Novel syntheses of 2,3-disubstituted benzofurans

Full text of DOI:10.1021/jo010278p

J . Org. Chem. 2001, 66, 5613-5615
5613
Notes
Sch em e 1
Novel Syn th eses of 2,3-Disu bstitu ted
Ben zofu r a n s
Alan R. Katritzky,* Yu J i, Yunfeng Fang,‡ and
Indra Prakash§
Center for Heterocyclic Compounds, University of Florida,
Department of Chemistry,Gainesville, Florida 32611-7200
katritzky@chem.ufl.edu
Received March 12, 2001
In tr od u ction
Benzofurans possess a broad range of biological activi-
ties, are constituents of important natural products, and
have been the subject of extensive experimental studies.1a-c
Major synthetic strategies utilized include the following
(Scheme 1): (i) dehydrative cyclization of R-(phenoxy)-
alkyl ketones;2a-e (ii) dehydration of o-hydroxybenzyl
ketones under acidic conditions;3a-b (iii) decarboxylation
of o-acylphenoxyacetic acids or esters on treatment with
a base;4a-d (iv) cyclofragmentation of oxiranes, prepared
in three or four steps from the corresponding o-hydroxy-
benzophenones;5 and (v) palladium(II)-catalyzed cycliza-
tion of arylacetylenes.6a-d
Sch em e 2
We now disclose the preparation of 2,3-disubstituted
benzofurans by reactions of o-hydroxyphenyl ketones
3a -c or o-(1-hydroxy-2,2-dimethylpropyl)phenol 8 with
1-benzotriazol-1-ylalkyl chlorides 2a -c in two or three
steps (Schemes 2 and 3). These new approaches make
the variety of benzofurans readily available by simple
‡ Present addresses: Triad Therapeutics, Inc., 5820 Nancy Ridge
Drive, #200, San Diego, CA 92121.
§ NutraSweet Co., 699 Wheeling Road, Mount Prospect, IL 60056.
(1) (a)Cagniant, P.; Cagniant, D. In Advances in Heterocyclic
Chemistry; Katritzky, A. R., Boulton, A. J ., Eds.; Academic Press: New
York, 1975; Vol. 18, p 337. (b) Comprehensive Heterocyclic Chemistry;
Katritzky, A. R., Rees, C. W., Eds.; Pergamon Press: England, 1984;
Vol. 4, p 531. (c) Comprehensive Heterocyclic Chemistry II; Katritzky,
A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon Press: Oxford,
1996; Vol. 2, p 259.
(2) (a) Wright, J . B. J . Org. Chem. 1960, 25, 1867. (b) Royer, R.;
Bisagni, E.; Hudry, C.; Cheutin, A.; Desvoye, M.-L. Bull. Soc. Chim.
Fr. 1963, 1003. (c) Pene, C.; Demerseman, P.; Cheutin, A.; Royer, R.
Bull. Soc. Chim. Fr. 1966, 586. (d) Kawase, Y.; Takata, S.; Hikishima,
E. Bull. Soc. Chim. J p. 1971, 44, 749. (e) Horaguchi, T.; Iwanami, H.;
Tanaka, T.; Hasegawa, E.; Shimizu, T. J . Chem. Soc., Chem. Commun.
1991, 44.
(3) (a) Adams, R.; Whitaker, L. J . Am. Chem. Soc. 1956, 78, 8. (b)
Kalyanasundaram, M.; Rajagopalan, K.; Swaminathan, S. Tetrahedron
Lett. 1980, 21, 4391.
(4) (a) Muller, A.; Meszaros, M.; Kormendy, K. J . Org. Chem. 1954,
19, 472. (b) Horaguchi, T.; Tanemura, K.; Suzuki, T. J . Heterocycl.
Chem. 1988, 25, 39. (c) Horaguchi, T.; Kobayashi, H.; Miyazawa, K.;
Hasegawa, E.; Shimizu, T. J . Heterocycl. Chem. 1990, 27, 935. (d)
Boehm, T. L.; Showalter, H. D. H. J . Org. Chem. 1996, 61, 6498.
(5) Nicolaou, K. C.; Snyder, S. A.; Bigot, A.; Pfefferkorn, J . A. Angew.
Chem., Int. Ed. 2000, 39, 1093.
(6) (a) Kondo, Y.; Shiga, F.; Murata, N.; Sakamoto, T.; Yamanaka,
H. Tetrahedron 1994, 50, 11803. (b) Arcadi, A.; Cacchi, S.; Rosario, M.
D.; Fabrizi, G.; Marinelli, F. J . Org. Chem. 1996, 61, 9280. (c) Cacchi,
S.; Fabrizi, G.; Moro, L. Tetrahedron Lett. 1998, 39, 5101. (d) Monteiro,
N.; Arnold, A.; Blame, G. Synlett. 1998, 1111.
procedures and in good overall yields and complements
a previous benzotriazole-mediated preparation of benzo-
furans.7
Resu lts a n d Discu ssion
Compounds 2a -c (available from aldehydes, benzo-
triazole, and thionyl chloride in 87-96% yields8) were
treated with sodium salts of o-hydroxybenzophenones
3a -c or of 8 to afford the corresponding intermediates
4a -h (Table 1) and 9a ,b in excellent yields (Schemes 2
10.1021/jo010278p CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/18/2001

5614 J . Org. Chem., Vol. 66, No. 16, 2001
Notes
Li under reflux in DME for 5 h under argon protection)9a
in DME under reflux for 12-24 h to give the correspond-
ing benzofurans 6a -h and 11a ,b. To support the reaction
path proposed, we isolated and characterized the inter-
mediate 5a . The structure of 5a was deduced from its
1H NMR, 13C NMR, and DEPT spectra. The 1H NMR
spectrum of 5a shows some change compared to that of
compound 4a in the aromatic region (7.00-8.00 ppm),
and the characteristic singlet of the methylene protons
(6.44 ppm) of 4a disappeared. The signal at 3.93 ppm
present in the spectrum of 5a disappeared after addition
of D2O, suggesting the existence of an OH group. In the
13C NMR spectrum of 5a , the signals corresponding to
the carbonyl (195.5 ppm) and methylene (74.8 ppm)
fragments of 4a have disappeared. Two new signals (at
83.5 and 97.8 ppm) in the 13C spectrum of 5a were
assigned to the two aliphatic carbons connected to the
OH and the benzotriazole groups. DEPT reveals that the
number of even carbons and odd carbons is 7 and 13,
respectively. These data taken together confirm the
structure of 5a . In previous work,9b we showed that pairs
of diastereomers of type 5 each gave the same olefin on
low-valent Ti treatment.
Sch em e 3
The structures of benzofurans 6a -h and 11a ,b were
1
1
assigned by their H and 13C NMR. The H NMR spectra
of 6a -h and 11a ,b show no signals corresponding to
those assigned to the N-substituted benzotriazole groups
of intermediates 4a -h or 10a ,b (7.0-8.2 ppm). In the
13C NMR spectra, the sets of signals assigned to the
N-substituted benzotriazole groups of 4a -h or 10a ,b
(around 110, 120, 124, 127, 132, 146 ppm) have disap-
peared. The new 13C signal at 140-155 ppm was assigned
to C(2) of benzofurans 6a -h and 11a ,b.
Ta ble 1. P r ep a r a tive Yield s of Or th o-Su bstitu ted
P h en on es 4a -h a n d Ben zofu r a n s 6a -h
R1
R2
R3
R4
4 (yield, %)
6 (yield, %)
a
b
c
d
e
f
H
H
H
H
H
H
H
MeO
MeO
H
H
H
Me
Me
Me
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
97
87
85
99
95
87
98
97
655
5511
65
Me
n-Pr
H
Me
n-Pr
H
6012
5713
40
g
h
7014
5615
In summary, an efficient and simple route to benzo-
furans was developed from R-benzotriazolylalkyl chlo-
rides and o-hydroxyphenyl ketones. The sequence works
well for 3-aryl- and 3-tert-butylbenzofurans but could not
be extended to other 3-alkyl analogues.
Me
H
Ta ble 2. P r ep a r a tive Yield s of Or th o-Su bstitu ted
P h en yl-2,2-d im eth yl-1-p r op a n ols 9a ,b, Or th o-Su bstitu ted
P h en yl-2,2-d im eth yl-1-p r op a n on es 10a ,b, a n d
Ben zofu r a n s 11a ,b
R1
9 (yield, %)
10 (yield, %)
11 (yield, %)
Exp er im en ta l Section
a
b
H
Me
99
95
97
98
6016
5617
Gen er a l Meth od s. Melting points were determined on a hot-
stage apparatus and are uncorrected. NMR spectra were re-
corded in CDCl3 or DMSO-d6 with TMS as the internal standard
for 1H (300 MHz) or a solvent as the internal standard for 13C
(75 MHz). Microanalyses were performed on a Carlo Erba-1106
elemental analyzer. Benzene and toluene were dried over
molecular sieves. Column chromatography was conducted with
silica gel 200-425 mesh.
and 3). The structures of 4a -h and 9a ,b are supported
by their 1H NMR and 13C NMR spectra. The 1H NMR
spectra of 4a -h and 9a ,b showed the disappearance of
the phenolic proton signal (5.0-6.0 ppm) of the o-
hydroxyphenyl ketones and the appearance of a new set
of signals at 7.0-8.2 ppm characteristic for the N-
substituted benzotriazole group. The 13C NMR spectra
of 4a -h and 9a ,b also showed new signals around 110,
120, 124, 127, 132, and 146 ppm, corresponding to the
N-substituted benzotriazole. Compounds 9a,b were treated
with pyridinium dichromate to afford intermediates
10a ,b in yields of 97-98% (Table 2).
Intermediates 4a -h or 10a ,b were treated with an
equivalent amount of LDA in THF at temperatures
ranging from -78 to +20 °C to give the corresponding
2-(benzotriazol-1-yl)-3-substituted-2,3-dihydro-1-benzofu-
ran-3-ols of type 5. Compounds 5 without further puri-
fication were treated with an equivalent amount of low-
valent titanium reagent (prepared by heating TiCl3 and
1-Benzotriazol-1-ylalkyl chlorides 2a -c were synthesized
according to the previously published procedure.10
Gen er a l P r oced u r e for t h e P r ep a r a t ion of Or t h o-
Su bstitu ted Ben zop h en on es 4a -h . To a stirred solution of
1-(2-hydroxyphenyl)ketones 3 (3 mmol) in ethanol (20 mL) was
added NaOH (120 mg, 3 mmol) at room temperature, and the
reaction mixture was stirred for 5 h. Ethanol was removed from
the reaction mixture in vacuo. The residue was dissolved in
DMF; to the solution obtained was added the corresponding
1-benzotriazol-1-ylalkyl chloride 2 (3 mmol), and the reaction
mixture was stirred at 70 °C for 12 h. After the starting
materials were consumed, the reaction mixture was poured into
ice-water and extracted with diethyl ether. Ether was removed
in vacuo, and the residue was purified by column chromatog-
raphy on silica gel.
(9) (a) Katritzky, A. R.; Li, J . J . Org. Chem. 1997, 62, 238. (b)
Katritzky, A. R.; Cheng, D.; Henderson, S. A.; Li, J . J . Org. Chem.
1998, 63, 6704.
(10) Zaugg, H. E.; de Net, R. W.; Michaels, R. J . J . Org. Chem. 1961,
26, 4821.
(7) Katritzky, A. R.; Lan, X.; Zhang, Z. J . Heterocycl. Chem. 1993,
30, 381.
(8) Katritzky, A. R.; Kuzmierkiewicz, W.; Rachwal, B.; Rachwal, S.;
Thomson, J . J . Chem. Soc., Perkin Trans. 1 1987, 811.

Notes
[2-(1-Ben zotr ia zol-1-ylm eth oxy)p h en yl](p h en yl)m eth a -
J . Org. Chem., Vol. 66, No. 16, 2001 5615
3.64-3.67 (m, 1H), 4.46 (d, J ) 3.3 Hz, 1H), 6.74-6.86 (m, 3H),
7.12 (t, J ) 6.9 Hz, 1H), 8.64 (s, 1H); 13C NMR δ 26.0, 37.1,
84.5, 117.0, 118.6, 124.1, 128.5, 129.6, 156.0.
n on e (4a ): white needles (hexanes/ethyl acetate 5:1); mp 72-
1
74 °C (97%); H NMR δ 6.44 (s, 2H), 7.08 (dt, J ) 7.5, 1.8 Hz,
1H), 7.21-7.47 (m, 9H), 7.55-7.60 (m, 2H), 7.93-7.98 (m, 1H);
13C NMR δ 74.3, 109.7, 115.2, 119.4, 122.8, 124.2, 127.8, 128.0,
129.2, 129.3, 130.2, 131.6, 132.3, 132.8, 137.0, 145.8, 153.2, 195.3.
Anal. Calcd for C20H15N3O2: C, 72.94; H, 4.59; N, 12.76. Found:
C, 72.36; H, 4.53; N, 12.79.
Gen er a l P r oced u r e for th e P r ep a r a tion of th e In ter -
m ed ia tes 9. To a stirred solution of 2-(1-hydroxy-2,2-dimeth-
ylpropyl)phenol 8 (540 mg, 3 mmol) in ethanol (20 mL) was
added NaOH (120 mg, 3 mmol) at room temperature, and the
reaction mixture was stirred for 5 h. Ethanol was removed from
the reaction mixture in vacuo. The residue was dissolved in
DMF, the corresponding 1-benzotriazol-1-ylalkyl chloride 2 (3
mmol) was added, and the reaction mixture was stirred at 70
°C for 12 h. After the starting materials were consumed, the
reaction mixture was poured into ice-water and extracted with
diethyl ether. Ether was removed in vacuo, and the residue was
purified by column chromatography on silica gel.
1-[2-(1-Ben zotr ia zol-1-ylm eth oxy)p h en yl]-2,2-d im eth yl-
1-p r op a n ol (9a ): white plates (hexanes/ethyl acetate 5:1); mp
97-98 °C (99%); 1H NMR δ 0.83 (s, 9H), 3.24 (d, J ) 3.3 Hz,
1H), 4.74 (d, J ) 3.0 Hz, 1H), 6.40 (s, 2H), 6.95 (t, J ) 7.0 Hz,
1H), 7.08-7.24 (m, 3H), 7.34 (d, J ) 8.1 Hz, 1H), 7.41 (d, J )
8.1 Hz, 1H), 7.56 (d, J ) 8.1 Hz, 1H), 7.81 (d, J ) 8.1 Hz, 1H);
13C NMR δ 25.4, 35.9, 73.8, 74.3, 109.3, 113.0, 119.3, 121.9, 124.1,
127.6, 127.7, 129.0, 132.0, 132.2, 145.4, 153.2. Anal. Calcd for
C18H21N3O2: C, 69.43; H, 6.80; N, 13.78. Found: C, 69.31; H,
7.36; N, 13.78.
Gen er a l P r oced u r e for th e P r ep a r a tion of th e In ter -
m ed ia tes 10. To a solution of an intermediate 9 (1.7 mmol) in
DMF (10 mL) was added pyridinium dichromate (3.2 g, 8.5
mmol), and the reaction mixture was stirred at room tempera-
ture for 16 h. The reaction mixture was extracted with diethyl
ether, and the organic fraction was dried over anhydrous sodium
sulfate. The solvent was removed in vacuo, and the residue was
purified by column chromatography on silica gel.
1-[2-(1-Ben zotr ia zol-1-ylm eth oxy)p h en yl]-2,2-d im eth yl-
1-p r op a n on e (10a ): white needles (hexanes/ethyl acetate 5:1);
mp 103-104 °C (97%); 1H NMR δ 1.05 (s, 9H), 6.44 (s, 2H), 6.90-
6.99 (m, 2H), 7.18 (s, 2H), 7.27 (t, J ) 7.5 Hz, 1H), 7.40(t, J )
7.5 Hz, 1H), 7.54 (d, J ) 8.4 Hz, 1H), 7.94 (d, J ) 8.4 Hz, 1H);
13C NMR δ 26.2, 44.4, 74.4, 109.4, 114.7, 119.4, 122.2, 124.1,
126.1, 127.8, 129.5, 131.9, 132.3, 145.6, 151.2, 211.8. Anal. Calcd
for C18H19N3O2: C, 69.88; H, 6.19; N, 13.58. Found: C, 69.63;
H, 6.11; N, 13.55.
P r ep a r a tion of 2-(1-Ben zotr ia zol-1-yl)-3-p h en yl-2,3-d i-
h yd r o-1-ben zofu r a n -3-ol (5a ). To a stirred solution of the
ortho-substituted phenone 4a (494 mg, 1.5 mmol) in THF was
added LDA (2.0 M, 0.85 mL, 1.7 mmol) at -78 °C. The reaction
mixture was stirred at the same temperature overnight and then
quenched with saturated aqueous NH4Cl and extracted with
diethyl ether. The organic layer was dried over anhydrous Na2-
SO4, and the solvent was removed in vacuo. The residue was
purified by column chromatography on silica gel to afford
compound 5a (97%) as white plates: mp 167-168 °C; 1H NMR
δ 3.93 (s, 1H), 7.05 (t, J ) 3.9 Hz, 2H), 7.13 (t, J ) 7.5 Hz, 1H),
7.25-7.45 (m, 10H), 7.87 (d, J ) 7.8 Hz, 1H); 13C NMR δ 83.5,
97.8, 110.9, 111.2, 120.1, 123.4, 124.6, 125.3, 125.6, 128.3, 128.5,
129.0, 130.7, 131.4, 133.3, 143.1, 146.0, 158.0. Anal. Calcd for
C20H15N3O2: C, 72.94; H, 4.59; N, 12.76. Found: C, 72.82; H,
4.91; N, 12.79.
Gen er a l P r oced u r e for th e P r ep a r a tion of Ben zofu r a n s
6a -h . To a stirred solution of ortho-substituted phenones 4 (1.5
mmol) in THF was added LDA (2.0 M, 0.85 mL, 1.7 mmol) at
-78 °C, and the reaction mixture was stirred at the same
temperature overnight. The reaction mixture was quenched by
saturated aqueous NH4Cl and extracted with diethyl ether. The
organic layer was dried over anhydrous Na2SO4, and the solvent
was removed in vacuo. The crude product was directly used in
the next step, for which TiCl3 (277 mg, 1.8 mmol), Li (38 mg,
5.4 mmol), and DME (15 mL) were loaded in a three-necked
round-bottom flask under argon. The reaction mixture was
heated under reflux for 5 h to generate the Ti(0) species. A
solution of the crude product in DME (10 mL) was added to the
Ti(0) solution and heated under reflux for 24 h. The reaction
mixture was quenched by addition of saturated aqueous NH4Cl
and extracted with diethyl ether. The organic layer was dried
over anhydrous Na2SO4, and the solvent was removed in vacuo.
The residue was purified by column chromatography on silica
gel.
Gen er a l P r oced u r e for th e P r ep a r a tion of Ben zofu r a n s
11a ,b. To a stirred solution of ortho-substituted phenones 10
(1.5 mmol) in THF was added LDA (0.85 mL, 2.0 M, 1.7 mmol)
at -78 °C, and the reaction mixture was stirred at the same
temperature overnight. The reaction mixture was quenched by
addition of saturated aqueous NH4Cl and extracted with diethyl
ether. The organic layer was dried over anhydrous Na2SO4, and
the solvent was removed in vacuo. The crude product was
directly used in the next reaction as follows. TiCl3 (277 mg, 1.8
mmol), Li (38 mg, 5.4 mmol), and DME (15 mL) were loaded in
a three-necked round-bottom flask under argon. The reaction
mixture was heated under reflux for 5 h to generate the Ti(0)
species. A solution of the crude product in DME (10 mL) was
added to the Ti(0) solution, and the reaction mixture was heated
under reflux for 24 h. The reaction mixture was quenched by
addition of saturated aqueous NH4Cl and extracted with ether.
The organic layer was dried over anhydrous Na2SO4, and the
solvent was removed in vacuo. The residue was purified by
column chromatography on silica gel.
3-P h en yl-1-ben zofu r a n (6a ): white plates (hexanes); mp
40-43 °C (65%) (lit.5,10 mp 40-42 °C); 1H NMR δ 7.22-7.37 (m,
3H), 7.45 (t, J ) 7.5 Hz, 2H), 7.53 (d, J ) 7.8 Hz, 1H), 7.62 (d,
J ) 7.5 Hz, 2H), 7.76 (s, 1H), 7.82 (d, J ) 7.5 Hz, 1H); 13C NMR
δ 111.9, 120.6, 122.4, 123.1, 124.7, 126.6, 127.7, 129.1, 132.2,
141.4, 156.0.
P r ep a r a tion of 2-(1-Hyd r oxy-2,2-d im eth ylp r op yl)p h en ol
8. To a solution of the aldehyde 7 (2.83 g, 23 mmol) in THF (10
mL) was added t-BuLi (1.7 M, 30 mL, 51 mmol) at -78 °C, and
the reaction mixture was stirred for 4 h in the temperature range
from -78 to 0 °C. The reaction mixture was quenched by
addition of saturated aqueous NH4Cl at 0 °C and extracted with
diethyl ether, and the organic layer was dried over anhydrous
sodium sulfate. The solvent was removed in vacuo. The residue
was purified by column chromatography on silica gel (hexanes/
ethyl acetate 4:1) to afford compound 8 (97%) as white needles:
mp 54-55 °C (no lit. mp provided18); 1H NMR δ 0.94 (s, 9H),
(11) Furstner, A.; J umbam, D. N. Tetrahedron 1992, 48, 5991.
(12) Chatterjea, J . N.; Roy, S. K. J . Indian Chem. Soc. 1963, 40,
144.
(13) Grinev, A. N.; Zotova, S. A.; Stolyarchuk, A. A.; Gaevoi, V. P.;
Matsak, V. V. Khim.-Farm. Zh. 1979, 13, 51.
(14) Brady, W. T.; Giang, Y. F.; Marchand, A. P.; Wu, A. J . Org.
Chem. 1987, 52, 3457.
3-ter t-Bu tyl-1-ben zofu r a n (11a ): white plates (hexanes/
ethyl acetate 10:1); mp 65-66 °C [lit.16 mp 66-68 °C] (60%); 1H
NMR δ 1.43 (s, 9H), 7.19-7.30 (m, 2H), 7.34 (s, 1H), 7.47 (d, J
) 8.7 Hz, 1H), 7.74 (d, J ) 7.5 Hz, 1H); 13C NMR δ 29.9, 30.9,
111.6, 121.6, 121.8, 123.6, 126.9, 130.2, 139.3, 156.0.
(15) Royer, R.; Hudry, C. Bull. Soc. Chim. Fr. 1961, 942.
(16) Ellsworth, E. L.; Domagala, J .; Prasad, J . V. N. V.; Hagen, S.;
Ferguson, D.; Holler, T.; Hupe, D.; Graham, N.; Nouhan, C.; Tummino,
P. J .; Zeikus, G.; Lunney, E. A. Biorg. Med Chem. Lett. 1999, 9, 2019.
(17) Adam, W.; Sauter, M. Tetrahedron 1994, 50, 11441.
(18) Guijarro, A.; Ramon, D. J .; Yus, M. Tetrahedron 1993, 49, 469.
Su p p or tin g In for m a tion Ava ila ble: Experimental data
for 4b-h , 6b-h , 9b, 10b, and 11b. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O010278P