Synthesis of benzo[b]furans via CuI-catalyzed ring closure

Article abstract of DOI:10.1021/jo050788+

A wide variety of benzo[6]furans were synthesized efficiently via a CuI-catalyzed ring closure of 2-haloaromatic ketones. The methodology was tolerant to various functional groups, affording benzofurans in 72-99% yields.

Full text of DOI:10.1021/jo050788+

SCHEME 1. Initial Research Goal
Synthesis of Benzo[b]furans via
CuI-Catalyzed Ring Closure
Cheng-yi Chen* and Peter G. Dormer
Department of Process Research, Merck & Co., Inc.,
P.O. Box 2000, Rahway, New Jersey 07065
cheng_chen@merck.com
Received April 18, 2005
on the C7a-O bond formation.4-6 Grimshaw and Thomp-
son reported three examples of 2-bromo deoxoybenzoins
undergoing ring closure to give benzofurans in 65-70%
yields using typical Ullmann coupling conditions.5,6 The
excessive use of activated bronze, harsh reaction condi-
tions (160 °C in DMAC), and narrow substrate scope
apparently limited the application of this method. Herein,
we wish to report that this very ring closure can be
effectively carried out with a catalytic amount of copper
iodide under much milder conditions (100-110 °C in
DMF). The catalytic process offers great advantages over
the conventional methods in that a wide array of benzo-
furans can be readily synthesized in excellent yields.
Our initial intention was to explore the synthesis of
indole 4 from 2-bromophenylacetone (Scheme 1).7 In
particular, we carried out the amination of 2-bromophe-
nylacetone with benzylamine under copper-catalyzed
conditions.8 We expected that amination followed by an
intramolecular ring closure would smoothly afford indole
4. Unexpectedly, the catalytic conditions afforded 2-me-
thylbenzo[b]furan exclusively in 72% yield. We subse-
quently found that the CuI-catalyzed ring closure of
2-bromophenyl acetone proceeded smoothly to the me-
thylbenzylfuran without use of ligand 5. This unexpected
result prompted us to investigate the potential for using
this protocol for the construction of benzo[b]furans.
We optimized the catalytic process using 2-bromophe-
nyl ketone 6 as a model compound and our results are
A wide variety of benzo[b]furans were synthesized efficiently
via a CuI-catalyzed ring closure of 2-haloaromatic ketones.
The methodology was tolerant to various functional groups,
affording benzofurans in 72-99% yields.
Benzo[b]furans are of great synthetic interest because
of their wide distribution in nature and useful biological
activities.1 The benzo[b]furan ring is often incorporated
in pharmaceutical agents as a core structural motif, and
as a result continues to attract extensive synthetic
efforts.2,3 Many reported synthetic approaches are based
on the construction of furan rings from various arene
derivatives via different bond formation.3h In contrast,
very few examples of benzo[b]furan synthesis are based
(1) (a) Donelly, D. M. X.; Meegan, M. J. Furans and Their Benzo
Derivatives: (iii) Synthesis and Applications. In Comprehensive Het-
erocyclic Chemistry; Katritzky, A. R., Ed.; Pergamon: New York, 1984;
Vol. 4, pp 657-712. (b) Cagniant, P.; Cagniant, D. Adv. Heterocycl.
Chem. 1975, 18, 337-482. (c) Bird, C. W.; Cheeseman, G. W. H.
Synthesis of Five-membered Rings with One Heteroatom. In Compre-
hensive Heterocyclic Chemistry; Katritzky, A. R., Ed.; Pergamon: New
York, 1984; Vol. 4, pp 89-153.
(2) For recent reviews on the synthesis of benzo[b]furans, see: (a)
Hou, X.-L.; Yang, Z.; Wong, H. N. C. Prog. Heterocycl. Chem. 2003,
15, 167-205. (b) Dell, C. P. Sci. Synth. 2001, 10, 11-86. McCallion,
G. D. Curr. Org. Chem. 1999, 3, 67-76.
(3) For recent, selected examples on the synthesis of benzo[b]furans,
see: (a) Kraus, G. A.; Kim, I. Org. Lett. 2003, 5, 1191-1192. (b) Kraus,
G. A.; Zhang, N.; Verkade, J. G.; Nagarajan, M.; Kisanga, P. B. Org.
Lett. 2000, 2, 2409-2410. (c) Hu, Y.; Yang, Z. Org. Lett. 2001, 3, 1387-
1390. (d) Kao, C.-L.; Chern, J.-W. J. Org. Chem. 2002, 67, 6772-6787.
(e) Wallez, V.; Durieux-Poissonnier, S.; Chavatte, P.; Boutin, J. A.;
Audinot, V.; Nicolas, J.-P.; Bennejean, C.; Delagrange, P.; Renard, P.;
Lesieur, D. J. Med. Chem. 2002, 45, 2788-2800. (f) Macleod, C.;
McKiernan, G. J.; Guthrie, E. J.; Farrugia, L. J.; Hamprecht, D. W.;
Macritchie, J.; Hartley, R. C. J. Org. Chem. 2003, 68, 387-401. (g)
Inoue, M.; Carson, M. W.; Frontier, A. J.; Danishefsky, S. J. J. Am.
Chem. Soc. 2001, 123, 1878-1889. (h) Katritzky, A. R.; Ji, Y.; Fang,
Y.; Prakash, I. J. Org. Chem. 2001, 66, 5613-5615. (i) Cruz, M. del
C.; and Tamariz, J. Tetrahedron Lett, 2004, 45, 2377-2380. (j) Thielges,
S.; Meddah, E.; Bisseret, P.; Eustache, J. Tetrahedron Lett. 2004, 45,
907-910. (k) Dupont R.; Cotelle, P. Tetrahedron 2001, 57, 5585-5589.
(l) Kao, C.-L.; Chern. J.-W. Tetrahedron Lett. 2001, 42, 1111-1113.
(m) Atsushi Sakai, A.; Aoyama, T.; Shioiri, T. Tetrahedron Lett. 1999,
40, 4211-4214. (n) Roshchin, A. I.; Kel’chevski, S. M.; Bumagin, N. A.
J. Organomet. Chem. 1998, 560, 163-167.
(4) Formation of dihydrobenzofuran by palladium-catalyzed ether
formation was reported: (a) Palucki, M.; Wolfe, J. P.; Buchwald, S. L.
J. Am. Chem. Soc. 1996, 118, 10333-10334. (b) Kataoka, N.; Shelby,
Q.; Stambuli, J. P.; Hartwig, J. F. J Org. Chem. 2002, 67, 5553-5566.
(c) Kuwabe, S.-I.; Torraca, K. E.; Buchwald, S. L. J. Am. Chem. Soc.
2001, 123, 12202-12206.
(5) Grimshaw, J.; Thompson, N. Chem. Commun. 1987, 240.
(6) Conversion of 1,2-dibromoarene and acetophenones to benzo[b]-
furan via in situ palladium-catalyzed arylation followed by ring closure
was reported: (a) Terao, Y.; Satoh, T.; Miura, M.; Nomura, M. Bull.
Chem. Soc. Jpn. 1999, 72, 2345-2350. (b) Veeramaneni, V. R.; Pal,
M.; Yeleswarapu, K. R. Tetrahedron 2003, 59, 3283-3290. (c) Recently,
a Pd-catalyzed intramolecular O-arylation of enolates was disclosed:
Willis, M. C.; Taylor, D.; Gillmore A. T. Org. Lett. 2004, 6, 4755-57.
(7) For leading references in the synthesis of indole, see: (a) Balme,
G.; Bouyssi, D.; Lomberget, T.; Monteiro, N. Synthesis 2003, 2115-
2134. (b) Li, J. J.; Gribble, G. W. Palladium in Heterocyclic Chemistry;
Pergamon: Oxford, UK, 2000. (c) Gribble, G. W. J. Chem. Soc., Perkin
Trans. 1 2000, 1045-1075. (d) Pindur, U.; Adam, R. J. Heterocycl.
Chem. 1988, 25, 1.
(8) Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2003, 5, 793-796.
10.1021/jo050788+ CCC: $30.25 © 2005 American Chemical Society
Published on Web 07/26/2005
6964
J. Org. Chem. 2005, 70, 6964-6967

TABLE 1. Optimization of the Ring-Closure Conditions
TABLE 3. Preparation of 2,3-Disubstituted
Benzo[b]furans
benzofuran
ketone
6, %
entry
base
7, %
1
2
3
4
5
Na2CO3
K2CO3
Cs2CO3
K3PO4
DABCO
17
81
89
93
10
60
19
3
4
88
TABLE 2. Preparation of 2-Ar Benzofuran
was extremely straightforward: crystallization from the
reaction mixture via addition of water afforded the
product in excellent yield and purity.
As summarized in Table 3, the CuI-catalyzed process
worked equally well for R-substituted ketones,which
afforded 2,3-disubstituted benzo[b]furans. Under the
same conditions, bromoketones as well as iodoketones
were readily cyclized to give benzofurans 13 and 14 in
good yields. Aromatic ketones (R2 ) Ar) cyclized to give
14a and 14b more readily than the alkyl ketone (R2 )
alkyl), which was not completely converted to benzo[b]-
furan 13 in 16 h. Presumably, the aromatic group
facilitates the enolization of the ketones. This is further
supported by the next example in which ketone 15
cyclized to benzo[b]furan 16 in 88% yield.11 In this
particular example, enolization was further enhanced by
the presence of the â-ester moiety. Similarly, cyano
ketone 17 gave 3-cyano-2-phenylbenzo[b]furan (18)
smoothly. Competitive cyclization of the dibromoketone
species 19 only afforded benzo[b]furan 20 without ben-
zopyran being detected. Finally, ring closure of aldehyde
21 afforded 3-benzylbenzo[b]furan 22 in 92% yield,12
which represented the first example using an aldehyde
for this type of process. It is thus anticipated that this
summarized in Table 1. All the reactions were carried
out by heating a mixture of substrate and base in DMF
for 6 h, and the yield of the product was assayed by HPLC
against a standard. Reactions proceeded smoothly when
K2CO3, Cs2CO3, and K3PO4 were used as bases, giving
product 7 in 81%, 81.5%, and 93.4% assayed yield,
respectively. Bases such as Na2CO3, DABCO were inef-
fective for the transformation. On the basis of these
results we chose the conditions in entry 4 (cat. CuI, K3-
PO4 in DMF) for the application of the method to the
cyclization of the 2-haloketone substrates.9
We found that the optimized conditions worked ex-
tremely well with several 2-halo deoxoybenzoins, afford-
ing benzo[b]furans in excellent yields (Table 2).10 For
example, benzo[b]furans 7, 8, 9, and 10 were all obtained
quantitatively. The catalytic system was effective for both
iodo and bromo ketones, but did not facilitate the ring
closure of 2-chloro derivatives. The reaction was also
applied to a heterocyclic substrate such as 11 to give
pyridyl furan 12 in 78% yield. Isolation of benzo[b]furans
(9) These substrates can be easily accessed via either the Friedel-
Crafts acylation of the 2-halo phenyl acetyl chloride or alkylation/
acylation of the 2-halo ketones/esters. See: (a) Friedel, C.; Crafts, J.
M. C. R. Hebd. Seances Acad. Sci. 1877, 84, 1392, 1450. (b) Desage-
El, M. M.; Nowczyk, S.; Le Gall, T.; Mioskowski, C.; Amekraz, B.;
Moulin, C. Angew. Chem., Int. Ed. 2003, 42, 1289-1293. (c) Shimizu,
S.; Suzuki, T.; Sasaki, Y.; Hirai, C. Synlett 2000, 11, 1664-1666. (d)
Supporting Information.
(10) For a recent example on a highly effective synthetic method
for substituted 2-arylbenzofurans using [3,3]-sigmatropic rearrange-
ment, see: Miyata, O.; Takeda, N.; Naito, T. Org. Lett. 2004, 6, 1761-
1763.
(11) Compound 16 was also prepared via the palladium-catalyzed
annulation between iodophenol and acetelyne in 69% yield with
formation of its regiosiomer in 32% yield, see: Larock, R. C.; Yum, E.
K.; Doty, M. J.; Sham, K. K. C. J. Org. Chem. 1995, 60, 3270-3271.
J. Org. Chem, Vol. 70, No. 17, 2005 6965

added directly to the reaction mixture over 0.5 h to precipitate
the product as pale organg solid 7 (0.43 g): mp 154-155 °C (lit.15
mp 153-155 °C).
SCHEME 2. Ring Closure of Bisbromoketone 23
2-Tolylbenzo[b]furan (8): yellow crystals; mp 128-129 °C
(lit.16 mp 128-129 °C).
2-(4′-Methylsulfanylphenyl)benzo[b]furan (9): pale yellow
solid; mp 159 °C dec; 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J )
7.9 Hz, 2H), 7.57 (d, J ) 6.8 Hz, 1H), 7.52 (d, J ) 7.8 Hz, 1H),
7.33 (d, J ) 7.9 Hz, 2H), 7.25 (m, 2H), 6.98 (s, 1H), 2.54 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 155.6, 154.8, 139.3, 129.3, 127.3,
126.5, 125.3, 124.2, 122.9, 120.8, 111.1, 100.9, 15.6. Anal. Calcd
for C15H12OS: C, 74.97; H, 5.03. Found: C, 74.60; H, 4.92.
2-(2′,4′,6′-Trimethylphenyl)benzo[b]furan (10): pale yel-
low oil; 1H NMR (400 MHz, CDCl3) δ 7.66 (m, 1H), 7.52 (m, 1H),
7.31 (td, J ) 7.6, 1.6 Hz, 1H), 7.27 (td, J ) 7.2, 1.6 Hz, 1H), 6.98
(s, 2H), 6.65 (s, 1H), 2.38 (s, 3H), 2.27 (s, 6H); 13C NMR (100
MHz, CDCl3) δ 155.1, 154.8, 139.0, 138.4, 128.9, 128.4, 127.7,
123.7, 122.6, 120.7, 111.2, 106.1, 21.2, 20.5; exact mass m/z calcd
for [M + H] 237.12739, found 237.12799.
2-(3′-Bromophenyl)furo[2,3-c]pyridine (12): pale yellow
solid; mp 101-103 °C; 1H NMR (400 MHz, CD2Cl2) δ 8.86 (s,
1H), 8.39 (d, J ) 5.2 Hz, 1H), 8.01 (t, J ) 1.7 Hz, 1H), 7.79 (dd,
J ) 8.0, 1.2 Hz, 1H), 7.52 (m, 2H), 7.33 (t, J ) 8.0 Hz, 1H), 7.02
(s, 1H); 13C NMR (100 MHz, CD2Cl2) δ 157.6, 152.7, 143.4, 135.6,
134.3, 133.1, 131.9, 131.1, 129.0, 124.7, 123.5, 116.2, 101.9. Anal.
Calcd for C13H8BrNO: C, 56.96; H, 2.94. Found: C, 56.49; H,
2.76.
procedure will prove useful for the synthesis of 3-substi-
tuted benzo[b]furans.
The reaction is believed to proceed via an intramolecu-
lar SRN1 mechanism where formation of five-membered
rings is preferred over the six-membered rings.6,13 This
proposed mechanism is supported by the observation that
the process relied on the enolization of the ketone, and
also by the exclusive formation of the five-membered ring
from ketone 19. To provide more evidence for the mech-
anism of this reaction, we prepared substrate 23 by the
treatment of ethyl 2-bromophenyl acetate with t-BuOK
under solvent-free conditions according to a reported
procedure.14 The crude mixture was used directly in the
benzo[b]furan formation. Though both bromo moieties are
available for cyclization to form a benzo[b]furan ring,
compound 24 was obtained as a sole product, again due
to the preferred enolization at C3 over C1 (Scheme 2). This
example highlights the versatility of our protocol for the
synthesis of a highly functionalized benzo[b]furan such
as 24 from a very simple substrate like 2-bromophenyl
acetate.
In summary, we have identified a highly efficient
protocol for the synthesis of benzo[b]furans via a CuI-
catalyzed ring closure of 2-halo aromatic ketones. This
process proved to be exceptionally effective with a wide
variety of aromatic ketones and can be extended to
aromatic aldehydes and heteroaromatic ketones. Many
structurally interesting benzo[b]furans were readily pre-
pared in a catalytic manner in good to excellent yields;
we believe that the broad scope of this reaction will lead
to easy access to other structurally diverse substrates.
2-(4′-Methoxyphenyl)-3-methylbenzo[b]furan (14a): col-
1
orless oil; H NMR (400 MHz, CDCl3) δ 7.76 (m, 2H), 7.53 (m,
1H), 7.48 (m, 1H), 7.29 (td, J ) 7.2, 2.0 Hz, 1H), 7.26 (td, J )
7.2, 1.6 Hz, 1H), 7.03 (m, 2H), 3.89 (s, 3H), 2.47 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 159.4, 153.7, 150.8, 131.35, 128.2, 124.2,
123.9, 122.3, 119.0, 114.1, 110.8, 109.7, 55.3, 9.4; exact mass
m/z calcd for [M + H] 239.10666, found 239.10754.
3-Benzyl-2-(4′-methoxyphenyl)benzo[b]furan (14b): white
solid; mp 98-99 °C; 1H NMR (400 MHz, CDCl3) δ 7.69 (m, 2H),
7.51 (d, J ) 8.1 Hz, 1H), 7.33 (d, J ) 7.6 Hz, 1H), 7.29-7.24 (m,
5H), 7.22 (m, 1H), 7.16 (t, J ) 7.6 Hz, 1H), 6.96 (m, 2H), 4.28 (s,
2H), 3.84 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 159.8, 154.0,
152.3, 139.5, 130.7, 128.6, 128.4, 128.2, 126.3, 124.0, 123.6,
122.5,119.7, 114.2, 112.3, 110.9, 55.3, 30.1. Anal. Calcd for
C22H18O2: C, 84.05; H, 5.77. Found: C, 83.69; H, 5.57.
2-Phenylbenzo[b]furan-3-carbonitrile (18):17 pale yellow
solid; mp 82-84 °C; 1H NMR (400 MHz, CDCl3) δ 8.22 (m, 2H),
7.74 (m, 1H), 7.61-7.53 (m, 4H), 7.44 (td, J ) 7.2, 1.6 Hz, 1H),
7.40 (td, J ) 7.2 Hz, 1H); 13C NMR (100 MHz, DMSO-d6
+
CDCl3) δ 160.8, 152.6, 130.7, 128.6, 127.0, 126.3, 126.0, 125.7,
124.2, 119.0, 113.4, 111.2, 87.2.
3-(2′-Bromobenzyl)-2-methylbenzo[b]furan (20): oil; 1H
NMR (400 MHz, CDCl3) δ 7.63 (m, 1H), 7.45 (d, J ) 8.2 Hz,
1H), 7.29 (d, J ) 7.6 Hz, 1H), 7.25 (dd, J ) 7.2, 1.6 Hz, 1H),
7.21 (dd, J ) 6.0, 1.6 Hz, 1H), 7.19-7.08 (m, 4H), 4.11 (s, 2H),
2.44 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 154.0, 152.1, 138.6,
132.7, 129.9, 129.5, 127.9, 127.4, 124.6, 123.2, 122.2, 119.1, 111.7,
110.6, 30.0, 12.2; exact mass m/z calcd for C16H13BrO, [M + Ag]
406.9201, found 406.9194.
1
3-(4′-Chlorobenzyl)benzo[b]furan (22): oil; H NMR (400
MHz, CDCl3) δ 7.49 (m, 1H), 7.39 (m, 2H), 7.32-7.17 (m, 7H),
4.00 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 155.6, 142.2, 127.7,
132.2, 130.0, 128.7, 127.8, 124.4, 122.5, 119.8, 111.5, 29.4; exact
mass m/z calcd for C15H11ClO, [M + Ag] 348.9549, found
348.9549.
Experimental Section
2-(4′-Methoxyphenyl)benzo[b]furan (7): A mixture of
bromoketone 6 (0.61 g, 2 mmol), K3PO4 (0.64 g, 3 mmol), and
CuI (39.0 mg, 0.2 mmol, 10 mol %) in DMF (5 mL) was degassed
via nitrogen/vaccum three cycles and subsequently heated to 105
°C. The mixture was held at the same temperature for 12 h,
and then cooled to ambient temperature. Water (20 mL) was
Ethyl 2-(2′-bromobenzyl)benzo[b]furan-3-carboxylic acid
1
ester (24): colorless oil; H NMR (400 MHz, CDCl3) δ 8.05 (m,
1H), 7.61 (dd, J ) 7.9, 1.2 Hz, 1H), 7.43 (m, 1H), 7.34 (td, J )
7.2, 1.6 Hz, 1H), 7.31 (td, J ) 7.2, 2.0 Hz, 1H), 7.23 (td, J ) 7.6,
1.2 Hz, 1H), 7.18 (dd, J ) 7.6, 2.0 Hz, 1H), 7.12 (td, J ) 7.6, 2.0
Hz, 1H), 4.73 (s, 2H), 4.44 (q, J ) 7.2 Hz, 2H), 1.44 (t, J ) 7.2
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 164.1, 162.9, 154.0, 136.5,
132.8, 130.4, 128.4, 127.5, 126.0, 124.7, 124.5, 123.9, 122.2, 111.2,
(12) Compound 21 was prepared from the DIBAL-H reduction of
the corresponding nitrile in toluene at ambient temperature in 90%
yield.
(13) For a review on SRN1 reaction, see: Rossi, R. A.; Pierini, A. B.;
Pen˜e´n˜ory, A. B. Chem. Rev. 2003, 103, 71-168.
(14) Yoshizawa, K.; Toyota, S.; Toda, F. Tetrahedron Lett. 2001, 42,
7983-7985.
(15) Hercouet, A.; Le Corre, M. Tetrahedron Lett. 1979, 2145.
(16) Colas, C.; Goeldner, M. Eur. J. Org. Chem. 1941, 6, 1357-1366.
(17) Takagi, K.; Ueda, T. Chem. Pharm. Bull. 1972, 20, 2053-2056.
6966 J. Org. Chem., Vol. 70, No. 17, 2005

110.3, 60.5, 34.5, 14.3; exact mass m/z calcd for [M + H]
Supporting Information Available: NMR spectra for all
new benzo[b]furans. This material is available free of charge
via the Internet at http://pubs.acs.org.
359.02773, found 359.02949.
Acknowledgment. We thank Mirlinda Biba and
Thomas J. Novak of Merck & Co., Inc. for HRMS
analysis.
JO050788+
J. Org. Chem, Vol. 70, No. 17, 2005 6967