One-pot preparation of arylalkynes by a tandem catalytic iodination of arenes and palladium-catalyzed coupling of iodoarenes with terminal alkynes

Article abstract of DOI:10.1021/jo060424x

Iodination of activated arenes by air-oxidation is carried out in the presence of catalytic bismuth salts at room temperature. Subsequently, the formed iodoarenes react with terminal alkynes to give arylalkynes under a selected palladium-catalyzed coupling condition in the same pot.

Full text of DOI:10.1021/jo060424x

conditions by using very strong acids, a large amount of oxidant,
special reagents, and so on. On the other hand, the palladium-
catalyzed coupling of iodoarenes with terminal alkynes proceeds
mainly under base and inert conditions. Thus, it is very hard to
perform a coupling reaction and an iodination of arenes in one
pot.
One-Pot Preparation of Arylalkynes by a
Tandem Catalytic Iodination of Arenes and
Palladium-Catalyzed Coupling of Iodoarenes with
Terminal Alkynes
Shun Wan, Sunewang R. Wang, and Wenjun Lu*
However, most recently, a few examples of iodination of
arenes under mild conditions were reported. Neumann and
Branytska discovered an aerobic oxidative iodination of arenes
in the presence of polyoxometalate, H5PV2Mo10O40, as catalyst
with 2 atm of O2 at 80 °C,7 and Samant and co-workers
disclosed an iodination of activated arenes with molecular iodine
using silica-supported stoichiometric bismuth(III) nitrate pen-
tahydrate [BNP], Bi(NO3)3‚5H2O as oxidant at room temper-
ature.8
Department of Chemistry, Shanghai Jiao Tong UniVersity,
Shanghai, China, 200240
luwj@sjtu.edu.cn
ReceiVed February 28, 2006
In addition, we have developed an efficient iodination of
activated arenes by air-oxidation with catalytic BNP-BiCl3 at
room temperature (Scheme 1). In this reaction, no acids or
special reagents are required and oxygen from air is the oxidant,
so it provides very mild conditions for iodination of arenes and
makes the one-pot preparation of arylalkynes by tandem
iodination of arenes and palladium-catalyzed coupling of
iodoarenes with terminal alkynes possible.
In the initial investigation of this iodination of arenes, based
on the work of Samant and co-workers,8 we found that
p-iodoanisole (2a) was produced in 92% yield from anisole and
iodine in the presence of 5.0 mol % of BNP in MeCN at room
temperature within 26 h. Meanwhile, just using 1.0 atm of pure
O2 instead of air under the same conditions, a quantitative
amount of 2a was detected by GC. On the other hand, without
any catalysts or with only 5 mol % of NaNO3 in the iodination
of anisole, a trace or 6% yield of 2a were observed by GC after
24 h, respectively. These results show that Bi(III) salts as catalyst
and oxygen as oxidant are necessary in this catalytic iodination
reaction. After the test of many other oxidants in catalytic
amount, including BiCl3, Bi2O3, Cu(OAc)2, CuCl2, Cu(NO3)2,
Fe(NO3)3, K2S2O8, KMnO4 and various combinations of them,9
the best result for the iodination of anisole was the use of 2.5
mol % of BNP-BiCl3 as catalyst, giving 2a in 90% yield in 6
h. Interestingly, BiCl3 as cocatalyst can notably accelerate the
rate of this iodination of arenes, although it is not an effective
catalyst alone.
Iodination of activated arenes by air-oxidation is carried out
in the presence of catalytic bismuth salts at room temperature.
Subsequently, the formed iodoarenes react with terminal
alkynes to give arylalkynes under a selected palladium-
catalyzed coupling condition in the same pot.
Arylalkynes are very useful intermediates for the preparation
of important compounds including natural products, pharma-
ceuticals,1 oligomers, and polymers.2 Their conjugated systems
also have received more and more attention in optical3 and
electronic applications.4
Palladium-catalyzed coupling of haloarenes, especially io-
doarenes with terminal alkynes is a versatile and convenient
method to form arylalkynes in organic synthesis.5 However,
iodoarenes as substrates in these coupling reactions have to be
generated from simple arenes first,6 and iodination of arenes is
not a catalytic process, which is normally carried out under harsh
(1) (a) Chemistry and Biology of Naturally-Occurring Acetylenes and
Related Compounds; Lam, J., Breteler, H., Arnason, T., Hansen, L., Eds.;
Elsevier: Amsterdam, The Netherlands, 1988. (b) Nova’k, Z.; Kotschy, A.
Org. Lett. 2003, 5, 3495.
Moreover, the effects of solvents on this reaction were also
studied. It was found that the reaction proceeded very well in
CH2Cl2, CH2ClCH2Cl, and HOAc, respectively,9 but a longer
reaction time was needed. Without any added solvent, the
iodination of anisole (6.0 mmol) with I2 (3.0 mmol), catalyzed
by only 0.4 mol % of BNP-BiCl3, gave 2a in 87% isolated
yield in 12 h.
In the same catalytic system, iodination of other arenes were
screened. The results are summarized in Table 1. Similarly to
the case of 1a, activated arenes, 1b-1e were readily iodinated
to produce their corresponding products 2b-2e in good to
excellent yields (Table 1, entries 2-5). Arenes having large
(2) (a) Ziener, U.; Godt, A. J. Org. Chem. 1997, 62, 6137. (b) Francke,
V.; Mangel, T.; Muellen, K. Macromolecules 1998, 31, 2447.
(3) (a) Cheng, L. T.; Tam, W.; Marder, S. R.; Stiegman, A. E.; Rikken,
G.; Spangler, C. W. J. Phys. Chem. 1991, 95, 10643. (b) Moroni, M.; Le
Moigne, J.; Luzzati, S. Macromolecules 1994, 27, 562.
(4) (a) Bumm, L. A.; Arnold, J. J.; Cygan, M. T.; Dunbar, T. D.; Burgin,
T. P.; Jones, L., II.; Allara, D. L.; Tour, J. M.; Weiss, P. S. Science 1996,
271, 1705. (b) Tour, J. M.; Jones, L.; Pearson, D. L.; Lamba, J. J. S.; Burgin,
T. P.; Whitesides, G. M.; Allara, D. L.; Parikh, A. N.; Atre, S. J. Am. Chem.
Soc. 1995, 117, 9529. (c) Schumm, J. S.; Pearson, D. L.; Tour, J. M. Angew.
Chem., Int. Ed. Engl. 1994, 33, 1360.
(5) (a) Cassar, L. J. Organomet. Chem. 1975, 93, 253. (b) Diek, H. A.;
Heck, F. R. J. Organomet. Chem. 1975, 93, 295. (c) Sonogashira, K.; Tohda,
Y.; Hagihara, N. Tetrahedron Lett. 1975, 36, 4467. (d) Sonogashira, K. J.
Organomet. Chem. 2002, 653, 46.
(6) (a) Adimurthy, S.; Ramachandraiah, G.; Ghosh, P. K.; Bedekar, A.
V. Tetrahedron Lett. 2003, 44, 5099. (b) Tajik, H.; Mohammadpoor-Baltork,
I.; Rasht-Abadi, H.R. Synth. Commun. 2004, 34, 3579. (c) Mohan, K. V.
V. K.; Narender, N.; Kulkarni, S. J. Tetrahedron Lett. 2004, 45, 8015. (d)
Kraszkiewicz, L.; Sosnowski, M.; Skulski, L. Tetrahedron, 2004, 60, 9113.
(e) Yadav, J. S.; Reddy, B. V. S.; Reddy, P. S. R.; Basak, A. K.; Narsaiah,
A. V. AdV. Synth. Catal. 2004, 346, 77.
(7) Branytska, O. V.; Neumann, R. J. Org. Chem. 2003, 68, 9510.
(8) Alexander, V. M.; Khadilkar, B. M.; Samant, S. D. Synlett 2003, 12,
1895.
(9) For details, see Supporting Information, Table 1, “Effects of
Catalysts”, and Table 2, “Effects of Solvents”.
10.1021/jo060424x CCC: $33.50 © 2006 American Chemical Society
Published on Web 05/06/2006
J. Org. Chem. 2006, 71, 4349-4352
4349

TABLE 2. Coupling of Anisole (1a) with Phenyl Acetylene (3a)
under Various Palladium-Catalyzed Coupling Conditionsa
SCHEME 1. Iodination of Activated Arenes by
Air-Oxidation with Catalytic BNP-BiCl3 at Room
Temperature
TABLE 1. Oxidative Iodination of Various Activated Arenes
entry
catalyst
base
yieldb (%)
a
Catalyzed by BNP-BiCl3
1c
2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2
Pd(OAc)2
Pd(PPh3)4
Pd(PPh3)4
piperidine
Et3N
pyrrolidine
DABCO
K2CO3
72
26
52
20
25
38
3d
4
5d
6d
KOH
a Conditions: anisole (1.0 mmol), iodine (0.5 mmol), BNP (0.025 mmol,
2.5 mol %), BiCl3 (0.025 mmol, 2.5 mol %), and MeCN (1.0 mL); air; 6
h; rt. Then, adding base (5.0 mmol), Pd catalyst (0.025 mmol, 2.5 mol %),
and phenyl acetylene (1.0 mmol); 24 h; rt. b GC yield. c 3 h, 70 °C. d H2O
(2.0 mL) added after iodination of anisole, 50 °C.
source to the catalytic iodination reaction of anisole just gave
a trace amount of product detected by GC in 24 h, which means
the I- anion could block the catalytic cycle and the anion might
not be generated during the Bi(III)-catalyzed oxidative iodination
of arenes with iodine.
For the palladium-catalyzed coupling of iodoarenes with
terminal alkynes, however, the conventional operation is under
an Ar or N2 atmosphere to avoid Glaser-type oxidative dimer-
ization of terminal alkynes. Therefore, those coupling reactions,
which can proceed under aerobic conditions, should be con-
sidered to connect the oxidative iodination of arenes in one pot.
For instance, Liang and co-workers reported a copper-free
Sonogashira coupling of iodoarenes with terminal acetylenes
in water under aerobic conditions.11 Li and co-workers described
a coupling reaction employing a relatively low palladium
catalyst loading under mild, aerobic, copper-free, and ligand-
free conditions.12 Leadbeater and Tominack disclosed a method
for easy and rapid copper-free Sonogashira coupling in the
presence of bis(triphenylphosphine) palladium dichloride with
piperidine at 70 °C.13
The first set of experiments was directed toward the estab-
lishment of the optimal conditions for the combination of both
the iodination of arenes and the subsequent palladium-catalyzed
coupling of iodoarenes with terminal alkynes. A variety of
coupling conditions including those mentioned above were
investigated, and anisole (1a) was chosen as a model arene for
oxidative iodination and coupling with phenyl acetylene (3a).
As shown in Table 2, we were pleased to find that the
coupling reaction proceeded very well under the aerobic
conditions reported by Leadbeater and Tominack.13 Compound
4a was obtained in a yield of 72%, and the oxidative dimer-
ization of phenyl acetylenes was not found by GC detection
(Table 2, entry 1).
It was also found that the coupling reaction could run well
to give 4a in 52% yield by using palladium dichloride as catalyst
and pyrrolidine as base in water and MeCN at 50 °C under
aerobic conditions (Table 2, entry 3). In this case, the merit of
using catalytic bismuth salts to avoid byproduct formation was
remarkable. By GC detection, no homocoupling products from
phenyl acetylenes were found in palladium-catalyzed couplings
a Conditions: arenes (1.0 mmol), iodine (0.5 mmol), BNP (0.025 mmol,
2.5 mol %), BiCl3 (0.025 mmol, 2.5 mol %), and MeCN (1.0 mL); air; 6
h; rt. b Isolated yield (average of two runs). c 1H NMR yield. d GC yield.
e After 12 h.
steric hindrance could also be iodinated effectively by this
method (Table 1, entries 6-9). All products were monoiodoare-
nes with high regioselectivity. However, this iodination reaction
is not available to deactivated arenes and benzene.
A possible mechanism suggests that molecular iodine is
directly oxidized by Bi(III) to I+-type species that attack arenes
to give iodoarenes, which is an electrophilic aromatic substitu-
tion, and bismuth salts shuttle between Bi(I) and Bi(III) in the
presence of oxygen, as described by Dun˜ach and Antoniotti.10
Adding 10 mol % of KI and 90 mol % of I2 as a mixed iodine
(11) Liang, B.; Dai, M. J.; Chen, J. H.; Yang, Z. J. Org. Chem. 2005,
70, 391.
(12) Li, J. H.; Liang, Y.; Xie, Y. X. J. Org. Chem. 2005, 70, 4393.
(13) Leadbeater, N. E.; Tominack, B. J. Tetrahedron Lett. 2003, 44, 8653.
(10) Antoniotti, S.; Dun˜ach, E. Eur. J. Org. Chem. 2004, 69, 3459.
4350 J. Org. Chem., Vol. 71, No. 11, 2006

TABLE 3. One-Pot Preparation of Arylalkynes from Anisole and
Various Terminal Alkynes by Tandem Catalytic Iodination of
Anisole and Palladium-Catalyzed Couplinga
SCHEME 2. One-Pot Preparation of Arylalkynes from
Benzene and Terminal Alkynes
All of the results above indicate that if both of the reaction
conditions for the iodination of arenes and for palladium-
catalyzed coupling are compatible, the one-pot preparation of
arylalkynes from simple arenes and terminal alkynes is feasible.
In summary, an efficient method has been established for the
one-pot synthesis of arylalkynes starting from simple arenes and
terminal alkynes by a tandem catalytic iodination of arenes and
palladium-catalyzed coupling.
Experimental Section
Typical Preparation of Iodoarenes. Preparation of 2-Ethoxy-
1-iodonaphthalene (2d): 1d (170.9 mg, 1.0 mmol), I2 (142.1 mg,
0.56 mmol), BNP (12.8 mg, 0.026 mmol, 2.6 mol %), BiCl3 (7.9
mg, 0.025 mmol, 2.5 mol %), MeCN (1.0 mL), and a magnetic
stir bar were placed in a dried flask. The mixture was stirred at
room temperature for 6 h until complete consumption of the starting
material, as detected by TLC and GC analysis. Then the reaction
mixture was desorbed by dichloromethane (3 × 10 mL). The
organic extracts were successively washed with aq Na2S2O3
solution, dried over anhydrous MgSO4, and then evaporated under
reduced pressure. The crude product was purified by column
chromatography over silica to produce 289.9 mg (98%) of 2d as a
white crystal (mp 76 °C).
a Conditions: anisole (1.0 mmol), iodine (0.5 mmol), BNP (0.025 mmol,
2.5 mol %), BiCl3 (0.025 mmol, 2.5 mol %), and MeCN (1.0 mL); air; 6
h; rt. Then, adding piperidine (0.5 mL, 5.0 mmol), PdCl2(PPh3)2 (0.025
mmol, 2.5 mol %), and terminal alkyne (1.0 mmol); 3 h; 70 °C. b Isolated
yield.
1H NMR (400 MHz, CDCl3): δ 2.31 (t, J ) 6.8 Hz, 3H), 4.26
(q, 2H), 7.18 (d, J ) 8.4 Hz, 1H), 7.407 (td, J1 ) 8.6 Hz, J2 ) 0.9
Hz, 1H), 7.553 (td, J1 ) 8 Hz, J2 ) 0.9 Hz, 1H), 7.74 (d, J ) 8.4
Hz, 1H), 7.80 (d, J ) 8.8 Hz, 1H), 8.15 (d, J ) 8.8 Hz, 1H). 13C
NMR (100 MHz, CDCl3): δ 15.4, 66.3, 89.1, 114.7, 124.6, 128.2,
128.4, 130.2, 130.4, 131.6, 135.9, 156.4. Anal. Calcd for C12H11-
OI: C, 48.35; H, 3.72. Found: C, 48.71; H, 3.99.
connected with the catalytic oxidative iodination of arenes, but
a large amount of them was formed in the coupling reaction
after the stoichiometric oxidative iodination of arenes. No
positive results were obtained in other cases of coupling
reactions due to a large amount of the byproducts generated
(Table 2, entries 2 and 4-6). Obviously, not any of palladium-
catalyzed couplings of iodoarenes with terminal alkynes can
proceed very well after the catalytic iodination of arenes in the
same pot.
To examine the scope of this one-pot preparation of aryla-
lkynes, couplings of various terminal alkynes with anisole were
studied. The results from these reactions are listed in Table 3.
The yields of products from terminal aryl acetylenes (Table 3,
entries 1-3, 5, and 6) were better than those from terminal alkyl
acetylenes (Table 3, entries 4 and 7). Another arene, 1-methoxy-
2-methylbenzene (1e) was also tried to couple with phenyl
acetylene (3a), and it was found that its corresponding product,
1-methoxy-2-methyl-4-(phenylethynyl)benzene (4h), was iso-
lated in a good yield, 84%.
Typical Preparation of Arylalkynes from Activated Arenes
and Terminal Alkynes. Preparation of 4-((4-Methoxyphenyl)-
ethynyl)-N,N-dimethylbenzenamine (4f): 1a (110.7 mg, 1.02
mmol), I2 (123.7 mg, 0.49 mmol), BNP (12.7 mg, 0.026 mmol,
2.6 mol %), BiCl3 (8.8 mg, 0.027 mmol, 2.7 mol %), MeCN (1.0
mL), and a magnetic stir bar were placed in a dried flask. The
mixture was stirred at room temperature for 6 h until complete
consumption of the starting material, as detected by TLC and GC
analysis. Then piperidine (0.5 mL, 5.0 mmol), PdCl2(PPh3)2 (17.8
mg, 0.025 mmol, 2.5 mol %), and 3f (116.2 mg, 0.8 mmol) were
added into the reaction flask. The reaction flask was sealed and
heated in an oil bath preheated at 70°C until the completion of the
coupling reaction (3 h). After cooling to room temperature, water
and dichloromethane (3 × 10 mL) were added to the mixture, and
the organic material was extracted and then washed with acid (15%
v/v HCl) until the washings were neutral. The organic layer was
washed with water (40 mL) again before being dried over MgSO4.
Finally, the dichloromethane was removed under reduced pressure
to obtain the crude product, which was purified by column
chromatography to produce 152.7 mg (76%) of 4f as a white crystal
(mp 135-136 °C).
For benzene and deactivated arenes, the iodination method
described by Zheng and Mulhollandand was used in this one-
pot method.14 Benzene was chosen to be iodinated using I2-
AgOTf reagent first, then iodobenzene reacted with 3a and 3b
to give 1,2-diphenylethyne (4i) in 82% yield and 4a in 56%
yield, respectively, in one pot (Scheme 2).
1H NMR (400 MHz, CDCl3): δ 2.98 (s, 6H), 3.82 (s, 3H), 6.66
(d, J ) 8.4 Hz, 2H), 6.85 (d, J ) 8.8 Hz, 2H), 7.39 (d, J ) 8.0 Hz,
2H), 7.43 (d, J ) 8.4 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ
(14) Mulhollandand, G. K.; Zheng Q. H. Synth. Commun. 2001, 31, 3059.
J. Org. Chem, Vol. 71, No. 11, 2006 4351

40.5, 55.5, 87.32, 89.3, 110.6, 112.1, 114.1, 116.5, 132.8, 132.9,
150.1, 159.3. EI-MS m/z: 251 (M+, 100), 236 (58). HRMS calcd
for C17H17NO, 251.1310; found, 251.1311.
(40 mL) again before being dried over MgSO4. Finally, the
dichloromethane was removed under reduced pressure to obtain
the crude product, which was purified by column chromatography
to produce 146.1 mg (82%) of 4i as a white crystal (mp 63-64
°C).
1H NMR (400 MHz, CDCl3): δ 7.33-7.37 (m, 6H), 7.53-7.55
(m, 4H).
Typical Preparation of Arylalkynes from Benzene and
Terminal Alkynes. Preparation of 1,2-Diphenylethyne (4i):
Benzene (78.0 mg, 1.0 mmol), silver triflate (256.7 mg, 1.0 mmol),
iodine (253.8 mg, 1.0 mmol), CH2ClCH2Cl (1.0 mL), and a
magnetic stir bar were placed in a darkened flask. The mixture
was stirred at room temperature for 5 min until complete consump-
tion of the starting material, as detected by TLC and GC analysis.
Then piperidine (0.5 mL, 5.0 mmol), PdCl2(PPh3)2 (17.6 mg, 0.025
mmol, 2.5 mol %), and 3a (102.0 mg, 1.0 mmol) were added into
the reaction flask. The reaction flask was sealed and heated in an
oil bath preheated at 70 °C until completion of the coupling reaction
(3 h). After cooling to room temperature, water and dichloromethane
(3 × 10 mL) were added to the mixture, and the organic material
was extracted and then washed with acid (15% v/v HCl) until the
washings were neutral. The organic layer was washed with water
Acknowledgment. Financial support by the National Natural
Science Foundation of China (20572069 and 20372045) is
gratefully acknowledged.
Supporting Information Available: Experimental procedures
and characterization of compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
JO060424X
4352 J. Org. Chem., Vol. 71, No. 11, 2006