An efficient synthesis and substitution of 3-aroyl-2-bromobenzo[b]furans

Article abstract of DOI:10.1021/jo701656z

(Chemical Equation Presented) A convenient method for the synthesis of 2-bromo-3-aroyl-benzo[b]furans from readily accessible precursors has been developed. The 2-bromo group has been employed as a versatile synthetic handle in both palladium-mediated cou

Full text of DOI:10.1021/jo701656z

An Efficient Synthesis and Substitution of
3-Aroyl-2-bromobenzo[b]furans
Gurmit S. Gill,* Damian W. Grobelny,
Jason H. Chaplin, and Bernard L. Flynn*
Bionomics Ltd., 31 Dalgleish Street, Thebarton,
South Australia 5031, Australia
bflynn@bionomics.com.au
FIGURE 1. 2-Aroylbenzo[b]furans.
ReceiVed August 14, 2007
In our ongoing medicinal chemistry efforts, aimed at the
identification of novel tubulin polymerization inhibitors (TPIs)
of the formula 2 (Figure 1), we have identified that, so long as
the substitution pattern at positions C3-7 are kept within the
range shown, considerable variation can be tolerated at C2 while
maintaining good activity.1f,4 We are interested in taking
advantage of this factor in the discovery of new TPIs with
improved pharmacokinetic properties. Accordingly, we wish to
introduce this C2-substituent very late in the synthetic process
in a manner that would facilitate the synthesis of a focused
library of C2 derivatives of 2 with different physiochemical
properties but have been struck by the dearth of existing methods
that provide for such a strategy. Most synthetic approaches to
2,3-disubstituted benzofurans introduce the C3-substituent at the
end of the synthesis.2,3 We envisage that a C2-bromo derivative
of 2 (R2 ) Br) should serve as a versatile intermediate that
would enable us to introduce a significant array of substituents
at C2 through subsequent palladium-mediated coupling and
nucleophilic substitution reactions. However, no methods for
the synthesis of 2-halo-3-aroyl(or acyl)benzo[b]furans have been
described. In this paper, we describe our efforts toward the
synthesis of such 3-aroyl-2-bromobenzo[b]furans and their
further substitution. This work should have broad applicability
for those seeking to utilize the benzo[b]furan scaffold in drug
discovery.
A convenient method for the synthesis of 2-bromo-3-aroyl-
benzo[b]furans from readily accessible precursors has been
developed. The 2-bromo group has been employed as a
versatile synthetic handle in both palladium-mediated cou-
plings and direct nucleophilic substitutions to give access to
a wide range of 2-substituted-3-aroyl-benzo[b]furans.
Benzofurans, in particular 3-aroylbenzo[b]furans 1 (Figure
1), are core structural components in a range of biologically
active compounds.1 Examples include anti-Alzheimer,1c anti-
arrhythmic,1d tubulin polymerization inhibitory,1e,f and anti-
estrogenic1g compounds among others. Accordingly, the devel-
opment of concise, flexible syntheses of 3-aroylbenzo[b]furans
1 has been the goal of numerous efforts in the development of
new synthetic methods.2,3
(1) (a) Felder, C. C.; Joyce, K. E.; Briley, E. M.; Glass, M.; Mackie, K.
P.; Kennan.; Fahey, J. G.; Cullinan, J.; Hunden, D. C.; Johnson, D. W.;
Chaney, M. O.; Koppel, G. A.; Brownstein, M. J. Pharmacol. Exp. Ther.
1998, 284, 291-297. (b) Sall, D. J.; Bailey, D. L.; Bastian, J. A.; Buben,
J. A.; Chirgadze, N. Y.; Clemens-Smith, A. C.; Denney, M. L.; Fisher, M.
J.; Giera, D. D.; Gifford-Moore, D. S.; Harper, R. W.; Johnson, L. M.;
Klimkowski, V. J.; Kohn, T. J.; Lin, H. S.; McCowan, J. R.; Palkowitz, A.
D.; Richett, M. E.; Smith, G. F.; Snyder, D. W.; Kumiko, John, T.; Toth,
E.; Zhang, M. J. Med. Chem. 2000, 43, 649-663. (c) Twyman, L. J.; Allsop,
D. Tetrahedron Lett. 1999, 40, 9383-9384. (d) Carlsson, B.; Singh, B. N.;
Temciuc, M.; Nilsson, S.; Li, Y. L.; Mellin, C.; Malm, J. J. Med. Chem.
2002, 45, 623-630. (e) Liou, J. P.; Chang, Y. L.; Kuo, F. M.; Chang, C.
W.; Tseng, H. Y.; Wang, C. C.; Yang, Y. N.; Chang, J. Y.; Lee, S. J.;
Hsieh, H. P. J. Med Chem. 2004, 47, 4247-4257. (f) Flynn, B. L.; Hamel,
E.; Katherine, M, J. J. Med. Chem. 2002, 45, 2670-2673. (g) Muchmore,
D. B. The Oncologist 2000, 5, 388-392.
(2) For reveiws, see: (a) Cacchi, S.; Fabrizi.; G.; Goggiamani, A. Curr.
Org. Chem. 2006, 10, 1423. (b) Hou, X.-L.; Yang, Z.; Yeung, K.-S.; Wong,
H. N. C. Prog. Heterocycl. Chem. 2005, 17, 142. (c) McCallion, G. D.
Curr. Org. Chem. 1999, 3, 67-76. (d) Kadieva, M. G.; Oganesyan, E. T.
Chem. Heterocycl. Comp. 1997, 33, 1245. (e) Donelly, D. M. X.; Meegan,
M. J. Furans and their Benzo Derivatives: Synthesis and Application. In
ComprehensiVe Heterocyclic Chemistry; Katritzky, A. R., Ed.; Pergamon:
New York, 1984; Vol. 4, pp 657-712 (f) Cagniant, P.; Cagniant, D. AdV.
Heterocycl. Chem. 1975, 18, 337-482.
Larock and co-workers have previously demonstrated that
2-silylbenzo[b]furans 5 can be prepared by palladium-catalyzed
annulation of o-iodophenol 3 with silylalkynes 4 (eq 1).5,6 We
sought to further develop this process by extending it to the
synthesis of 3-aroyl-2-silylbenzo[b]furans that could then be
converted to 3-aroyl-2-bromobenzo[b]furans by bromo substitu-
tion of the silyl group. This work was undertaken with the
specific objective of producing compounds of the formula 2
(R2 ) Br) to aid our medicinal chemistry studies on TPIs
(Scheme 1). Iodophenol 8a was prepared as previously de-
scribed.7 Iodophenol 8b was prepared from o-vanillin through
a sequence of isopropyl ether protection, Baeyer-Villiger
10.1021/jo701656z CCC: $40.75 © 2008 American Chemical Society
Published on Web 01/05/2008
J. Org. Chem. 2008, 73, 1131-1134
1131

SCHEME 1. Synthesis of 3-Aroyl-2-bromobenzo[b]furans
zaldehydes 9a and 9b, respectively, followed by MnO2 oxidation
of the intermediate alcohols.
Palladium-mediated annulation of 2-iodophenol 8a with 10b
afforded 11a (59%), while a similar reaction of 8b with 10a
and 10b afforded 11b (64%) and 11c (69%), respectively. In
all cases, the reactions proceeded with complete regioselectivity
to provide only the 3-aroyl-2-silylbenzo[b]furan derivatives. The
2-tert-butyldimethylsilyl group in 11a was readily substituted
for a bromide to give 12a (53%) upon reaction with bromine
in 1,2-dichloroethane. However, in the case of 11c it was first
necessary to replace the isopropyl group with an acetyl group,
giving 11d (93%), to avoid competitive electrophilic bromina-
tion of the C4-position of the benzo[b]furan. Treatment of 11d
with bromine in 1,2-dichloroethane gave the 2-bromo derivative
12b in 66% yield. Alternatively, the 2-TBDMS group could
also be removed to provide the corresponding 2-H system as
demonstrated by the transformation of 11a to 13 upon treatment
with TBAF in THF (86%).
Having achieved efficient access to 12a and 12b, we then
turned to studying various means of substitution of the C2-
bromo group (eq 2, Table 1). Both 12a and 12b reacted readily
with various boronic acids/esters under standard Suzuki condi-
tions, in the presence of Pd(PPh3)4 and Na2CO3 at 80-100 °C
in aqueous 1,4-dioxane. The reactions were complete within
1-2 h (the crude reaction mixtures of 7-OAc compounds were
further treated with K2CO3 and methanol to ensure complete
deacetylation), providing the corresponding coupled products
15a-e in good yields (entries 1-5). Negishi coupling reactions
of 12b with alkyl- and arylzinc bromides proceeded at room
temperature to give the products 15f-h in excellent yields
(entries 6-8, in situ deacetylation was observed for entries 6
and 8). Heck coupling of 12b with methyl acrylate and
subsequent deacetylation gave 15i in low yield even in the
presence of excess acrylate (>10-fold) and considerable amounts
of catalyst (20%) (entry 9). The 2-bromo substituent of 12b
was also exploited in a range of direct substitution reactions
with various nucleophiles. Reaction with sodium cyanide in
DMSO proceeded with in situ cleavage of the acetyl group to
give the 2-cyano derivative 15j in good yield (entry 10), while
reaction with the sodium salt of 1,2,4-triazole in THF/toluene
gave the phenol 15k in moderate yield (entry 11). Both
imidazole and ethanolamine were successfully reacted with 12b
in refluxing pyridine to provide 15l (92%) and 15m (67%),
respectively (entries 12 and 13).
oxidation, and iodination (49% over 3 steps, Scheme 2). The
requisite 1-aryl-3-silylpropynones 10a and 10b were prepared
by addition of lithium tert-butyldimethylsilylacetylide to ben-
(3) (a) Nakamura, M.; Ilies, L.; Otsubo, S.; Nakamura, E. Org. Lett. 2006,
8, 2803-2805. (b) Arcadi, A.; Cacchi, S.; Rosario, M. D.; Fabrizi, G.;
Marinelli, F. J. Org. Chem. 1996, 61, 9280-9288. (c) Chaplin, J. H.; Flynn,
B. L. Chem. Commun. 2001, 1594-1595. Hu, Y.; Zhang, Y.; Yang, Z.;
Fathi, R. J. Org. Chem. 2002, 67, 2365-68.
(4) Chaplin, J. H.; Gill, G. S.; Grobelny D. W.; Flynn, B. L. Int. Pat.
Appl. No. WO2006084338.
In conclusion, a concise and convergent protocol for the
synthesis of 2-bromo-3-aroylbenzo[b]furan systems has been
developed. The 2-bromo substituent provides a versatile syn-
thetic handle in both palladium-mediated cross-coupling and
direct nucleophilic substitution reactions to give a wide range
(5) (a) Larock, R. C. J. Organomet. Chem. 1999, 576, 111-124. (b)
Larock, R. C.; Yum, E. K.; Doty, M. J.; Sham, K. C. J. Org. Chem. 1995,
60, 3270-3271.
(6) Bishop, B. C.; Cottrell, I. F.; Hands, D. Synthesis 1997, 1315-1320.
(7) Tsukayama, M.; Utsumi, H.; Kunugi, A.; Nozaki, H. Heterocycles
1997, 45, 1131-1142.
1132 J. Org. Chem., Vol. 73, No. 3, 2008

TABLE 1. Substitution of 12a and 12b (See Also eq 2)
of C2-substituted 3-aroylbenzo[b]furans. The process as a whole
is quite functional group tolerant and efficient.
Experimental Section
2-tert-Butyldimethylsilyl-7-isopropoxy-6-methoxy-3-(3,4,5-tri-
methoxybenzoyl)benzo[b]furan (11a). A suspension of 2-iodo-
5-methoxyphenol (8a, 250 mg, 1 mmol), 3-(tert-butyldimethylsilyl)-
1-(3,4,5-trimethoxyphenyl)propynone (10b, 468 mg, 1.40 mmol),
lithium chloride (42 mg, 1 mmol), and sodium carbonate (424 mg,
4 mmol) in dry dimethylformamide (2.5 mL) was deoxygenated
with nitrogen gas. Palladium acetate (100 mg, 0.45 mmol) was
added, the reaction mixture was then stirred at 100 °C under
nitrogen for 2 h (TLC), and the solvent was removed by distillation
under vacuum. The residue was dissolved in ethyl acetate (40 mL),
stirred well, and filtered. The solvent was distilled, and the crude
was purified by silica gel flash chromatography (eluent ) hexane/
diethyl ether; 95:5 to 8:2) to give the title compound as a light
yellow paste (268 mg, 59%): 1H NMR (300 MHz, CDCl3) δ 7.14
(s, 2H), 7.05 (s, 1H), 7.04 (d, J ) 8.49 Hz, 1H), 6.77 (dd, J )
8.73, 2.19 Hz, 1H), 3.93 (s, 3H), 3.84 (s, 6H), 3.78 (s, 3H), 1.00
(s, 9H), 0.28 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 191.1, 165.4,
158.6, 158.5, 153.0, 142.6, 133.6, 131.7, 121.5, 120.1, 112.6, 107.4,
95.4, 61.0, 56.3, 55.7, 26.8, 17.7, -5.7; LRMS m/z 457 (M + 1,
100); HRMS ESI (M + H)+ calcd for C25H32O6Si 457.2046, found
457.2054.
2-Bromo-6-methoxy-3-(3,4,5-trimethoxybenzoyl)benzo[b]-
furan (12a). To a stirred solution of 2-tert-butyldimethylsilyl-6-
methoxy-3-(3,4,5-trimethoxybenzoyl)benzo[b]furan (10a, 200 mg,
0.44 mmol) in 1,2-dichloroethane (2 mL) at room temperature under
nitrogen was added bromine (23 µL, 0.44 mmol) dropwise, and
the reaction mixture was stirred for 10 min. After this time, the
solution was diluted with extracted with ethyl acetate (20 mL),
washed with brine (30 mL), the organic layer dried over magnesium
sulfate, and the solvent evaporated under reduced pressure. The
crude product was directly crystallized from acetonitrile to afford
the title compound as a colorless crystalline solid (98 mg, 53%,
mp ) 136-38 °C): 1H NMR (300 MHz, CDCl3) δ 7.45 (d, J )
8.73 Hz, 1H), 7.15 (s, 2H), 7.01 (d, J ) 2.19 Hz, 1H), 6.90 (dd, J
) 8.74, 2.27 Hz, 1H), 3.94 (s, 3H), 3.85 (s, 9H); 13C NMR (75
MHz, CDCl3) δ 188.2, 158.3, 155.8, 152.7, 142.6, 132.0, 130.7,
121.0, 120.0, 119.7, 112.9, 107.0, 95.3, 60.7, 55.9, 55.4; LRMS
m/z 423/421 (M + H, 100), 421 (M+, 91); HRMS ESI (M)+ calcd
for C19H17O6Br 421.0287, found 421.0284.
2-(1-Isobutyl-1H-pyrazol-4-yl)-7-hydroxy-6-methoxy-3-(3,4,5-
trimethoxybenzoyl)benzo[b]furan (15a). To a stirred solution of
7-acetoxy-2-bromo-6-methoxy-3-(3,4,5-trimethoxybenzoyl)benzo-
[b]furan (12b, 40 mg, 0.084 mmol) and 1-isobutyl-4-(4,4,5,5-
tetramethyl-1,2,3-dioxaborolon-2-yl)1H-pyrazole (14a, 42 mg, 0.168
mmol) in 1,4-dioxane (3 mL) at 90 °C was added Pd(PPh3)4 (8
mg, 0.008 mmol) followed by the addition of a solution of sodium
bicarbonate (40 mg, 0.48 mmol) in distilled water (1 mL). The
reaction mixture turned brown after 5 min. After 25 min (TLC),
the reaction mixture was cooled to room temperature and diluted
with ethyl acetate (10 mL). The organic layer was washed with
water, the solvent was removed by distillation under vacuum, and
the crude residue was treated with potassium carbonate (100 mg,
excess) in methanol (10 mL). The material thus obtained was
purified by preparative thin layer chromatography to give the title
compound as a crystalline yellow solid (26 mg, 65%, mp )
146-48 °C): 1H NMR (300 MHz, CDCl3) δ 8.04 (s, 1H), 7.99 (s,
1H), 7.14 (s, 2H), 6.81 (d, J ) 8.61 Hz, 1H), 6.75 (d, J ) 8.58 Hz,
1H), 5.70 (bs, 1H), 3.93 (s, 3H), 3.92 (s, 3H), 3.89 (d, J ) 7.38
Hz, 2H), 3.77 (s, 6H), 2.23-2.16 (m, 1H), 0.89 (d, J ) 6.69 Hz,
6H); 13C NMR (75 MHz, CDCl3) δ 190.1, 154.0, 152.6, 143.4,
141.9, 140.9, 138.7, 133.3, 130.5, 130.2, 123.26, 113.4, 111.8,
111.2, 108.0, 106.7, 106.7, 60.7, 59.58, 56.8, 55.9, 29.2, 19.5;
LRMS m/z 481 (M + 1, 100); HRMS ESI (M + H)+ calcd for
C26H28N2O7 481.1975, found 481.1979.
J. Org. Chem, Vol. 73, No. 3, 2008 1133

2-Methyl-7-hydroxy-6-methoxy-3-(3,4,5-trimethoxybenzoyl)-
benzo[b]furan (15f). Zinc bromide dihydrate (950 mg, 3.67 mmol)
was dried under vacuum at 120-140 °C for 2 h with stirring, cooled
to room temperature, and dissolved in 4 mL of dry THF. To this
solution was added methyllithium (1.6 M in diethyl ether, 3.3 mL,
5.28 mmol) dropwise at -78 °C under nitrogen. The resulting
mixture was allowed to warm to room temperature, stirred for 15
min, and cooled again to -78 °C. To the cooled reaction mixture
was added solid 7-acetoxy-2-bromo-6-methoxy-3-(3,4,5-trimeth-
oxybenzoyl)benzo[b]furan (12b, 480 mg, 1 mmol) followed by
(PPh3)2PdCl2 (92 mg, 0.131 mmol) and copper(I) iodide (160 mg,
0.084 mmol). The resulting mixture was stirred in vacuo for 3 min
at -78 °C, back-filled with dry nitrogen, allowed to warm to room
temperature, and stirred for 30 h under nitrogen. After this time,
methanol (5 mL) was added, and the resulting mixture was stirred
for 30 min at room temperature and evaporated to dryness. The
residue was diluted to with ethyl acetate (50 mL) and washed with
saturated ammonium chloride (20 mL). The insoluble material was
removed by filtration and the organic phase separated, washed with
brine, dried over anhydrous magnesium sulfate, and evaporated to
dryness. The crude product was purified by flash column chroma-
tography to give pure product as colorless crystals recrystallized
from methanol (360 mg, 94%, mp ) 156-58 °C): 1H NMR (300
MHz, CDCl3) δ 7.09 (s, 2H), 6.93 (d, J ) 8.54 Hz, 1H), 6.83 (d,
J ) 8.56 Hz, 1H), 5.69 (bs, 1H), 3.93 (s, 3H), 3.92 (s, 3H), 3.83
(s, 6H), 2.54 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 190.3, 161.2,
152.6, 143.7, 141.8, 141.4, 133.7, 130.5, 122.4, 116.5, 110.9, 108.2,
106.5, 60.6, 56.8, 55.9, 17.4;LRMS m/z 373 (M + 1, 100); HRMS
ESI (M + H)+ calcd for C20H20O7 373.1287, found 373.1285.
2-(1,2,4-Triazol-1-yl)-7-hydroxy-6-methoxy-3-(3,4,5-trimeth-
oxybenzoyl)benzo[b]furan (15k). To a solution of 1,2,4-triazole
(14k, 22 mg, 0.32 mmol) in dry tetrahydrofuran (2 mL) was added
sodium hydride (60%, 24 mg, 0.60 mmol), and resulting suspension
was treated with a solution of 7-acetoxy-2-bromo-6-methoxy-3-
(3,4,5-trimethoxybenzoyl)benzo[b]furan (12b, 50 mg, 0.10 mmol)
in dry toluene (2 mL). The mixture was stirred at reflux for 6 h
(TLC), quenched with saturated ammonium chloride solution,
extracted with dichloromethane (10 mL), and dried over magnesium
sulfate and the solvent distilled under vacuum. The crude residue
was purified over silica gel plate to give the title compound as a
yellow solid (22 mg, 50%, mp ) 78-80 °C): 1H NMR (300 MHz,
CDCl3) δ 8.61 (s, 1H), 8.07(s, 1H), 7.11 (d, J ) 8.60 Hz, 1H),
7.06 (s, 2H), 6.97 (d, J ) 8.65 Hz, 1H), 6.19 (bs, 1H), 3.97 (s,
3H), 3.89 (s, 3H), 3.77 (s, 6H); 13C NMR (75 MHz, CDCl3) δ
187.5, 152.9, 145.9, 145.4, 144.8, 143.0, 140.1, 131.7, 131.5, 121.3,
11.9, 110.4, 110.1, 106.68, 60.8, 57.0, 56.0; LRMS m/z 426 (M +
1, 100); HRMS ESI (M + H)+ calcd for C21H19N3O7 426.1301,
found 426.1283.
Acknowledgment. We thank Dr Chinh Bui for assistance
in obtaining LCMS data.
Supporting Information Available: Synthetic procedures and
copies of 1H and 13CNMR spectra and for all synthesized
compounds not included in the Experimental Section. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO701656Z
1134 J. Org. Chem., Vol. 73, No. 3, 2008