Sequential Pd(II)-Pd(0) catalysis for the rapid synthesis of coumarins

Article abstract of DOI:10.1021/jo050671l

Electrophilic palladium-catalyzed cycloisomerization of brominated aryl propiolates produces brominated coumarins. The brominated coumarins can be diversified by reduction of the Pd(II) catalyst to Pd(0) followed by Suzuki, Sonogashira, Heck, or Hartwig-B

Full text of DOI:10.1021/jo050671l

SCHEME 1
SCHEME 2
Sequential Pd(II)-Pd(0) Catalysis for the
Rapid Synthesis of Coumarins
Kelin Li, Yibin Zeng, Ben Neuenswander, and
Jon A. Tunge*
Department of Chemistry, 1251 Wescoe Hall Drive,
2010 Malott Hall, University of Kansas, Lawrence, Kansas
66045-7582, and the KU Chemical Methodologies and
Library Development Center of Excellence, University of
Kansas, 1501 Wakarusa Drive, Lawrence, Kansas 66047
tunge@ku.edu
tandem Pd(II)- and Pd(0)-catalyzed reactions that exploit
the compatibility of electrophilic palladium(II) catalysts
with aryl or vinyl halides.6 Such a method could be a
powerful tool for combinatorial synthesis because a single
precatalyst could be used to form two new C-C bonds
(Scheme 1). Herein the application of sequential Pd(II)-
Pd(0) catalysis toward the rapid synthesis of coumarins
is described.
Received April 5, 2005
Fujiwara reported that electrophilic palladium cata-
lysts effect the cycloisomerization of arylated alkynoates
(1) to provide coumarins (2), and in one example, an aryl
bromide was carried through the reaction (Scheme 2).7
It seemed logical that the Pd(II) catalyst used for the
Fujiwara cyclization could be reduced to Pd(0), which
would allow the subsequent diversification of the cou-
marin core by use of cross-coupling reactions.
Initial investigation focused on examining the electro-
philic cycloisomerization of brominated aryl alkynoates
using the conditions of Fujiwara. For example, treatment
of 1a (R1 ) CMe3, R2 ) p-BrC6H4) with 5 mol % Pd(OAc)2
in trifluoroacetic acid for 1 h at room temperature
provided the brominated coumarin 2a in 87% yield (Chart
1). The analogous m-bromo (2b) and o-bromo (2c) cou-
marins were isolated in slightly lower yields. Bromine
could also be incorporated on the coumarin arene (2f and
2g); however, additional donor groups are needed to
provide the requisite nucleophilicity for successful hydro-
arylation. The fact that bromoarenes are not reduced
under the conditions of Pd(II)-catalyzed hydroarylation
highlights the complementary functional group compat-
ibility of Pd(II) and Pd(0).8
Electrophilic palladium-catalyzed cycloisomerization of bro-
minated aryl propiolates produces brominated coumarins.
The brominated coumarins can be diversified by reduction
of the Pd(II) catalyst to Pd(0) followed by Suzuki, Sonoga-
shira, Heck, or Hartwig-Buchwald coupling. Thus, a single
loading of precatalyst can be used to conduct sequential
reactions, allowing the synthesis of functionalized cou-
marins. Extension of this methodology toward the synthesis
of coumarin libraries is discussed.
The ability to change a catalyst’s function through
modification of reaction conditions is a powerful strategy
for generating complex structures using a single catalyst
source.1 For instance, Grubbs’ ring-closing metathesis
catalyst can be transformed into a hydrogenation cata-
lyst, thus allowing the synthesis of saturated cyclic
molecules.2 Similarly, Evans has shown that Rh(I) cata-
lysts can be used for tandem allylic alkylation/Pauson-
Khand annulations.3 Such systems take advantage of the
diversity of reactions catalyzed by ruthenium and rho-
dium. Since palladium is arguably the most versatile
transition metal for catalysis, it is not surprising that
palladium features prominently in a number of tandem
transformations.4,5 These tandem palladium-catalyzed
reactions often involve at least one step that is a
palladium-catalyzed cross-coupling of aryl or vinyl ha-
lides; however, we are unaware of any reports involving
Next, the conditions necessary for Suzuki cross-
coupling of the brominated coumarins were investigated.
While a variety of conditions have been reported for cross-
couplings of coumarins,9 a slight modification of the
general cross-coupling procedure developed by Buchwald
(6) Pd(0)-catalyzed tandem coupling wherein vinyl C-Br bonds are
kinetically stable: Comer, E.; Organ, M. G.; Hynes, S. J. J. Am. Chem.
Soc. 2004, 126, 16087-16092.
(1) Ajamian, A.; Gleason, J. L. Angew. Chem., Int. Ed. 2004, 43,
3754-3760.
(2) Louie, J.; Bielawski, C. W.; Grubbs, R. H. J. Am. Chem. Soc.
2001, 123, 11312-11313.
(7) (a) Jia, C.; Piao, D.; Oyamada, J.; Lu, W.; Kitamura, T.; Fujiwara,
Y. Science 2000, 287, 1992-1995. (b) Jia, C.; Lu, W.; Oyamada, J.;
Kitamura, T.; Matsuda, K.; Irie, M.; Fujiwara, Y. J. Am. Chem. Soc.
2000, 122, 7252-7263. (c) Jia, C.; Piao, D.; Kitamura, T.; Fujiwara,
Y. J. Org. Chem. 2000, 65, 7516-7522.
(3) Evans, P. A.; Robinson, J. E. J. Am. Chem. Soc. 2001, 123, 4609-
4610.
(4) (a) Lira, R.; Wolfe, J. P. J. Am. Chem. Soc. 2004, 126, 13906-
13907. (b) Loones, K. T. J.; Maes, B. U. W.; Dommisse, R. A.; Lemiere,
G. L. F. Chem. Commun. 2004, 2466-2467. (c) Zhu, G.; Zhang, Z. Org.
Lett. 2004, 6, 4041-4044.
(8) Bromoarenes are reduced under the conditions of an analogous
Pd(0)-catalyzed hydroarylation: Trost, B. M.; Toste, F. D.; Greenman,
K. J. Am. Chem. Soc. 2003, 125, 4518-4526.
(5) (a) Tietze, L. F.; Sommer, K. M.; Zinngrebe, J.; Stecker, F. Angew.
Chem., Int. Ed. 2004, 44, 257-259. (b) Wasilke, J.-C.; Obrey, S. J.;
Baker, R. T.; Bazan, G. C. Chem. Rev. 2005, 105, 1001-1020. (c) Tietze,
L. F. Chem. Rev. 1996, 96, 115-136.
(9) (a) Scheidel, M.-S.; Briehn, C. A.; Bauerle, P. J. Organomet.
Chem. 2002, 653, 200-208. (b) Wu, J.; Liao, Y.; Yang, Z. J. Org. Chem.
2001, 66, 3642-3645. (c) Wu, J.; Yang, Z. J. Org. Chem. 2001, 66,
7875-7878.
10.1021/jo050671l CCC: $30.25 © 2005 American Chemical Society
Published on Web 07/13/2005
J. Org. Chem. 2005, 70, 6515-6518
6515

CHART 1
SCHEME 5a
a Conditions: (a)
5 mol % Pd(OAc)2, 1:3 TFA/CH2Cl2;
(b) PhCCH, piperidine, 10 mol % (o-biphenyl)P(tBu)2, 10 mol %
CuI, CH3CN, 50 °C; (c) p-MeOC6H4NHMe, NaOtBu, 10 mol %
(o-biphenyl)P(tBu)2, toluene, 50 °C
SCHEME 3
Suzuki coupling was investigated with a variety of aryl
boronic acids (Chart 2). The sequential coupling reaction
is rather general as is shown by the consistent yields with
electron-rich and electron-poor boronic acids. Isolated
yields for the product coumarins ranged from 62 to 80%.
A variety of coumarins with multiple electron-donating
substituents are obtained in somewhat higher yields
(77-88%). The donor groups are important for facile,
high-yielding Fujiwara hydroarylation. A limitation is
encountered upon varying the position of bromination of
the 4-phenyl ring. While p-bromo- and m-bromophenyl-
propiolate substrates that give rise to intermediates 2a
and 2b afford 70 and 80% yield of the phenylated
products 3a and 3o, respectively, the analogous
o-bromophenylpropiolate substrate gives <10% of the
expected coumarin. This low yield likely reflects a poor
Suzuki coupling since the intermediate ortho-brominated
coumarin 2c is formed in 68% yield.
SCHEME 4
While the initial focus was on sequential hydroaryl-
ation-Suzuki couplings, the general concept laid out
herein is likely to be applicable to many Pd(0)-catalyzed
cross-couplings. Thus, the analogous hydroarylation/
Sonogashira coupling occurs to give 3n in 79% yield
(Scheme 5). Additionally, sequential hydroarylation/Heck
gives rise to olefinated coumarin 3o in 59% yield and
hydroarylation/Hartwig-Buchwald amination provides
access to aminated coumarin 3m in 52% yield. While this
is a somewhat lower yield, it corresponds to a moderate
average yield (72%) for two steps.
Finally, the methods developed herein were tested by
synthesizing a small demonstration library of 16 biaryl
coumarins. Four brominated aryl propiolates (A1-A4) as
well as four aryl boronic acids (B1-B4, Chart 3) were
selected for the initial library. The sequential coupling
was run in parallel by the previously described procedure,
modified only by utilization of parallel centrifugal solvent
evaporation. The results are shown in Table 1. The
purities of the crude products were generally good;
however, the coupling of A2 with electron-deficient aryl
boronic acids B3 and B4 gave crude products in unac-
ceptably low purity. Importantly, purification by mass-
directed fractionation raised the purity levels of 13 of the
16 products to >95%. In the interest of optimizing the
purity of product coumarins, only center cuts of HPLC
proved to be particularly effective (Scheme 3).10 Since the
procedures being developed are for application in com-
binatorial synthesis of coumarins on a small scale, yields
were optimized rather than catalyst and ligand loadings.
Having established the viability of the individual
reactions, the next goal was to perform the cyclization
and Suzuki coupling sequentially using a single pal-
ladium precatalyst. The protocol developed involves
performing the hydroarylation with 5 mol % Pd(OAc)2
in CF3CO2H for 1-6 h at room temperature, followed by
removal of the TFA. The flask is then charged with THF,
10 mol % (o-biphenyl)PCy2, ArB(OH)2, and 3 equiv of KF.
It was gratifying to find that, under these conditions,
product 3x could be isolated in 88% yield from aryl ester
1f (Scheme 4). This yield compares favorably with the
79% overall yield for the two-step sequence. Then,
utilizing 1a as a standard substrate, the cyclization/
(10) (a) Yin, J.; Rainka, M. P.; Zhang, X.-X.; Buchwald, S. L. J. Am.
Chem. Soc. 2002, 124, 1162-1163. (b) Wolfe, J. P.; Singer, R. A.; Yang,
B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 9550-9561.
6516 J. Org. Chem., Vol. 70, No. 16, 2005

CHART 2
CHART 3
TABLE 1. Yields and Purities of Coumarins
Synthesized in Parallel
larger coumarin libraries as well as developing other
transformations on the basis of tandem Pd(II)-Pd(0)
catalysis.
crude
%
%
yield
purity
product
puritya
recoveryb
after MDFa,b
A1B1
A1B2
A1B3
A1B4
A2B1
A2B2
A2B3
A2B4
A3B1
A3B2
A3B3
A3B4
A4B1
A4B2
A4B3
A4B4
87
90
87
86
78
85
61
44
94
91
82
88
73
70
83
70
43
52
78
27
41
57
42
19
40
50
50
45
30
35
64
31
52
66
83
33
47
65
35
22
52
62
47
53
31
40
62
36
96
95
98
98
95
89
73
98
99
100
100
100
96
97
91
Experimental Section
General Procedure for the Sequential Hydroary-
lation/Suzuki Coupling. Aryl alkynoate 1 (0.14 mmol)
and Pd(OAc)2 (1.5 mg, 0.007 mmol) were dissolved in a
3:1 mixture of TFA/CH2Cl2 (0.5 mL). The resulting
solution was stirred at room temperature for 1-6 h. The
solvent was removed under vacuum, and arylboronic acid
(0.21 mmol), KF (0.42 mmol), and 2-(dicyclohexylphos-
phino)biphenyl (0.014 mmol) were added under an inert
atmosphere (N2 or Ar). THF (1 mL) was added, and the
reaction mixture was heated at 50 °C for 16 h. After
removal of the solvent, the crude mixture was purified
by column chromatography on silica gel using CH2Cl2 as
the eluent.
Preparation of 6-tert-Butyl-4-(4-(methyl(phenyl)-
amino)phenyl)-2H-chromen-2-one (3m). 4-tert-Butyl-
phenyl-3-(4-bromophenyl)propiolate (50 mg, 0.14 mmol)
and Pd(OAc)2 (1.5 mg, 0.007 mmol) were dissolved in a
3:1 mixture of TFA/CH2Cl2 (0.5 mL). The resulting
solution was stirred at room temperature for 1 h. The
solvent was removed under vacuum, and p-anisidine
(21 mg, 0.17 mmol), sodium tert-butoxide (19 mg,
0.20 mmol), and 2-(ditertbutylphosphino)biphenyl (10 mol
%) were added under an Ar atmosphere. Next, 1 mL of
97
a HPLC area % using UV detection from 245 to 355 nm.
b Purified by mass-directed fractionation.
peaks were collected. Thus, the overall yields are some-
what lower than those observed for compounds prepared
individually.
In conclusion, a simple procedure for the rapid syn-
thesis of coumarins was developed on the basis of
sequential Pd(II)- and Pd(0)-catalyzed reactions. These
methods are currently being applied to the synthesis of
J. Org. Chem, Vol. 70, No. 16, 2005 6517

toluene was added and the reaction mixture was heated
to 50 °C for 16 h. The product was purified by column
31.2). IR νmax (NaCl)/cm-1: 3055, 1720, 1614, 1570, 1510,
1371, 1186, 1018. HR-MS: C27H23O2 calcd, 379.1698 (M
+ 1); found, 379.1701.
1
chromatography on silica gel. H NMR (CDCl3): δ 7.68
(d, J ) 2.3 Hz, 1H, tBuPh); 7.58 (dd, J ) 2.3, 8.8 Hz, 1H,
tBuPh); 7.41 (t, J ) 7.6 Hz, 2H, PhNPhCdCH); 7.36 (d,
J ) 8.8 Hz, 2H, PhCdCH); 7.26 (dt, J ) 2.6, 7.3 Hz, 2H,
Preparation of (E)-Butyl-3-(4-(6-tert-butyl-2-oxo-
2H-chromen-4-yl)phenyl)acrylate (3o). 4-tert-Butyl-
phenyl-3-(4-bromophenyl)propiolate (50 mg, 0.14 mmol)
and Pd(OAc)2 (1.5 mg, 0.007 mmol) were dissolved in a
3:1 mixture of TFA/CH2Cl2 (0.5 mL). The resulting
solution was stirred at room temperature for 1 h. The
solvent was removed under vacuum, and Cs2CO3 (52 mg,
0.16 mmol) and tri(o-tolyl)phosphine (10 mol %) were
added under an argon atmosphere. Next, butyl acrylate
(29 µL, 0.20 mmol) and 1 mL of DMA were added, and
the reaction was heated at 120 °C for 16 h. The product
was purified by column chromatography on silica gel
t
PhNPhCdCH); 7.34 (d, J ) 8.8 Hz, 1H, BuPh); 7.19 (t,
J ) 7.3 Hz, 1H, PhNPhCdCH); 6.98 (d, J ) 8.8 Hz, 2H,
PhCdCH); 6.33 (s, 1H, CHCO); 3.42 (2, 3H, NCH3), 1.30
t
(s, 9H, Bu). 13C{1H} NMR: δ 161.5 (CO), Ph ring and
CdC (155.8, 152.3, 150.2, 147.8, 146.9, 129.7, 129.6,
129.2, 125.0, 124.9, 124.6, 123.3, 118.3, 116.8, 115.6,
113.5), 40.2 (NCH3), tBu (34.6, 31.3). IR νmax (NaCl)/cm-1
:
3058, 1717, 1705, 1610, 1591, 1614, 1495, 1369, 1354,
1193, 1130. HR-MS: C26H26NO2 calcd, 384.1964 (M + 1);
found, 384.1956.
1
(ether/hexane ) 1/2). H NMR (CDCl3): δ 7.75 (d, J )
Preparation of 6-tert-Butyl-4-(4-(2-phenylethynyl)-
phenyl)-2H-chromen-2-one (3n). 4-tert-Butylphenyl-
3-(4-bromophenyl)propiolate (50 mg, 0.14 mmol) and
Pd(OAc)2 (1.5 mg, 0.007 mmol) were dissolved in a 3:1
mixture of TFA/CH2Cl2 (0.5 mL). The resulting solution
was stirred at room temperature for 1 h. The solvent was
removed under vacuum, and CuI (0.9 mg, 0.005 mmol)
and 2-(ditertbutylphosphino)biphenyl (10 mol %) were
added under an Ar atmosphere. Next, phenylacetylene
(17 µL, 0.15 mmol), piperidine (27 µL, 0.23 mmol), and
1 mL of CH3CN were added, and the reaction mixture
was heated to 50 °C for 16 h. The product was purified
by column chromatography on silica gel using CH2Cl2 as
the eluent. 1H NMR (CDCl3): δ 7.71 (d, J ) 8.2 Hz, 2H,
16.1 Hz, 1H, CH)CHCO2,); 7.70 (d, J ) 8.0 Hz, 2H,
t
PhCHdCH); 7.61 (dd, J ) 2.3, 8.8 Hz, 1H, BuPh);
7.51(d, J ) 8.0 Hz, 2H, PhCHdCH); 7.45 (d, J ) 2.3 Hz,
1H, tBuPh); 7.36 (d, J ) 8.8 Hz, 1H, tBuPh); 6.56 (d, J )
16.1 Hz, 1H, CHdCHCO2); 6.37 (s, 1H, CHCOPh); 4.24
(t, J ) 6.6 Hz, 2H, OCH2); 1.67-1.75 (m, 2H, OCH2CH2);
1.41-1.50 (m, 2H, CH2CH3); 1.27 (s, 9H, tBu), 0.98
(t, J ) 7.6 Hz, 3H, CH2CH3). 13C{1H} NMR: δ 166.7,
160.9, 155.0, 152.2, 147.3, 143.2, 136.9, 135.8, 129.7,
129.0, 128.4, 122.9, 119.8, 117.8, 116.9, 115.1, 64.6, 34.5,
31.2, 30.7, 19.2, 13.7. IR νmax (NaCl)/cm-1: 3055, 1720,
1637, 1614, 1568, 1371, 1312, 1205, 1178, 1128. HR-MS:
m/z C26H29O4 calcd, 405.2066 [M + H]; found, 405.2070.
Acknowledgment. We acknowledge support of this
work by the National Institutes of Health (KU Chemical
Methodologies and Library Development Center of
Excellence, P50 GM069663).
t
PhCdCH); 7.62 (dd, J ) 2.3, 8.8 Hz, 1H, BuPh); 7.58
(dd, J ) 2.0, 7.6 Hz, 2H, PhCtC); 7.49 (d, J ) 2.3 Hz,
t
1H, BuPh); 7.48 (d, J ) 8.2 Hz, 2H, PhCdCH); 7.37-
t
7.40 (m, 3H, PhCtC); 7.36 (d, J ) 8.8 Hz, 1H, BuPh);
t
6.39 (s, 1H, CHCO); 1.28 (s, 9H, Bu). 13C{1H} NMR: δ
Supporting Information Available: Spectroscopic data
for new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
160.9 (CO), Ph ring and CdC (155.2, 152.2, 147.3, 135.0,
132.0, 131.7, 129.7, 128.7, 128.5, 128.4, 124.9, 122.9,
t
122.7, 117.9, 116.9, 115.0), CtC (91.3, 88.4), Bu (34.6,
JO050671L
6518 J. Org. Chem., Vol. 70, No. 16, 2005