillin-resistant Staphylococcus aureus (MRSA).21
Particularly, 4-biaryl-b-lactams have been reported as
Subsequently, the reaction of a variety of aryl halides and Thus, biaryl-b-lactams (3am–ap) were obtained in very high
pseudohalides under the optimized coupling conditions was isolated yield (entries 14 to 17, Table 2). Another synthetic
examined (Table 2 and Fig. 1). Generally speaking, yields are objective of great interest in medicinal chemistry are the
very high for electron-withdrawing aryl halides and non- coumarin derivatives which are well known for their diverse
substituted aryl halides (entries 1–7), independently of using pharmacological properties.22 Neoavonoids (4-arylcoumarins)
an iodide or a bromide derivative. In the case of electron- in particular, have shown relevant anticancer activity,23 while
This journal is © The Royal Society of Chemistry 2017
RSC Adv., 2017, 7, 34994–35003 | 34997

View Article Online
RSC Advances
Paper
Scheme 2 Further transformation of supported aldehyde 3af to biologically interesting heterocycles.
this moiety is found in a variety of plants belonging to the inamatory,28 antibacterial/antifungal agents,29,30 CFTR activa-
families Guttiferae, Rubiaceae, Leguminosae, Passioraceae and tors,31 and, particularly, the (S,R)-3-(4-hydroxyphenyl)-4,5-
Compositae.24 In this case, the triate derivative of 4-hydrox- dihydro-5-isoxazole acetic acid methyl ester (ISO-1) has been re-
ycoumarin (2q00)25 was subjected to the optimized conditions in ported as a potent inhibitor of MIF tautomerase activity.32
the presence of the immobilized boronic acid (1a), to give 48%
isolated yield of the expected 4-arylcoumarin (3aq) (entry 18).
Alternatively, biologically promising imidazole33 can be
readily obtained by the four-component condensation of alde-
Solid-phase chemistry is an appreciated tool for the devel- hydes, 1,2-diketones, amines and ammonium acetate in reuxing
opment of many alternative synthetic route to diverse struc- acetic acid as ammonia source. As an example, supported 3af was
tures. Biaryl derivatives, like the ones we have synthesized, can treated with excess of benzil (10) and benzylamine, in the pres-
be interesting precursors in that sense. Thus, the immobilized ence of NH4OAc in acetic acid at reux to give the supported
version of aldehyde 3af (supported 3af) was used as a versatile product 8af that afforded the 1-benzyl-2-substituted-4,5-diphenyl-
intermediate for the generation of other biologically promising 1H-imidazole derivative 9af aer removing from the resin and
compounds. For instance, we carried out the synthesis of methylation (20% overall isolated yield).34
secondary amines such as the N-benzyl-1-(biphenyl-4-yl)
In summary, we report herein an efficient application of the
methanamine derivative (5af) by a straightforward two step Suzuki–Miyaura coupling to the solid-phase synthesis of
reductive amination (Scheme 2). The imine formation was per- a variety of biaryl and related derivatives using the under-
formed by treating supported 3af with benzylamine in the pres- recognized but promising alternative based on immobilized
ence of trimethyl orthoformate as dehydrating agent. Reduction boronic acid. Yields were very high for electron-withdrawing or
of the imine 4af with sodium borohydride gave the correspond- unsubstituted aryl halides regardless of the halide used. We
ing secondary N-benzyl amine 5af in a very good overall isolated have demonstrated that biologically relevant structures,
yield of 60%, based on loading level of resin 1a. Supported 3af including heterocycles such as 4-biaryl-b-lactams, 4-arylcou-
was also the starting point for the synthesis of biologically marins, imidazoles and isoxazolines, can be easily generated by
interesting heterocycles such as isoxazolines and imidazoles. this methodology. Biological evaluation of the synthesized
Thus, this compound was rst treated with hydroxylamine/trie- compounds are currently in progress.
thylamine26 to generate the Wang resin-bound oxime 6af
(Scheme 2). A one-pot oxidation/1,3-dipolar cycloaddition was
then performed using solution of sodium hypochlorite and
acrylic acid as dipolarophile.27 The biphenyl-isoxazoline 7af was
Experimental procedures
General
obtained in a regioselective manner aer removing from the
resin with TFA followed by methylation (21% overall isolated
Chemical reagents were purchased from commercial sources
and were used without further purication unless noted
yield, always based on loading level of resin 1a). Isoxazolines are
otherwise. Solvents were analytical grade or were puried by
a well-known privileged structure and the corresponding 3,5-
standard procedures prior to use. Resins were purchased from
disubstituted derivatives have been lately described as anti-
Sigma-Aldrich. 1H NMR spectra were recorded in a Bruker
34998 | RSC Adv., 2017, 7, 34994–35003
This journal is © The Royal Society of Chemistry 2017

View Article Online
Paper
RSC Advances
Avance spectrometer at 300 MHz in CDCl3 with tetramethylsi- excess of solvent and oxalyl chloride were removed by evapo-
lane (TMS) as internal standard. 13C NMR spectra were recorded ration under reduced pressure and that crude was immediately
on the same apparatus at 75 MHz with CDCl3 as solvent and used for the formation of the corresponding b-lactam.
reference (76.9 ppm). The chemical shis (d) are reported
1-Benzyl-4-(4-iodophenyl)-3-phenoxyazetidin-2-one
(2m).
in ppm downeld from TMS and coupling constants (J) are Obtained following the general procedure A, starting from 4-
expressed in hertz. Gas Chromatography-Mass Spectra (GC-MS) iodobenzaldehyde (290 mg, 1.25 mmol) and benzylamine (109
were recorded on a Shimadzu QP2010 Plus apparatus at an mL, 1 mmol). Then, phenoxyacetyl chloride (207 mL, 1.5 mmol)
ionization voltage of 70 eV equipped with a SPB™-1 capillary was added dropwise. Column chromatography (86/14-hexane/
column (internal diameter 0.25 mm, length 30 m). The High EtOAc) provided the desired compound in 80% yield as yellow
Resolution Mass Spectra (HRMS) were obtained with a Bruker solid.
1
MicroTOF-Q II instrument (Bruker Daltonics, Billerica, MA).
Characterization of 2m. H NMR (CDCl3, 300 MHz) d (ppm):
Detection of the ions was performed in electrospray ionization, 3.87 (d, J ¼ 14.7 Hz, 2H), 4.68 (d, J ¼ 4.5 Hz, 2H), 4.87 (d, J ¼
positive ion mode. Solvents were dried using a MBraun solvent 14.7 Hz, 2H), 5.39 (d, J ¼ 4.5 Hz, 2H), 6.72 (d, J ¼ 7.8 Hz, 2H),
system (SPS-800). Analytical thin-layer chromatography (TLC) 6.89 (t, J ¼ 7.1 Hz, 1H), 7.01 (d, J ¼ 8.3 Hz, 2H), 7.10–7.16 (m,
was carried out with silica gel 60 F254 pre-coated aluminum 4H), 7.29–7.33 (m, 3H), 7.61 (d, J ¼ 8.3 Hz, 2H). 13C NMR (CDCl3,
sheets. Flash column chromatography was performed using 75 MHz) d (ppm): 44.3, 60.9, 82.0, 94.7, 115.5, 122.2, 128.1,
Merck silica gel 60 (230–400 mesh). Elution was carried out with 128.7, 128.9, 129.3, 130.5, 132.7, 134.5, 137.5, 156.8, 165.4.
hexane–EtOAc mixtures, under positive pressure and employing HRMS (ESI) m/z 478.0279 [(M + Na+); calcd for C22H18INNaO2:
gradient of solvent polarity techniques.
478.0274].
2-(1-Benzyl-2-(4-iodophenyl)-4-oxoazetidin-3-yl)isoindoline-
Solid-phase reactions were carried out in polypropylene
cartridges equipped with a frit (Supelco, Bellefonte, PA), unless 1,3-dione (2n). Obtained following the general procedures A,
reux conditions were required, in that cases standard glass- starting from 4-iodobenzaldehyde (298 mg, 1.3 mmol) and
ware was used. All solid-phase reaction mixtures were stirred at benzylamine (115 mL, 1.05 mmol). Then, phthalylglycyl chlo-
the slowest rate.
ride prepared in situ (procedure B) (350 mg, 1.56 mmol).
Except 2m, 2n, 2o, 2p, 3ak, 3am, 3an, 3ao and 3ap which are Column chromatography (75/25-hexane/EtOAc) provided the
1
new compound and thoroughly characterized by H NMR, 13C desired compound in 41% yield as colorless glass-like solid.
1
NMR, HSQC, HMBC, HH-COSY and HRMS, the other
Characterization of 2n. H NMR: (CDCl3, 300 MHz) d (ppm):
compounds obtained have been previously described in litera- 4.15 (d, J ¼ 14.8 Hz, 1H), 4.76 (d, J ¼ 5.3 Hz, 1H), 5.03 (d, J ¼
ture: 3aa,35 3ab,36 3ac,37 3ad,36 3ae,35 3af,38 3ag,39 3ah,36 3ai,40 14.9 Hz, 1H), 5.23 (d, J ¼ 5.2 Hz, 1H), 6.95 (d, J ¼ 8.2 Hz, 2H),
3aj,10f 3al36 and 3aq.41
7.20–7.25 (m, 2H), 7.30–7.34 (m, 3H), 7.51 (d, J ¼ 8.3 Hz, 2H),
7.62–7.70 (m, 4H). 13C NMR: (CDCl3, 75 MHz) d (ppm): 45.6,
59.7, 60.2, 94.3, 123.6, 128.1, 128.6, 129.0, 129.3, 131.1, 132.8,
134.4, 137.6, 163.6, 166.7. HRMS (ESI) m/z 531.0177 [(M + Na+);
calcd for C24H17IN2NaO3: 531.0176].
General procedure for the preparation of b-lactams as starting
materials (procedure A)42
A mixture of 4-iodobenzaldehyde (290 mg, 1.25 mmol), few
grains of molecular sieves (4 A) and the corresponding amine (1
4-(4-iodophenyl)-1-(4-methoxyphenyl)-3-phenoxyazetidin-2-
one (2o). Obtained following the general procedure A, starting
from 4-iodobenzaldehyde (298 mg, 1.3 mmol) and p-anisidine
(160 mg, 1.05 mmol). Then, phenoxyacetyl chloride (215 mL,
1.56 mmol) was added dropwise. Column chromatography (88/
12-hexane/EtOAc) provided the desired compound in 70%
yield as yellow solid.
˚
mmol) in dichloromethane (5 mL) was stirred at 0 ꢀC under
nitrogen atmosphere for 1 h. The solution was ltered, the
solvent evaporated and the residue analyzed by 1H NMR to
ensure complete consumption of the amine. The crude thus
obtained was dissolved in dry dichloromethane (3 mL) and
cooled to 0 ꢀC under nitrogen atmosphere. To the resulting
solution were successively added triethylamine (0.5 mL, 3.5
mmol) and, dropwise, the corresponding acyl chloride (1.5
mmol). The resulting mixture was stirred overnight at room
temperature and then was washed with water (3 ꢁ 5 mL), 0.1 N
HCl (3 ꢁ 5 mL) and a saturated solution of NaHCO3 (5 mL). The
organic layer was dried over MgSO4 and ltered; the solvent was
evaporated under reduced pressure to give the corresponding
crude b-lactam, which was further puried by column chro-
matography (hexane/EtOAc).
1
Characterization of 2o. H NMR: (CDCl3, 300 MHz) d (ppm):
3.76 (s, 3H), 5.31 (d, J ¼ 4.9 Hz, 1H), 5.55 (d, J ¼ 4.9 Hz, 1H),
6.78–6.83 (m, 4H), 6.92–7.00 (m, 2H), 7.11 (d, J ¼ 8.3 Hz, 2H),
7.11 (t, J ¼ 7.6 Hz, 1H), 7.27 (d, J ¼ 7.1 Hz, 2H), 7.62 (d, J ¼
8.3 Hz, 2H). 13C NMR: (CDCl3, 75 MHz) d (ppm): 55.5, 61.7, 81.2,
94.6, 114.5, 115.7, 118.8, 122.4, 129.4, 129.6, 130.1, 132.7, 137.6,
156.7, 156.9, 162.3. HRMS (ESI) m/z 494.0226 [(M + Na+); calcd
for C22H18INNaO3: 494.0224].
4-(4-iodophenyl)-3-phenoxy-1-(p-tolyl)azetidin-2-one
(2p).
Obtained following the general procedure A, starting from 4-
iodobenzaldehyde (298 mg, 1.3 mmol) and p-toluidine (140 mg,
1.05 mmol). Then, phenoxyacetyl chloride (215 mL, 1.56 mmol)
was added dropwise. Column chromatography (90/10-hexane/
Procedure for the preparation of phthalylglycyl chloride
(procedure B)43
Oxalyl chloride (386 mL, 4.5 mmol) was added to a solution of EtOAc) provided the desired compound in 40% yield as yellow
anhydrous N-phthaloylglycine (615 mg, 3 mmol) in toluene (8 solid.
ꢀ
mL) and the reaction mixture was stirred at 60 C for 3 h. The
This journal is © The Royal Society of Chemistry 2017
RSC Adv., 2017, 7, 34994–35003 | 34999

View Article Online
RSC Advances
Paper
1
chromatography (98/2-hexane/EtOAc) provided the desired
compound in 89% yield as white crystals.
Characterization of 2p. H NMR: (CDCl3, 300 MHz) d (ppm):
2.29 (s, 3H), 5.32 (d, J ¼ 4.9 Hz, 1H), 5.55 (d, J ¼ 4.9 Hz, 1H), 6.79
(d, J ¼ 8.3 Hz, 2H), 6.94 (t, J ¼ 7.4 Hz, 1H), 7.07–7.12 (m, 4H),
7.16–7.24 (m, 4H), 7.62 (d, J ¼ 8.3 Hz, 2H). 13C NMR: (CDCl3, 75
MHz) d (ppm): 20.9, 61.5, 81.1, 94.6, 115.9, 117.4, 122.4, 129.4,
129.8, 129.9, 132.6, 134.2, 134.6, 137.6, 156.9, 162.6. HRMS (ESI)
m/z 478.0268 [(M + Na+); calcd for C22H18INNaO2: 478.0274].
1
Characterization of 3ac. H NMR (CDCl3, 300 MHz) d (ppm):
3.95 (s, 6H), 7.69 (d, J ¼ 8.5 Hz, 4H), 8.12 (d, J ¼ 8.5 Hz, 4H). 13
C
NMR (CDCl3, 75 MHz) d (ppm): 52.2, 127.2, 129.7, 130.2, 144.3,
166.8.
Methyl [1,10-biphenyl]-4-carboxylate (3ad). Obtained
following the general procedure D, using resin-bound boronic
acid 1a (Procedure C) (99.6 mg, 0.0448 mmol) as starting
material and iodobenzene (2d) (20 mL, 0.18 mmol). Column
chromatography (99/1-hexane/EtOAc) provided the desired
compound in 98% yield as white crystals.
Procedure for the synthesis of Wang resin-supported aryl
boronic acid 1a (procedure C)
0.4 g of Wang resin (0.9 mmol gꢂ1, 0.36 mmol) was swelled by
gentle stirring in anhydrous dichloromethane (20 mL). Then, 4-
carboxyphenylboronic acid (0.179 g, 1.08 mmol), DCC (N,N0-
diisopropylcarbodiimide) (0.223 g, 1.08 mmol) and DMAP
(catalytic amount) were added at that suspension. The mixture
was shaked at 250 rpm overnight at room temperature. Aer
ltration, the resin was sequentially washed with CH2Cl2 (3 ꢁ
10 mL), MeOH (3 ꢁ 10 mL), THF (3 ꢁ 10 mL), CH2Cl2 (1 ꢁ 10
mL) and nally dried under high vacuum. Mass recovery was
used to determine resin loading aer cleavage of an aliquot with
1
Characterization of 3ad. H NMR (CDCl3, 300 MHz) d (ppm):
3.95 (s, 3H), 7.36–7.51 (m, 3H), 7.60–7.70 (m, 4H), 8.11 (d, J ¼
8.6 Hz, 2H). 13C NMR (CDCl3, 75 MHz) d (ppm): 52.1, 127.0,
127.3, 128.1, 128.9, 130.1, 140.0, 145.6, 167.0.
Methyl 40-formyl-[1,10-biphenyl]-4-carboxylate (3af). Obtained
following the general procedure D, using resin-bound boronic
acid 1a (procedure C) (97.7 mg, 0.0439 mmol) as starting material
and 4-bromobenzaldehyde (2f0) (32 mg, 0.175 mmol). Column
chromatography (98/2-hexane/EtOAc) provided the desired
compound in 78% yield as white crystals.
10% TFA/CH2Cl2: 0.45 mmol gꢂ1
.
1
Characterization of 3af. H NMR (CDCl3, 300 MHz) d (ppm):
General procedure for the solid-phase Suzuki coupling
(procedure D)
0.1 g of the supported arylboronic acid 1a (0.45 mmol gꢂ1, 0.045 NMR (CDCl3, 75 MHz) d (ppm): 52.3, 127.4, 128.0, 130.3, 130.3,
3.95 (s, 3H), 7.70 (d, J ¼ 8.5 Hz, 2H), 7.78 (d, J ¼ 8.3 Hz, 2H), 7.98
(d, J ¼ 8.3 Hz, 2H), 8.14 (d, J ¼ 8.5 Hz, 2H), 10.08 (s, 1H). 13C
mmol) was suspended in MeCN (2 mL) in a dram vessel. Aryl- 144.0, 145.9, 166.7, 191.8.
halide or pseudo-halide 2 (0.18 mmol), Pd(OAc)2 (1 mg, 0.0045
Methyl 40-(diethylamino)-[1,10-biphenyl]-4-carboxylate (3ak).
mmol) and a solution of K2CO3 in H2O (0.54 M, 0.108 mmol) were Obtained following the general procedure D, using resin-bound
ꢀ
added. The reaction was stirred 5 h at 100 C. Aer cooling to boronic acid 1a (procedure C) (92.1 mg, 0.041 mmol) as starting
room temperature, the resin was ltered, washed with MeCN (2 ꢁ material and N,N-diethyl-4-iodoaniline (2k) (49 mg, 0.18 mmol).
5 mL), H2O (2 ꢁ 5 mL), MeOH (3 ꢁ 5 mL) and DCM (3 ꢁ 5 mL) Column chromatography (98/2-hexane/EtOAc) provided the
drying under high vacuum, the compound was cleaved from the desired compound in 9% yield as yellow uorescent crystals.
resin with 5 mL of a 10% solution of TFA in DCM for 50 minutes
Characterization of 3ak. 1H NMR (CDCl3, 300 MHz) d (ppm): 1.20
at room temperature. Then it was ltered and washed with MeOH (t, J ¼ 7.0 Hz, 6H), 3.40 (q, J ¼ 7.0 Hz, 4H), 3.91 (s, 3H), 6.75 (d, J ¼
(2 ꢁ 3 mL) and CH2Cl2 (2 ꢁ 3 mL). The product-containing 8.9 Hz, 2H), 7.53 (d, J ¼ 8.9 Hz, 2H), 7.61 (d, J ¼ 8.9 Hz, 2H), 8.04 (d,
solution was concentrated under reduced pressure and dried J ¼ 8.9 Hz, 2H). 13C NMR (CDCl3, 75 MHz) d (ppm): 12.6, 44.4, 51.9,
under high vacuum. Esterication with diazomethane afforded 111.8, 125.5, 126.3, 127.1, 128.1, 130.0, 145.7, 147.8, 167.3. HRMS
the crude product that was analyzed by 1H NMR and GC/MS and (ESI) m/z 284.1656 [(M + H+); calcd for C18H22NO2: 284.1645].
then puried by ash column chromatography (hexane/EtOAc).
Methyl 40-(1-benzyl-4-oxo-3-phenoxyazetidin-2-yl)-[1,10-
Dimethyl 2-nitro-[1,10-biphenyl]-4,40-dicarboxylate (3ab). biphenyl]-4-carboxylate (3am). Obtained following the general
Obtained following the general procedure D, using resin-bound procedure D, using resin-bound boronic acid 1a (procedure C)
boronic acid 1a (procedure C) (103.5 mg, 0.0465 mmol) as (93.3 mg, 0.042 mmol) as starting material and 1-benzyl-4-(4-
starting material and methyl 4-iodo-3-nitrobenzoate (2b) iodophenyl)-3-phenoxyazetidin-2-one (2m) (76 mg, 0.168
(57 mg, 0.186 mmol). Column chromatography (96/4-hexane/ mmol). Column chromatography (86/14-hexane/EtOAc) provided
EtOAc) provided the desired compound in 92% yield as white the desired compound in 76% yield as yellowish white crystals.
crystals.
Characterization of 3am. 1H NMR: (CDCl3, 300 MHz) d (ppm):
1
Characterization of 3ab. H NMR (CDCl3, 300 MHz) d (ppm): 3.92 (d, J ¼ 14.5 Hz, 1H), 3.94 (s, 3H), 4.81 (d, J ¼ 4.4 Hz, 1H), 4.92
3.95 (s, 3H), 4.00 (s, 3H), 7.40 (d, J ¼ 8.4 Hz, 2H), 7.54 (d, J ¼ (d, J ¼ 14.7 Hz, 1H), 5.44 (d, J ¼ 4.4 Hz, 1H), 6.75 (d, J ¼ 7.8 Hz,
8.0 Hz, 1H), 8.11 (d, J ¼ 8.5 Hz, 2H), 8.29 (dd, J ¼ 8.0, 1.7 Hz, 2H), 6.87 (t, J ¼ 7.3 Hz, 1H), 7.11 (t, J ¼ 8.3 Hz, 2H), 7.18 (m, 2H),
1H), 8.55 (d, J ¼ 1.7 Hz, 1H). 13C NMR (CDCl3, 75 MHz) d (ppm): 7.33 (m, 2H), 7.37 (d, J ¼ 8.3 Hz, 2H), 7.54 (d, J ¼ 8.2 Hz, 2H), 7.62
52.3, 52.9, 125.5, 127.9, 130.0, 130.5, 131.0, 132.1, 133.1, 139.5, (d, J ¼ 8.3 Hz, 2H). 13C NMR: (CDCl3, 75 MHz) d (ppm): 44.3, 52.2,
141.1, 148.9, 164.7, 166.5.
61.1, 82.3, 115.6, 122.1, 127.0, 127.1, 128.0, 128.7, 128.9, 129.1,
Dimethyl [1,10-biphenyl]-4,40-dicarboxylate (3ac). Obtained 129.2, 130.1, 132.8, 134.7, 140.2, 156.9, 165.5, 166.9. HRMS (ESI)
following the general procedure D, using resin-bound boronic m/z 486.1670 [(M + Na+); calcd for C30H25NNaO4: 486.1676].
acid 1a (procedure C) (93.5 mg, 0.042 mmol) as starting material
and methyl 4-iodobenzoate (2c) (44 mg, 0.168 mmol). Column din-2-yl)-[1,10-biphenyl]-4-carboxylate (3an). Obtained following
Methyl 40-(1-benzyl-3-(1,3-dioxoisoindolin-2-yl)-4-oxoazeti-
35000 | RSC Adv., 2017, 7, 34994–35003
This journal is © The Royal Society of Chemistry 2017

View Article Online
Paper
RSC Advances
the general procedure D, using resin-bound boronic acid 1a 7.60 (m, 3H), 8.20 (d, J ¼ 8.3 Hz, 2H); 13C NMR (CDCl3, 75 MHz)
(procedure C) (90 mg, 0.0405 mmol) as starting material and 2- d (ppm): 52.5, 115.6, 117.5, 118.6, 124.4, 126.7, 128.6, 130.1,
(1-benzyl
2-(4-iodophenyl)-4-oxoazetidin-3-yl)isoindoline-1,3- 131.4, 132.2, 139.6, 154.2, 154.6, 160.4, 166.3.
dione (2n) (82.3 mg, 0.162 mmol). Column chromatography
(78/22-hexane/EtOAc) provided the desired compound in 60%
yield as white crystals.
Procedure for the solid-phase reductive amination (procedure E)
0.3 g of the supported compound 3af (0.438 mmol gꢂ1, 0.135
mmol) was suspended in anhydrous THF (2 mL) in a dram
vessel. Benzylamine (75 mL, 0.673 mmol) and methyl ortho-
formate (15 mL, 0.135 mmol) were added and the reaction was
stirred 18 h at room temperature. Aer that time, the imine-
resin was ltered, washed with THF (2 ꢁ 5 mL), absolute
MeOH (2 ꢁ 5 mL), DCM (2 ꢁ 5 mL) and MeOH (2 ꢁ 5 mL) and
dried under high vacuum. This resin was suspended in
a mixture of THF-MeOH 3 : 1 v/v and treated with NaBH4
(51 mg, 1.347 mmol) for 6 to 8 hours. The resin was washed with
THF (2 ꢁ 5 mL), EtOH (2 ꢁ 5 mL), H2O (2 ꢁ 5 mL), EtOH (2 ꢁ 5
mL), THF (2 ꢁ 5 mL) and MeOH (2 ꢁ 5 mL) and dried under
high vacuum. The compound was cleaved from the support
with 5 mL of a 10% solution of TFA in DCM for 50 minutes at
room temperature. Then it was ltered and washed with MeOH
(2 ꢁ 3 mL) and CH2Cl2 (2 ꢁ 3 mL). The product-containing
solution was concentrated under reduced pressure and dried
under high vacuum. Esterication with diazomethane afforded
the crude product that was analyzed by 1H NMR and GC/MS and
then puried by column chromatography (hexane/EtOAc).
Methyl 40-((benzylamino)methyl)-[1,10-biphenyl]-4-carboxylate
(5af). Employing procedure E, with supported 3af. Column
chromatography (90/10-hexane/EtOAc) provided the desired
product in 63% overall isolated yield (ve reactions steps) as
white crystals.
Characterization of 3an. 1H NMR: (CDCl3, 300 MHz) d (ppm):
3.91 (s, 3H); 4.21 (d, J ¼ 14.8 Hz, 1H), 4.90 (d, J ¼ 5.2 Hz, 1H),
5.10 (d, J ¼ 14.8 Hz, 1H), 5.52 (t, J ¼ 5.2 Hz, 1H), 7.28–7.36 (m,
7H), 7.47 (d, J ¼ 8.4 Hz, 2H), 7.50 (d, J ¼ 8.4 Hz, 2H), 7.59–7.69
(m, 4H), 8.02 (d, J ¼ 8.3 Hz, 2H). 13C NMR: (CDCl3, 75 MHz)
d (ppm): 45.7, 52.1, 60.0, 60.3, 123.5, 126.8, 127.3, 128.0, 128.1,
128.7, 129.0, 129.1, 130.0, 131.2, 133.0, 134.2, 134.8, 139.9,
144.5, 163.7, 166.8. HRMS (ESI) m/z 539.1587 [(M + Na+); calcd
for C32H24N2NaO5: 539.1577].
Methyl 40-(1-(4-methoxyphenyl)-4-oxo-3-phenoxyazetidin-2-
yl)-[1,10-biphenyl]-4-carboxylate (3ao). Obtained following the
general procedure D, using resin-bound boronic acid 1a
(procedure C) (89.3 mg, 0.04018 mmol) as starting material and
4-(4-iodophenyl)-1-(4-methoxyphenyl)-3-phenoxyazetidin-2-one
(2o) (76.3 mg, 0.162 mmol). Column chromatography (86/14-
hexane/EtOAc) provided the desired compound in 90% yield
as yellowish white crystals.
1
Characterization of 3ao. H NMR: (CDCl3, 300 MHz) d (ppm):
3.75 (s, 3H), 3.93 (s, 3H), 5.41 (d, J ¼ 4.8 Hz, 1H), 5.65 (d, J ¼
4.8 Hz, 1H), 6.82 (d, J ¼ 8.9 Hz, 2H), 6.92 (t, J ¼ 7.3 Hz, 1H), 7.16 (t,
J ¼ 8.0 Hz, 2H), 7.33 (d, J ¼ 8.9 Hz, 2H), 7.46 (d, J ¼ 8.2 Hz, 2H),
7.55 (d, J ¼ 8.2 Hz, 2H), 7.60 (d, J ¼ 8.3 Hz, 2H), 8.07 (d, J ¼ 8.3 Hz,
2H). 13C NMR: (CDCl3, 75 MHz) d (ppm): 52.2, 55.5, 61.8, 81.4,
114.5, 115.8, 118.9, 122.3, 127.0, 127.2, 128.7, 129.1, 129.3, 130.1,
130.4, 132.8, 140.3, 144.8, 156.6, 157.0, 162.4, 166.9. HRMS (ESI)
m/z 502.1634 [(M + Na+); calcd for C30H25NNaO5: 502.1625].
Methyl 40-(4-oxo-3-phenoxy-1-(p-tolyl)azetidin-2-yl)-[1,10-
biphenyl]-4-carboxylate (3ap). Obtained following the general
procedure D, using resin-bound boronic acid 1a (procedure C)
(90 mg, 0.0405 mmol) as starting material and 4-(4-iodophenyl)-3-
phenoxy-1-(p-tolyl)azetidin-2-one (2p) (73.7 mg, 0.162 mmol).
Column chromatography (88/12-hexane/EtOAc) provided the
desired compound in 86% yield as white crystals.
1
Characterization of 5af. H NMR (CDCl3, 300 MHz) d (ppm):
3.85 (s, 2H), 3.87 (s, 2H), 3.94 (s, 3H), 7.27–7.37 (m, 5H), 7.52–
7.60 (m, 3H), 7.45 (d, J ¼ 8.3 Hz, 2H), 7.59 (d, J ¼ 8.2 Hz, 2H),
7.66 (d, J ¼ 8.3 Hz, 2H), 8.10 (d, J ¼ 8.3 Hz, 2H); 13C NMR (CDCl3,
75 MHz) d (ppm): 52.1, 52.7, 53.2, 126.9, 127.0, 127.3, 128.2,
128.5, 128.8, 130.1, 138.7, 140.1, 140.4, 145.4, 167.0. HRMS (ESI)
m/z 332.1659 [(M + H+); calcd for C22H22NO2: 332.1645].
Procedure for the solid-phase synthesis of D2-isoxazoline
(procedure F)
Characterization of 3ap. 1H NMR: (CDCl3, 300 MHz) d (ppm):
2.28 (s, 3H); 3.93 (s, 3H); 5.43 (d, J ¼ 4.8 Hz, 1H), 5.60 (d, J ¼
4.8 Hz, 1H), 6.82 (d, J ¼ 8.0 Hz, 2H), 6.92 (t, J ¼ 7.4 Hz, 1H), 7.09 0.24 g of the supported 3af (0.736 mmol gꢂ1, 0.178 mmol) was
(d, J ¼ 8.2 Hz, 2H), 7.17 (t, J ¼ 8.0 Hz, 2H), 7.29 (d, J ¼ 8.3 Hz, suspended in a mixture of anhydrous MeOH (1 mL) and DCM
2H), 7.46 (d, J ¼ 8.3 Hz, 2H), 7.54 (d, J ¼ 8.3 Hz, 2H), 7.61 (d, J ¼ (1 mL) in a dram vessel. Anhydrous triethylamine (124 mL, 0.89
8.3 Hz, 2H), 8.07 (d, J ¼ 8.3 Hz, 2H). 13C NMR: (CDCl3, 75 MHz) mmol) and hydroxylamine hydrochloride (62 mg, 0.89 mmol)
d (ppm): 21.0, 52.2, 61.7, 81.3, 115.8, 117.5, 122.3, 126.9, 127.2, were added and the reaction was stirred 36 h at room
128.7, 129.1, 129.3, 129.7, 130.1, 132.8, 134.5, 134.5, 140.2, temperature. Aer that time, the oxime-resin was ltered,
144.8, 157.0, 162.8, 166.9. HRMS (ESI) m/z 486.1677 [(M + Na+); washed with DMF (2 ꢁ 5 mL), DCM (2 ꢁ 5 mL), MeOH (2 ꢁ 5
calcd for C30H25NNaO4: 486.1676].
mL) and DCM (2 ꢁ 5 mL) and dried under high vacuum. This
Methyl 4-(2-oxo-2H-chromen-4-yl)benzoate (3aq). Obtained oxime-resin was suspended in THF and treated with bleach (6
following the general procedure D, using resin-bound boronic mL, 0.0018 mmol) and acrylic acid (62 mL, 0.9 mmol) at room
acid 1a (procedure C) (92.9 mg, 0.0418 mmol) as starting temperature for 4 hours. The resin was washed with MeOH (2
material and 4-iodo-2H-chromen-2-one (2q00) (49.1 mg, 0.167 ꢁ 5 mL), H2O (2 ꢁ 5 mL), MeOH (2 ꢁ 5 mL) and DCM (2 ꢁ 5
mmol). Column chromatography (90/10-hexane/EtOAc) mL) and dried under high vacuum. The compound was cleaved
provided the desired compound in 48% yield as white crystals. from the support with 5 mL of a 20% solution of TFA in DCM
1
Characterization of 3aq. H NMR (CDCl3, 300 MHz) d (ppm): for 50 minutes at room temperature. Then it was ltered and
3.98 (s, 3H), 6.40 (s, 1H), 7.24 (m, 1H), 7.38–7.45 (m, 2H), 7.52– washed with MeOH (2 ꢁ 3 mL) and CH2Cl2 (2 ꢁ 3 mL). The
This journal is © The Royal Society of Chemistry 2017
RSC Adv., 2017, 7, 34994–35003 | 35001

View Article Online
RSC Advances
Paper
product-containing solution was concentrated under reduced
pressure and dried under high vacuum. Methylation with
diazomethane afforded the crude product that was analyzed by
1H NMR and GC/MS and then puried by column chromatog-
raphy (hexane/EtOAc).
Notes and references
1 (a) T. E. Nielsen and S. L. Schreiber, Angew. Chem., Int. Ed.,
2008, 47, 48; (b) C. J. O'Connor, L. Laraia and D. R. Spring,
Chem. Soc. Rev., 2011, 40, 4332.
Methyl 3-(40-(methoxycarbonyl)-[1,10-biphenyl]-4-yl)-4,5-
dihydroisoxazole-5-carboxylate (7af). Employing procedure
F, with supported 3af. Column chromatography (92/8
hexane/EtOAc) provided the desired compound in 21%
overall isolated yield (ve reactions steps), as white crystals.
Characterization of 7af. 1H NMR (CDCl3, 300 MHz) d (ppm):
3.69 (ABX, J ¼ 17.1, 11.5, 9.5, 5.2 Hz, 2H), 3.84 (s, 3H), 3.95 (s,
3H), 5.23 (dd, J ¼ 10.7, 7.4 Hz, 1H), 7.67 (d, J ¼ 8.3 Hz, 4H),
7.78 (d, J ¼ 8.6 Hz, 2H), 8.12 (d, J ¼ 8.3 Hz, 2H). 13C NMR
(CDCl3, 75 MHz) d (ppm): 38.8, 52.2, 52.9, 78.1, 127.0, 127.5,
127.6, 128.2, 129.5, 130.2, 142.0, 144.4, 155.7, 166.8, 170.7.
HRMS (ESI) m/z 362, 0998 [(M + Na+); calcd for C19H17NNaO5:
362, 0999].
2 (a) W. R. J. D. Galloway, A. Isidro-Llobet and D. R. Spring,
Nat. Commun., 2010, 1, 80; (b) H. Beckmann,
C. J. O'Connor and D. R. Spring, Chem. Soc. Rev., 2012, 41,
4444.
´
´
¨
3 E. Schutznerova, P. Verdıa and V. Krchnak, ACS Comb. Sci.,
2016, 18, 655.
4 D. D. Young and A. Deiters, Solid-phase organic synthesis:
concepts, strategies, and applications, ed. P. H. Toy and Y.
Lam, John Wiley & Sons, Inc., Hoboken, New Jersey, 2012,
pp. 171–201.
5 G. S. Yellol and C.-M. Sun, Solid-Supported Synthesis en Green
Techniques for Organic Synthesis and Medicinal Chemistry, ed.
W. Zhang and B. W. Cue Jr, John Wiley & Sons, Ltd, 2012, p.
394.
6 N. Miyaura and A. Suzuki, Chem. Rev., 1995, 95, 2457.
7 For articles related to the suppression of the oxidative
homocoupling, see: (a) W. D. Miller, A. H. Fray,
J. T. Quatroche and C. D. Sturgill, Org. Process Res. Dev.,
2007, 11, 359; (b) N. Miyaura, Metal-Catalyzed Cross-
Coupling Reaction, ed. F. Diederich and A. de Meijere,
Wiley-VCH, New York, 2004, p. 41; (c) A. J. J. Lennox and
G. C. Lloyd-Jones, Isr. J. Chem., 2010, 50, 664; (d)
A. J. J. Lennox and G. C. Lloyd-Jones, J. Am. Chem. Soc.,
2012, 134, 7431; (e) A. J. J. Lennox and G. C. Lloyd-Jones,
Angew. Chem., Int. Ed., 2013, 52, 7362; (f) A. J. J. Lennox
and G. C. Lloyd-Jones, Chem. Soc. Rev., 2014, 43, 412.
Procedure for the solid-phase synthesis of imidazole
(procedure G)
0.13 g of the supported 3af (0.736 mmol gꢂ1, 0.097 mmol) was
suspended in Glacial AcOH in a dram vessel. Benzylamine
(212 mL, 1.94 mmol), benzil (408 mg, 1.94 mmol) and
ammonium acetate (9 mL, 0.136 mmol) were added and the
ꢀ
reaction was stirred 4 h at 100 C. Aer that time, the resin
was ltered, washed MeOH (2 ꢁ 5 mL), H2O (2 ꢁ 5 mL),
MeOH (2 ꢁ 5 mL) and DCM (2 ꢁ 5 mL) and dried under high
vacuum. The compound was cleaved from the support with 5
mL of a 20% solution of TFA in DCM for 50 minutes at room
temperature. Then it was ltered and washed with MeOH (2
ꢁ 3 mL) and CH2Cl2 (2 ꢁ 3 mL). The product-containing
solution was concentrated under reduced pressure and
dried under high vacuum. Methylation with diazomethane
afforded the crude product that was analyzed by 1H NMR
and then puried by column chromatography (hexane/
EtOAc).
¨
¨
8 (a) S. Brase, J. H. Kirchhoff and J. Kobberling, Tetrahedron,
2003, 59, 885; (b) N. Ljungdahl, K. Bromeld and N. Kann,
Top. Curr. Chem., 2007, 278, 89; (c) S. A. Testero and
E. G. Mata, J. Comb. Chem., 2008, 10, 487.
9 To the best of our knowledge, two examples have been
reported dealing with the use of immobilized boronic acid
in organic synthesis, in both cases, the sticky PEG-PS resin
was the favorite support used: (a) B. Ruhland, A. Bombrun
and M. A. Gallop, Tetrahedron Lett., 2006, 47, 19; (b) X. Li,
A. K. Szardenings, C. P. Holmes, L. Wang, A. Bhandari,
L. Shi, M. Navre, L. Jang and J. R. Grove, Tetrahedron Lett.,
2006, 47, 19.
10 (a) S. A. Testero and E. G. Mata, Org. Lett., 2006, 8, 4783; (b)
A. A. Poeylaut-Palena, S. A. Testero and E. G. Mata, J. Org.
Chem., 2008, 73, 2024; (c) A. A. Poeylaut-Palena and
E. G. Mata, J. Comb. Chem., 2009, 11, 791; (d)
A. A. Poeylaut-Palena, S. A. Testero and E. G. Mata,
Chem. Commun., 2011, 47, 1565; (e) A. La-Venia,
S. A. Testero, M. Mischne and E. G. Mata, Org. Biomol.
Chem., 2012, 10, 2514; (f) C. I. Tracante,
C. M. L. Delpiccolo and E. G. Mata, ACS Comb. Sci.,
Methyl 40-(1-benzyl-4,5-diphenyl-1H-imidazol-2-yl)-[1,10-
biphenyl]-4-carboxylate (9af). Employing procedure G, with
supported 3af. Column chromatography (96/4 hexane/EtOAc)
provided the desired compound in 20% overall isolated yield
(four reactions steps), as yellow crystals.
1
Characterization of 9af. H NMR (CDCl3, 300 MHz) d (ppm):
3.94 (s, 3H), 5.16 (s, 3H), 6.86 (m, 2H), 7.20 (m, 8H), 7.32 (m,
3H), 7.59 (m, 2H), 7.67 (m, 4H), 7.77 (d, J ¼ 8.4 Hz, 2H), 8.11 (d, J
¼ 8.0 Hz, 2H). 13C NMR (CDCl3, 75 MHz) d (ppm): 48.4, 52.2,
125.9, 126.5, 126.8, 127.0, 127.6, 128.1, 128.7, 128.8, 129.2,
129.5, 130.2, 130.4, 130.6, 130.9, 131.0, 134.3, 137.5, 138.3,
140.3, 144.8, 147.5, 166.9. HRMS (ESI) m/z 521, 2222 [(M + H+);
calcd for C36H29N2O2: 521, 2223].
´
2014, 16, 211; (g) L. Mendez and E. G. Mata, ACS Comb.
Acknowledgements
´
Sci., 2015, 17, 81; (h) C. I. Tracante, C. Fagundez,
Support from CONICET, ANPCyT and Universidad Nacional de
Rosario from Argentina is gratefully acknowledged. MMA
thanks CONICET for fellowship.
G. L. Serra, E. G. Mata and C. M. L. Delpiccolo, ACS
Comb. Sci., 2016, 18, 225.
35002 | RSC Adv., 2017, 7, 34994–35003
This journal is © The Royal Society of Chemistry 2017

View Article Online
Paper
RSC Advances
11 The large P-Pd-P angle of the dppf ligand is believed to make 26 N. Zou and B. Jiang, J. Comb. Chem., 2000, 2, 6.
the reductive elimination of the coupling product much 27 J. F. Cheng and A. M. Mjalli, Tetrahedron Lett., 1998, 39, 939.
faster than the b-elimination. See: T. Hayashi, M. Konishi, 28 A. Alam, C. Pal, M. Goyal, M. K. Kundu, R. Kumar,
Y. Kobori, M. Kumada, T. Higuchi and K. Hirotsu, J. Am.
Chem. Soc., 1984, 106, 158.
12 M. Ruda, N. Kann, S. Gordon, J. Bergman, W. Nelson,
M. S. Iqbal, S. Dey, S. Bindu, S. Sarkar, U. Pal, N. C. Maiti,
S. Adhikari and U. Bandyopadhyay, Bioorg. Med. Chem.,
2011, 19, 7365.
P. Agback, L. Hagberg and K. F. Koehler, J. Comb. Chem., 29 B. S. Priya and K. S. Rangappa, Heterocycl. Commun., 2006,
2005, 7, 567. 12, 35.
13 V. Cerezo, M. Amblard, J. Martinez, P. Verdie, M. Planas and 30 S. L. Gaonkar, K. L. Rai and B. Prabhuswamy, Med. Chem.
L. Feliu, Tetrahedron, 2008, 64, 10538. Res., 2007, 15, 407.
14 A. A. Poeylaut-Palena and E. G. Mata, Org. Biomol. Chem., 31 R. E. Sammelson, T. Ma, L. J. Galietta, A. S. Verkman and
´
2010, 8, 3947.
M. J. Kurth, Bioorg. Med. Chem. Lett., 2003, 13, 2509.
32 (a) Y. Al-Abed and S. VanPatten, Future Med. Chem., 2011, 3,
45; (b) Y. Al-Abed, D. Dabideen, B. Aljabari, A. Valster,
D. Messmer, M. Ochani, M. Tanovic, K. Ochani, M. Bacher,
F. Nicoletti, C. Metz, V. A. Pavlov, E. J. Miller and
K. J. Tracey, J. Biol. Chem., 2005, 280, 36541.
15 C. O. Kappe and D. Dallinger, Mol. Diversity, 2009, 13, 71.
16 C. Amatore, G. Le Duc and A. Jutand, Chem.–Eur. J., 2013, 19,
10082.
17 Y. Liu, C. Khemtong and J. Hu, Chem. Commun., 2004, 398.
18 S. A. Testero, J. F. Fisher and S. Mobashery, b-Lactam
Antibiotics in Burger's Medicinal Chemistry, Drug Discovery 33 For recent reviews on the biological activity of imidazoles,
and Development, Vol. 7 (Antiinfectives), ed. D. J. Abraham
and D. P. Rotella, Wiley and Sons, 2010, pp. 259–404.
19 D. A. Burnett, Curr. Med. Chem., 2004, 11, 1873.
20 E. Martinez, J. J. Talley, S. Antonelli, T. Barden,
R. Lundrigan-Soucy, W. Schairer, J. J. Yang and D. Zimmer,
see: (a) M. M. Heravi, M. Daraie and V. Zadsirjan, Mol.
Diversity, 2015, 19, 577; (b) N. Rani, A. Sharma and
R. Singh, Mini-Rev. Med. Chem., 2013, 13, 1812; (c)
A. Mumtaz, A. Saeed, N. Fatima, M. Dawood, H. Raque
and J. Iqbal, Bangladesh J Pharmacol, 2016, 11, 756.
4-Biarylyl-1-phenylazetidin-2-ones, US Pat., 2005/0209165 34 (a) G. V. M. Sharma, Y. Jyothi and P. S. Lakshmi, Synth.
A1, 22 September 2005.
21 E. Turos, C. Coates, J.-Y. Shim, Y. Wang, J. M. Leslie,
Commun., 2006, 36, 2991; (b) S. Sarshar, D. Siev and
A. M. Mjalli, Tetrahedron Lett., 1996, 37, 835.
T. E. Long, G. S. K. Reddy, A. Ortiz, M. Culbreath, 35 F. Izquierdo, M. Corpet and S. P. Nolan, Eur. J. Org. Chem.,
S. Dickey, D. V. Lim, E. Alonso and J. Gonzalez, Bioorg.
Med. Chem., 2005, 13, 6289.
22 D. Ashok, B. V. Lakshmi, S. Ravi, A. Ganesh and S. Adam,
Chem. Heterocycl. Compd., 2015, 51, 462.
2015, 1920.
36 C. Liu, T. Li and N. L. Rosi, J. Am. Chem. Soc., 2012, 134,
18886.
37 Y. A. Chen and C. Y. Liu, RSC Adv., 2015, 5, 74180.
23 (a) W. Kemnitzer, S. Kashibhatla, S. Jiang, H. Zhang, J. Zhao, 38 T. Cornilleau, P. Hermange and E. Fouquet, Chem. Commun.,
S. Jia, L. Xu, C. Crogan-Gundy, R. Denis, N. Rarriault, 2016, 52, 10040.
L. Vaillancourt, S. Charron, J. Dodd, G. Attardo, 39 C. I. Tracante, E. G. Mata and C. M. L. Delpiccolo, RSC Adv.,
D. Labreque, S. Lamothe, H. Gourdeau, B. Tseng, J. Drewe 2015, 5, 26796.
and S. X. Cai, Bioorg. Med. Chem. Lett., 2005, 15, 4745; (b) 40 K. Kawabata, M. Takeguchi and H. Goto, Macromolecules,
S. Combes, P. Barbier, S. Douillard, A. McLeer-Florin, 2013, 46, 2078.
V. Bourgarel-Rey, J.-T. Pierson, A. Y. Fedorov, J.-P. Finet, 41 N. P. Cheval, A. Dikova, A. Blanc, J. M. Weibel and P. Pale,
J. Boutonnat and V. Peyrot, J. Med. Chem., 2011, 54, 3153. Chem.–Eur. J., 2013, 19, 8765.
24 M. L. Yao and M. Z. A. Deng, Chem. Heterocycl. Compd., 2000, 42 C. Palomo, M. Oiarbide, A. Esnal, A. Landa, J. I. Miranda and
11, 380.
A. Linden, J. Org. Chem., 1998, 63, 5838.
25 S. Wattanasin, Synth. Commun., 1988, 18, 1919.
43 D. L. Boger and J. B. Myers Jr, J. Org. Chem., 1991, 56, 5385.
This journal is © The Royal Society of Chemistry 2017
RSC Adv., 2017, 7, 34994–35003 | 35003