General synthesis of polysubstituted benzo[b]furans

Article abstract of DOI:10.1021/jo9710846

2-(Benzotriazol-1-ylmethyl)furans 4a-c, on treatment with n-BuLi followed by various α,β-unsaturated ketones and aldehydes, gave the adducts 6a-f which underwent intramolecular cyclization to form substituted benzo[b]furans 10a-f. Lithiation and subsequen

Full text of DOI:10.1021/jo9710846

J . Org. Chem. 1997, 62, 8205-8209
8205
Gen er a l Syn th esis of P olysu bstitu ted Ben zo[b]fu r a n s
Alan R. Katritzky,* Clara N. Fali, and J ianqing Li
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida,
Gainesville, Florida 32611-7200
Received J une 16, 1997X
2-(Benzotriazol-1-ylmethyl)furans 4a -c, on treatment with n-BuLi followed by various R,â-
unsaturated ketones and aldehydes, gave the adducts 6a -f which underwent intramolecular
cyclization to form substituted benzo[b]furans 10a -f. Lithiation and subsequent alkylation of 4a -c
afforded intermediates 8a -c, which underwent similar transformations with R,â-unsaturated
ketones or aldehydes to give the corresponding polysubstituted benzo[b]furans 7a -c. o-Iodophenol
(11) with 1-propargylbenzotriazole (1) in the presence of (PPh3)2PdCl2, CuI, and Et3N gave
2-(benzotriazol-1-ylmethyl)benzo[b]furan (12). The benzotriazolyl-CH2 side chain of 12 was further
elaborated by (i) alkylation with trans-cinnamaldehyde to give the adduct 14, followed by
intramolecular cyclization to give dibenzofuran 17; (ii) alkylation with benzyl bromide followed by
elimination or nucleophilic displacement of the benzotriazolyl moiety with Grignard reagent and
subsequent dehydrogenation to give 2-alkenylbenzofurans 15 or 20, respectively; (iii) alkylation
with (CH3)3CCHO followed by low-valent titanium-promoted olefination to give olefin 19; and (iv)
alkylation with benzaldehyde followed by Lewis acid catalyzed pinacol type reaction to give 18.
In tr od u ction
However, recent efforts have centered around the con-
struction of benzo[b]furan structures by C-C bond
formation using transition metal reagents including
copper and especially palladium catalysts.9 Alkyne-based
palladium-catalyzed reactions provide some of the most
versatile and efficient routes to heterocyclic derivatives.10
In previous reports, we demonstrated the use of
2-(benzotriazol-1-ylmethyl)-pyrroles11 and -indoles12 as
versatile building blocks for the synthesis of functional-
ized heterocycles. We also reported the synthesis of
indoles via [3 + 3] annulation of 2-(benzotriazole-1-
ylmethyl)pyrroles with R,â-unsaturated aldehydes and
ketones.13 The anion stabilizing and good leaving abili-
ties of benzotriazolyl moieties in the above ring systems
motivated us to extend these methodologies to elaborate
furans. We now report investigations on the use of
2-(benzotriazol-1-ylmethyl)furans 4a -c and 2-(benzo-
triazol-1-ylmethyl)benzofuran (12) for the synthesis of
polysubstituted benzo[b]furans 7a -c, 10a -f, 16a ,b, 15,
and 17-20 (Schemes 1 and 2).
Benzo[b]furan derivatives are important because of
their occurrence in nature and their physiological proper-
ties.1 Recently there has been a growing interest in
developing general and versatile synthetic methods for
the synthesis of benzo[b]furan derivatives due to their
activity as modulators of androgen biosynthesis (furano-
steroids),2 as inhibitors of 5-lipoxygenase,3 as antagonists
of the angiotensin II receptor,4 as blood coagulation factor
Xa inhibitors,5 and as ligands of adenosine A1 receptor.6
1-[[4-(Aminoalkoxy)phenyl]sulfonyl]benzo[b]furan deriva-
tives have been synthesized and tested as a potent class
of calcium blockers.7
Various methods exist for the synthesis of benzo[b]-
furans1,8 of which the intramolecular cyclization of a
suitably substituted benzene is the most often employed.8a
X Abstract published in Advance ACS Abstracts, October 1, 1997.
(1) Cagniant, P.; Cagniant, D. Adv. Heterocycl. Chem. 1975, 18, 337.
(2) Kumar, V.; Ackerman, J . H.; Alexander, M. D.; Bell, M. R.;
Christiansen, R. G.; Dung, J . S.; J aeger, E. P.; Herrmann, J . L. J r.;
Krolski, M. E.; McKloskey, P.; Batzold, F. H.; J uniewicz, P. E.; Reel,
J .; Snyder, B. W.; Winneker, R. C. J . Med. Chem. 1994, 37, 4227.
(3) Ohemeng, K. A.; Appollina, M. A.; Nguyen, V. N.; Schwender,
C. F.; Singer, M.; Steber, M.; Ansell, J .; Argentieri, D.; Hageman, W.
J . Med. Chem. 1994, 37, 3663.
(4) J udd, D. B.; Dowle, M. D.; Middlemiss, D.; Scopes, D. I. C.; Ross,
B. C.; J ack, T. I.; Pass, M.; Tranquillini, E.; Hobson, J . E.; Panchal, T.
A.; Stuart, P. G.; Paton, J . M. S.; Hubbard, T.; Hilditch, A.; Drew, G.
M.; Robertson, M. J .; Clark, K. L.; Travers, A.; Hunt, A. A. E.; Polley,
J .; Eddershaw, P. J .; Bayliss, M. K.; Manchee, G. R.; Donnelly, M. D.;
Walker, D. G.; Richards, S. A. J . Med. Chem. 1994, 37, 3108.
(5) Nagahara, T.; Yokoyama, Y.; Inamura, K.; Katakura, S.; Ko-
moriya, S.; Yamaguchi, H.; Hara, T.; Iwamoto, M. J . Med. Chem. 1994,
37, 1200.
Resu lts a n d Discu ssion
Syn th esis of 3,4,5,6-Su bstitu ted Ben zo[b]fu r a n s
10a -f a n d 2,3,4,5,6-Su bstitu ted Ben zo[b]fu r a n s 7a -
c. 2-(Benzotriazol-1-ylmethyl)furans 4a -c are readily
available from alkynyloxiranes 3a -c, themselves derived
from 1-propargylbenzotriazole (1) and R-bromo ketones
2a -c.14 Treatment of 4a -c with 1 equiv of n-BuLi at
-78 °C, followed by 1 equiv of R,â-unsaturated ketones
or aldehydes 5a -e, gave 1,4-addition intermediates 6a -
f. The intermediates 6a -f (obtained as mixtures of
diastereomers), without further purification, were treated
with p-toluenesulfonic acid in 1,4-dioxane under reflux
to undergo intramolecular cyclization to intermediates
(6) Yang, Z.; Liu, H. B.; Lee, C. M.; Chang, H. M.; Wong, H. N. C.
J . Org. Chem. 1992, 57, 7248.
(7) Gubin, J .; Vogelaer, H.; Inion, H.; Houben, C.; Lucchetti, J .;
Mahaux, J .; Rosseels, G.; Peiren, M.; Clinet, M.; Polster, P.; Chatelain,
P. J . Med. Chem. 1993, 36, 1425.
(8) (a) Donnelly, D. M. X.; Meegan, M. J . In Comprehensive
Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W., Eds.; Pergamon
Press: Oxford, 1984; Vol. 4, p 657. (b) Larock, R. C.; Stinn, D. E.
Tetrahedron Lett. 1988, 29, 4687.
(9) (a) Casiraghi, G.; Casnati, G.; Puglia, G.; Sartori, G; Terenga,
G. Synthesis 1977, 122. (b) Schneiders, G. E.; Stevenson, R. Synth.
Commun. 1980, 10, 699. (c) Arcadi, A.; Marinelli, F.; Cacchi, S.
Synthesis 1986, 749. (d) Larock, R. C.; Babu, S. Tetrahedron Lett. 1987,
28, 5291.
(10) (a) Kundu, N. G.; Pal, M.; Mahanty, J . S.; Dasgupta, S. K. J .
Chem. Soc., Chem. Commun. 1992, 41. (b) Arcadi, A.; Cacchi, S.;
Rosario, M. D.; Fabrizi, G.; Marinelli, F. J . Org. Chem. 1996, 61, 9280.
(11) Katritzky, A. R.; Li, J .; Stevens, C. V. J . Org. Chem. 1995, 60,
3401.
(12) Katritzky, A. R.; Li, J . J . Org. Chem. 1996, 61, 1624.
(13) Katritzky, A. R.; Levell, J . R.; Li, J . Tetrahedron Lett. 1996,
37, 5641.
(14) Katritzky, A. R.; Li, J . J . Org. Chem. 1995, 60, 638.
S0022-3263(97)01084-0 CCC: $14.00 © 1997 American Chemical Society

8206 J . Org. Chem., Vol. 62, No. 23, 1997
Katritzky et al.
Sch em e 1
Sch em e 2
9a -f, followed by spontaneous elimination of benzotria-
zole and water to give the benzo[b]furans 10a -f. We
found that the best solvent was 1,4-dioxane; initial
attempts to carry out these cyclization reactions in THF
failed, probably due to the lower boiling temperature of
THF.
Alternatively, the 2-(benzotriazol-1-yl)methyl moiety
can be alkylated by lithiation of 4a -c with 1 equiv of
n-BuLi at -78 °C for 30 min, followed by reactions with
n-butyl iodide or benzyl bromide as electrophiles for 12
h, to give 8a -c in good yields. Reactions of 8a -c with
R,â-unsaturated ketones followed by cyclization gave
polysubstituted benzo[b]furans 7a -c.
Syn th esis of 2-(Ben zotr ia zol-1-ylm eth y)lben zo[b]-
fu r a n (12) a n d Syn th etic Ma n ip u la tion of th e Ben -
zotr ia zol-1-ylm eth yl-Atta ch ed Sid e Ch a in . The syn-
thesis of 2-substituted benzo[b]furans via palladium-
catalyzed heteroannulation of acetylenic compounds has
been reported.10a The presence of a benzotriazolyl group
at the 2-position of the benzo[b]furan ring should allow

Synthesis of Polysubstituted Benzo[b]furans
J . Org. Chem., Vol. 62, No. 23, 1997 8207
pared according to literature procedure.17 1-Propargylbenzo-
triazole (1)18 and 2-(benzotriazol-1-ylmethyl)furan (4a ) were
prepared according to previously reported procedures and
compounds 4b,c were prepared using the same procedure.14
2-(Ben zotr iazol-1-ylm eth yl)-4-ter t-bu tylfu r an (4b): white
further elaboration to generate various products by
sequential lithiation, alkylation, and elimination or
substitution of the benzotriazolyl group.
The reaction of o-iodophenol (11) with 1-propargylben-
zotriazole (1) in the presence of (PPh3)2PdCl2, CuI, and
Et3N, at 60 °C using DMF as solvent, gave 2-(benzotria-
zol-1-ylmethyl)benzofuran (12) in 70% yield after 12 h.
Lithiation of 12 with 1 equiv of n-BuLi, followed by
addition of R,â-unsaturated aldehyde 13, gave the 1,4-
addition product 14, which without further purification
was refluxed in 1,4-dioxane in the presence of p-toluene-
sulfonic acid to give dibenzofuran 17 in good yield.
Lithiation of 12 with 1 equiv of n-BuLi followed by
alkylation with electrophiles gave 16a -c in good yields.
Refluxing 16a in a 1:1 mixture of t-BuOH/THF in the
presence of t-BuOK for 24 h gave exclusively 2-(trans-2-
phenylethenyl)benzofuran (15) in excellent yield. No
formation of the cis isomer was observed by NMR or
GCMS. Surprisingly, nucleophilic substitution of the
benzotriazole group in 16a with Grignard reagent was
followed by dehydrogenation to give the alkene 20.
Intermediate 16b, when treated with zinc bromide and
heated at 150 °C (neat) for 12 h, underwent a pinacol
type reaction with elimination of benzotriazole to give
the ketone 18.15
Recently, we found that stereoselective olefination of
aldehydes and ketones with N-benzyl- and N-allylben-
zotriazoles was promoted by low-valent titanium.16 In
the present study, this method was applied to 2-(benzo-
triazol-1-ylmethyl)benzofuran (12). Thus, compound 12
was treated with 1 equiv of n-BuLi followed by the
reaction with trimethylacetaldehyde to give a mixture
of distereomers 16c, which upon treatment with low-
valent titanium underwent dehydroxybenzotriazolation
stereospecifically to give trans-1-(benzofuran-2-yl)-2-tert-
butylethylene (19) exclusively. The trans structure was
confirmed by the large coupling constant (16.2 Hz) of the
double-bond protons.
1
microcrystals, yield 74%; mp 63-65 °C; H NMR δ 8.06 (d, J
) 8.1 Hz, 1 H), 7.59 (d, J ) 8.4 Hz, 1 H), 7.48 (t, J ) 7.7 Hz,
1 H), 7.37 (t, J ) 7.7 Hz, 1 H), 7.12 (s, 1 H), 6.39 (s, 1 H), 5.77
(s, 2 H), 1.54 (s, 9 H); 13C NMR δ 147.8, 146.1, 137.3, 137.2,
132.8, 127.4, 123.8, 119.8, 109.8, 109.2, 45.2, 30.6, 29.8. Anal.
Calcd for C15H17N3O: C, 70.56; H, 6.71; N, 16.46. Found: C,
70.62; H, 7.07; N, 16.58.
2-(Ben zot r ia zol-1-ylm et h yl)-4-p h en yl-5-m et h ylfu r a n
(4c): yellow microcrystals, yield 60%; mp 109-110 °C; 1H
NMR δ 8.04 (d, J ) 8.4 Hz, 1 H), 7.62 (d, J ) 8.2 Hz, 1 H),
7.45 (t, J ) 7.3 Hz, 1 H), 7.38-7.21 (m, 6 H), 6.56 (s, 1 H),
5.78 (s, 2 H), 2.36 (s, 3 H); 13C NMR δ 148.7, 146.3, 145.5,
133.4, 132.9, 128.6, 127.4, 126.6, 123.8, 123.9, 122.1, 120.0,
111.2, 109.8, 45.2, 13.0. Anal. Calcd for C18H15N3O: C, 74.72;
H, 5.23; N, 14.52. Found: C, 74.94; H, 5.27; N, 14.67.
P r ep a r a tion of 2-(Ben zotr ia zol-1-ylm eth yl)ben zo[b]-
fu r a n (12). A mixture of o-iodophenol (5.5 g, 25 mmol),
(PPh3)2PdCl2 (0.61 g, 0.88 mmol), CuI (0.62 g, 3.3 mmol), and
triethylamine (5.1 g, 50 mmol) was stirred in DMF (60 mL)
under nitrogen for 1 h. 1-Propargylbenzotriazole (1) (7.9 g,
50 mmol) was added, and the mixture was stirred at room
temperature for an additional 1 h and heated at 60 °C for 16
h. The mixture was then cooled, poured into water (150 mL),
and extracted with CH2Cl2 (3 × 50 mL). The combined
extracts were washed with NaOH (5 N, 3 × 100 mL) followed
by water (3 × 100 mL) and dried (MgSO4). After evaporation
of the solvent, the residue was purified by column chroma-
tography using EtOAc/hexane (1:3) to give the product 12 as
1
brown needles, yield 70%: mp 160-162 °C; H NMR δ 8.03
(d, J ) 8.5 Hz, 1 H), 7.91 (d, J ) 8.5 Hz, 1 H), 7.62-7.52 (m,
2 H), 7.49-7.37 (m, 2 H), 7.30-7.18 (m, 2 H), 7.05 (s, 1 H),
6.20 (s, 2 H); 13C NMR δ 154.4, 151.0, 145.2, 132.6, 127.4,
127.3, 124.5, 123.8, 122.8, 121.1, 119.1, 110.9, 110.3, 106.1,
44.6. Anal. Calcd for C15H11N3O: C, 72.28; H, 4.45; N, 16.86.
Found: C, 72.12; H, 4.42; N, 16.70.
Gen er a l P r oced u r e for th e P r ep a r a tion of 8a -c a n d
16a -c via th e Alk yla tion of 2-(Ben zotr ia zol-1-ylm eth yl)-
fu r a n s 4a -c a n d -ben zofu r a n (12). To a solution of
2-(benzotriazol-1-ylmethyl)furan 4a -c or -benzofuran (12) (16
mmol) in THF (100 mL) was added a solution of n-BuLi (16
mmol, 9.8 mL, 1.6 M in hexane) at -78 °C. After 30 min, a
solution of the electrophile (benzyl bromide, n-butyl iodide,
benzaldehyde, or trimethylacetaldehyde (16 mmol) in THF (10
mL) was added. The reaction mixture was stirred at this
temperature for 4 h and allowed to warm to room temperature
overnight. The reaction was quenched with a saturated NH4-
Cl solution (50 mL), extracted with EtOAc, washed with brine
(3 × 50 mL), and dried (MgSO4). The solvent was removed to
give the crude product which was purified by column chroma-
tography to give the corresponding compounds 8a -c or 16a .
The crude products 16b,c were used directly for the synthesis
of compounds 18 and 19 without further purification, and the
yields were determined by GCMS.
2-(1-Ben zot r ia zol-1-yl-2-p h en yl)et h yl-4-ter t-b u t ylfu -
r a n (8a ): purified by column chromatography using EtOAc/
hexane (1:1), white powder, yield 78%; mp 104-105 °C; 1H
NMR δ 8.01 (d, J ) 8.1 Hz, 1 H), 7.45-7.26 (m, 3 H), 7.12 (d,
J ) 6.0 Hz, 4 H), 6.99-6.93 (m, 2 H), 6.35 (s, 1 H), 6.13 (t, J
) 7.3 Hz, 1 H), 3.90-3.70 (m, 2 H), 1.18 (s, 9 H); 13C NMR δ
150.6, 146.1, 137.2, 136.8, 136.3, 132.6, 128.8, 128.5, 127.1,
126.9, 123.7, 119.9, 109.9, 108.3, 59.2, 38.8, 30.7, 29.8. Anal.
Calcd for C22H23N3O: C, 76.49; H, 6.71; N, 12.16. Found: C,
76.65; H, 6.93; N, 12.27.
Con clu sion s
In conclusion, general syntheses of polysubstituted
benzo[b]furans have been described. These approaches
utilize readily available starting materials and involve
sequential lithiation and alkylation of the 2-(benzotriazol-
1-yl)methyl side chain of furans 4a -c and 8a -c and
benzo[b]furan 12 with R,â-unsaturated ketones or alde-
hydes, followed by intramolecular cyclization with elimi-
nation of benzotriazole and water to give 7a -c, 10a -g,
and 17, base-assisted elimination to give 15, Lewis acid
assisted elimination of benzotriazole to give 18, and low-
valent titanium-promoted olefination to give 19.
Exp er im en ta l Section
Gen er a l Com m en ts. Melting points were determined on
a hot-stage microscope and are uncorrected. 1H NMR spectra
were recorded on a 300 MHz spectrometer using TMS as the
internal standard and CDCl3 as the solvent. 13C NMR spectra
were recorded at 75 MHz on the same instrument with the
solvent peak (CDCl3) as the reference. HRMS and elemental
analyses (C,H,N) were carried out within the department.
Dichlorobis(triphenylphosphine)palladium(II) was freshly pre-
2-(1-Ben zotr ia zol-1-ylp en tyl)-4-p h en ylfu r a n (8b): puri-
fied by column chromatography using EtOAc/hexane (1:1),
white powder, yield 76%; mp 113-115 °C; 1H NMR δ 8.08 (d,
J ) 8.1 Hz, 1 H), 7.64 (s, 1 H), 7.55 (d, J ) 8.1 Hz, 1 H), 7.45-
7.23 (m, 7 H), 6.72 (s, 1 H), 6.07 (t, J ) 7.5 Hz, 1 H), 2.61-
(15) (a) Katritzky, A. R.; Xie, L.; Toader, D.; Serdyuk, L. J . Am.
Chem. Soc. 1995, 117, 12015. (b) Katritzky, A. R.; Toader, D.; Xie, L.
J . Org. Chem. 1996, 61, 7571.
(16) Katritzky, A. R.; Li, J . J . Org. Chem. 1997, 62, 238.
(17) Four, P.; Guibe, F. J . Org. Chem. 1981, 46, 4439.
(18) Katritzky, A. R.; Li, J .; Malhotra, N. Liebigs Ann. Chem. 1992,
843.

8208 J . Org. Chem., Vol. 62, No. 23, 1997
Katritzky et al.
2.52 (m, 2 H), 1.44-1.17 (m, 4 H), 0.87 (t, J ) 7.1 Hz, 3 H);
13C NMR δ 152.5, 146.4, 138.2, 132.2, 131.7, 128.8, 128.7,
127.3, 127.2, 125.7, 123.8, 120.1, 110.1, 107.5, 57.7, 31.9, 28.1,
22.0, 13.7. Anal. Calcd for C21H21N3O: C, 76.11; H, 6.39; N,
12.68. Found: C, 75.80; H, 6.55; N, 12.54.
125.2, 123.7, 117.6, 108.1, 12.6. Anal. Calcd for C27H20O: C,
89.97; H, 5.59. Found: C, 89.69; H, 5.70.
3-ter t-Bu tyl-4-m eth yl-6-p h en ylben zo[b]fu r a n (10e): pu-
rified by column chromatography using CH2Cl2/hexane (1:4)
as the eluent, yellow crystals, yield 48%; mp 55-57 °C; 1H
NMR δ 7.56 (d, J ) 7.5 Hz, 2 H), 7.46 (s, 1 H), 7.36-7.33 (m,
3 H), 7.27-7.23 (m, 2 H), 2.77 (s, 3 H), 1.41 (s, 9 H); 13C NMR
δ 157.8, 141.0, 140.9, 137.3, 131.0, 130.8, 128.7, 127.2, 127.1,
125.4, 124.8, 107.9, 31.6, 30.5, 24.2. Anal. Calcd for
C19H20O: C, 86.32; H, 7.63. Found: C, 86.60; H, 7.94.
3-ter t-Bu t yl-6-m et h ylb en zo[b]fu r a n (10f): purified by
column chromatography using CH2Cl2/hexane (1:4) as the
eluent, yellow oil, yield 46%; 1H NMR δ 7.50 (d, J ) 8.0 Hz, 1
H), 7.17 (s, 2 H), 6.95 (d, J ) 8.0 Hz, 1 H), 2.36 (s, 3 H), 1.31
(s, 9 H); 13C NMR δ 156.5, 138.7, 133.9, 130.2, 124.4, 123.3,
121.1, 111.9, 30.0, 29.7, 29.4. HRMS calcd for C13H16 188.1201,
found 188.1203. Anal. Calcd for C13H16O: C, 82.94; H, 8.57.
Found: C, 82.94; H, 8.85.
3-ter t-Bu tyl-4,6-d ip h en yl-7-ben zylben zo[b]fu r a n (7a ):
purified by column chromatography using CH2Cl2/hexane (1:
4) as the eluent, white crystals, yield 50%; mp 148-149 °C;
1H NMR δ 7.43 (s, 3 H), 7.35-7.30 (m, 8 H), 7.20-7.05 (m, 5
H), 6.98 (s, 1 H), 4.31 (s, 2 H), 1.05 (s, 9 H); 13C NMR δ 155.7,
143.8, 141.5, 141.0, 140.7, 137.1, 134.7, 131.2, 130.5, 129.7,
128.4, 128.1, 128.0, 127.9, 127.4, 127.3, 126.9, 125.7, 124.4,
121.0, 32.7, 31.0, 30.5. Anal. Calcd for C31H28O: C, 89.38; H,
6.78. Found: C, 89.37; H, 6.96.
2-(1-Be n zot r ia zol-1-ylp e n t yl)-4-p h e n yl-5-m e t h ylfu -
r a n (8c): purified by column chromatography using EtOAc/
hexane (1:1), white powder, yield 72%; mp 110-111 °C; 1H
NMR δ 8.08 (d, J ) 8.1 Hz, 1 H), 7.59 (d, J ) 8.1 Hz, 1 H),
7.46-7.23 (m, 7 H), 6.54 (s, 1 H), 6.03 (t, J ) 7.8 Hz, 1 H),
2.59-2.52 (m, 2 H), 2.37 (s, 3 H), 1.43-1.17 (m, 4 H), 0.87 (t,
J ) 6.9 Hz, 3 H); 13C NMR δ 149.0, 148.1, 146.4, 133.5, 132.2,
128.6, 127.4, 127.1, 126.6, 123.8, 121.7, 120.1, 110.3, 109.7,
57.8, 31.8, 28.3, 22.1, 13.8, 13.1. Anal. Calcd for C22H23N3O:
C, 76.49; H, 6.71; N, 12.16. Found: C, 76.57; H, 6.85; N, 12.19.
2-(1-Ben zot r ia zol-1-yl-2-p h en yl)et h ylb en zo[b]fu r a n
(16a ): purified by column chromatography using EtOAc/
hexane (1:1), white powder, yield 74%; mp 134-135 °C; 1H
NMR δ 8.03 (d, J ) 8.0 Hz, 1 H), 7.53-7.21 (m, 8 H), 7.18-
7.04 (m, 4 H), 6.74 (s, 1 H), 6.33 (t, J ) 7.7 Hz, 1 H), 3.95 (d,
J ) 7.7 Hz, 2 H); 13C NMR δ 153.3, 146.2, 144.8, 136.1, 132.7,
128.8, 128.6, 127.7, 127.4, 127.1, 124.9, 123.9, 123.2, 121.3,
120.1, 111.4, 109.8, 105.5, 59.4, 38.7. Anal. Calcd for
C22H17N3O: C, 77.86; H, 5.05; N, 12.38. Found: C, 77.86; H,
5.07; N, 12.43.
Gen er a l P r oced u r e for th e P r ep a r a tion of P olysu b-
st it u t ed Ben zo[b]fu r a n s 10a -g a n d 7a -c a n d 3-P h en -
yld iben zo[b]fu r a n (17). To a solution of compound 4 or 8
or 12 (7.3 mmol) in THF (100 mL) was added a solution of
n-BuLi (7.3 mmol, 4.6 mL, 1.6 M in hexane) at -78 °C, and
2-Meth yl-3,4,6-tr iph en yl-7-bu tylben zo[b]fu r an (7b): pu-
rified by column chromatography using CH2Cl2/hexane (1:4)
as the eluent, white crystals, yield 66%; mp 95-96 °C; 1H NMR
δ 7.44-7.33 (m, 5 H), 7.12-6.92 (m, 11 H), 2.96 (t, J ) 8.0
Hz, 2 H), 2.48 (s, 3 H), 1.72-1.64 (m, 2 H), 1.39-1.30 (m, 2
H), 0.88 (t, J ) 7.3 Hz, 3H); 13C NMR δ 153.6, 152.2, 141.7,
139.2, 137.2, 133.4, 132.6, 129.9, 129.7, 129.3, 128.0, 127.4,
127.1, 126.9, 126.7, 126.5, 126.1, 124.6, 122.9, 117.8, 32.4, 26.7,
22.9, 13.8, 12.7. Anal. Calcd for C31H28O: C, 89.38; H, 6.78.
Found: C, 89.06; H, 7.18.
the solution was stirred at this temperature for 30 min.
A
solution of an appropriate R,â-unsaturated ketone or aldehyde
(5 or 13) (7.3 mmol) in THF (10 mL) was added, and the
reaction mixture was stirred at -78 °C for 20 h. A saturated
NH4Cl solution (100 mL) was added, and the solution was
extracted with EtOAc (100 mL). The organic phase was
separated, washed with saturated NH4Cl solution (3 × 100
mL), and dried (MgSO4). After removal of the solvent, the
residue was dissolved in 1,4-dioxane (50 mL), p-toluenesulfonic
acid (2.8 g, 15 mmol) added, and the solution was refluxed for
24 h. The mixture was cooled, diluted with water (50 mL),
and extracted with Et2O (3 × 50 mL). The combined extracts
were washed with water (3 × 50 mL) and dried (MgSO4). The
solvent was removed and the residue was subjected to column
chromatography or recrystallization to afford the correspond-
ing product 10a -f or 7a -c or 17.
3-t er t-Bu t yl-5-m e t h yl-6-p h e n yl-7-b e n zylb e n zo[b]fu -
r a n (7c): purified by column chromatography using CH2Cl2/
1
hexane (1:4) as the eluent, yellow oil, yield 48%; H NMR δ
7.41 (s, 1 H), 7.26-7.22 (m, 4 H), 6.99-6.94 (m, 5 H), 6.80 (d,
J ) 6.0 Hz, 2 H), 3.92 (s, 2 H), 2.01 (s, 3 H), 1.34 (s, 9 H); 13C
NMR δ 153.8, 140.7, 140.1, 139.5, 137.9, 130.3, 130.1, 129.9,
128.6, 128.1, 127.9, 126.8, 125.6, 125.5, 122.7, 120.2, 33.2, 31.0,
30.0, 21.7. Anal. Calcd for C26H26O: C, 88.09; H, 7.39.
Found: C, 87.67; H, 7.56.
3,4,6-Tr ip h en ylben zo[b]fu r a n (10a ): purified by recrys-
tallization from pentane, white microcrystals, yield 53%; mp
108-109 °C; H NMR δ 7.75 (s, 1 H), 7.69 (d, J ) 7.4 Hz, 2
3-P h en yld iben zo[b]fu r a n (17): purified by column chro-
matography using CH2Cl2/hexane (1:4) as the eluent, white
crystals, yield 62%; mp 128-130 °C; 1H NMR δ 7.93-7.89 (m,
2 H), 7.74 (s, 1 H), 7.64 (d, J ) 7.4 Hz, 2 H), 7.54 (d, J ) 7.7
Hz, 2 H), 7.46-7.28 (m, 5 H); 13C NMR δ 156.9, 156.7, 141.1,
140.8, 128.9, 127.5, 127.4, 127.1, 124.1, 123.3, 122.8, 122.1,
120.7, 120.6, 111.7, 110.1. Anal. Calcd for C18H12O: C, 88.50;
H, 4.95. Found: C, 88.31; H, 4.94.
1
H), 7.46-7.32 (m, 5 H), 7.07-6.91 (m, 10 H); 13C NMR δ 156.8,
143.1, 141.0, 139.3, 138.2, 136.8, 132.0, 129.4, 129.1, 128.9,
127.5, 127.4, 127.3, 126.8, 126.6, 124.0, 123.3, 109.0. Anal.
Calcd for C26H18O: C, 90.14; H, 5.24. Found: C, 90.09; H, 5.48.
4-Meth yl-3,6-d ip h en ylben zo[b]fu r a n (10b): purified by
column chromatography using CH2Cl2/hexane (1:4) as the
eluent, white crystals, yield 50%; mp 119-121 °C; 1H NMR δ
7.62-7.48 (m, 3 H), 7.54 (s, 1 H), 7.46-7.26 (m, 9 H), 2.30 (s,
3 H); 13C NMR δ 142.4, 141.2, 138.1, 132.8, 132.1, 130.1, 128.8,
128.0, 127.6, 127.4, 127.3, 127.1, 125.1, 124.0, 123.3, 107.8,
19.9. Anal. Calcd for C21H16O: C, 88.70; H, 5.67. Found: C,
88.37; H, 5.94.
P r ep a r a tion of 2-(tr a n s-2-P h en yleth en yl)ben zo[b]fu -
r a n (15). 2-(1-Benzotriazol-1-yl-2-phenyl)ethylbenzo[b]furan
(16a ) (1.0 g, 3.0 mmol) and t-BuOK (0.66 g, 5.9 mmol) were
dissolved in a mixture of dry THF (20 mL) and t-BuOH (30
mL). The mixture was refluxed for 24 h. After cooling, the
reaction was quenched with water (100 mL) and extracted with
Et2O (3 × 100 mL). The combined extracts were washed with
water (3 × 100 mL) and dried (MgSO4). Evaporation of the
solvent followed by column chromatography, using CH2Cl2/
hexane (1:4) as the eluent, gave the product as white crys-
3-ter t-Bu tyl-5-m eth yl-6-p h en ylben zo[b]fu r a n (10c): pu-
rified by column chromatography using CH2Cl2/hexane (1:4)
as the eluent, yellow crystals, yield 52%; mp 54-55 °C; 1H
NMR δ 7.63 (d, J ) 7.2 Hz, 2 H), 7.54 (s, 1 H), 7.45-7.40 (m,
3 H), 7.35-7.30 (m, 2 H), 2.84 (s, 3 H), 1.47 (s, 9 H); 13C NMR
δ 157.8, 141.0, 140.9, 137.3, 131.0, 130.8, 128.7, 127.2, 127.1,
125.4, 124.7, 107.9, 31.5, 30.4, 24.2. Anal. Calcd for
C19H20O: C, 86.32; H, 7.63. Found: C, 86.60; H, 7.94.
2-Meth yl-3,4,6-tr ip h en ylben zo[b]fu r a n (10d ): purified
by column chromatography using CH2Cl2/hexane (1:4) as the
eluent, white crystals, yield 46%; mp 102-103 °C: 1H NMR δ
7.69-7.66 (m, 3 H), 7.45-7.40 (m, 3 H), 7.32 (t, J ) 7.2 Hz, 1
H), 7.07-6.88 (m, 8 H), 6.87 (d, J ) 7.8 Hz, 2 H), 2.42 (s, 3 H);
13C NMR δ 155.1, 152.8, 141.2, 139.1, 136.9, 135.8, 133.1,
129.8, 129.2, 128.8, 127.4, 127.3, 127.2, 127.1, 126.4, 126.2,
1
tals: yield 87%; mp 125-126 °C; H NMR δ 7.47 (t, J ) 8.9
Hz, 4 H), 7.35-7.17 (m, 6 H), 6.95 (d, J ) 16.2 Hz, 1 H), 6.61
(s, 1 H); 13C NMR δ 155.1, 154.9, 136.6, 130.3, 129.1, 128.7,
128.1, 126.7, 124.6, 122.8, 120.8, 116.4, 110.9, 105.1. Anal.
Calcd for C16H12O: C, 87.25; H, 5.49. Found: C, 87.11; H, 5.57.
P r ep a r a tion of 2-(tr a n s-2-ter t-Bu tyleth en yl)ben zo[b]-
fu r a n (19). To a solution of 2-(benzotriazol-1-ylmethyl)benzo-
[b]furan (12) (2.0 g, 8.0 mmol) in THF (80 mL) under argon
was added a solution of n-BuLi (5.0 mL, 8.0 mmol, 1.6 M in
hexane) at -78 °C. The mixture was stirred at -78 °C for 1
h, and a solution of trimethylacetaldehyde (0.7 g, 8.1 mmol)
in THF (10 mL) was added. After being stirred for 2 h at -78

Synthesis of Polysubstituted Benzo[b]furans
J . Org. Chem., Vol. 62, No. 23, 1997 8209
°C, the reaction was quenched with saturated NH4Cl solution
(100 mL) and extracted with diethyl ether (100 mL). The
organic phase was separated, washed with brine (3 × 100 mL),
and dried (MgSO4). The solvent was removed under reduced
pressure to give the crude product 16c which was used in the
following reaction without further purification.
h at room temperature. The solid was filtered off, and the
solution was washed with water (2 × 100 mL) and dried
(MgSO4). The solvent was removed, and the residue was
subjected to column chromatography (EtOAc/hexane, 1:7) to
give the product as yellow crystals, yield 64%: ; mp 105-106
1
°C; H NMR δ 7.96 (d, J ) 8.3 Hz, 2 H), 7.50 (d, J ) 8.2 Hz,
A mixture of TiCl3 (3.9 g, 25 mmol) and zinc dust (5.4 g, 83
mmol) in dry DME (100 mL) was refluxed for 1 h under argon.
After cooling, the above crude compound 16c in dry DME (10
mL) was added and refluxed for 12 h. The reaction mixture
was cooled, diluted with diethyl ether (100 mL), and filtered.
The filtrate was washed with NaOH (5%, 3 × 100 mL) and
brine (3 × 100 mL) and dried (MgSO4). After removal of the
solvent, the residue was purified by short column chromatog-
raphy using hexane as the eluent to give the product as an
oil, yield 68%; 1H NMR δ 7.47-7.39 (m, 2 H), 7.20-7.14 (m, 2
H), 6.53 (d, J ) 16.2 Hz, 1 H), 6.44 (s, 1 H), 6.23 (d, J ) 16.2
Hz, 1 H), 1.13 (s, 9 H); 13C NMR δ 155.5, 154.6, 144.2, 129.2,
123.9, 122.6, 120.5, 114.0, 110.7, 102.9, 33.5, 29.4. Anal. Calcd
for C14H16O: C, 83.96; H, 8.05. Found: C, 84.07; H, 8.38.
P r ep a r a tion of 1-(4-Ch lor op h en yl)-2-(ben zofu r a n -2-
yl)eth a n on e (18). To a solution of 2-(benzotriazol-1-ylmeth-
yl)benzo[b]furan (12) (1.0 g, 4 mmol) in THF (50 mL) at -78
°C under argon was added n-BuLi (1.6 M, 2.74 mL, 4.4 mmol).
After 30 min, a solution of 4-chlorobenzaldehyde (0.62 g, 4.4
mmol) in THF (10 mL) was added. The mixture was stirred
at -78 °C for 4 h and allowed to warm to room temperature
overnight. A solution of zinc bromide (15 mmol) in THF (15
mL) was added. THF was removed, and the residue was
heated at 150 °C for 12 h. Ethyl acetate (100 mL) and diethyl
ether (100 mL) were added, and the mixture was stirred for 1
1 H), 7.42 (d, J ) 8.4 Hz, 3 H), 7.23-7.18 (m, 2 H), 6.62 (s, 1
H), 4.39 (s, 2 H); 13C NMR δ 193.1, 154.9, 151.0, 140.0, 134.5,
130.0, 129.1, 129.0, 123.9, 122.8, 120.7, 111.0, 105.5, 38.8.
Anal. Calcd for C16H11O2Cl: C, 70.99; H, 4.10. Found: C,
70.93; H, 4.00.
P r ep a r a tion of 2-(1-Eth yl-2-p h en yleth en yl)ben zofu r a n
(20). To a solution of compound 16a (2 mmol) in toluene (30
mL) under argon was added a solution of ethyl magnesium-
bromide (4 mmol) in Et2O, and the reaction mixture was
refluxed for 3 h. The solvent was removed under reduced
pressure, and the residue was extracted with Et2O (2 × 50
mL). The combined diethyl ether solution was washed with
water (2 × 50 mL) and dried (MgSO4). After removal of the
solvent, the residue was purified by column chromatography
using CH2Cl2/hexane (1:4) as the eluent to give the product
as a yellow powder, 52% yield: mp 63-64 °C; 1H NMR δ 7.79
(d, J ) 7.4 Hz, 2 H), 7.36 (t, J ) 7.8 Hz, 2 H), 7.18 (t, J ) 7.2
Hz, 2 H), 7.09-7.05 (m, 2 H), 6.97 (t, J ) 7.4 Hz, 1 H), 6.44 (s,
1 H), 5.59 (s, 1 H), 2.40 (q, J ) 7.1 Hz, 2 H), 1.28 (t, J ) 7.4
Hz, 3 H); 13C NMR δ 152.3, 149.7, 136.1, 134.7, 128.7, 128.3,
128.2, 125.9, 125.6, 122.5, 121.6, 121.4, 114.7, 101.6, 24.7, 12.2.
Anal. Calcd for C18H16O: C, 87.06; H, 6.49. Found: C, 87.24;
H, 6.60.
J O9710846