Phenyliodonium zwitterion as an efficient electrophile in the palladium-catalyzed suzuki-type reaction: A novel method for the synthesis of 3-aryl-4-hydroxycoumarins

Article abstract of DOI:10.1021/ol020159b

equation presented A palladium-catalyzed coupling reaction of phenyliodonium zwitterions with aryl boronic acids has been developed. The unique characteristics of the mild reaction conditions and convenient synthetic accessibility of phenyliodonium zwitterions make this method a valuable tool for generating diversified 3-aryl-4-hydroxycoumarins.

Full text of DOI:10.1021/ol020159b

ORGANIC
LETTERS
2002
Vol. 4, No. 19
3333-3336
Phenyliodonium Zwitterion as an
Efficient Electrophile in the
Palladium-Catalyzed Suzuki-Type
Reaction: A Novel Method for the
Synthesis of 3-Aryl-4-hydroxycoumarins
,†
,‡,§
Qiang Zhu,* Jie Wu,† Reza Fathi,‡ and Zhen Yang*
The Aaron Diamond AIDS Research Center (ADARC), The Rockefeller UniVersity,
455 First AVenue, New York, New York 10016, ViVoQuest, Inc., 711 ExecutiVe BlVd.,
Valley Cottage, New York 10989, and College of Chemistry and Molecular
Engineering, Peking UniVersity, Beijing 100871, P. R. China
z.yang@ViVoquest.com
Received August 8, 2002
ABSTRACT
A palladium-catalyzed coupling reaction of phenyliodonium zwitterions with aryl boronic acids has been developed. The unique characteristics
of the mild reaction conditions and convenient synthetic accessibility of phenyliodonium zwitterions make this method a valuable tool for
generating diversified 3-aryl-4-hydroxycoumarins.
In recent years, we have witnessed a rapid growth in the
field of organic hypervalent iodine chemistry, mainly due
Scheme 1
to its versatility in chemical transformations, lower-toxicity,
and ease of preparation.1 As an important branch of this
family, zwitterionic iodonium compound (ZIC, or ylide)
represents a molecule with a positive charge at iodine
compensated by an internal negative charge that is localized
formally at an R-carbon or nitrogen atom (1,2-dipole 2,
Scheme 1) or, in some instances, delocalized to a neighboring
oxygen or nitrogen (1,4-zwitterionic structure 3, Scheme 1).2
as a synthetic equivalent of the corresponding diazo com-
The widely used ZIC can be simply prepared from 1,3-
pound as a precursor of carbene generated by photochemical
dicarbonyl compound 1 with DIB in aqueous or alcoholic
or Rh, Cu salt-catalyzed decomposition.1
alkali in high yield (Scheme 1).3 ZIC has been recognized
The prototypical transformations are cyclopropanation,4a,b
carbon-hydrogen4c or heteroatom-hydrogen4d bond inser-
† The Rockefeller University.
‡ VivoQuest, Inc.
§ Peking University.
(3) For synthesis of â-dicarbonyl and â-disulfonyl iodonium ylides,
see: (a) Schank, K.; Lick, C. Synthesis 1983, 392. (b) Moriarty, R. M.;
Prakash, I.; Prakash, O.; Freeman, W. A. J. Am. Chem. Soc. 1984, 106,
6082. (c) Moriarty, R. M.; Bailey, B. R.; Prakash, O.; Prakash, I. J. Am.
Chem. Soc. 1985, 107, 1375.
(1) (a) Stang, P. J.; Zhdankin, V. V. Chem. ReV. 1996, 96, 1123-1178.
(b) Zhdankin, V. V.; Stang, P. J. Chem. ReV. 2002, 102, 2523-2584.
(2) Margolis, A. HyperValent Iodine In Organic Synthesis; Academic
Press: San Diego, 1997.
10.1021/ol020159b CCC: $22.00 © 2002 American Chemical Society
Published on Web 08/24/2002

tion, cycloaddition,4e-g and miscellaneous reactions.4h,i To
our surprise, transition-metal-catalyzed cross-coupling using
ZIC as an electrophile has not been reported, although 1,4-
zwitterionic structure 3 has a structural similarity to the
iodonium salt (iodonium cation is compensated by an
external anion), which has been widely used in cross-
coupling in recent years.5
As a privileged scaffold, coumarin is a ubiquitous subunit
in many natural products with remarkable biological activities
and unique physical properties.7 Methodology toward its
synthesis has attracted considerable interest during the past
decade.8 We report herein the utilization of coumarin-based
zwitterionic iodonium compounds as effective electrophiles
in the palladium-catalyzed Suzuki-type coupling with various
aryl boronic acids to generate 3-substituted coumarins.
Strategically, we would like to generate our coumarin
library by introducing diversities at C-3 and C-4 positions-
(Figure 1), which would be more efficient than the construc-
ing 4-hydroxycoumarin derivatives.9e,f However, methods for
the synthesis of 3-substituted coumarins from coumarin
scaffolds are limited to a few examples, such as ligand
coupling reaction10 and transition-metal-catalyzed cross-
coupling reaction of 3-bromocoumarins with some organo-
metallics.9a Neverheless, the above-mentioned methods are
either less efficient or associated with toxic reagents.11
Although compound 4 was prepared more than twenty
years ago, its synthetic application was limited to a few
examples of diversified coumarin scaffolds.10 Since the vinyl
or diaryl iodonium salts are remarkable substituents for vinyl
or aryl halides or triflates in the transition-metal-catalyzed
cross-coupling,5 we anticipated that the coumarin-based
phenyl iodonium zwitterion 4 (Scheme 2) may have a similar
Scheme 2
property. Considering its pronounced thermoinstability,12 we
preferred to select the palladium-catalyzed Suzuki-type
coupling reaction to test our hypothesis, since this reaction
can be carried out at room temperature.
Figure 1. Retrosynthetic analysis of coumarin library.
Initially, we evaluated the Suzuki reaction by coupling of
compound 4 with 4-methoxyphenylboronic acid using 10 mol
% of Pd(PPh3)4 as a catalyst (Scheme 2).5 Gratifyingly, this
reaction indeed proceeded to give compound 5, albeit in a
low yield (10%), concurrent with the starting material
recovered.
tion of the diversified lactone moiety by condensation of the
preassembled acyclic precursors.9
We have previously developed the chemistry for diversi-
fication of coumarin at the C-4 position from its correspond-
We then focused on improving the reaction yield. Pro-
longing the reaction time gave no improvement of the yield
at all. Increasing the loading level of Pd(PPh3)4 resulted in
an even poorer yield of desired compound 5. On the contrary,
increased concentration of Pd(PPh3)4 led to a significant
amount of a side product, which was finally identified as
the phosphonium ylide 6 (Scheme 2), derived from transyli-
dation of triphenylphosphine from catalysts Pd(PPh3)4 with
iodonium ylide 4.13
(4) (a) Gallos, J. K.; Koftis, T. V.; Koumbis, A. E. J. Chem. Soc., Perkin
Trans. 1 1994, 611. (b) Hatjiarapoglou, L.; Schank, K. Tetrahedron Lett.
1989, 30, 6673. (c) Hatjiarapoglou, L.; Varvoglis, A. J. Heterocycl. Chem.
1988, 25, 1599. (d) Kume, M.; Kubota, T.; Iso, Y. Tetrahedron Lett. 1995,
36, 8043. (e) Spyroudis, S.; Tarantili, P. J. Org. Chem. 1993, 58, 4885. (f)
Papoutsis, I.; Spyroudis, S.; Varvoglis, A. Tetrahedron Lett. 1994, 35, 8449.
(g) Spyroudis, S.; Tarantili, P. Tetrahedron 1994, 50, 11541. (h) Nikas, S.;
Rodios, A.; Terzis, A.; Varvoglis, A. Phosphorus, Sulfur Silicon Relat. Elem.
1994, 90, 285. (i) Ochial, M.; Kitagawa, Y. J. Org. Chem. 1999, 64, 3181.
(5) (a) Radhakrishnan, U.; Stang, P. J. Org. Lett. 2001, 6, 859. (b) Kang
S.-K.; Yoon, S.-K.; Kim, Y.-M. Org. Lett. 2001, 3 (17), 2697. (c) Kang,
S.-K.; Ryu, H.-C.; Lee, S.-W. J. Chem. Soc., Perkin Trans. 1 1999, 2661.
(d) Kang, S.-K.; Kang, S.-K.; Yamaguchi, T.; Kim, T.-H.; Ho, P.-S. J. Org.
Chem. 1996, 61, 9082. (e) Kang, S.-K.; Lee, H.-W.; Jang, S.-B.; Ho, P.-S.
J. Org. Chem. 1996, 61, 4720. (f) Kang, S.-K.; Lee, H.-W.; Jang, S.-B.;
Kim, T.-H.; Pyun, S.-J. J. Org. Chem. 1996, 61, 2604.
(6) (a) Schreiber, S. L. Science 2000, 287, 1964. (b) Nicolaou, K. C.;
Pfefferkorn, J. A.; Barluenga, S.; Mitchell, H. J.; Roecker, A. J.; Cao, G.-
Q. J. Am. Chem. Soc. 2000, 122, 9968.
(7) (a) O’Kennedy, R.; Thornes, R. D. Coumarins: Biology, Applications
and Mode of Action; Wiley & Sons: Chichester, UK, 1997. (b) Zahradnik,
M. The Production and Application of Fluorescent Brightening Agents;
Wiley & Sons: Chichester, UK, 1992. (c) Murray, R. D. H.; Mendez, J.;
Brown, S. A. The Natural Coumarins: Occurrence, Chemistry and
Biochemistry; Wiley & Sons: New York, 1982.
(9) (a) Schiedel, M.-S.; Briehn, C. A.; Bauerle, P. Angew. Chem., Int.
Ed. 2001, 40, 4677. (b) Mitra, A. K.; De, A.; Karchaudhuri, N.; Mitra, J.
J. Chem. Res., Synop. 1998, 766. (c) Boland, G. M.; Donnelly, D. M. X.;
Finet, J.-P.; Rea, M. D. J. Chem. Soc., Perkin Trans. 1 1996, 2591. (d)
Yao, M.-L.; Deng, M.-Z. Heteroat. Chem. 2000, 11, 380. (e) Wu, J.; Liao,
Y.; Yang, Z. J. Org. Chem. 2001, 66, 3642. (f) Wu, J.; Yang, Z. J. Org.
Chem. 2001, 66, 7875.
(10) Finet, J.-P. Ligand Coupling Reactions with Heteroatomic Com-
pounds; Elsevier Science. Ltd.: Oxford, 1998.
(11) (a) Barton, D. H. R.; Donnelly, D. M. X.; Finet, J.-P.; Stenson, P.
H. Tetrahedron Lett. 1988, 44, 6387; (b) J. Chem. Soc., Perkin Trans. 1
1995, 2531. (c) Kowalski, C. J.; Weber, A. E.; Fields, K. W. J. Org. Chem.
1982, 47, 5088. (d) Kamigata, N.; Satoh, T.; Yoshida, M. Bull. Chem. Soc.
Jpn. 1988, 61, 449. (e) Ley, S. V.; Whittle, A. J. Tetrahedron Lett. 1981,
22, 3301. (f) Righi, G.; Bovicelli, P.; Sperandio, A. Tetrahedron Lett. 1999,
40, 5889.
(12) (a) Thomas, K.; Gertraud, K.; Wolfgang, S. Chem. Ber. 1978, 111,
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(8) (a) Clerici, A.; Porta, O. Synthesis 1993, 99. (b) Trost, B. M.; Toste,
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(e) Ochiai, M.; Kitagawa, Y. J. Org. Chem. 1999, 64, 3181. (f) Bigi, F.;
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(13) Hadjiarapoglou, L.; Varvoglis, A. Synthesis 1988, 913.
3334
Org. Lett., Vol. 4, No. 19, 2002

Table 1. Palladium-Catalyzed Cross-Coupling of
Phenyl-iodonium Zwitterion 4 with Aryl Boronic Acidsa
Table 2. Palladium-Catalyzed Cross-Coupling of Zwitterions 8
with 4-Methoxyphenyl Boronic Acida
a Conditions: phenyliodonium zwitterion (0.55 mol), boronic acid (1.21
mmol), Pd(OAc)2 (6.2 mg, 0.06 mmol), P(t-Bu)3 (27 µL, 0.24 mmol), and
LiOH (69.0 mg, 2.9 mmol) in DME (10 mL) and H2O (2.5 mL) at 25 °C
for 20 h under Ar.
20% of H2O and LiOH as ideal solvents and base. An
excellent result was eventually obtained (See entry 1, Table
1).
The above results indicate that the present reaction is rather
general and high yielding for the aromatic-based boronic
acids (entries 1-10), while the benzyl-based borane (entry
11) provides a rather low yield (Table 1). It is noteworthy
that all the bicyclic-based boronic acids (entries 7-10)
generate their corresponding products 7g-j in high yields,
including the thianaphthene-2-boronic acid (entry 10), which
results in a satisfactory yield.
a Conditions: phenyliodonium zwitterion 4 (0.55 mol), boronic acid (1.21
mmol), Pd(OAc)2 (6.2 mg, 0.06 mmol), P(t-Bu)3 (27 µL, 0.24 mmol), and
LiOH (69.0 mg, 2.9 mmol) in DME (10 mL) and H2O (2.5 mL) at 25 °C
for 20 h under Ar.
To evaluate the substitution effect on the aromatic ring of
the coumarin-based phenyliodonium zwitterions, five dif-
ferent substituted coumarin phenyl-iodonium zwitterions
(8a-e) were synthesized accordingly15 and coupled with
4-methoxyphenyl boronic acid,16 under the identical condi-
tions described in Table 1. The results are shown in Table
This rather intriguing observation eventually led us to use
P(t-Bu)3 as a ligand by taking advantage of its bulkiness
14
to prevent the observed transylidation. Accordingly, we set
up the reaction by using Pd(OAc)2 and P(t-Bu)3 as a catalyst,
and the coupling yield was indeed improved dramatically.
We next optimized the reaction conditions by a survey of
solvents (CH2Cl2, DMF, THF, CH3CN, and DME) and bases
(Et3N, K3PO4, K2HPO4, Ba(OH)2, CsHCO3, CsOAc, LiOH,
KF, NaOAc, and NaHCO3), which established DME with
(15) Detailed procedure for the synthesis of compounds 4 and 8a-e:
Iodobenzene diacetate (10 mmol) was suspended in a solution of Na2CO3
(10 mmol) in water (100 mL) and stirred for 30 min at room temperature.
To this solution was added a mixture of 4-hydroxycoumarin (10 mmol)
and Na2CO3 (10 mmol) in water (100 mL). After the mixture was stirred
at room temperature for 2 h, the precipitate was collected by filtration,
washed with water (20 mL × 5), and dried under vacuum. The resulting
white solid was used without further purification. Detailed spectra data for
these compounds are provided in the Supporting Information.
(14) Littke, A. F.; Schwarz, L.; Fu, G. C. J. Am. Chem. Soc. 2002, 124,
6343.
Org. Lett., Vol. 4, No. 19, 2002
3335

2. These monosubstituted coumarin zwitterions 8a-d afford
their corresponding products 9a-d in acceptable yields,
except the dichlorocoumarin zwitterion 8e, which provides
9e in only 47% yield (entry 5, Table 2).
In summary, we have developed a successful palladium-
catalyzed Suzuki-type reaction using phenyliodonium zwit-
terions as effective electrophiles to generate 3-arylcoumarins
that would not be otherwise easily synthesized via alternative
methods. The mild reaction conditions and the commercial
availability of both 4-hydroxycoumarins and boronic acids
make this method a valuable tool for generating diversified
3-aryl-4-hydroxy-coumarins. Together with the well-estab-
lished methods for diversifying the C-4 position of coumarin,
the present method will benefit 3,4-disubstituted coumarin
library construction. Further studies to address this reaction
mechanism and to expand the scope of both iodonium
zwitterions and the type of transition-metal-mediated cross-
coupling reactions are underway in our laboratories.
Acknowledgment. We thank Professor David Ho for his
encouragements during the course of this research. Financial
support from VivoQuest, Inc., is gratefully acknowledged.
(16) General procedure for the cross-coupling: A degassed solution of
boronic acid (1.209 mmol, 2.2 equiv) and P(t-Bu)3 (27 µL) in DME and
water (4:1, 12.5 mL) was added to a mixture of iodonium ylide (200 mg,
0.55 mmol), LiOH‚H2O (69 mg, 3.0 equiv), and Pd(OAc)2 (6.2 mg, 5 mol
%) under argon at room temperature. After being stirred overnight (14 h),
silica gel (3-5 g) was added to the reaction mixture. The mixture was
dried completely under vacuum, and the residue was then purified by flash
silica gel chromatography.
Supporting Information Available: Experimental pro-
cedures and NMR and LC-MS spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL020159B
3336
Org. Lett., Vol. 4, No. 19, 2002