Facile assembly of fused benzo[4,5]furo heterocycles

Article abstract of DOI:10.1021/jo8000595

(Chemical Equation Presented) A concise synthesis of fused benzo[4,5]furo heterocycles 18 has been developed. Chemo/regioselective Suzuki coupling between 1,2-dihaloarene 17 and α-hydroxyphenylboronic acid or ester 20 gives biaryl phenol 19, which then undergoes copper(I) thiophene-2-carboxylate (CuTC)-mediated intramolecular cyclization to afford 18 in good overall yield. This method has broad substrate scope and allows facile assembly of a wide variety of benzo[4,5]furo heterocycles.

Full text of DOI:10.1021/jo8000595

SCHEME 1. Synthetic Approaches for Benzofuro
Heterocycles 5
Facile Assembly of Fused Benzo[4,5]furo
Heterocycles
Jing Liu,* Anne E. Fitzgerald, and Neelakandha S. Mani
Johnson & Johnson Pharmaceutical Research & DeVelopment,
L.L.C., 3210 Merryfield Row, San Diego, California 92121
jliu30@prdus.jnj.com
ReceiVed January 10, 2008
first, followed by the construction of the heterocyclic ring5
(Scheme 1). This approach usually requires lengthy multistep
synthesis. Alternatively, the retrosynthetic disconnection can be
made at the C3-C4 bond of the central furan ring. This bond
is often formed by the reductive dehalocoupling of diaryl ether
7a,6 dehydrohalogenation of 7b,7 or oxidative coupling of 7c.8
Finally, a more classical but less utilized route involves the
intramolecular cyclization of biaryl phenol 8.9 This approach
offers distinctly different synthetic opportunities but is often
avoided owing to the harsh conditions usually required for the
intramolecular cyclization and the lack of a general method for
the preparation of biaryl phenol 8.
In our lead optimization studies, benzofuropyrimidine 9 was
identified as a key intermediate. Initially, 9 was prepared from
2-cyanophenol 10 via a multistep sequence, in which the furan
and pyrimidine rings were constructed sequentially (Scheme 2a).
We envisioned that 9 might be synthesized via a more concise
route (Scheme 2b). A regioselective Suzuki coupling between
boronic acid 11 and 2,4,5,6-tetrachloropyrimidine (12) could
A concise synthesis of fused benzo[4,5]furo heterocycles 18
has been developed. Chemo/regioselective Suzuki coupling
between 1,2-dihaloarene 17 and R-hydroxyphenylboronic
acid or ester 20 gives biaryl phenol 19, which then undergoes
copper(I) thiophene-2-carboxylate (CuTC)-mediated intramo-
lecular cyclization to afford 18 in good overall yield. This
method has broad substrate scope and allows facile assembly
of a wide variety of benzo[4,5]furo heterocycles.
Fused benzofuro heterocycles are common structural motifs
in biologically active compounds and drug candidates (Figure
1). For example, Elbfluorene (1) and its derivatives are
interesting leads as cyclin-dependent kinase (CDK) inhibitors.1
Benzofurocoumarins such as 2 were found to inhibit the growth
of several human cancer cell lines.2 Benzofuropyrimidine 3 (MP-
470, SuperGen Inc.)3 is a novel multitarget tyrosine kinase
inhibitor currently in Phase I clinical trials, while compound 4
and its analogues were found to be histamine H4 modulators.4
(5) (a) Dixit, M.; Raghunandan, R.; Kumar, B.; Maulik, P. R.; Goel, A.
Tetrahedron 2007, 63, 1610-1616. (b) Liebeskind, L. S.; Wang, J. J. Org.
Chem. 1993, 58, 3550-3556. (c) Ando, Y.; Ando, K.; Yamaguchi, M.;
Kunitomo, J.; Koida, M.; Fukuyama, R.; Nakamuta, H.; Yamashita, M.;
Ohta, S.; Ohishi, Y. Bioorg. Med. Chem. Lett. 2006, 16, 5849-5854. (d)
Gerster, M.; Wicki, R. Synthesis 2004, 249-254. (e) Isomura, K.; Noguchi,
S.; Saruwatari, M.; Hatano, S.; Taniguchi, H. Tetrahedron Lett. 1980, 21,
3879-3882. (f) Degl’Innocenti, A.; Funicello, M.; Scafato, P.; Spagnolo,
P. Tetrahedron Lett. 1997, 38, 2171-2174. (g) Gonza´lez-Go´mez, J. C.;
Uriarte, E. Synlett 2002, 2095-2097. (h) Shafiee, A.; Behnam, E. J.
Heterocycl. Chem. 1978, 15, 1459-1462. (i) Yamaguchi, S.; Tsuzuki, K.;
Sannomiya, Y.; Oh-hira, Y.; Kawase, Y. J. Heterocycl. Chem. 1989, 26,
285-287. (j) Sargent, M. V.; Stransky, P. O. J. Chem. Soc., Perkin Trans.
1 1982, 1605-1610.
(6) Sanz, R.; Ferna´ndez, Y.; Castroviejo, M. P.; Pe´rez, A.; Fan˜ana´s, F.
J. J. Org. Chem. 2006, 71, 6291-6294.
(7) (a) Liu, Z.; Larock, R. C. Tetrahedron 2007, 63, 347-355. (b) Zhang,
Y.-M.; Razler, T.; Jackson, P. F. Tetrahedron Lett. 2002, 43, 8235-8239.
(c) Ames, D. E.; Opalko, A. Synthesis 1983, 234-235.
(8) (a) Åkermark, B.; Eberson, L.; Jonsson, E.; Pettersson, E. J. Org.
Chem. 1975, 40, 1365-1367. (b) De Lombaert, S.; Blanchard, L.; Stamford,
L. B.; Tan, J.; Wallace, E. M.; Satoh, Y.; Fitt, J.; Hoyer, D.; Simonsbergen,
D.; Moliterni, J.; Marcopoulos, N.; Savage, P.; Chou, M.; Trapani, A. J.;
Jeng, A. Y. J. Med. Chem. 2000, 43, 488-504. (c) Zeller, K.-P.; Petersen,
H. Synthesis 1975, 532-533. Also see ref 5j.
FIGURE 1. Biologically active benzo[4,5]furo heterocycles.
Numerous syntheses of benzo[4,5]furo heterocycle 5 have
been reported. Most often, a benzofuran derivative 6 is prepared
(9) For the synthesis of dibenzofurans via this approach, see: (a)
Kawaguchi, K.; Nakano, K.; Nozaki, K. J. Org. Chem. 2007, 72, 5119-
5128. (b) Mart´ınez, A.; Ferna´ndez, M.; Este´vez, J. C.; Este´vez, R. J.;
Castedo, L. Tetrahedron 2005, 61, 1353-1362. (c) Litinas, K. E.;
Nicolaides, D. N. J. Chem. Soc., Perkin Trans. 1 1985, 429-435. For
benzofuropyridines, see: (d) Yue, W. S.; Li, J. J. Org. Lett. 2002, 4, 2201-
2203. (e) Abramovitch, R. A.; Inbasekaran, M. N.; Kato, S.; Radzikowska,
T. A.; Tomasik, P. J. Org. Chem. 1983, 48, 690-695. (f) Parmentier, M.;
Gros, P.; Fort, Y. Tetrahedron 2005, 61, 3261-3269. For benzofuropyra-
zines, see: (g) Coates, W. J.; McKillop, A. J. Org. Chem. 1990, 55, 5418-
5420.
(1) Voigt, B.; Meijer, L.; Lozach, O.; Scha¨chtele, C.; Totzke, F.;
Hilgeroth, A. Bioorg. Med. Chem. Lett. 2005, 15, 823-825.
(2) Oliveira, A. M. A. G.; Raposo, M. M. M.; Oliveira-Campos, A. M.
F.; Machado, A. E. H.; Puapairoj, P.; Pedro, M.; Nascimento, M. S. J.;
Portela, C.; Afonso, C.; Pinto, M. Eur. J. Med. Chem. 2006, 41, 367-372.
(3) Hurley, L. H.; Mahadevan, D.; Han, H.; Bearss, D. J.; Vankayalapati,
H.; Bashyam, S.; Munoz, R. M.; Warner, S. L.; Della, C. K.; Von Hoff, D.
D.; Grand, C. L. PCT Int. Appl. WO 2005/037825, 2005.
(4) Harris, N.; Higgs, C.; Wren, S.; Dyke, H. J.; Price, S.; Cramp, S.
PCT Int. Appl. WO 2006/050965, 2006.
10.1021/jo8000595 CCC: $40.75 © 2008 American Chemical Society
Published on Web 03/11/2008
J. Org. Chem. 2008, 73, 2951-2954
2951

TABLE 2. Preparation of Dibenzofuran Derivatives 15
SCHEME 2. Syntheses of Benzofuropyrimidine 9
afford phenylpyrimidine 13. After demethylation, intramolecular
cyclization of biaryl phenol 14 should give benzofuropyrimidine
9.
First, regioselective Suzuki coupling between 11 and 12 was
studied. Similar reactions with 2,4-dihalo- and 2,4,5-trihalopy-
rimidines are known to occur preferentially at the C4-position,
but C2-coupling is also often observed.10 On the other hand,
Suzuki reaction with tetrachloropyrimidine 12 has never been
reported. Systematic screening of a Pd catalyst, ligand, base,
and solvent was conducted. Under the optimized conditions [Pd-
(OAc)2, PPh3, and K3PO4 in CH3CN/H2O], the reaction gave
phenylpyrimidine 13 in 87% yield and 7:1 regioselectivity
(Table 1). The use of more active ligands, such as dppf or
tricyclohexylphosphine, resulted in significantly lower regiose-
lectivity (2:1 or less). The product 13 was then demethylated
(BBr3, CH2Cl2) to give biaryl phenol 14.
a Isolated yield after Suzuki coupling and demethylation.
cally, far more reactive 2- and 6-chloro groups often interfere
with the reaction. Thus, cyclization under basic conditions failed
because 14 decomposes quickly even in the presence of weak
bases (Table 1, entries 1 and 2). This instability also precludes
the use of traditional Ullmann-type reactions in which a base
is required. On the other hand, no reaction was observed under
neutral or acidic conditions even at high temperature (entries
3-5). Several attempts to affect the cyclization with Pd or Ni
catalysts were also unsuccessful (entry 6). Interestingly, CuCl
promoted the cyclization quite well in polar solvents (entry 9).
Upon further screening, commercially available copper(I)
thiophene-2-carboxylate (CuTC)11 was found to be the most
active promoter for this transformation. The reaction can be
carried out under neutral conditions in DMA or NMP to provide
product 9 in good yield (entry 10).
TABLE 1. Optimization of Cyclization Conditions
entry
reagent
solvent
T/t
result
We then explored the scope of this concise route for the
synthesis of other tricyclic benzofuro compounds. Under the
same reaction conditions, dibenzofuran 15a (Table 2, entry 1)
can be prepared from the corresponding dihalobenzene and
2-methoxyphenylboronic acid. Furthermore, commercially avail-
able 2-hydroxyphenylboronic acids and esters are also excellent
substrates for the halogen-selective Suzuki coupling under the
same conditions (entries 2-4).12 The reactions occur exclusively
at the position with the most active halogen to give biaryl
phenols 16b-d directly, and O-deprotection is no longer
necessary. Using this method, various substituted dibenzofurans
15b-d were synthesized in two simple steps.
1
2
3
4
5
6
7
8
9
K2CO3
acetone rt, 90 min
CH2Cl2 rt, overnight
toluene 170 °C, 1 h
decomposition
decomposition
no reaction
iPr2NEt
none
HCl
BF3Et2O
THF
50 °C, 2 days
no reaction
CH2Cl2 100 °C, 20 min no reaction
Pd(OAc)2/PPh3 toluene 140 °C, 20 min no reaction
CuCl2
CuCl
CuCl
DMAc 100 °C, 40 min no reaction
dioxane 100 °C, 20 min no reaction
DMAc 100 °C, 2 h
NMP 80 °C, 2 h
9 (∼70% by HPLC)
10
9 (83%)
The scope of this method is not limited to the synthesis of
benzofuropyrimidines and dibenzofurans. With the appropriate
The intramolecular cyclization of 14 proved to be more
difficult than expected. Although the desired intramolecular
cyclization at the 5-chloro position should be favored entropi-
(11) CuTC promotes many coupling reactions very effectively and often
demonstrates unique reactivities. See: (a) Zhang, S.; Zhang, D.; Liebeskind,
L. S. J. Org. Chem. 1997, 62, 2312-2313. (b) Allred, G. D.; Liebeskind,
L. S. J. Am. Chem. Soc. 1996, 118, 2748-2749. (c) Innitzer, A. Synlett
2005, 2405-2406 and references therein.
(12) For isolated literature examples of halogen-selective Suzuki cou-
plings between 1,2-dihalobenzenes and R-hydroxyphenylboronic acid
derivatives, see: (a) Buchwald, S. L.; Huang, X.; Zim, D. PCT Int. Appl.
WO 2004/052939, 2004. (b) Buchwald, S. L.; Old, D. W.; Wolfe, J. P.;
Palucki, M.; Kamikawa, K. U.S. Patent 6,307,087, 2001.
(10) (a) Ceide, S. C.; Montalban, A. G. Tetrahedron Lett. 2006, 47,
4415-4418. (b) Blackaby, W. P.; Atack, J. R.; Bromidge, F.; Castro, J. L.;
Goodacre, S. C.; Hallett, D. J.; Lewis, R. T.; Marshall, G. R.; Pike, A.;
Smith, A. J.; Street, L. J.; Tattersall, D. F. D.; Wafford, K. A. Bioorg. Med.
Chem. Lett. 2006, 16, 1175-1179. (c) Peng, Z.-H.; Journet, M.; Humphrey,
G. Org. Lett. 2006, 8, 395-398. (d) Delia, T. J.; Schomaker, J. M.; Kalinda,
A. S. J. Heterocycl. Chem. 2006, 43, 127-130.
2952 J. Org. Chem., Vol. 73, No. 7, 2008

TABLE 3. Preparation of Benzofuro Heterocycles 18
then be deprotected to afford biaryl phenol 19 in good overall
yields. In the subsequent intramolecular cyclization, CuTC
promotes the transformation very effectively and allows most
cyclizations with heterocyclic substrates to be carried out at 70-
100 °C. The versatility of this concise route is illustrated by
the facile synthesis of all four benzo[4,5]furopyridine isomers
from the appropriate dihalopyridines in two or three steps and
high overall yield (entries 2-5). To the best of our knowledge,
this is the first reported synthesis of all four benzofuro[4,5]-
pyridines via one common route.9d
One important advantage of this new method is the neutral
and relatively mild conditions in the CuTC-mediated cyclization
step. While the same transformation can sometimes also be
accomplished under basic conditions, strong base and high
temperature are often required. For instance, CuTC-mediated
cyclizations of pyridyl phenols 19b and 19c were conducted at
100 °C in good yields (Table 3, entries 3 and 4), but the same
cyclizations under basic conditions require NaOtBu in refluxing
DMSO and the yields are moderate (57 and 34% for 19b and
19c, respectively).9d The current conditions also compare
favorably to classical Ullmann-type biaryl ether formations.14
Most importantly, base-sensitive substrates, such as phenylpy-
rimidine 14 (vide supra), are well tolerated under the neutral
reaction conditions in the current synthesis.
Finally, from a practical standpoint, it is worth noting that
all starting materials listed in Tables 1-3 are purchased from
commercial vendors and used directly. Since many R-hydrox-
yphenylboronic acid derivatives and 1,2-dihaloarenes are com-
mercially available, a wide variety of dibenzofurans, benzofu-
ropyridines, benzofuropyrazines, as well as benzofuropyrimidines
can be readily synthesized in two or three steps via this route.
The general substrate scope and simple reaction conditions for
both Suzuki coupling and intramolecular cyclization make this
new method suitable for library preparations.
In conclusion, we have developed a concise synthesis for the
facile assembly of fused benzo[4,5]furo heterocycles. The key
reactions are chemo/regioselective Suzuki coupling and CuTC-
mediated intramolecular cyclization under neutral and relatively
mild conditions. This route has broad substrate scope and should
be applicable for the preparation of many pharmacologically
interesting molecules.
a Isolated yield after Suzuki coupling and demethylation.
choice of 1,2-dihalo heterocycles 17 as starting materials, a wide
variety of other benzofuro heterocycles 18 can also be easily
prepared in two or three steps (Table 3). There are three possible
scenarios for the chemo- or regioselective Suzuki coupling
reaction: If the two halogen atoms of 1,2-dihalo heterocycle
17 are different (Table 3, entries 1, 2, 4, and 6), the coupling
occurs at the position with the most active halogen. If the
halogen atoms are the same but their positions on the heterocycle
are different, the reaction takes place selectively at the most
active position (entries 3 and 5). If compound 17 is symmetrical
and the two halogen atoms are completely identical, monocou-
pling is observed under the reaction conditions when stoichio-
metric or a slight excess of boronic acid is used (entry 7).13
For all the above scenarios, the Suzuki reaction conditions
again proved to be very general, giving the desired product in
good yield and excellent chemo- or regioselectivity. Unprotected
2-hydroxyphenylboronic acid derivatives are the preferred
starting material since it provides biaryl phenol 19 directly.
However, R-methoxyphenylboronic acids and other O-protected
R-hydroxyphenylboronic acids are more widely available and
often much less expensive. They are equally efficient in the
selective Suzuki coupling reaction. The coupling products can
Experimental Section
General Procedure for the Suzuki Coupling between 1,2-
Dihaloarene and 2-Hydroxyphenylboronic Acid/Ester. 1,2-
Dihaloarene (1.0 equiv), boronic acid or ester (1.1-1.5 equiv),
Pd(OAc)2 (0.05 equiv), PPh3 (0.1 equiv), and K3PO4 (2.5-3.5
equiv) were added to degassed acetonitrile/H2O (3:1 v/v) solvents.
The reaction mixture was stirred under a N2 atmosphere at room
temperature to 80 °C until the 1,2-dihaloarene substrate was
completely consumed as indicated by HPLC or TLC. Acetonitrile
was removed, and the crude product was extracted into dichlo-
romethane. Pure product was obtained after silica gel flash column
chromatography purification.
General Procedure for the CuTC-Mediated Cyclization.
Biaryl phenol (1.0 equiv) and CuTC (1.1-1.3 equiv) were added
to degassed DMA (N,N-dimethylacetamide) or NMP (N-methylpyr-
rolidone) solvent. The mixture was heated under a N2 atmosphere
at 70-140 °C until the reaction was complete as indicated by HPLC
or TLC. The reaction mixture was partitioned between 0.1 M HCl/
(13) The Suzuki coupling between 2,3-dichloroquinoxaline and R-meth-
oxyphenylboronic acid has been reported: Mao, L.; Sakurai, H.; Hirao, T.
Synthesis 2004, 2535-2539.
(14) Frlan, R.; Kikelj, D. Synthesis 2006, 2271-2285 and references
therein.
J. Org. Chem, Vol. 73, No. 7, 2008 2953

dichloromethane or 0.1 M NaOH/0.2 M EDTA (ethylenediamine
tetraacetic acid)/dichloromethane.15 Dichloromethane extract was
washed with water several times to remove residual DMA or NMP.
The crude residue was purified by silica gel flash column chro-
matography to afford the product.
Characterization Data for Representative Compounds. 2-Chlo-
ro-8-fluorodibenzofuran (15c): White crystalline solid; 1H NMR
(600 MHz, CDCl3, δ) 7.83 (d, J ) 2.1 Hz, 1H), 7.81 (dd, J ) 8.6,
5.4 Hz, 1H), 7.45 (d, J ) 8.7 Hz, 1H), 7.37 (dd, J ) 8.7, 2.2 Hz,
1H), 7.26 (dd, J ) 8.8, 2.2 Hz, 1H), 7.09 (td, J ) 9.0, 2.3 Hz, 1H);
13C NMR (150 MHz, CDCl3, δ) 162.7 (d, JC-F ) 246.5 Hz), 157.1
(d, JC-F ) 13.5 Hz), 155.1 (d, JC-F ) 2.2 Hz), 128.6, 126.7, 125.1,
121.4 (d, JC-F ) 10.4 Hz), 120.8, 119.6 (d, JC-F ) 2.1 Hz), 112.6,
111.2 (d, JC-F ) 24.0 Hz), 99.9 (d, JC-F ) 26.9 Hz); MS (EI+)
calcd for C12H6ClFO [M•+], 220.0; m/z found, 220.1. Anal. Calcd
for C12H6ClFO: C, 65.33; H, 2.74; N, 0.00. Found: C, 65.14; H,
2.65; N, <0.05.
8-Chloro-3-trifluoromethylbenzo[4,5]furo[3,2-b]pyridine (18d):
1
White crystalline solid; H NMR (500 MHz, CDCl3, δ) 8.95 (s,
1H), 8.27 (s, 1H), 8.10 (s, 1H), 7.65-7.61 (m, 2H); 13C NMR (126
MHz, CDCl3, δ) 156.9, 149.1, 146.5, 142.6 (q, JC-F ) 4.1 Hz),
130.8, 130.1, 124.8 (q, JC-F ) 27.6 Hz), 123.7, 123.6 (q, JC-F
)
272.8 Hz), 121.7, 116.3 (q, JC-F ) 3.8 Hz), 113.7; HRMS (ESI+)
calcd for C12H6ClF3NO [M + H+], 272.0085; m/z found, 272.0077.
Acknowledgment. The authors wish to thank Dr. X. Deng
for insightful discussions. Analytical supports provided by Dr.
J. Wu, H. McAllister, and B. Naderi are gratefully acknowl-
edged.
Supporting Information Available: Detailed representative
1
experimental procedures; characterization data and H/13C NMR
spectra for all new compounds reported in Tables 1-3. This
material is available free of charge via the Internet at http://pubs.acs.
org.
(15) It should be noted that if a routine aqueous extractive workup were
employed, a heavy emulsion would often form due to the formation of
insoluble Cu complex, which could result in product loss. The use of aqueous
HCl or EDTA/NaOH solution, for non-basic and basic substrates, respec-
tively, significantly alleviates and often eliminates this problem.
JO8000595
2954 J. Org. Chem., Vol. 73, No. 7, 2008