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
References
over 8 min. UV detection at = 280 nm. 1.0 mL/min
flowrate with injection volume of 1.0 L.
(
1) (a) Keay, B. A. Chem. Soc. Rev. 1999, 28, 209. (b) Hou, X.
L.; Cheung, H. Y.; Hon, T. Y.; Kwan, P. L.; Lo, T. H.; Tong,
S. Y.; Wong, H. N. C. Tetrahedron 1998, 54, 1955.
(
19) The palladium-catalyzed preparation of 5-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)-2-furaldehyde from 5-
bromo-2-furaldehyde may have been an attractive
alternative approach: (a) Baudoin, O.; Guénard, D.;
Guéritte, F. J. Org. Chem. 2000, 65, 9268. (b) Ishiyama, T.;
Itoh, Y.; Kitano, T.; Miyaura, N. Tetrahedron Lett. 1997, 38,
(
c) Friedrichsen, W. In Comprehensive Heterocyclic
Chemistry, Vol. II; Bird, C. W., Ed.; Elsevier: New York,
996, 351.
1
(
2) (a) Lai, S.; Shizuri, Y.; Yamamura, S.; Kawai, K.; Niwa, M.;
Furukawa, H. Heterocycles 1991, 32, 307. (b) Nakatsuka,
S.; Feng, B.; Goto, T.; Kihara, K. Tetrahedron Lett. 1986,
3447. (c) Murata, M.; Watanabe, S.; Masuda, Y. J. Org.
Chem. 1997, 62, 6458. (d) Ishiyama, T.; Murata, M.;
Miyaura, N. J. Org. Chem. 1995, 60, 7508; however, the
high price tag of 5-bromo-2-furaldehyde and the boron
2
7, 3399. (c) Dvo á ková, S.; Sedmera, P.; Pot šilová, H.;
Santavý, F.; Šimánek, V. Coll. Czech. Chem. Commun.
984, 49, 1536.
1
Synthesis 2001, No. 11, 1681–1685 ISSN 0039-7881 © Thieme Stuttgart · New York