A practical one-pot synthesis of 5-aryl-2-furaldehydes

Article abstract of DOI:10.1055/s-2001-16759

A useful one-pot synthesis of 5-aryl-2-furaldehydes via palladium-mediated Suzuki coupling of aryl halides with in situ generated 5-(diethoxymethyl)-2-furylboronic acid is described. The procedure has general applicability, delivers high yields, and is amenable to scale-up.

Full text of DOI:10.1055/s-2001-16759

PAPER
1681
A Practical One-Pot Synthesis of 5-Aryl-2-furaldehydes
O
M
ne-Pot Synthesis of
5
i
-Aryl-2
c
-furaldehy
h
des ael S. McClure, Frank Roschangar,* Stephen J. Hodson, Alan Millar, Martin H. Osterhout
GlaxoSmithKline, Chemical Development – Synthetic Chemistry, Five Moore Drive, P.O. Box 13398, Research Triangle Park, NC 27709,
USA
Fax +1(919)3158735; E-mail: fr83278@gsk.com
Received 25 April 2001; revised 18 May 2001
Abstract: A useful one-pot synthesis of 5-aryl-2-furaldehydes via
palladium-mediated Suzuki coupling of aryl halides with in situ
generated 5-(diethoxymethyl)-2-furylboronic acid is described. The
procedure has general applicability, delivers high yields, and is
amenable to scale-up.
Cl
O
F
R
O
B(OH)2
HN
N
2a: R = CHO
I
b: R = CH(OEt)2
N
Key words: furylboronic acids, Suzuki cross-coupling, Pd/C,
"
Pd(0)"
5
-aryl-2-furaldehydes
1
Cl
The synthesis of substituted furans continues to stimulate
the interest of synthetic organic chemists, as is reflected
by a number of recent review articles. In particular,
O
F
1
HN
N
OHC
5
-aryl-2-furaldehydes and their derivatives are key struc-
O
N
2
tural units in natural products and important pharmaco-
logically active compounds, and therefore render
3
3
themselves as valuable synthetic targets. Our interest in
the preparation of 5-aryl-2-furaldehyde moieties derived
from the need to assemble 5-(4-{3-chloro-4-[(3-fluo-
robenzyl)oxy]anilino}-6-quinazolinyl)-2-furaldehyde (3,
Scheme 1). This compound has been identified as an im-
portant building block for the synthesis of compounds of
GlaxoSmithKline’s erbB family of protein tyrosine kinase
inhibitors, which are potential targets for the treatment of
Scheme 1
formyl-2-furylboronic acid (2a) or its corresponding di-
ethyl acetal 2b.14
Although furylboronic acid 2a was available from a single
chemical supplier, its use was considered cost-prohibi-
1
5
10,16
tive. Furthermore, the scant number of published
and
4
patented17 reports describing the preparation of 2a/b suf-
fer from low temperature requirements, capricious repro-
ducibility, tedious workup, as well as unsuitably low
purity and isolated yields (26–45%). Indeed, we experi-
enced the aforementioned problems when following liter-
ature procedures using THF as the reaction solvent, and
typically observed 71% of 5-(diethoxymethyl)-2-furylbo-
ronic acid (2b) and 24% of 2-(diethoxymethyl)furan (4;
Scheme 2) prior to isolation, as determined by HPLC.18
Raising the reaction temperature above –40 °C gave less
favorable results.19
solid tumors. Our objective was to develop a synthetic
route that would minimize raw material costs and be ame-
nable to the preparation of multi-kilogram quantities of 3.
Typical approaches to the 5-aryl-2-furaldehyde moiety in-
clude coupling of aryldiazonium salts with 2-furaldehyde
5
in the presence of cupric chloride, photochemical aryla-
6
tion of 5-halo-2-furaldehydes, oxidative cross-coupling
between 2-furaldehyde and arenes by palladium(II) salts,7
palladium-catalyzed coupling of 5-bromo-2-furaldehyde
8
with arylboronic acids, as well as palladium-catalyzed
9
coupling of 5-(tributylstannyl)-2-furaldehyde or 5-
formyl-2-furylboronic acid (2a) with aryl halides and tri-
A significant process improvement was achieved by sol-
vent change from THF to DME. Not only did DME allow
9
,10
flates. Other less direct methods rely on the regioselec-
1
1
12
tive Vilsmeier formylation
of air-sensitive
2-
arylfurans, which can be prepared by palladium-catalyzed
cross-coupling of chloro(2-furyl)zinc or 2-furyllithium
1
2,13
with aryl halides and triflates.
For our purpose, it ap-
EtO
EtO
. n-BuLi, DME, -20 o
EtO
EtO
1
C
Li
peared most appropriate to assemble 5-(4-anilino-6-
quinazolinyl)-2-furaldehyde 3 through a Suzuki coupling
of readily available N-{3-chloro-4-[(3-fluoroben-
zyl)oxy]phenyl}-6-iodo-4-quinazolinamine (1) with 5-
O
. B(Oi-Pr)3, -20 o
O
B(OiPr)3
2
C
4
5
3
. -20 oC to 20 o
C
EtO
EtO
O
B(OH)2
4
5
. AcOH, 20 o
. H2O, 20 o
C
Synthesis 2001, No. 11, 28 08 2001. Article Identifier:
2b
C
1
©
437-210X,E;2001,0,11,1681,1685,ftx,en;M01701ss.pdf.
Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881
Scheme 2

1
682
M. S. McClure et al.
PAPER
for lithiation of 2-(diethoxymethyl)furan (4) at higher kg with isolated yields ranging from 79 – 88%. The prod-
temperatures (–20 °C), but treatment of the resulting [5- uct, 5-(4-{3-chloro-4-[(3-fluorobenzyl)oxy]anilino}-6-
(diethoxymethyl)-2-furyl]lithium intermediate with tri- quinazolinyl)-2-furaldehyde (3), displayed a typical puri-
isopropyl borate also provided substantially higher con- ty of 96.7% (HPLC, 220 nm) with low levels of palladium
version to furylboronic acid 2b (92%, plus 3% of contamination (19–52 ppm).
unreacted furan 4) (Scheme 2). The higher conversion ob-
To evaluate the scope and limitations of this procedure,
we investigated the coupling of several aryl and heteroaryl
halides 7 with in situ generated 5-(diethoxymethyl)-2-fu-
rylboronic acid (2b) as illustrated in Scheme 3. The re-
tained with DME may be attributable to its increased abil-
ity to coordinate to the lithiated furan.2 Upon resolving
0
the issue of reaction efficiency, we faced the problem of
product isolation. It is well known that the relatively high
sults are shown in the Table.
solubility of boronic acids in aqueous media often compli-
cates their isolation and purification. In fact, numerous at-
EtO
EtO
ArX 7, 10% Pd-C, NEt3
tempts in our own laboratories to improve the isolation of
OHC
2
5
a/b were unsuccessful. However, the crude solution of
-(diethoxymethyl)-2-furylboronic acid (2b), liberated
O
B(OH)2
EtOH, 60 oC;
O
Ar
2b
aqueous acidic workup
8
2
1
from the presumed boron “ate” complex 5 by acidic hy-
Scheme 3
drolysis, displayed only modest signs of decomposition
2
2
upon storage at ambient temperature. Consequently, ad-
vancement of the in situ generated solution of 2b to the We observed that electron-deficient aryl iodides 7a–f (en-
2
3
Suzuki coupling was investigated.
tries 1–6) afforded facile and clean conversion with the
heterogeneous Pd/C catalyst, while electron-rich aryl io-
dides such as 4-methoxyanisole 7g (entry 7) required pro-
longed reaction times and yielded incomplete
conversions. Interestingly, none of the aryl bromides 7a
and h–j (entry 1, X = Br, and entries 8–10) reacted under
the Pd/C conditions, not even highly reactive 1-bromo-4-
Fortunately, it proved unnecessary to isolate the boronic
acid. Its crude solution could successfully be utilized in
the subsequent Suzuki reaction, even several weeks after
preparation and without affecting the purity profile. Ini-
tially, we employed standard Suzuki coupling
conditions using organophosphorous complexes of pal-
ladium. While these transformations turned out to be effi-
cient, isolated 5-(4-anilino-6-quinazolinyl)-2-furaldehyde
2
4
nitrobenzene. However, use of the PdCl (dppf) catalyst in
2
these instances provided excellent conversion (entries 7–
1
0). With either catalyst, reactive functional groups such
3
, prepared using dichloro[1,1’-bis(diphenylphosphi-
as the ester and formyl moieties were well tolerated (en-
tries 4 and 8).
no)ferrocene]palladium(II) [PdCl (dppf)], was contami-
2
nated with residual palladium at undesirably high levels of
5
20–850 ppm as determined by Inductively Coupled Plas- In summary, we have developed a practical and efficient
ma (ICP) analysis. Removal of residual palladium is a ma- one-pot synthesis of 5-aryl-2-furaldehydes utilizing in
jor concern in the pharmaceutical industry and often situ generated boronic acid in a Suzuki coupling strategy.
necessitates involved workup procedures utilizing Pd- This has been shown to have general applicability and has
2
5
complexing agents. To minimize palladium contamina- been used to prepare kilogram quantities of the elaborate
tion and to avoid potential phosphine-related side-reac- 5-(4-anilino-6-quinazolinyl)-2-furaldehyde 3. The key
2
6
tions, we considered phosphine-free and ligandless advantages of this synthesis are the improved generation
heterogeneous palladium catalysts which had successfully of 5-(diethoxymethyl)-2-furylboronic acid (2b), its direct
been employed in Suzuki coupling reactions. These cata- advancement into the coupling step, and the use of inex-
8
,27
lysts include palladium(II) acetate, palladium(II) chlo- pensive and readily removable Pd/C for the Suzuki reac-
2
8
29
ride, and palladium supported on activated carbon.
tion.
Indeed, we were able to develop a highly efficient process
for the Suzuki coupling of in situ generated 5-(diethoxym-
ethyl)-2-furylboronic acid (2b) with N-{3-chloro-4-[(3-
fluorobenzyl)oxy]phenyl}-6-iodo-4-quinazolinamine (1)
Melting points were determined on a Electrothermal IA9100 digital
melting point apparatus and are uncorrected. IR spectra were re-
1
13
corded on a Nicolet 20DXC FT-IR spectrometer. H NMR and
C
3
0
using a catalytic amount of Pd/C. The fact that solvent spectra were obtained in CDCl with Varian INOVA 300 and Vari-
3
degassing is not required illustrates the robustness of the an INOVA 400 NMR instruments, respectively, and chemical shifts
are reported in values (ppm) relative to the internal reference of
aforementioned Pd/C catalyzed coupling. The use of Pd/C
greatly facilitated the removal of palladium during prod-
uct isolation by simple filtration through a Celite pad or a
1
13
CDCl ( 7.25 for H and 77.0 for C spectra). Exact mass data
3
were obtained with a modified Finnigan MAT 311A with an AMD
hard and software data acquisition system. Elemental analyses were
performed by Atlantic Microlab, Inc. Methyl-4-iodobenzoate was
purchased from Avocado. All other reagents and solvents were pur-
0
.45 micron filter. The solvent of choice is DME, whose
superiority over THF extended from the boronic acid gen-
eration to the Suzuki coupling by providing more consis- chased from Aldrich, and were used without purification or degas-
tent yields, shorter reaction times, and enhanced purity sing.
profiles. Interestingly, addition of EtOH was required for
optimum conversion. The one-pot boronic acid genera-
tion/Suzuki coupling was successful on scales of up to 1.1
3
1
5-(Diethoxymethyl)-2-furylboronic Acid (2b)
To a cooled (–20 °C) solution of 2-(diethoxymethyl)furan (4; 33.8
mL, 200 mmol) in DME (340 mL) was added BuLi (2.5 M solution
Synthesis 2001, No. 11, 1681–1685 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
One-Pot Synthesis of 5-Aryl-2-furaldehydes
1683
Table One-Pot Synthesis of 5-Aryl-2-formylfuran Derivatives 8a–ja
Entry
1
Aryl Halide
Catalyst
Time
5-Aryl-2-formylfuran 8
Yieldb
(%)
(
h)
X
7a
10% Pd/C
2
8a
X = Br: 0
X = I: 81
OHC
O
NO2
NO2
NO2
2
3
7b
10% Pd/C
10% Pd/C
2
8b
91
84
I
OHC
NO2
O
7c
16
18
6
8c
I
OHC
O
O N
2
O2N
4
5
7d
7e
10% Pd/C
10% Pd/C
8d
78
91
I
OHC
O
CO2Me
CO2Me
8e
I
OHC
O
CF3
CF3
6
7
8
9
7f
7g
7h
7i
10% Pd/Cc
36
20
2
8f
79
63
90
83
84
I
I
S
OHC
O
O
O
O
O
S
d,e
PdCl (dppf)
8g
8h
8i
2
OHC
OHC
OMe
OMe
CHO
f
PdCl (dppf)
Br
Br
Br
2
S
CHO
S
N
e,f
PdCl (dppf)
36
18
N
2
OHC
OHC
f
1
0
7j
PdCl (dppf)
8j
2
N
N
a
b
c
d
e
f
All reactions were performed at 60 °C in the presence of 10 wt% 10% Pd/C or 5 mol% PdCl (dppf) and 2.0 equiv of Et N.
Yields of isolated pure products.
Additional 10% Pd/C (10 wt%) was required to effect complete conversion.
Only 61% conversion was achieved with 10% Pd/C.
2
3
Additional PdCl (dppf) (2.5 mol%) was required to effect complete conversion.
2
No conversion with 10% Pd/C.
Synthesis 2001, No. 11, 1681–1685 ISSN 0039-7881 © Thieme Stuttgart · New York

1
684
M. S. McClure et al.
PAPER
(3) (a) Bailey, T. R.; Young, D. C. International Patent WO-
in hexanes, 96 mL, 240 mmol) at a rate such that the internal tem-
perature was maintained below –15 °C. The reaction mixture was
stirred at –20 °C for 2 h before adding triisopropyl borate (55.4 mL,
0010573, 2000. (b) Chem. Abstr. 2000, 132, 189652.
(c) Bailey, T. R.; Young, D. C. International Patent WO-
0013708, 2000. (d) Chem. Abstr. 2000, 132, 203127.
(e) Young, D. C.; Bailey, T. R. International Patent WO-
0018231, 2000. (f) Chem. Abstr. 2000, 132, 260668.
(g) Kobayashi, K.; Nishiyama, T.; Nakaide, S. Japanese
Patent JP-11302280, 1999. (h) Chem. Abstr. 1999, 131,
299442. (i) Scott, I. L.; Biediger, R. J.; Market, R. V.
International Patent WO-9853790, 1998. (j) Chem. Abstr.
1999, 130, 38375.
2
40 mmol). The cooling was suspended, and the mixture was al-
lowed to warm to 20 °C. To this mixture was added, at 20 °C, AcOH
15 mL, 260 mmol) followed by H O (18 mL, 1000 mmol). The so-
(
2
lution of 5-(diethoxymethyl)-2-furylboronic acid (2b) was analyzed
for purity by HPLC18 and then used directly in the Suzuki coupling
reaction.
5
-Aryl-2-furaldehydes 8; General Procedure
To the crude boronic acid solution 2b (ca 0.27 M assuming 100%
yield; 40 mL, 10.8 mmol) was added aryl halide 7 (4.32 mmol). The
resulting mixture was then treated successively with EtOH (14 mL),
(4) (a) Cockerill, G. S.; Lackey, K. E. International Patent WO-
0104111, 2001. (b) Chem. Abstr. 2001, 134, 100886.
(5) (a) Pong, S. F.; Pelosi, S. S. Jr.; Wessels, F. L.; Yu, C.-N.;
Burns, R. H.; White, R. E.; Anthony, D. R. Jr.; Ellis, K. O.;
Wright, G. C.; White, R. L. Jr. Arzneim.-Forsch. 1983, 33,
1411. (b) Burch, H. A.; White, R. E.; Wright, G. C.;
Goldenberg, M. M. J. Pharm. Sci. 1980, 69, 107.
(c) Snyder, H. R. Jr.; Davis, C. S.; Bickerton, R. K.;
Halliday, R. P. J. Med. Chem. 1967, 101, 807.
Et N (1.21 mL, 8.64 mmol), and 10% Pd/C (50% water wet, Degus-
3
sa type E101NE/W, 108 mg). It was heated to 60 °C (internal) and
stirred at this temperature until the reaction was deemed completed
by HPLC. The mixture was cooled to 25 °C, and the precipitates
were removed by vacuum filtration through Hyflo Super Celite and
washed with DME (3 5 mL or until the wash was colorless). The
filtrate was treated with deionized water (20 mL) and trifluoroacetic
acid (1.66 mL, 21.5 mmol) and stirred until complete acetal removal
was verified by HPLC. The resulting solution was washed with a
(6) D’Auria, M. Gazz. Chim. Ital. 1989, 119, 419.
(7) (a) Itahara, T. J. Org. Chem. 1985, 50, 5272. (b) Itahara, T.
J. Org. Chem. 1985, 50, 5546.
1
:4 mixture of aq sat. NaCl and aq sat. NaHCO solutions (2 100
(8) Bussolari, J. C.; Rehborn, D. C. Org. Lett. 1999, 1, 965.
(9) (a) Hanefeld, W.; Jung, M. Liebigs Ann. Chem. 1994, 59.
(b) For an elegant one-pot synthesis of 5-(tributylstannyl)-2-
furaldehyde from 2-furaldehyde, see: Denat, F.; Gaspard-
Iloughmane, J. D. Synthesis 1992, 954.
(10) (a) Starling, S. M.; Raslan, D. S.; de Oliveira, A. B. Synth.
Commun. 1998, 28, 1013. (b) Bracher, F.; Hildebrand, D.
Liebigs Ann. Chem. 1992, 1315.
3
mL). The organic layer was dried (Na SO ) and vacuum filtered,
2
4
and the filtrate was concentrated in vacuo. The crude 5-aryl-2-
formylfuran 8 was purified by flash column chromatography (silica
gel, 200–400 mesh, 60 Å) using an appropriate solvent system (Rf
value of ca 0.2).
5
-(5-Formyl-2-thienyl)-2-furaldehyde (8h)
Yield: 90%; yellow powder; mp 184–185 °C.
(11) Davis, C. S.; Lougheed, G. S. J. Heterocycl. Chem. 1967, 4,
1
53.
IR (neat): = 3113, 2841, 1656, 1530, 1439, 1393, 1384, 1279,
–
1
(12) Pelter, A.; Rowlands, M.; Clements, G. Synthesis 1987, 51.
13) Arcadi, A.; Burini, A.; Cacchi, S.; Delmastro, M.; Marinelli,
F.; Pietroni, B. Synlett 1990, 47.
14) Although initial investigations indicated 2-(2-furyl)-1,3-
dioxolane to be superior to 2-(diethoxymethyl)furan (4) for
boronic acid generation, it has limited availability, and the
resulting in situ generated boronic acid is less reactive in the
Suzuki coupling. Therefore, our studies were focused on
acetal 4.
1
228, 1027, 965, 890, 812, 807, 770, 672 cm .
(
(
1H NMR (300 MHz): = 9.93 (s, 1 H, OCCHO), 9.69 (s, 1 H,
SCCHO), 7.74 [d, 1 H, J = 4.0 Hz, SC(CHO)=CHCH], 7.58 [d, 1
H, J = 4.0 Hz, SC(CHO)=CH], 7.31 [d, 1 H, J = 3.8 Hz,
OC(CHO)=CHCH], 6.88 [d, 1 H, J = 3.8 Hz, OC(CHO)=CH].
13C NMR (100 MHz):
= 182.8, 177.6, 153.0, 152.7, 144.3, 140.1,
1
36.9, 126.5, 122.8, 110.7.
+
HRMS (FAB pos.): m/z Calcd for C H O S (M + H ): 207.0116.
1
0
7
3
(
15) 5-Formyl-2-furylboronic acid (2a), available from Frontier
Scientific, costs ca. $26,000/mol, while 2-
Found: 207.0115.
Anal. Calcd for C H O S (206.2): C, 58.24; H, 2.93; S, 15.55.
Found: C, 58.71; H, 3.25; S, 15.42.
(diethoxymethyl)furan (4) retails at Aldrich for ca. $1,000/
mol ($340/kg for bulk quantities).
10
6
3
(
(
(
16) (a) Florentin, D.; Roques, B. P.; Fournie-Zaluski, M. C. Bull.
Soc. Chim. Fr. 1976, 13, 1999. (b) Florentin, D.; Roques, B.
C. R. Acad. Sc. Paris, Ser. C 1970, 270 , 1608.
17) (a) Guerry, P.; Jolidon, S.; Masciadri, R.; Stalder, H.; Then,
R. International Patent WO-9616046, 1996, 29. (b) Chem.
Abstr. 1996, 125, 142773.
Acknowledgements
We thank Joanne E. Anderson, Angelique N. Danek, Brian P. Dow-
ney, and Bobby N. Glover for technical support and Roman Davis
and Maria F. Tymoschenko for helpful discussions.
18) Column: Phenomenex Luna C18(2) 50 mm 2.0 mm 3
micron. Mobile phase: A = 0.05 % (v/v) TFA in H O, B =
2
0
.05 % (v/v) TFA in MeCN. Gradient Profile: 0% to 95% B
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Synthesis 2001, No. 11, 1681–1685 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
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One-Pot Synthesis of 5-Aryl-2-furaldehydes
1685
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(29) (a) Dyer, U. C.; Shapland, P. D.; Tiffin, P. D. Tetrahedron
Lett. 2001, 42, 1765. (b) Ennis, D. S.; McManus, J.; Wood-
Kaczmar, W.; Richardson, J.; Smith, G. E.; Carstairs, A.
Org. Process Res. Dev. 1999, 3, 248. (c) Gala, D.;
Stamford, A.; Jenkins, J.; Kugelman, M. Org. Process Res.
Dev. 1997, 1, 163. (d) Marck, G.; Villiger, A.; Buchecker,
R. Tetrahedron Lett. 1994, 35, 3277.
EtO
OEt
OEt
O
B
O
EtO
OH
6b
(
30) The only type of Pd/C employed for this and all other
experiments described herein was 10 wt% (dry
basis)palladium on activated carbon, 50% water wet,
Degussa type E101NE/W; it was used as purchased from
Aldrich.
Figure
(
(
23) Suzuki cross-coupling reactions with in situ generated
boronic acids have been described: (a) O’Neill, B. T.;
Yohannes, D.; Bundesmann, M. W.; Arnold, E. P. Org. Lett.
(31) It is conceivable that EtOH enhances solubilization of the
reaction components. We determined that omission of EtOH
or use of EtOH–DME ratios less than 1:2 resulted in
competitive degradation of 5-(diethoxymethyl)-2-
furylboronic acid (2b) to 2-(diethoxymethyl)furan (4),
thereby preventing complete conversion.
2000, 2, 4201. (b) Andersen, N. G.; Maddaford, S. P.; Keay,
B. A. J. Org. Chem. 1996, 61, 9556. (c) Maddaford, S. P.;
Keay, B. A. J. Org. Chem. 1994, 59, 6501. (d) Cristofoli,
W. A.; Keay, B. A. Tetrahedron Lett. 1991, 32, 5881.
24) (a) Stanforth, S. P. Tetrahedron 1998, 54, 263. (b) Suzuki,
A. Pure Appl. Chem. 1994, 66, 213. (c) Miyaura, N.;
Yanagi, T.; Suzuki, A. Synth. Commun. 1981, 11, 513.
Synthesis 2001, No. 11, 1681–1685 ISSN 0039-7881 © Thieme Stuttgart · New York