Pd-catalyzed copper-free carbonylative Sonogashira reaction of aryl iodides with alkynes for the synthesis of alkynyl ketones and flavones by using water as a solvent

Article abstract of DOI:10.1021/jo050498t

The Pd-catalyzed copper-free carbonylative Sonogashira coupling reaction to synthesize alkynyl ketones from terminal alkynes and aryl iodides was achieved by using water as a solvent. The reaction was carried out at room temperature under balloon pressure of CO with Et₃N as a base. The developed method was successfully applied to the synthesis of flavones.

Full text of DOI:10.1021/jo050498t

The metal-catalyzed coupling reaction of alkynes or
their metalated derivatives (such as alkynylstannanes5
or alkynylsilanes6) with organic halides in the presence
of CO provides an alternative approach to the synthesis
of alkynyl ketones under atmospheric conditions with
atom economy. In this regard, Mori’s recent contribution
to the direct coupling of terminal alkynes with aryl
iodides is a preferred method.7 This transformation was
accomplished by using aqueous ammonia as a base in
THF, and the reaction was carried out at room temper-
ature in the presence of PdCl2(PPh3)2 with or without
CuI.
We recently reported a mild protocol for the copper-
free Sonogashira coupling of aryl iodides with terminal
alkynes in water under aerobic conditions. The use of
PdCl2 (1 mol %) in the presence of pyrrolidine allows the
coupling reaction to proceed at room temperature or at
50 °C with good to excellent yields.8
Pd-Catalyzed Copper-Free Carbonylative
Sonogashira Reaction of Aryl Iodides with
Alkynes for the Synthesis of Alkynyl
Ketones and Flavones by Using Water as a
Solvent
Bo Liang,† Mengwei Huang,† Zejin You,†
Zhengchang Xiong,† Kui Lu,† Reza Fathi,*,‡
Jiahua Chen,*,† and Zhen Yang*,†,‡
Key Laboratory of Bioorganic Chemistry and Molecular
Engineering of Ministry of Education, College of Chemistry,
State Key Laboratory of Natural and Biomimetic Drugs,
School of Pharmaceutical Science, and Laboratory of
Chemical Genetics, ShenZhen Graduate School, Peking
University, Beijing, 100871, China, and VivoQuest, Inc., 711
Executive Boulevard, Valley Cottage, New York 10989
zyang@pku.edu.cn
Presently, the use of water as a reaction medium for
organic synthesis attracts further attention due to its
potential ecological impact.9 We report herein our con-
tinual efforts to utilize water as a reaction medium to
synthesize alkynyl ketones by the Pd-catalyzed carbo-
nylative reactions of terminal alkynes with phenyl io-
dides.
Received March 11, 2005
We initated our study for the Pd-catalyzed carbonyla-
tive coupling reaction in water with 4-iodoanisal and
1-hexyne as substrates and pyrrolidine as a base in the
presence of PPh3 under the conditions listed in Scheme
1. Interestingly, under such conditions, aryl amide A was
generated as the major product (ca. 40%), jointly with
the direct Sonogashira coupling product B (ca. 25%). On
The Pd-catalyzed copper-free carbonylative Sonogashira
coupling reaction to synthesize alkynyl ketones from termi-
nal alkynes and aryl iodides was achieved by using water
as a solvent. The reaction was carried out at room temper-
ature under balloon pressure of CO with Et3N as a base.
The developed method was successfully applied to the
synthesis of flavones.
(3) (a) Sheng, H.; Lin, S.; Huang, Y. Tetrahedron Lett. 1986, 27,
4893. (b) Trost, B. M.; Schmidt, T. J. Am. Chem. Soc. 1988, 110, 2301.
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Alkynyl ketones appear in many biologically active
molecules1 and play crucial roles as intermediates in the
synthesis of natural products2 and druglike molecules.3
Direct coupling of alkynyl organometallic reagents4 with
acid chlorides has played an important role in making
alkynyl ketones. However, these methods have to be
handled in dry solvents under an inert atmosphere.
(4) (a) Davis, R. B.; Scheiber, D. H. J. Am. Chem. Soc. 1956, 78,
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† Peking University.
‡ VivoQuest, Inc.
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Taguchi, T.; Yamada, A.; Kobayashi, N.; Hosoda, A.; Kobayashi, Y.
Tetrahedron Lett. 1987, 28, 259. (d) Chowdhury, C.; Kundu, N. G.
Tetrahedron 1999, 55, 7011. (e) Quesnelle, C. A.; Gill, P.; Dodier, M.;
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10.1021/jo050498t CCC: $30.25 © 2005 American Chemical Society
Published on Web 06/17/2005
J. Org. Chem. 2005, 70, 6097-6100
6097

TABLE 2. Pd-Catalyzed Carbonylative Reaction with
Different Ligands
SCHEME 1. Carbonylative Reaction with
Pyrrolidine as a Base
entry
ligand
yield (%)a
1
2
3
4
PPh3 (10%)
DPPF (5%)
BINAP (5%)
DPPP (5%)
95
91
0
88
TABLE 1. Pd-Catalyzed Carbonylative Reaction
a Isolated yield after silica gel chromatography.
TABLE 3. Carbonylative Coupling of Terminal Alkynes
and Substituted Aryl Iodide
entry
solvent
base (quiv)
yield (%)a
1
2
3
4
5
6
H2O
Et3N (3.0)
NH3 (0.5 M)
Et3N (3.0)
Et3N (3.0)
Et3N (3.0)
Et3N (3.0)
95
H2O
0
THF
12b
30b
31b
38b
CH2Cl2
toluene
CH3CN
a Isolated yield. b GC yields.
the other hand, the phosphine-free Pd-catalyzed
carbonylative coupling reaction was also tested; however,
the palladium precipitate was formed very rapidly under
the reductive reaction conditions (CO, H2O).
Subsequently, we carried out the PdCl2-catalyzed car-
bonylative coupling reaction using 2 eqiuv of ammonia
(0.5 M) as a base.7 However, the reaction did not occur,
and the starting materials were recovered completely.
Finally, we tried to use Et3N as a base to perform the
reaction in water in the presence of Ph3P. Fortunately,
the desired compound 1a was obtained in 95% yield.
However, when the reactions were carried out under
identical conditions with organic solvents (such as THF,
CH2Cl2, toluene, and CH3CN), the results were less
satisfactory (Table 1).
It should be pointed out that in the above carbonylative
coupling reaction (see entry 1 in Table 1), 3.0 equiv of
Et3N was used to achieve the high yield, which probably
indicates that Et3N acts not only as a base but also as a
cosolvent to help the organic substrates to distribute into
water.
a Isolated yield after silica gel chromatography. b Reaction time
) 24 h. c PdCl2 (6%) and Ph3P (12%) were used; the reaction was
carried out at 15 °C for 36 h.
To further evaluate the ligand effect on reaction
outcome, three additional ligands (dppf, dppp, and BI-
NAP) were screened in the reaction. Among these ligands,
PPh3 proved to be the ideal (Table 2).
As a result of these studies, we were encouraged to
examine the reaction with a broad range of substrates
to determine the specificity and scope of substrates. Thus,
various aryl iodides were reacted with a diverse array of
terminal alkynes, and the results are summarized in
Table 3.
From the results, it is evident that most of the
reactions provided good to excellent yields of coupling
products and that many functional groups are tolerated
in these reactions. Interestingly, the unprotected o-
amino-phenyl iodide (entry 7 in Table 3) can participate
in the reaction, and a good result can be obtained. On
the other hand, as discussed in Mori’s research,7
a
mixture of carbonylative and noncarbonylative coupling
products were obtained when electron-deficient aryl
iodide was used as the electrophile in the coupling
reaction, presumably because the alkyne reacts too
rapidly with the palladium complex derived from the
oxidative addition of aryl iodide to palladium without
insertion of CO. Thus, to get the desired carbonylative
product, we eventually carried out the reaction at 15 °C,
and product 1h was obtained in 46% yield (entry 8 in
6098 J. Org. Chem., Vol. 70, No. 15, 2005

TABLE 5. Syntheses of Flavones
FIGURE 1. Possible Explanation for Carbonylative Coupling
Reactions.
TABLE 4. Carbonylative Coupling of Acetylene and
Aryl Iodides
a Isolated yield after silica gel chromatography. b Performed
with 2 equiv of acetylene for 48 h. c Reaction time ) 48 h.
this method to be particularly attractive.12 We, therefore,
started to test the feasibility of synthesizing flavones by
the sequential carbonylative coupling of o-iodophenols
with terminal acetylenes to make R,â-unsaturated ke-
tones, followed by an intramolecular cyclization to afford
flavones in a one-pot operation.
a Isolated yield after silica gel chromatography. b Reaction time
To our satisfaction, all the selected substrates gave the
desired flavones in good to acceptable yields (Table 5).
) 24 h. c Reaction time ) 16 h.
Table 3), along with 32% yield of noncarbonylative
coupling product.
(10) (a) Harborne, J. B. The Flavonoids: Advances in Research since
1986; Chapman and Hall: London, 1994. (b) Harborne, J. B. The
Flavonoids: Advances in Research since 1980; Chapman and Hall:
London, 1988. (c) Harborne, J. B.; Mabry, T. J. The Flavonoids:
Advances in Research; Chapman and Hall: London, 1982. (d) Har-
borne, J. B.; Mabry, T. J.; Mabry, H. The Flavonoids; Chapman and
Hall: London, 1975. (e) Harborne, J. B.; Baxter, H. The Handbook of
Natural Flavonoids: John Wiley & Son: Chichester, UK, 1999; Vols.
1 and 2.
(11) (a) Allan, J.; Robinson, R. J. Chem Soc. 1926, 2335. (b)
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M.; Bodo B.; Deschamps-Vallet, C.; Molho, D. Tetrahedron Lett. 1978,
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1986, 51, 4432. (g) McGarry, L. W.; Detty, M. R. J. Org. Chem. 1990,
55, 4349. (h) Pinto, D. C. G. A.; Silva, A. M. S.; Cavaleiro, J. A. S. J.
Heterocycl. Chem. 1996, 33, 1887. (i) Riva, C.; Toma, C. D.; Donadel,
L.; Boi, C.; Pennini, R.; Motta, G.; Leonardi, A. Synthesis 1997, 195.
(j) Marder, M.; Viola, H.; Bacigaluppo, J. A.; Colombo, M. I.; Wasowski,
C.; Wolfman, C.; Medina, J. H.; Ru´veda, E. A.; Paladini, A. C. Biochem.
Biophys. Res. Commun. 1998, 249, 481. (k) Costantino, L.; Rastelli,
G.; Gamberini, M. C.; Vinson, J. A.; Bose, P.; Iannone, A.; Staffieri,
M.; Antolini, L.; Corso, A. D.; Mura, U.; Albasini, A. J. Med. Chem.
1999, 42, 1881. (l) Dekermendjian, K.; Kahnberg, P.; Witt, M.-R.;
Sterner, O.; Nielsen, M.; Liljefors, T. J. Med. Chem. 1999, 42, 4343.
(m) Lokshin, V.; Heynderickx, A.; Samat, A.; Pe`pe, G.; Guglielmetti,
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Pal, K.; Teleha, C. A. Org. Process Res. Dev. 1999, 3, 256.
It is noteworthy that the coupling reaction of aryl
iodides with the alkynes bearing alkyl substituents was
achieved by running the reaction without CuI as a
cocatalyst. We reasoned that in the absence of CuI, the
less reactive alkyne (compared with its corresponding
alkynyl copper ate complex) would easily react with the
electron-deficient acylpalladium (II) rather than its pre-
cursor palladium complex (I) derived from the oxidative
addition of aryl iodide to palladium (Figure 1); thus, the
desired carbonylative coupling reaction could be secured.
To further evaluate the reaction, the methyl- and
methoxyl-substituted aryl iodides were used to couple
with aryl- and alkyl-substituted terminal acetylenes. The
results listed in Table 4 show that good to excellent yields
were obtained under aqueous conditions.
Flavone represents a major class of naturally occurring
products,10 and a number of routes to its synthesis have
been published.11 Recent advances in the palladium-
catalyzed carbonylation of o-iodophenol derivatives with
terminal acetylenes to synthesize flavones have shown
J. Org. Chem, Vol. 70, No. 15, 2005 6099

PPh3 (52.4 mg, 0.2 mmol), 4-iodoanisole (468 mg, 2.0 mmol), and
H2O (2.5 mL), and then Et3N (0.84 mL, 6.0 mmol) was injected
into the tube. The mixture was first stirred for 5 min, and then
1-hexyne (0.28 mL, 2.4 mmol) was added to the tube. The
reaction mixture was stirred at room temperature for 12 h under
a balloon pressure of CO. The mixture was extracted with ethyl
acetate (5 × 5 mL), and the combined organic layers were dried
over Na2SO4. The solvent was removed under vacuum, and the
residue was purified by flash chromatography (hexane/ethyl
acetate ) 40/1) to give product 1a (410 mg) in 95% yield as a
colorless oil.
General Procedure for Synthesis of Flavone. To a 25 mL
Schlenk tube equipped with a magnetic stirring bar were added
PdCl2 (17.7 mg, 0.1 mmol), PPh3 (52.4 mg, 0.2 mmol), 2-iodo-
phenol (440 mg, 2.0 mmol), and H2O (2.5 mL), and then Et3N
(0.84 mL, 6.0 mmol) was injected into the tube. After the mixture
was stirred for 5 min, 1-hexyne (0.28 mL, 2.4 mmol) was added
to the tube, and the mixture was stirred under a balloon pressure
of CO for 12 h. The reaction mixture was extracted with ethyl
acetate (4 × 5 mL), and the combined organic phases were dried
over Na2SO4. The solvent was removed under vacuum, and the
residue was purified by flash chromatography (hexane/ethyl
acetate ) 8/1) to give the product 3a (368 mg) in 91%.
Importantly, the reaction with alkyl-substituted terminal
acetylenes can also give the expected flavones, a result
that was not achieved in our previous approach by using
iodophenyl acetates as substrates for flavone synthesis.12g
It is interesting to notice that unlike our previous
investigation for the synthesis of flavones from iodo-
phenols,12g the side reaction for the competitive formation
of five-membered aurones did not occur using the present
procedure.
In summary, the copper-free Pd-catalyzed carbonyla-
tive coupling reaction to synthesize various alkynyl
ketones from phenyl iodides and terminal acetylenes was
achieved by using water as a solvent. This reaction was
carried out at room temperature under balloon pressure
of CO with Et3N as a base. Application of this synthetic
method to generate flavones from iodophenols and ter-
minal alkynes was also achieved. This protocol will serve
as an efficient way to synthesize alkynyl ketones and
2-substituted flavones.
Experimental Section
General Procedure for the Carbonylative Sonogashira
Coupling in Water. To a 25 mL of Schlenk tube equipped with
a magnetic stirring bar were added PdCl2 (17.7 mg, 0.1 mmol),
Acknowledgment. We gratefully acknowledge
financial support by the National Science Foundation
of China (Grants 20272003 and 20325208), Ministry of
Education of China (985 program, and Grant 2001-
0001027), and VivoQuest, Inc., through a sponsored
research program.
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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.
JO050498T
6100 J. Org. Chem., Vol. 70, No. 15, 2005