Regioselective palladium-catalyzed arylation of 3-carboalkoxy furan and thiophene

Article abstract of DOI:10.1021/ol027266q

(Matrix presented) The regioselective palladium(0)-catalyzed arylation of 3-furoate and 3-thiophenecarboxylate esters with aryl bromides is described. Conditions were developed that allow for the selective synthesis of either 2-aryl or 5-aryl products.

Full text of DOI:10.1021/ol027266q

ORGANIC
LETTERS
2003
Vol. 5, No. 3
301-304
Regioselective Palladium-Catalyzed
Arylation of 3-Carboalkoxy Furan and
Thiophene
Bobby Glover, Kimberly A. Harvey, Bing Liu, Matthew J. Sharp,* and
Maria F. Tymoschenko
GlaxoSmithKline, Chemical DeVelopment, FiVe Moore DriVe, P. O. Box 13398,
Research Triangle Park, North Carolina 27709
matthew.j.sharp@gsk.com
Received November 11, 2002
ABSTRACT
The regioselective palladium(0)-catalyzed arylation of 3-furoate and 3-thiophenecarboxylate esters with aryl bromides is described. Conditions
were developed that allow for the selective synthesis of either 2-aryl or 5-aryl products.
In support of an ongoing medicinal chemistry program, an
efficient, scalable synthesis of 2-aryl-3-carboxy-furans and
thiophenes, 3, was required. Previously, these intermediates
were prepared by the copper(II)-catalyzed decomposition of
aryl diazonium salts 1 in the presence of 3-carboalkoxy
heterocycles 2. However, this coupling reaction was found
to be nonselective, affording a 1:1 mixture of 2-aryl- and
5-aryl-substituted products in moderate yield (Scheme 1).
such as 3 include cross-coupling methods, for example, the
Suzuki coupling of the 2-furan and 2-thiophene boronic acids
with aryl halides,1 the Stille coupling of the corresponding
2-stannylfurans,2 or the coupling of trifuranylzincates.3
These methods, however, suffer from being multistep
syntheses or requiring expensive starting materials. We were
interested in developing a regioselective, direct arylation of
the readily available 3-carboalkoxy furan and thiophene
utilizing readily available aryl halides. Palladium-catalyzed
arylations of furan and thiophene with aryl halides are well
precedented.4 We have also previously published work from
our laboratories on the regioselective, palladium-catalyzed
arylation of 2-furaldehyde in which the 5-aryl product is
obtained exclusively.5
Scheme 1
(1) Yang, Y.; Hornfeldt, A.; Gronowitz, S. J. Heterocycl. Chem. 1989,
26, 865.
(2) Gronowitz, S.; Timari, G. J. Heterocycl. Chem. 1990, 27, 1159.
(3) Gauthier, D. R., Jr.; Szumigala, R. H., Jr.; Dormer, P. G.; Armstrong,
J. D.; Volante, R. P.; Reider, P. J. Org. Lett. 2001, 4, 375.
(4) (a) Ohta, A.; Akita, Y.; Ohkuwa, T.; Chiba, M.; Fukunaga, R.;
Miyafuji, A.; Nakata, T.; Tani, N.; Aoyagi, Y. Heterocyles 1990, 31, 1951.
(b) Aoyagi, Y.; Inoue, A.; Koizumi, A.; Hashimoto, R.; Tokunaga, K.;
Gohma, K.; Komatsu, J.; Sekine, K.; Miyafuji, A.; Kunoh, J.; Honma, R.;
Akita, Y.; Ohta, A. Heterocycles 1992, 33, 257. (c) Okazawa, T.; Satoh,
T.; Miura, M.; Nomura, M. J. Am. Chem. Soc. 2002, 124, 5286.
A more efficient synthesis of the desired 2-aryl-3-carbo-
alkoxy furan and thiophene was desired that would allow
ready access to large quantities of these intermediates. Other
approaches that could be used to synthesize intermediates
10.1021/ol027266q CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/11/2003

Thus, we decided to study the direct palladium-catalyzed
arylation of 3-carboalkoxy furan and thiophene with aryl
bromides. For our test reaction, we selected the coupling of
ethyl 3-furoate (5) with 3-bromonitrobenzene (6a). In this
first reaction, we screened three parameters (solvent, base,
and catalyst) in a full factorial design6 (total of 36 experi-
ments, see Table 1) and measured the regioselectivity of the
arylation by HPLC analysis.
Table 1. Screening Factors
Figure 1. Conversion to arylation isomer (%). Results of the
experiments that gave the highest conversion to the 2-aryl product
for each factor are shown. The amounts of the 5-aryl isomer formed
in these reactions are also shown.
solvent
toluene
catalyst (0.05 equiv)
base (1.5 equiv)
Pd(PPh3)4
Pd/C
KOAc
triethylamine
DMA
DMF
NMP
Pd2(dba)3
found that the use of the polar solvent NMP and ligandless
palladium Pd/C (Method B) afforded a 3:1 mixture of the
5-aryl and 2-aryl isomers, respectively, in 69% yield.
isobutyronitrile
1,2-diethoxyethane
Following the successful demonstration of the regioselec-
tive palladium-catalyzed arylation of ethyl 3-furoate with
3-bromonitrobenzene, we then proceeded to test the general-
ity of the reaction with a number of aryl halides with both
furan and thiophene substrates. The results of arylation of
ethyl 3-furoate are shown in Table 2. Two major trends can
Statistical analysis of the results of the 36 experiments
indicated that solvent and catalyst were the most significant
factors in controlling the regioselectivity of the reaction. The
major factor controlling the regioselectivity of the arylation
was found to be solvent polarity, with a good correlation
observed between the dielectric constant of the solvent and
the ratio of products (2-arylation vs 5-arylation). Less polar
solvents favored the desired 2-aryl product 7a, with toluene
being the preferred solvent. The catalyst choice was also an
important factor, with the phosphine-containing Pd(PPh3)4
being preferred over the “ligandless” palladium catalysts. It
was also found that the use of potassium acetate as the base
in the reaction is key to achieving a successful arylation since
use of triethylamine resulted in very low conversion to the
undesired 5-aryl product 8a. The above trends are depicted
graphically in Figure 1.
The preferred conditions found in the above reaction screen
for the formation of the 2-aryl product (Method A) were the
use of Pd(PPh3)4 as the catalyst and KOAc as the base in
toluene at 110 °C. Indeed, it was found that with little
modification, this reaction could be scaled to give an efficient
process for the preparation of 7a. On a preparative scale (50
g of aryl bromide), these optimum conditions (1.4 equiv of
ethyl 3-furoate, 5 mol % Pd(PPh3)4, toluene reflux 24 h)
afforded the 2-aryl product 7a in 76% yield. Interestingly,
this series of experiments also provided conditions that
afforded the 5-aryl product 8a as the major isomer. It was
Table 2. Arylation of Ethyl 3-Furoate
entry
Ar (6a -g)
methoda
product (yield)
1
2
(6a ) 3-NO2C6H4
(6a ) 3-NO2C6H4
A
B
7a (73%)
8a (42%)b
7a (13%)
7b (60%)
7c (69%)
7d (59%)
7e (66%)
3
4
5
6
7
8
9
(6b) 3-CNC6H4
(6c) 3-MeO2CC6H4
(6d ) 4-NO2C6H4
(6e) 4-AcC6H4
(6f) 3-MeOC6H4
(6f) 3-MeOC6H4
(6g) C6H5
A
A
A
A
A
B
A
8f (15%)
a Method A: Pd(PPh3)4, KOAc, toluene, 110 °C. Method B: Pd/C,
KOAc, NMP, 110 °C. b Method B also afforded <5% of the 2,5-diarylated
product.
(5) McClure, M. S.; Glover, B.; McSorley, E.; Millar, A.; Osterhout,
M. H.; Roschangar, F. Org. Lett. 2001, 3, 1677.
(6) Federov, V. V. Theory of Optimal Experiments; Academic Press:
New York, 1972.
be observed. First, it is evident from Table 2 that efficient
arylation reactions require the use of aryl bromides substi-
tuted with electron-withdrawing groups. Attempted arylation
302
Org. Lett., Vol. 5, No. 3, 2003

of the furan with bromobenzene or 3-bromoanisole using
Method A (entries 9 and 7) resulted in a complex mixture
of products from which no product, or starting aryl bromide,
could be isolated.7 Arylation of the furan with 3-bromo-
anisole using Method B was slightly more successful, giving
the 5-arylated product 8f in 15% yield (entry 8). Interestingly,
Ohta4a reported the need for electron-withdrawing groups on
the aryl halide in the palladium-catalyzed arylation of the
parent furan.
Table 3. Thiophene Arylations
entry
Ar 6a , 6g
methoda
product (yield)
Second, it is clear that Method A [toluene, Pd(PPh3)4]
consistently afforded the 2-aryl adduct in high selectivity,
while Method B (NMP, Pd/C) yielded a less selective
reaction favoring the 5-aryl adduct.
1
2
3
(6a ) 3-NO2C6H4
(6a ) 3-NO2C6H4
(6a ) 3-NO2C6H4
A
B
C
14a (67%)
15a (51%)
14a (15%)
14g (52%)
4
(6g) C6H5
A
A possible explanation for the reversal of selectivity on
going from Method A to Method B is a change in the reaction
mechanism (Scheme 2).8 The nonpolar solvent and phosphine
ligands present in Method A are expected to stabilize the
σ-bonded Pd(II) species favoring the Heck-type R,â-insertion
reaction proximal to the electron-withdrawing group, there-
fore affording the Heck-type intermediate 9, which leads to
the 2-aryl product 7 after â-elimination. Conversely, the polar
solvent and the absence of stabilizing phosphine ligands are
likely to promote the ionization of the Pd-X σ-bond to form
an electrophilic Pd(II) species. This species would be
a Method A: Pd(PPh3)4, KOAc, toluene, 110 °C. Method B: Pd/C,
KOAc, NMP, 110 °C. Method C: Pd2(dba)3, KOAc, NMP, 110 °C.
and reductive elimination. Analogous cationic mechanisms
have been used to explain the regioselectivity of the
palladium-catalyzed arylation of azoles with aryl halides9 as
well as the intramolecular Heck coupling of a vinyl triflate
with a benzofuran.10 Further evidence of the electrophilic
character of this reaction is the known susceptibility of the
5-position of 3-methylfuroate to electrophilic substitution,
for example, bromination.11
To examine the generality of this reaction further, we
proceeded to study the palladium-catalyzed arylation of the
corresponding thiophene. The results of the arylation of
methyl-3-thiophenecarboxylate are shown in Table 3. The
same reactivity trends as the furan case were observed. The
nonpolar solvent and phosphine-bound palladium (Method
A) afforded the 2-aryl thiophene 14 in high selectivity
(entries 1 and 4). While the polar solvent and ligandless
palladium catalyst afforded predominantly the 5-aryl adduct
15, it should be noted that the use of Pd/C as the source of
“ligandless palladium” (Method B) was not successful in the
thiophene cases, presumably due to poisoning of the het-
erogeneous catalyst. However, this problem was overcome
by switching to the “phosphine-less” homogeneous catalyst
Pd2(dba)3 (Method C, see Table 3, entry 3). Another
difference observed with the thiophene substrate is the higher
reactivity of the thiophene over that of the furan to arylation
with aryl bromides lacking electron-withdrawing groups.
Where the attempted arylation of the furan with bromoben-
zene with Method A was unsuccessful and failed to give
any detectable desired product (Table 2, entry 9), the
analogous reaction with the thiophene afforded the 2-phenyl
adduct 14g in 52% yield (Table 3, entry 4).
Scheme 2
To demonstrate the synthetic utility of the furan arylation
described above, we applied the chemistry to the synthesis
of the furo[3,2-c]quinolinone 16 as shown in Scheme 3. The
furoquinolinone ring system is common in nature, particularly
in alkaloids derived from Rutaceae species.12 These alkaloids
expected to react preferentially at the more electron-rich
5-position of the furan giving the cationic intermediate 11,
thus favoring the 5-aryl product 8 after proton abstraction
(7) Use of the corresponding aryl iodides or aryl triflates did not lead to
any improvement in these reactions, suggesting that the oxidative addition
is not the rate-limiting step.
(8) For reviews of the mechanism of the Heck reaction, see: (a) Crisp,
G. T. Chem. Soc. ReV. 1998, 27, 427. (b) Amatore, C.; Jutand, A. Acc.
Chem. Res. 2000, 33, 314.
(9) Pivsa-Art, S.; Tetsuya, S.; Kawamura, Y.; Miura, M.; Nomura, M.
Bull. Chem. Soc. Jpn. 1998, 71, 467.
(10) Hughes, C. C.; Trauner, D. Angew. Chem., Int. Ed. 2002, 41, 1569.
(11) Sornay, R.; Meunier, J. M.; Fournari, P. Bull. Soc. Chim. Fr. 1971,
990.
Org. Lett., Vol. 5, No. 3, 2003
303

presence of Pd(PPh3)4 afforded 2-aryl furoate in 80% yield.
Hydrogenation of the nitro group with Pd/C as the catalyst
and subsequent cyclization occurred uneventfully to provide
furo[3,2-c]quinolinone 16 in 75% yield. Thus, two sequential
palladium-catalyzed reactions afforded the furoquinolinone
in 60% overall yield.
Scheme 3
In summary, we have developed a regioselective, pal-
ladium-catalyzed arylation of 3-carboxy furan and thiophene,
and conditions have been developed that allow the selective
formation of either the 2-aryl or 5-aryl isomers in good
yields. This method was utilized in an efficient two-step
synthesis of furo[3,2-c]quinolinone.
are also of considerable interest because of their reported
biological activities, including antimicrobial, antimalarial,
insecticidal, antineoplastic, antidiuretic, and antiarrhythmic.13
A number of synthetic approaches to the furoquinolinone
ring system have been reported;13 however, we envisaged
that the palladium-catalyzed arylation of ethyl 3-furoate
described above would lead to a very rapid and efficient
synthesis of this ring system. In practice, arylation of ethyl
3-furoate (5) with 1-bromo-2-nitrobenzene (6h) in the
Acknowledgment. We thank Tom O’Connell for as-
sistance with NMR spectroscopy.
Supporting Information Available: Experimental pro-
cedures and characterizations for compounds 7a-e, 8a, 8f,
14a, 14g, 15a, and 16. This material is available free of
charge via the Internet at http://pubs.acs.org.
(12) (a) Grundon, M. F. Nat. Prod. Rep. 1990, 7, 131. (b) Michael, J. P.
Nat. Prod. Rep. 1997, 14, 605.
(13) See: Lee, Y. R.; Kim, B. S.; Kweon, H. I. Tetrahedron 2000, 56,
3867 and references therein.
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