An efficient continuous flow approach to furnish furan-based biaryls

Article abstract of DOI:10.1039/c4ob01641f

Suzuki cross-couplings of 5-formyl-2-furanylboronic acid with activated or neutral aryl bromides were performed under continuous flow conditions in the presence of (Bu)₄N⁺F^- and the immobilised t-butyl based palladium cata

Full text of DOI:10.1039/c4ob01641f

Organic &
Biomolecular Chemistry
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An efficient continuous flow approach to furnish
furan-based biaryls†
Cite this: Org. Biomol. Chem., 2014,
12, 9562
Trieu N. Trinh,a Lacey Hizartzidis,a Andrew J. S. Lin,a David G. Harman,b,c
Adam McCluskey*a and Christopher P. Gordon*‡a
Suzuki cross-couplings of 5-formyl-2-furanylboronic acid with activated or neutral aryl bromides were
performed under continuous flow conditions in the presence of (Bu)4N+F− and the immobilised t-butyl
based palladium catalyst CatCart™ FC1032™. Deactivated aryl bromides and activated aryl chlorides were
cross-coupled with 5-formyl-2-furanylboronic in the presence of (Bu)4N+OAc− using the bis-triphenyl-
phosphine CatCart™ PdCl2(PPh3)2-DVB. Initial evidence indicates the latter method may serve as a
universal approach to conduct Suzuki cross-couplings with the protocol successfully employed in the
synthesis of the current gold standard Hedgehog pathway inhibitor LDE225.
Received 1st August 2014,
Accepted 10th October 2014
DOI: 10.1039/c4ob01641f
www.rsc.org/obc
Introduction
The furan-based biaryl motif is an intriguing molecular frame-
work which serves as a pivotal core for a range of bioactive
molecules. The furan biaryl motif is an integral feature of a
number of kinase inhibitors including pan-Pim (1)1 and class I
phosphoinositide 3-kinase2 inhibitors (2), a family of Bcl-xL
inhibitors (3),3 HIV-1 fusion inhibitors (4),4 in addition to a
class of antibacterial agents (5)5 (Fig. 1). However, of particular
interest to our research, the furan-based biaryl motif forms the
core of a number of small molecules possessing inhibitory
activity within the Hedgehog signalling pathway such as 6.6–8
It is unknown if the diverse bioactivities of furan-biaryl
based molecules are related to unique molecular recognitions
or is simply a reflection of the scaffold being overrepresented
in high-throughput-screening libraries. Nevertheless, a note-
worthy feature of the furanyl–biaryl scaffold is that in contrast
to the majority of biaryl molecular frameworks, modelling9
and crystallographic data10 demonstrate that this system pre-
ferentially adopts a planar conformation (Fig. 2).
Fig. 1 Illustrative examples of bioactive compounds constructed
around the furanyl–biaryl core. Structure of the pan-Pim (1)1 and class I
phosphoinositide 3-kinase (2)2 inhibitors, along with the Bcl-xL inhibitor
(3),3 the HIV-1 fusion inhibitors (4),4 the gram-negative antibacterial
agent (5), and the Hedgehog signalling pathway inhibitor (6).6,7
aChemistry, Centre for Chemical Biology, The University of Newcastle, University
Drive, Callaghan, NSW 2308, Australia. E-mail: Adam.McCluskey@newcastle.edu.au;
Fax: +61 (0)249 215472; Tel: +61 (0)249 216486
Given the abundance of furanyl–biaryl analogues in the
literature it is unsurprising that synthetic methodologies to
access the scaffold have been extensively reported. Typical
approaches involve the use of a furanylboronic acid or furanyl-
bromide in Suzuki cross-coupling conditions with a range of
Pd-based catalysts including Pd(OAc)2,2,11–17 PdCl2(PPh3)2,18–20
Pd(PPh3)4,18–26 Pd2(dba)3,27 and Pd(OH)2.28
Whilst these methodologies typically afford the furanyl–
biaryl scaffold in good to excellent yields a common problem
faced, particularly by the pharmaceutical industry, in using
bOffice of the Deputy Vice-Chancellor (Research and Development), University of
Western Sydney, Penrith, NSW 2751, Australia
cMolecular Medicine Research Group, School of Medicine, Building 30, University of
Western Sydney, Goldsmith Avenue, Campbelltown, NSW 2560, Australia
†Electronic supplementary information (ESI) available: GS MS chromatographic
traces, 1H and 13C NMR spectra. See DOI: 10.1039/c4ob01641f
‡Present address: Nanoscale Organisation and Dynamics Group, School of
Science and Health, University of Western Sydney, Locked Bag 1797, Penrith
South DC, Australia. E-mail: c.gordon2@uws.edu.au; Fax: +61 (02) 4620 3025;
Tel: +61 (02) 4620 3201.
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The effect of recycling through the catalyst was evaluated by
HPLC-MS analysis.
The initial reaction conditions gave a 1 : 1.2 ratio of 7 to 9
obtained after a single cycle (Table 1), increasing to 2 : 1 after 4
cycles using FibreCat® 1001. However, given that the Suzuki
reaction coupling efficiencies can be significantly affected by
the ligand utilised, we investigated a number of alternative
FibreCat® columns (Table 1, entries 2–4). Each FibreCat®
catalyst furnished the desired Suzuki reaction with relatively
high efficiencies with Pd-Tetrakis providing the most efficient
coupling with a near 4 : 1 ratio of 7 to 9 afforded within two
catalyst cycles (Table 1, entry 4).
Further improvements in the Pd-Tetrakis coupling
efficiency were noted on increasing reaction temperature to
120 °C with a 1 : 0.08 ratio of 7 : 9 observed at a 0.5 mL min−1
Fig. 2 Co-crystallised structure of 3-{5-[5-(4-chloro-phenyl)-furan-2-
ylmethylene]-4-oxo-2-thioxo-thiazolidin-3-yl}-propionic acid with the
Bacillus anthracis lethal factor metalloproteinase. This structure indi-
cates that in contrast to the majority of biaryl systems the furanyl–biaryl flow rate (a 1.3 min catalyst residence time) (Fig. 3b). However,
motif adopts a planar conformation (PDB accession code 1ZXV.pdb).10
at T > 100 °C increased aryl-bromide homocoupling with
the excessive formation of 10 observed at 140 °C (Fig. 3b).
Increased reaction pressures at 80 °C afforded similar results,
with pressures above 60 bar enhancing the formation of both 7
and 10 (Fig. 3c). At elevated pressure the aryl-bromide homo-
coupled product 10 was the major product.
Given the undesired production of 10, we re-examined
FC1032™ (Table 1, entry 3). While not as effective as
homogeneous catalysts is the removal of residual Pd from
catalyst leaching.29–33 This has in part been negated by the use
of immobilised solid supported catalysts that can be simply
partitioned from reaction mixtures. To this end, a suite of
solid supported precursors to L2Pd(0) catalysts, known as
FibreCats® are now commercially available.29–33 A number of
Pd-Tetrakis, it did produce a higher level of coupling selectivity
these FibreCats® systems are available in pre-packed cartridges
with only trace levels of homocoupled product after 4 catalyst
which are compatible with a number of flow reactors including
cycles. Consequently FC1032™ was subjected to
a
the ThalesNano X-Cube™. Further various flow systems utilis-
ing a range of immobilised catalysts have previously been suc-
cessfully utilised to conduct a number of cross-coupling
reactions.34–37 Herein we report the development of a Fibre-
Cats® compatible flow chemistry methodology that provides a
robust and expedient means of accessing furanyl–biaryl based
analogues as building blocks for drug development programs.
temperature screen as with Pd-Tetrakis (Scheme 1 & Table 2).
Optimisation of the reaction temperature and flow rate
revealed near quantitative conversion to 7 at 120 °C and
0.5 mL min−1. After two catalyst cycles (2.6 min retention time)
only trace levels of starting material (9) and homocoupled (10)
were evident (Table 2). Workup furnished the desired product
7 in a 93% isolated yield, which compares favourably with
the reported batch yield of 88%.38 Further, consistent with
the previous studies which examined palladium leaching,29,30
ICP MS analysis demonstrated negligible levels of palladium
leaching with a maximum total recoverable palladium content
of 5.2 ppm observed for a crude sample of compound 7.
As context the European Agency for the Evaluation of Medi-
cines states that for oral administration the permitted daily
exposure of class A1 metals such as palladium should not
exceed 10 mg kg−1 and thus the Pd content of 7 is within this
guideline.39,40
Results and discussion
Our primary interest in the furan-based biaryl motif relates to
our current interest in developing a series of Hedgehog signal-
ling pathway inhibitors. To this end our primary aim was to
develop a series of furfural-based analogues, e.g. 7 (Scheme 1),
as the aldehyde moiety readily permits further synthetic
manipulations. To this end, our investigations commenced
with flowing a methanolic solution of 5-formyl-2-furanyl-
boronic acid (8), 3-bromobenzyl alcohol (9), and three equi-
valents of (Bu)4N+F− through an X-cube™ charged with an
FC1001 FibreCat® at 0.5 mL min−1 at a temperature of 80 °C
(Scheme 1). This equated to a 2.2 min catalyst residence time.
While the optimised protocol efficiently furnished 7, the
practicality of this continuous flow approach could only be
judged by amenability to aryl bromide variations. Thus,
the coupling of a small library of aryl bromides, sulfonamide
based aryl bromides, and an amide based aryl bromide was
investigated. The data presented in Table 3 illustrates the
utility of FC1032™, (Bu)4N+F−, at a flow rate of 0.5 mL min−1
,
over two catalyst cycles and temperature of 120 °C in furnish-
ing a small library in excellent isolated yields (82–92%).
Given our success with FC1032™ we next turned our
attention to the Suzuki cross-coupling of deactivated aryl
bromides such as 4-bromophenol (13, Scheme 2). The synthesis
Scheme 1 Reagents and conditions: (i) 5-formyl-2-furanylboronic acid
(8) (1 mmol), 3-bromobenzyl alcohol (9) (1 mmol), (Bu)4N+F− (3 mmol),
MeOH (30 mL), FibreCat® 1001, X-Cube™, 0.5 mL min−1, and 80 °C.
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Table 1 Ratio of 7 and 9 peak areas obtained after subsequent cycles through various FibreCat® catalysts. Reagents and conditions are as
per Scheme 1
Number of catalyst cycles
Ratio of 7 : 9a
Entry
1
Pd-ligand
FibreCat®
1
2
3
4
FC1001™
1 : 1.2
1 : 0.7
1 : 0.5
1 : 0.4
2
3
4
FC1007™
FC1032™
Pd-Tetrakis
1 : 1.3
1 : 0.7
1 : 0.4
1 : 0.7
1 : 0.4
1 : 0.3
1 : 0.4
1 : 0.3
1 : 0.3
1 : 0.2
1 : 0.2
1 : 0.2
a Ratio of peak areas determined by HPLC analysis at 220 nm.
of the desired analogue 14 had been previously reported via efficiency ratio of 0.24 : 1, essentially identical to that of
coupling of 4-iodophenol and 8 using Pd-Tetrakis to afford 14 (Bu)4N+OAc− alone (Table 4, entries 9 and 7 respectively), sup-
in an 87% yield,19 however, equivalent Pd-Tetrakis coupling porting the hypothesized additional role of the −OAc. Perform-
with 4-bromophenol (13) gave 14 in only 10%.2 Using our flow ing the cross-coupling reaction with only Cs2CO3 the yield of
protocol resulted in an improvement on the batch synthesis 14 was reduced to ∼20% whilst the aryl bromide homocoupled
with an approximate 30% conversion (and 23% isolated yield) product was obtained in a 52% yield confirming the crucial
of 14 after three catalyst cycles (Table 3, entry 1). This however, nature of the tetrabutylammonium salt.
was not the near quantitative yields obtained with the more
Using (Bu)4N+OAc− in conjunction with FC1032™ gave 14
activated aryl bromides (9a–f). Given that our prior studies in a 72% yield from 13. However other deactivated aryl bro-
with Pd-Tetrakis highlighted increasing homocoupled product mides such as the dimethylamino analogues 15a and 15b, the
with increased temperature and pressures, our initial reaction methoxy analogue 15c, and the indole 15d, aryl chlorides 15e
optimisation examined the effect of varying the tetrabutyl- and 15f gave unacceptably low levels of the desired cross
ammonium salt which has previously been observed to impart coupled products (Table 5).
subtle variations on cross-coupling yields.41
We consequently investigated the more activated CatCart™
Varying the halogen counterion from –F to –Cl, –Br and –I PdCl2(PPh3)2-DVB catalysts which has been shown to be highly
resulted in reduced coupling efficiencies (Table 4, entries 2–5), effective in Sonogashira couplings.42 The flow coupling steps
−
−
as with the BF4 (Table 4, entry 5), and HSO4 salts (Table 4, were optimised as before with the CatCart™ PdCl2(PPh3)2-DVB
entry 6). However, the use of (Bu)4N+OAc− (Table 4, entry 7) catalyst and we noted that clean coupling, with near quantitat-
resulted in improved coupling efficiency with a near to 80% ive conversions was accomplished at 120 °C, after three catalyst
conversion after a single catalyst cycle. Presumably the excess cycles at 0.3 mL min−1 (Table 5).
acetate ions activate the boronic acid (as is the case with
We subsequently used this protocol to effect the cross-
K2CO3), and halogen abstraction from the first organo- coupling of 16 and 17 and gained expedient access to the
palladium intermediate in the Suzuki cycle.
potent smoothened inhibitor LDE225 (18) which is a crucial
Binary mixtures of (Bu)4N+F− and Cs2CO3 improved the component of our Hedgehog pathway inhibitor development
efficiency of the cross coupling from 0.46 : 1 with (Bu)4N+F− program (Scheme 3).
alone (Table 4, entry 1) to 0.2 : 1 (Table 4, entry 8). The binary
Thus whilst increasing catalyst retention time and catalysts
combination of (Bu)4N+OAc− and Cs2CO3 gave a coupling cycles significantly enhanced coupling efficiencies of deacti-
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Table 3 Suzuki cross-couplings using a series of aryl bromides (9a–f)
with FC1032™a
Compound
R
Conversion (%)
96
Isolated yield (%)
87
12a
12b
12c
12d
95
90
95
82
91
85
12e
12f
91
98
87
92
a Reagents and conditions: 5-formyl-2-furanylboronic acid (8) (1 mmol),
aryl bromides (9a–9f) (1 mmol), (Bu)4N+F−·3H2O (3 mmol), MeOH,
FC1032™, X-Cube™, and 0.5 mL min−1 over two catalyst cycles.
Fig. 3 (a) Reagents and conditions: (i) 5-formyl-2-furanylboronic acid
(8) (1 mmol), 3-bromobenzyl alcohol (9) (1 mmol), (Bu)4N+F− (3 mmol),
and MeOH (30 mL) at 0.5 mL min−1, Pd-tetrakis; (b) Comparison of the
relative quantities of aryl bromide (9), desired product (7), and aryl
bromide homocoupled (10) product returned at temperatures of 60 to
140 °C with 0 bar pressure; (c) Comparison of the relative quantities of
aryl bromide (9), desired product (7), and aryl bromide homocoupled
product returned at pressures of 0 to 100 bar at 80 °C. HPLC analysis
conducted at 220 nm. Maximum total recoverable Pd content by ICP MS
analysis 5.2 ppm.
Scheme 2 Reagents and conditions: (i) 5-formyl-2-furanylboronic
acid (8) (1 mmol), 4-bromophenol benzyl alcohol (13) (1 mmol),
(Bu)4N+F−·3H2O (3 mmol), MeOH (30 mL), FC1032™, X-Cube™, 0.5 mL
min−1, and 120 °C.
Table 2 Temperature screen using FC1032™ at
0 bar pressure.
Table 4 Tetrabutylammonium salt screen using FC1032™
Reagents and conditions are as per Fig. 3
Ratio of peak
areaa
Ratio of peak area after two cyclesa
Entry
Tetrabutylammonium salt
13
14
Temperature (°C)
7
9
10
1
2
3
4
5
6
7
8
9
(Bu)4N+F−
(Bu)4N+Cl−
(Bu)4N+Br−
(Bu)4N+I−
0.46
1
1
1
1
1
1
1
1
1
60
80
100
120
1
1
1
1
7.8
1.1
0.37
0.05
0
0
0
0
0.65
21.82
30.11
2.47
1.51
0.22
−
(Bu)4N+BF4
a Ratio of peak areas determined HPLC analysis at 220 nm. Maximum
total recoverable Pd content by ICP MS analysis 5.2 ppm.
(Bu)4N+HSO4
−
(Bu)4N+OAc−
(Bu)4N+F− + Cs2CO3
(Bu)4N+OAc− + Cs2CO3
0.20
0.24
a Ratio of peak areas determined by HPLC analysis at 220 nm.
vated aryl-bromides and aryl-chlorides, we were cognisant that
these conditions may promote increased levels of palladium
leaching. However as outlined in Table 6, negligible levels of
palladium leaching were observed with a maximum total re-
coverable Pd content by ICP MS analysis of 5.2 ppm for 15d,
5.2 ppm for 15e, whilst the remainder of samples analysed
contenting less than 1 ppm palladium content.
Conclusion
A combination of un-distilled methanol, (Bu)4 OAc−, 5-formyl-
+
2-furanylboronic acid, an activated or neutral aryl bromide,
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Table 5 Suzuki couplings with deactivated aryl bromides and aryl chlorides
Percent conversionb
Aryl halide
Producta
FC1032™
PdCl2(PPh3)2-DVB
96
15a
15b
28
12
87
15c
15d
15e
16
16
<5
92
92
83
15f
<5
87
a Reagents and conditions: (i) 5-formyl-2-furanylboronic acid (1 mmol), aryl halide (1 mmol), (Bu)4N+OAc− (3 mmol), MeOH (30 mL), X-Cube™,
0.3 mL min−1, and 120 °C, three catalyst cycles. b Percentage conversion determined by HPLC analysis at 220 nm.
Table 6 Total recoverable trace palladium by ICP MS of selected
samples
PdCl2(PPh3)2-DVB
(yield %)
Palladium
contenta
Producta
15a
15c
96
0.65 ppm
Scheme 3 Reagents and conditions: (i) 4-(trifluoromethoxy)phenyl-
boronic acid (16), 3-bromo-N-(6-((2R,6S)-2,6-dimethylmorpholino)
pyridin-3-yl)-2-methylbenzamide (17), (Bu)4N+OAc−, MeOH (30 mL),
PdCl2(PPh3)2-DVB, 0.3 mL min−1, and 120 °C.
92
0.48 ppm
15e
18
83
87
0.72 ppm
5.2 ppm
along with the X-cube™ continuous flow reactor charged with
the t-butyl based palladium catalyst FC1032™ efficiently
afforded Suzuki cross-coupled products in excellent yield
(>80%) with negligible homocoupling observed. In relation to
deactivated aryl bromides or aryl chlorides the use of a more
active Pd-based catalyst such as PdCl2(PPh3)2-DVB, provided
efficient coupling to the desired products. This optimised con-
tinuous flow Suzuki cross-coupling methodology appears
amenable with a range of boronic acids. However, we note that
when CatCart™ PdCl2(PPh3)2-DVB was employed to perform
the initial cross-coupling investigation (i.e. Scheme 1), as was
the case with Pd-Tetrakis, a significant (∼30%) amount of aryl
bromide homocoupling product was observed. Consequently
we propose that FC1032™ serves as a more effective catalyst
for the cross-coupling of activated or neutral aryl bromides.
We have used this protocol to provide expedient access to the
a ICP MS analysis was conducted by the Australian National
Measurement Institute.
potent smoothened inhibitor LDE225 (18). Significantly, negli-
gible palladium leaching was observed with the immobilised
catalysts29,31 and thus this continuous flow Suzuki cross-coup-
ling protocol is ideally suited to medicinal chemistry research
programs. We are currently investigating the versatility of these
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conditions with other palladium catalysed cross-coupling reac- dried (MgSO4), concentrated in vacuo, and the crude was sub-
tions and the outcomes of these investigations will be reported jected to flash silica gel chromatography (1 : 1 EtOAc–hexanes)
in due course.
to afford biphenyl-3,3′-diyldimethanol (10) as a colourless oil
(0.01 g, 3%). LRMS (ESI+) m/z 215(M + 1). H NMR (400 MHz,
1
CDCl3) δ 7.61 (s, 1H), 7.54 (d, J = 7.7 Hz, 1H), 7.44 (t, J =
7.6 Hz, 1H), 7.36 (d, J = 7.5 Hz, 1H), 4.76 (d, J = 7.7 Hz, 2H);
13C NMR (101 MHz, CDCl3) δ 141.4, 141.3, 129.0, 129.0, 126.5,
126.0, 125.8, 65.4; RP-HPLC Alltima™ C18 5u 150 mm ×
4.6 mm, 10–100% B in 15 min, tR 10.39 min. Continued
elution (1 : 1 EtOAc–hexanes) afforded 5-(3-(hydroxymethyl)-
phenyl)furan-2-carbaldehyde (7) as an orange oil (0.37 g, 82%).
LRMS (ESI+) m/z 203 (M + 1); HRMS (ES+) for C12H11O3; calcu-
lated 201.0630, found 202.0681; 1H NMR (400 MHz, CDCl3)
δ 9.51 (s, 1H), 7.74 (s, 1H), 7.67–7.57 (m, 1H), 7.32 (m, 2H),
7.25 (d, J = 3.7 Hz, 1H), 6.76 (d, J = 3.7 Hz, 1H), 4.67 (s, 2H).
13C NMR (101 MHz, CDCl3) δ 177.34, 159.5, 151.8, 142.1, 129.0
(C × 2), 128.9, 128.2, 124.3, 123.6, 107.9, 77.5, 77.2, 76.9, 64.4.
RP-HPLC Alltima™ C18 5u 150 mm × 4.6 mm, 10–100% B
in 15 min, tR 9.10 min.
Experimental section
All reagents were purchased from Sigma Aldrich and were
used without purification, with the exception of furfural,
which was distilled through glass prior to use. Solvents were
bulk, and distilled through glass prior to use.
1H and 13C NMR spectra were recorded on a Bruker
Advance™ AMX 400 MHz spectrometer at 400.13 and
100.62 MHz, respectively. Chemical shifts (δ) are reported in
parts per million (ppm) measured to relative the internal stan-
dards. Coupling constants (J) are expressed in hertz (Hz). Mass
spectra were recorded on a Shimadzu LCMS 2010 EV using
a mobile phase of 1 : 1 acetonitrile–H2O with 0.1% formic
acid. Gas chromatography-mass spectrometry (GC-MS) was
performed on a Shimadzu GC-MS QF2010 EI/NCI System
equipped with a ZB-5MS capillary column of 5% phenyl-
arylene stationary phase. High-resolution mass spectra
(HRMS) were determined on a Micromass QToF2 spectrometer
using polyethylene glycol or polypropylene glycol as lockmass.
Monoisotopic molecular masses were calculated utilising
ChemDraw Ultra 8.0.
5-(4-Acetylphenyl)-2-furancarboxaldehyde (12a)
General procedure 1. A solution of 4-bromoanisole (0.40 g,
2.1 mmol), 5-formyl-2-furanylboronic acid (0.30 g, 2.1 mmol)
and TBAF (2.16 g, 6.86 mmol) was diluted with MeOH (30 mL)
to afford a 0.05 M solution. This solution was flowed through
an X-Cube™ fitted with a FC1032™ catalyst at flow rate of
0.5 mL min−1, at a temperature of 120 °C, and 0 bar pressure
for 2 h (i.e. total of two catalyst cycles). The eluent was concen-
trated in vacuo, diluted with DCM (30 mL), washed with 1 M
HCl (2 × 30 mL), dried (MgSO4), concentrated in vacuo, and the
crude was subjected to flash silica gel chromatography (1 : 1
EtOAc–hexanes) to afford 5-(4-acetylphenyl)-2-furancarboxalde-
hyde (12a) as a yellow oil (0.36 g, 87%). LRMS (ESI+) m/z 215
(M + 1); HRMS (ES+) for C13H11O3; calculated 215.0630, found
214.0637; 1H NMR (CDCl3, 400 MHz); δ 9.60 (s, 1H), 7.77 (d,
J = 8.9 Hz, 2H), 7.30 (d, J = 3.7 Hz, 1H), 6.96 (d, J = 8.9 Hz, 2H),
6.72 (d, J = 3.7 Hz, 1H), 3.86 (s, 3H); 13C NMR (CDCl3,
101 MHz): δ 176.9, 160.91, 159.8, 151.6, 129.0, 127.0, 121.8,
114.4, 106.3, 55.4; RP-HPLC Alltima™ C18 5u 150 mm ×
4.6 mm, 10–100% B in 15 min, tR 14.26 min.
Analytical HPLC traces were obtained using a Shimadzu
system possessing a SIL-20A auto-sampler, dual LC-20AP
pumps, CBM-20A bus module, CTO-20A column heater, and a
SPD-20A UV/vis detector. This system was fitted with an
Alltima™ C18 5u 150 mm × 4.6 mm column with solvent
A: 0.06% TFA in water and solvent B: 0.06% TFA in CH3CN–
H2O (90 : 10). In each case HPLC traces were acquired at a flow
rate of 2.0 mL min−1, gradient 10–100 (%B), curve = 6, over
15.0 min, with detection at 220 nm and 265 nm.
Where applicable, melting points were recorded on a
Buchi Melting Point M-565. IR spectra were recorded on a
PerkinElmer Spectrum Two™ FTIR Spectrometer. Thin
layer chromatography (TLC) was performed on Merck 60 F254
pre-coated aluminium plates with a thickness of 0.2 mm.
Column chromatography was performed under ‘flash’ con-
ditions on Merck silica gel 60 (230–400 mesh).
2-(4-(5-Formylfuran-2-yl)phenyl)acetonitrile (12b)
ICP MS analysis was conducted by the Australian National
Measurement Institute 105 Delhi Road, North Ryde NSW 2113
(http://www.measurement.gov.au).
Compound (12b) was synthesised as described in general pro-
cedure
1 from 4-bromoacetonitrile (0.44 g, 2.2 mmol),
5-formyl-2-furanylboronic acid (0.31 g, 2.2 mmol) and TBAF
(2.04 g, 6.7 mmol). The crude reaction mixture was subjected
to flash silica chromatography (4 : 1 Hex–EtOAc) to afford 12b
Biphenyl-3,3′-diyldimethanol (10) and 5-(3-(hydroxymethyl)
phenyl)furan-2-carbaldehyde (7)
A solution of (3-bromophenyl)methanol (0.28 mL, 2.3 mmol), as an orange solid (0.38 g, 82%). LRMS (ESI+) m/z 212 (M + 1);
5-formyl-2-furanylboronic acid (0.32 g, 2.3 mmol) and TBAF HRMS (ES+) for C13H10NO2; calculated 212.0630, found
(2.16 g, 6.86 mmol) was diluted with MeOH (30 mL) to afford a 212.0637; 1H NMR (CDCl3, 400 MHz): δ 9.67 (s, 1H), 7.84 (d,
0.05 M solution. This solution was flowed through an X-Cube™ J = 8.4 Hz, 2H), 7.43 (d, J = 8.5 Hz, 2H), 7.33 (d, J = 3.7 Hz, 1H),
fitted with a Fibrecat®1001 catalyst at flow rate of 0.5 mL min−1
,
6.87 (d, J = 3.7 Hz, 1H), 3.81 (s, 2H); 13C NMR (CDCl3,
at a temperature of 80 °C, and 0 bar pressure for 2 h (i.e. total of 101 MHz): δ 177.3, 158.37, 152.2, 131.3, 128.9, 128.6, 126.0,
two catalyst cycles). The eluent was concentrated in vacuo, 108.2,23.6. RP-HPLC Alltima™ C18 5u 150 mm × 4.6 mm,
diluted with DCM (30 mL), washed with 1 M HCl (2 × 30 mL), 10–100% B in 15 min, tR 14.27 min.
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5-(4-Methylphenyl)-2-furancarboxaldehyde (12c)
C17H14NO4S; calculated 328.0565, found 327.0556; 1H NMR
(400 MHz, CDCl3) δ 9.61 (s, 1H), 7.85–7.78 (m, 2H), 7.69 (d, J =
8.7 Hz, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 7.7 Hz, 2H), 7.30
(d, J = 3.7 Hz, 1H), 7.26 (s, 1H), 7.18 (d, J = 8.7 Hz, 3H), 6.76 (d,
J = 3.7 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 177.0, 158.6,
151.89, 138.8, 137.8, 129.2, 127.2, 126.6, 125.8, 121.1 (C × 2),
107.6. RP-HPLC Alltima™ C18 5u 150 mm × 4.6 mm, 10–100%
B in 15 min, tR 15.58 min.
Compound 12c was prepared utilising general procedure 1,4-
bromotoluene (0.28 mL, 2.3 mmol), 5-formyl-2-furanylboronic
acid (0.32 g, 2.3 mmol), TBAF (2.16 g, 6.86 mmol), and MeOH
(30 mL). The eluent was concentrated in vacuo and the
crude material was diluted with DCM (30 mL) and washed
with 1 M HCl (2 × 30 mL). The organic layer was dried
(MgSO4), and concentrated in vacuo to yield an oil which was
further purified using flash chromatography (1 : 9 EtOAc–
hexanes) to afford 5-(4-methylphenyl)-2-furancarboxaldehyde
as an orange oil/solid (0.39 g, 91%) m.p. 50–56 °C. LRMS
(ESI+) m/z 187 (M + 1); HRMS (ES+) for C12H11O2; calculated
N-(2,4-Dimethoxyphenyl)-4-(5-formylfuran-2-yl)benzamide
(12f)
Compound 12f was synthesised utilising general procedure
1, 4-bromo-N-(2,4-dimethoxyphenyl)benzamide (0.73 g,
2.2 mmol), 5-formyl-2-furanylboronic acid (0.31 g, 2.2 mmol)
and TBAF (2.14 g, 6.6 mmol) to afford N-(2,4-dimethoxy-
phenyl)-4-(5-formylfuran-2-yl)benzamide as a light brown solid
(0.71. g, 92%). LRMS (ESI−) m/z 352 (M − 1); HRMS (ES−) for
C20H18NO5; calculated 352.1107, found 352.1113; 1H NMR
(400 MHz, DMSO-d6): δ 9.66 (s, 1H), 9.54 (s, NH), 8.09 (d, J =
8.3 Hz, 2H), 8.01 (d, J = 8.4 Hz, 2H), 7.70 (d, J = 3.8 Hz, 1H),
7.48 (d, J = 8.6 Hz, 1H), 7.45 (d, J = 3.7 Hz, 1H), 6.67 (d, J =
2.6 Hz, 1H), 6.55 (dd, J = 8.7, 2.6 Hz, 1H), 3.81 (s, 3H), 3.79
(s, 3H); 13C NMR (400 MHz, DMSO-d6): δ 178.6, 164.8, 158.5,
157.6, 154.1, 152.6, 135.55, 131.6, 128.9, 127.1, 125.3, 120.0,
110.7, 104.7, 99.4, 56.2, 55.8; RP-HPLC Alltima™ C18 5u
150 mm × 4.6 mm, 10–100% B in 15 min, tR 18.12 min.
1
187.0681, found 186.0678; H NMR (CDCl3, 400 MHz): δ 9.63
(s, 1H), 7.72 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 3.7 Hz, 1H), 7.25 (d,
J = 8.9 Hz, 2H), 6.78 (d, J = 3.7 Hz, 1H), 2.39 (s, 3H); 13C NMR
(CDCl3, 101 MHz): δ 177.1, 159.8, 151.8, 140.0, 129.7, 126.3,
125.3, 107.1, 21.5; RP-HPLC Alltima™ C18 5u 150 mm ×
4.6 mm, 10–100% B in 15 min, tR 17.41 min.
5-(Dimethylamino)-N-(4-(5-formylfuran-2-yl)phenyl)-
naphthalene-1-sulfonamide (12d)
Compound 12d was prepared utilising general procedure 1,
and N-(4-bromophenyl)-5-(dimethylamino)naphthalene-1-sul-
fonamide (0.92 g, 2.3 mmol), 5-formyl-2-furanylboronic acid
(0.32 g, 2.3 mmol), TBAF (2.16 g, 6.86 mmol), and MeOH
(30 mL). The eluent was concentrated in vacuo, the crude
material was diluted with DCM (30 mL) and washed with 1 M 5-(4-Hydroxyphenyl)-2-furancarboxaldehyde (14)
HCl (2 × 30 mL). The organic layer was dried (MgSO4), and
concentrated in vacuo to yield an oil which was further purified
using flash chromatography (5 : 1 EtOAc–hexanes) to afford
5-(4-methylphenyl)-2-furancarboxaldehyde as an yellow oil/
Compound 14 was synthesised utilising general procedure 1,4-
bromophenol (0.38 g, 2.3 mmol), 5-formyl-2-furanylboronic
acid (0.32 g, 2.3 mmol) and TBAF (2.10 g, 6.9 mmol). The
crude was subjected to silica gel chromatography (4 : 1 EtOAc–
Hex) to afford 5-(4-hydroxyphenyl)-2-furancarboxaldehyde
as an orange oil/solid (0.09 g, 30%). LRMS (ESI−) m/z 187
solid (0.82 g, 87%). LRMS (ESI+) m/z 421 (M + 1); HRMS (ES+)
for C23H21N2O4S; calculated 421.1144, found 421.1144; 1H
NMR (400 MHz, CDCl3) δ 9.55 (s, 1H), 8.51 (d, J = 8.4 Hz, 1H),
(M − 1); HRMS (ES−) for C11H7O3; calculated 187.0473,
8.46–8.25 (m, 2H), 8.13 (s, 1H), 7.56–7.51 (m, 1H), 7.50 (d, J =
found 187.0468; 1H NMR (CDCl3, 400 MHz): δ 9.60 (s, 1H),
8.7 Hz, 2H), 7.47–7.42 (m, 1H), 7.23 (d, J = 3.7 Hz, 1H), 7.16 (d,
7.73 (d, J = 8.8 Hz, 2H), 7.31 (d, J = 3.7 Hz, 1H), 6.92 (d, J =
J = 7.9 Hz, 1H), 7.09 (d, J = 8.7 Hz, 2H), 6.62 (d, J = 3.7 Hz, 1H),
8.8 Hz, 2H), 6.71 (d, J = 3.7 Hz, 1H); 13C NMR (CDCl3,
2.85 (s, 6H). 13C NMR (CDCl3, 101 MHz): δ 177.2, 158.9, 151.7,
101 MHz): δ 176.9, 157.1, 128.0, 127.3, 122.0, 116.0, 115.6,
106.3. RP-HPLC Alltima™ C18 5u 150 mm × 4.6 mm, 10–100%
B in 15 min, tR 10.68 min.
138.2, 134.1, 132.1, 131.0, 130.4, 129.7, 129.6, 128.7, 126.3,
125.0, 123.2, 122.7, 120.3, 115.5, 111.1, 107.3, 45.4; RP-HPLC
Alltima™ C18 5u 150 mm × 4.6 mm, 10–100% B in 15 min,
tR 9.60 min.
5-(3-(Dimethylamino)phenyl)-2-furancarboxaldehyde (15a)
General procedure 2. A solution of 3-bromo-N,N-dimethyl-
aniline (0.28 mL, 2.3 mmol), 5-formyl-2-furanylboronic acid
N-(4-(5-Formylfuran-2-yl)phenyl)benzenesulfonamide (12e)
Compound 12e was prepared utilising general procedure (0.32 g, 2.3 mmol) and TBAA (2.08 g, 6.86 mmol) was diluted
1, and N-(4-bromophenyl)benzenesulfonamide (0.77 g, with MeOH (30 mL) to afford a 0.05 M solution. This solution
2.3 mmol), 5-formyl-2-furanylboronic acid (0.32 g, 2.3 mmol), was flowed through an X-Cube™ fitted with a CatCart®
TBAF (2.16 g, 6.86 mmol), and MeOH (30 mL). The eluent was PdCl2(PPh3)2-DVB catalyst at flow rate of 0.3 mL min−1, at a
concentrated in vacuo, the crude material was diluted with temperature of 120 °C, and 0 bar pressure for 3 h (i.e. total of
DCM (30 mL) and washed with 1 M HCl (2 × 30 mL). The three catalyst cycles). The eluent was concentrated in vacuo,
organic layer was dried (MgSO4), and concentrated in vacuo to diluted with DCM (30 mL) and washed with 1 M HCl (2 ×
yield an oil which was further purified using flash chromato- 30 mL), dried (MgSO4), concentrated in vacuo, and the
graphy (4 : 1 EtOAc–hexanes) to afford N-(4-(5-formylfuran- crude was subjected to flash silica gel chromatography (7 : 1
2-yl)phenyl)benzenesulfonamide as an yellow oil/solid (0.65 g, EtOAc–hexanes) to afford 5-(3-(dimethylamino)phenyl)-2-furan-
87%). LRMS (ESI+) m/z 328 (M + 1); HRMS (ES+) for carboxaldehyde as a colourless oil (0.43 g, 87%). LRMS (ESI+)
9568 | Org. Biomol. Chem., 2014, 12, 9562–9571
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m/z 216 (M + 1); HRMS (ES+) for C13H14NO2; calculated 5-(4-Benzoylphenyl)-2-furancarboxaldehyde (15e)
216.0946, found 216.0942; 1H NMR (DMSO-d6, 400 MHz):
Compound 15e was synthesised using general procedure 2,
(4-chlorophenyl)(phenyl)methanone (0.41 g, 2.2 mmol),
5-formyl-2-furanylboronic acid (0.31 g, 2.2 mmol) and TBAF
(1.99 g, 6.60 mmol). The crude was subjected to flash silica gel
chromatography (4 : 1 Hex–EtOAc) to afford 5-(4-benzoyl-
phenyl)-2-furancarboxaldehyde as a off-white solid (0.38. g,
87%). LRMS (ESI+) m/z 277 (M + 1); HRMS (ES+) for C18H13O3;
calculated 277.0786, found 277.0791; 1H NMR (DMSO-d6,
100 MHz): δ 9.67 (s, 1H), 8.05 (d, J = 8.4 Hz, 2H), 7.86 (d, J =
δ 9.59 (s, 1H), 7.64 (d, J = 3.7 Hz, 1H), 7.30 (d, J = 7.9 Hz, 1H),
7.27 (d, J = 3.7 Hz, 1H), 7.16 (d, J = 7.6 Hz, 1H), 7.13 (d, J =
2.0 Hz, 1H), 6.81 (dd, J = 8.3, 2.4 Hz, 1H), 2.97 (s, 6H). 13C
NMR (DMSO-d6, 101 MHz): δ 178.1, 159.7, 151.9, 151.2, 130.2,
129.7, 114.3, 113.5, 109.0, 108.5, 40.5. RP-HPLC Alltima™ C18
5u 150 mm × 4.6 mm, 10–100% B in 15 min, tR 9.60 min.
5-(4-(Dimethylamino)phenyl)-2-furancarboxaldehyde (15b)
Compound 15b was synthesised utilising general procedure 2 8.4 Hz, 2H), 7.78–7.75 (m, 2H), 7.73–7.69 (m, 2H), 7.59 (t, J =
and 4-bromo-N,N-dimethylaniline (0.46 g, 2.3 mmol), 5-formyl- 7.6 Hz, 2H), 7.48 (d, J = 3.8 Hz, 1H); 13C NMR (CDCl3,
2-furanylboronic acid (0.32 g, 2.3 mmol) and TBAA (2.08 g, 101 MHz): δ 195.5, 178.7, 157.3, 152.8, 137.7, 137.3, 133.3,
6.90 mmol). The crude was subject to flash silica gel chromato- 132.6, 131.0, 130.1, 129.1, 125.4, 111.3; RP-HPLC Alltima™
graphy (7 : 1 EtOAc–Hex) to afford 5-(4-(dimethylamino) C18 5u 150 mm × 4.6 mm, 10–100% B in 15 min, tR 18.21 min.
phenyl)-2-furancarboxaldehyde as a yellow solid (0.43 g, 87%).
M.p. 96–98 °C (Lit m.p.: 95–98 °C). LRMS (ESI−) m/z 216 (M +
1); HRMS (ES+) for C13H14NO2; calculated 216.0946, found
216.0950; H NMR (DMSO-d6, 400 MHz): δ 9.48 (d, J = 3.2 Hz,
5-(3-Formylphenyl)furan-2-carbaldehyde (15f)
1
Compound 15f was synthesised using general procedure,
3-chlorobenzaldehyde (0.28 g, 2.0 mmol), 5-formyl-2-furanyl-
boronic acid (0.28 g, 2.0 mmol) and TBAF (1.81 g, 6.0 mmol).
The crude was subjected to flash silica gel chromatography
(9 : 1 Hex–EtOAc) to afford 5-(4-benzoylphenyl)-2-furancarb-
oxaldehyde as a off-white solid (0.34. g, 85%). LRMS (ESI−) m/z
199 (M − 1); HRMS (ES−) for C12H7O3; calculated 199.0473,
found 199.0482; 1H NMR (400 MHz, DMSO) δ 10.11 (s, 1H),
9.66 (s, 1H), 8.38 (s, 1H), 8.21 (d, J = 7.9 Hz, 1H), 7.98 (d, J =
7.6 Hz, 1H), 7.76 (t, J = 7.7 Hz, 1H), 7.70 (d, J = 3.7 Hz, 1H),
7.46 (d, J = 3.7 Hz, 1H); 13C NMR (101 MHz, DMSO) δ 193.33,
178.61, 157.24, 152.51, 137.38, 131.03, 130.65, 130.63, 129.99,
126.09, 125.91, 125.67, 110.34; RP-HPLC Alltima™ C18 5u
150 mm × 4.6 mm, 10–100% B in 15 min, tR 10.68 min.
1H), 7.69 (dd, J = 8.2, 3.6 Hz, 2H), 7.59 (t, J = 3.8 Hz, 1H), 7.00
(t, J = 3.9 Hz, 1H), 6.81 (dd, J = 8.3, 3.4 Hz, 2H), 3.00 (d, J =
3.2 Hz, 6H); 13C NMR (DMSO-d6, 101 MHz): δ 176.9, 160.6,
151.6, 151.1, 126.9, 116.4, 112.5, 106.0; RP-HPLC Alltima™
C18 5u 150 mm × 4.6 mm, 10–100% B in 15 min, tR 10.68 min.
5-(4-Methoxyphenyl)-2-furancarboxaldehyde (15c)
Compound 15c was synthesised utilised general procedure 2,
4-bromoanisole (0.41 g, 2.2 mmol), 5-formyl-2-furanylboronic
acid (0.31 g, 2.2 mmol) and TBAA (1.99 g, 6.6 mmol). The
crude was subjected to flash silica gel chromatography (5 : 1
Hex–EtOAc) to afford 5-(4-methoxyphenyl)-2 furancarbox-
aldehyde as a pale yellow oil (0.42 g, 92%). LRMS (ESI−) m/z
201 (M − 1); HRMS (ES−) for C12H9O3; calculated 201.0630,
found 201.0637; 1H NMR (CDCl3, 400 MHz): δ 9.60 (s, 1H),
7.77 (d, J = 8.9 Hz, 2H), 7.30 (d, J = 3.7 Hz, 1H), 6.96 (d, J =
8.9 Hz, 2H), 6.72 (d, J = 3.7 Hz, 1H), 3.86 (s, 3H); 13C NMR N-(6-((2S,6R)-2,6-Dimethylmorpholino)pyridin-3-yl)-2-methyl-
(CDCl3, 101 MHz): δ 176.9, 160.91, 159.8, 151.6, 129.0, 127.0, 4′-(trifluoromethoxy)biphenyl-3-carboxamide (LDE225) (18)
121.8, 114.4, 106.3, 55.4; RP-HPLC Alltima™ C18 5u 150 mm ×
4.6 mm, 10–100% B in 15 min, tR 18.92 min.
Compound 18 was synthesised using general procedure 2,
3-bromo-N-(6-((2R,6S)-2,6-dimethylmorpholino)pyridin-3-yl)-2-
methylbenzamide (0.48 g, 1.2 mmol), 4-(trifluoromethoxy)-
phenylboronic acid (0.25 g, 1.2 mmol), and TBAF (1.08 g,
5-(1H-Indol-6-yl)-2-furancarboxaldehyde (15d)
Compound 15d was synthesised utilising general procedure 2, 3.6 mmol). The crude was subjected to flash silica gel
6-bromo-1H-indole (0.41 g, 2.1 mmol), 5-formyl-2-furanylboro- chromatography (9 : 1 DCM–MeOH) to afford LDE225 as a
nic acid (0.29 g, 2.1 mmol) and TBAA (1.90 g, 6.3 mmol). The off-white solid (0.55 g, 94%). LRMS (ESI+) m/z 486 (M + 1);
crude was subjected to flash silica gel chromatography (3 : 1 1H NMR (400 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.43 (d, J =
EtOAc–Hex) to afford 5-(1H-indol-6-yl)-2-furancarboxaldehyde 2.4 Hz, 1H), 7.94 (dd, J = 9.1, 2.5 Hz, 1H), 7.47 (s, 4H),
as an off-white solid (0.48. g, 83%). LRMS (ESI+) m/z 212 7.42–7.25 (m, 2H), 6.86 (d, J = 9.1 Hz, 1H), 4.06 (d, J = 12.0 Hz,
(M + 1); HRMS (ES+) for C13H10NO2; calculated 212.0633, 2H), 3.67–3.54 (m, 2H), 2.41–2.27 (m, 2H), 2.22 (s, 3H), 1.16 (d,
found 212.0635; 1H NMR (CDCl3, 400 MHz): δ 9.61 (s, 1H), J = 6.2 Hz, 6H); 13C NMR (101 MHz, DMSO-d6) δ 0.19, 156.18,
8.43 (s, NH), 7.95 (s, 1H), 7.68 (d, J = 8.3 Hz, 1H), 7.54 (dd, J = 148.00, 141.40, 140.63, 139.87, 139.05, 132.53, 131.52, 131.14,
8.3, 1.4 Hz, 1H), 7.34 (d, J = 3.7 Hz, 1H), 7.33–7.31 (m, 1H), 130.66, 127.49, 127.05, 126.26, 121.85, 121.38, 119.31, 107.32,
6.83 (d, J = 3.7 Hz, 1H), 6.60–6.56 (m, 1H). 13C NMR (CDCl3, 71.32, 51.25, 19.30, 17.71;193.33, 178.61, 157.24, 152.51,
101 MHz): δ 176.8, 161.3, 151.6, 135.9, 129.2, 126.5, 122.9, 137.38, 131.03, 130.65, 130.63, 129.99, 126.09, 125.91, 125.67,
121.2, 117.7, 108.4, 106.8, 103.1; RP-HPLC Alltima™ C18 5u 110.34; RP-HPLC Alltima™ C18 5u 150 mm × 4.6 mm,
150 mm × 4.6 mm, 10–100% B in 15 min, tR 15.58 min.
10–100% B in 15 min, tR 17.41 min.
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15 M. L. N. Rao, D. K. Awasthi and J. B. Talode, Synlett, 2012,
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Acknowledgements
This project is supported by the Australian Cancer Research 16 J. G. A. Walton, S. V. Chankeshwara and M. Bradley, Appli-
Foundation, and the Australian Research Council. CPG is the cation: WO Pat, 2011-GB658 2011135303, 2011.
recipient of an ARC DECRA fellowship. LH acknowledges 17 J. Yang, S. Liu, J.-F. Zheng and J. Zhou, Eur. J. Org. Chem.,
the receipt of a Postgraduate Scholarship from the University 2012, 2012, 6248–6259.
of Newcastle. T.N.T. is the recipient of a Prime Minister’s 18 D. Balachari, L. Quinn and G. A. O’Doherty, Tetrahedron
Australia Asia Postgraduate Award.
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