Hu et al.
stirred at 50 °C for 1 h. To this solution was added a solution
of o-alkylnylphenol (1.0 mmol, 100 mol %) in acetonitrile (2
mL), and the reaction mixture was stirred at 50 °C for 5 h
under Ar2 atmosphere. The reaction mixture was then con-
centrated, and the residue was filtered through a silica gel
pad and eluted with EtOAc. The filtrate was concentrated, and
the residue was purified by flash chromatography on silica gel
to give the corresponding cyclization product.
pools for the palladium-catalyzed cyclization with aryl
iodide to give 2,3-disubstituted benzo[b]furans, which
after cleavage from the solid support by HF/Py and
TMSOMe afforded a 210-membered library A1-5BnC1-6
(see the Supporting Information for details).
To confirm the results, all the final products were
subjected to LC-MS analysis, and 35 of them were
1
selectively identified by H NMR. Based on the LC-MS
Com p ou n d 4. Purification by flash chromatography (hex-
ane/EtOAc ) 20/1) gave 4 in 70% yield: 1H NMR δ 7.71 (d, J
) 7.5 Hz, 2H), 7.57 (d, J ) 8.5 Hz, 1H), 7.51 (d, J ) 8.0 Hz,
1H), 7.45 (d, J ) 8.0 Hz, 2H), 7.34 (m, 4H), 7.26 (m, 1H), 7.03
(d, J ) 8.0 Hz), 3.90 (s, 3H); 13C NMR δ 159.1, 153.9, 150.3,
130.9, 130.8, 130.5, 128.4, 128.2, 126.9, 124.9, 124.6, 122.8,
120.0, 117.1, 114.4, 111.1, 55.3; MS (APCI) [C21H16O2] m/z (M+
+ 1) calcd 301, found 301.
Com p ou n d 4a . Purification by flash chromatography (hex-
ane/EtOAc ) 20/1) gave 4a in 64% yield: 1H NMR δ 7.70 (d,
J ) 8.0 Hz, 2H), 7.58 (d, J ) 8.0 Hz, 1H), 7.53 (d, J ) 8.0 Hz,
1H), 7.42 (d, J ) 7.5 Hz, 2H), 7.37-7.24 (m, 9H), 2.47 (s, 3H);
13C NMR δ 153.9, 150.3, 137.3, 130.8, 130.3, 129.7, 129.6,
129.5, 128.3, 128.2, 126.9, 124.5, 122.8, 120.0, 117.4, 111.0,
21.3; MS (APCI) [C21H16O] m/z (M+) calcd 284, found 284.
analysis results, among the 210 compounds that were
synthesized, 104 gave the desired products with over 80%
purity; 51 were between 70 and 80% purity; 29 were
around 60% purity, and the rest of the 26 compounds
were under 50% purity. As observed in the solution-phase
synthesis, the aryl iodides with electron-withdrawing
groups gave better annulations results than other types
of aryl iodides.
In summary, we have described herein a practical
method for the combinatorial synthesis of conformation-
ally restrained molecules. In parallel with established
methods in medicinal chemistry which seek to restrict
the free bond rotation as a powerful tool for lead
optimization, we have constructed a priori a large
number of complex and diverse 2-substituted 3-arylben-
zo[b]furans,12 which encompass all the properties that are
important in finding the lead molecule in advance. In
addition, the synthesized compounds have been utilized
directly in various biological assays without further
purifications and some interesting compounds have been
identified from our in-house target-based assays. This
demonstrates the effectiveness of our approach in the
exploration of molecular diversity in combination with
rational and classical approaches for drug discovery.
Com p ou n d 4b. Purification by flash chromatography (hex-
ane/EtOAc ) 15/1) gives 4b in 84% yield: 1H NMR δ 8.32 (d,
J ) 8.5 Hz, 2H), 7.69 (d, J ) 9.0 Hz, 2H), 7.60 (m, 3H), 7.52
(d, J ) 8.0 Hz, 1H), 7.37 (m, 4H), 7.30 (dd, J ) 8.0 Hz, 1H);
13C NMR δ 154.2, 151.9, 147.1, 140.2, 130.5, 129.8, 129.2,
128.9, 128.8, 127.5, 125.3, 124.3, 123.5, 119.5, 115.4, 111.5;
MS (APCI) [C20H13NO3] m/z (M+) calcd 315, found 315.
Com p ou n d 4c. Purification by flash chromatography (hex-
ane/EtOAc ) 20/1) gave 4c in 74% yield: 1H NMR δ 7.71 (dd,
J ) 6.5, 1.5 Hz, 2H), 7.57 (d, J ) 8.0 Hz, 1H), 7.54 (d, J ) 7.5
Hz, 1H), 7.40 (m, 1H), 7.34 (m, 5H), 7.26 (m, 1H), 7.11 (d, J )
7.0 Hz), 7.07 (m, 1H), 6.98 (dd, J ) 8.0, 1.5 Hz, 1H), 3.82 (s,
3H); 13C NMR δ 160.0, 153.9, 150.6, 134.2, 130.6, 130.2, 130.0,
128.4, 128.4, 127.1, 124.7, 122.9, 122.2, 120.1, 117.4, 115.02,
113.5, 111.1, 55.3; MS (APCI) [C21H16O2] m/z (M+ + 1) calcd
301, found 301.
Exp er im en ta l Section
Syn th esis of r-Alk yn ylp h en ol 1C. A mixture of phenyl
iodide A (0.2 mmol), acetylene B (0.3 mmol), copper(I) iodide
(3.8 mg, 0.02 mmol), and dichlorobis(triphenylphosphine)-
palladium (70.1 mg, 0.01 mmol) in dry acetonitrile (40 mL)
was degassed with argon for 10 min. The reaction mixture was
treated with triethylamine (280 µL, 2.0 mmol) and stirred at
25 °C for 24 h. The reaction mixture was concentrated, and
the residue was purified by a flash column chromatography
to afford the coupling product. The coupling product was
treated with NH3‚H2O (0.5 mL) in a solvent of THF and MeOH
(1:1, 10 mL) at 25 °C for 30 min, followed by concentration;
the residue was purified by a flash column chromatography
to give the pure product in 72% yield: 1H NMR δ 11.35 (s,
1H), 7.94 (d, J ) 1.5 Hz, 1H), 7.72 (d, J ) 1.5 Hz, 1H), 7.35
(m, 1H), 6.87 (m, 2H), 4.37 (s, 2H), 3.95 (s, 3H), 3.45 (s, 3H);
13C NMR δ 170.2, 161.8, 139.4, 131.1, 130.9, 130.5, 130.4,
125.9, 112.7, 111.8, 111.7, 104.7, 104.5, 104.3, 90.6, 81.0, 60.5,
57.8, 52.7; MS [C18H14F2O4], m/z (M+) calcd 332, found 332.
For information regarding the synthesis of intermediates
1, 1a and 1d , see ref 4l.
Com p ou n d 4d . Purification by flash chromatography (hex-
ane/EtOAc ) 10/1) gave 4d in 85% yield: 1H NMR δ 8.06 (dm,
J ) 8.5 Hz, 2H), 7.63 (m, 4H), 7.58 (d, J ) 8.5 Hz, 1H), 7.51
(dd, J ) 7.5, 1.0 Hz, 1H), 7.37 (dd, J ) 7.5, 1.0 Hz, 1H), 7.33
(m, 3H), 7.27 (dd, J ) 8.0, 1.0 Hz, 1H), 2.67 (s, 3H); 13C NMR
δ 197.7, 154.1, 151.3, 138.2, 136.2, 130.2, 129.9, 129.7, 129.5,
129.0, 128.8, 128.6, 127.3, 124.9, 123.2, 119.8, 116.5, 111.3,
26.7; MS (APCI) [C22H16O2] m/z (M+ + 1) calcd 313, found
313.
Com p ou n d 4e. Purification by flash chromatography (hex-
ane/EtOAc ) 20/1) gives 4e in 52% yield: 1H NMR δ 7.65 (dm,
J ) 8.5 Hz, 2H), 7.56 (d, J ) 8.0 Hz, 1H), 7.50 (m, 3H), 7.47
(m, 2H), 7.41 (d, J ) 7.5 Hz, 1H), 7.34-2.28 (m, 4H), 7.24 (m,
1H); 13C NMR δ 154.0, 150.5, 132.9, 130.7, 130.2, 129.8, 128.9,
128.4, 128.4, 127.6, 127.0, 124.7, 122.9, 120.0, 117.5, 111.1;
MS (APCI) [C20H14O] m/z (M+ + 1) calcd 271, found 271.
Com p ou n d 4f. Purification by flash chromatography (hex-
ane/EtOAc ) 10/1) gave 4f in 66% yield: 1H NMR δ 7.76 (d, J
) 6.5 Hz, 2H), 7.62 (d, J ) 7.5 Hz, 1H), 7.55 (d, J ) 8.5 Hz,
1H), 7.45 (d, J ) 5.0 Hz, 1H), 7.35 (m, 4H), 7.28 (m, 1H), 7.20
(d, J ) 3,5 Hz, 1H), 7.17 (m, 1H); 13C NMR δ 153.8, 151.7,
133.3, 130.3, 130.2, 128.7, 128.5, 127.6, 127.4, 127.3, 126.2,
Gen er a l P r oced u r e for th e P a lla d iu m -Ca ta lyzed F or -
m a tion of 2,3-Bia r ylben zo[b]fu r a n s. To a solution of ac-
etonitrile (3.0 mL), ArI (2.0 mmol, 200mol %), bpy (16 mg, 0.1
mmol, 10 mol %), and K2CO3 (552 mg, 4.0 mmol) was added
Pd2(dba)3 (46 mg, 0.05 mmol, 5 mol %), and the mixture was
124.9, 123.1, 120.2, 110.7; MS (APCI) [C18H12OS], m/z (M+
+
1) calcd. 277, found 277; MS (APCI) [C18H12OS] m/z (M+ + 1)
calcd 227, found 227.
(12) During preparation of our manuscript, a related paper was
published: Bossharth, E.; Desbordes, P.; Monteiro, N.; Balme, G. Org.
Lett. 2003, 5, 2441. The paper reported a similar approach to synthesize
furo[2,3-b]pyridones by one-pot coupling of 3-iodopyridones, alkynes,
and organic halides. The authors proposed that the complexation of
palladium catalyst to the o-alkoxy group on the phenyl ring might
contribute to generation of the desired compounds, which might limit
the scope of substrate for the reaction.
Com p ou n d 4g. Purification by flash chromatography (hex-
ane/EtOAc ) 3/1) gave 4g in 82% yield: 1H NMR δ 8.05 (d, J
) 8.0 Hz, 2H), 7.65 (m, 2H), 7.61 (d, J ) 8.5 Hz, 2H), 7.32 (m,
3H), 7.05 (s, 1H), 6.91 (s, 1H), 4.80 (s, 2H), 4.08 (s, 3H), 2.67
(s, 3H), 0.95 (s, 6H), 0.01 (s, 9H); 13C NMR δ 197.9, 151.9,
145.4, 142.9, 138.5, 138.0, 136.4, 131.1, 130.4, 130.1, 129.2,
2238 J . Org. Chem., Vol. 69, No. 7, 2004