Microwave-accelerated, palladium-catalyzed carbonylative cyclization reactions of 2-iodophenol with alkynes - Rapid and efficient synthesis of chromen-2-one derivatives

Article abstract of DOI:10.1139/v05-094

Rapid palladium-catalyzed carbonylative cyclization reactions of 2-iodophenol with various alkynes have been carried out by the use of commercially available molybdenum hexacarbonyl as a convenient and solid carbon monoxide source. The reactions were cond

Full text of DOI:10.1139/v05-094

826
Microwave-accelerated, palladium-catalyzed
carbonylative cyclization reactions of 2-
iodophenol with alkynes — Rapid and efficient
synthesis of chromen-2-one derivatives1
Hong Cao and Wen-Jing Xiao
Abstract: Rapid palladium-catalyzed carbonylative cyclization reactions of 2-iodophenol with various alkynes have
been carried out by the use of commercially available molybdenum hexacarbonyl as a convenient and solid carbon
monoxide source. The reactions were conducted at 160 °C for 30 min with microwave heating in the presence of
DIEA and DMAP in 1,4-dioxane, and afford the corresponding chromen-2-one derivatives in good yields.
Key words: microwave, palladium, carbonylation, 2-iodophenol, chromen-2-one.
Résumé : Faisant appel à l’hexacarbonyle de molybdène disponible commercialement comme source solide et pratique
de monoxyde de carbone, il est possible d’effectuer des réactions du 2-iodophénol avec de divers alcynes qui condui-
sent rapidement à des cyclisations accompagnées d’une carbonylation. Les réactions ont été en 30 min par chauffage
microonde à 160 °C, en présence de DIEA et de DMAP dans le 1,4-dioxane, et elles ont conduit aux chrom-2-énones
correspondantes avec de bons rendements.
Mots clés : microonde, palladium, carbonylation, 2-iodophénol, chrom-2-énone.
[Traduit par la Rédaction] Cao and Xiao 831
Introduction
The second and third limitations are of particular concern
since special gas delivery systems are needed. Therefore, the
search for the improvement of carbonylation technology
continues, with the goal of the development of fast, reliable,
and convenient protocols. During the past 10 years, the tech-
niques of high-throughput chemistry have been well-
established and have been widely used in organic synthesis
and pharmaceutical industry (6). In particular, microwave ir-
radiation has emerged as a potential energy source for accel-
erated transition metal catalyzed reactions, and has proven
very useful in many different applications (7). These modern
methodologies offer an opportunity for the improvement of
carbonylation. Consequently, Alterman and Hallberg and co-
workers developed a microwave-assisted, palladium-catalyzed
aminocarbonylation of aryl halides using dimethylforma-
mide (DMF) (8) or formamide (9) as a liquid carbon monox-
ide source. Based on the concept that microwave-promoted
thermal decomposition of metal carbonyl complexes, Larhed
and co-workers reported a palldium-catalyzed carbonylation
using molybdenum hexacarbonyl (Mo(CO)6) as a solid car-
bon monoxide source (10, 11). This method, to some extent,
overcomes the trouble caused by using gaseous carbon mon-
oxide from a cylinder, and it could be suitable for high-
throughput synthesis of amides and esters. Thus, Alterman
and co-workers (12) subsequently explored the microwave-
mediated intramolecular carbonylative cyclization reactions
of bromobenzyl alcohols utilizing DMF and Mo(CO)6 as
two alternative CO sources.
Palladium-catalyzed carbonylative cyclizations are widely
recognized as a unique, powerful, and versatile synthetic
approach toward various structural cores of complex
organocarbo- and heterocycles (1). Mainly because of the
contributions from Alper (2), Larock (3), and Negishi (4) as
well as their co-workers, the intra- and intermolecular carbo-
and heteroannulations of unsaturated substrates such as al-
kynes, 1,2- and 1,3-dienes, vinyl cyclopropanes, homoallylic
alcohols, and imines with functionally substituted aromatic
or vinyl halides have been well documented in the literature
(5). Although a large number of catalytic systems have been
developed for the carbonylative cyclizations of a wide range
of compounds, there are some limitations associated with
this methodology: (1) slow reaction rate that results in long
reaction time; (2) high pressure in the reaction system; and
(3) less efficient utilization of toxic carbon monoxide gas.
Received 13 January 2005. Published on the NRC Research
Press Web site at http://canjchem.nrc.ca on 6 July 2005.
This paper is dedicated to Professor Howard Alper for his
great contributions to chemistry.
H. Cao and W.-J. Xiao.2 The Key Laboratory of Pesticide
and Chemical Biology, Ministry of Education, College of
Chemistry, Central China Normal University, 152 Luoyu
Road, Wuhan, Hubei 430079, China.
1This article is part of a Special Issue dedicated to Professor
Howard Alper.
Accordingly, we started to investigate the carbonylation
reaction of 2-iodophenol with alkynes under microwave irra-
diation using Mo(CO)6 as the CO source, and herein we
2Corresponding author (e-mail: wxiao@mail.ccnu.edu.cn).
Can. J. Chem. 83: 826–831 (2005)
doi: 10.1139/V05-094
© 2005 NRC Canada

Cao and Xiao
827
Table 1. Optimization of the reactions on the model reaction.a
Et
O
O
O
I
Et
O
Et
Et
+
Et
+
Et
OH
1
2a
3a
4a
Entry
Catalyst
Base
Temp (°C)
Solvent
DMF
Time (min)
Yield (%)b
3a:4ac
1
2
0d
52
43
60
59
54
54
60
74
55
Mo(CO)6
DIEA
180
160
160
180
180
180
180
180
160
200
30
30
30
30
30
30
30
60
30
30
—
Pd(OAc)2–PPh3
Pd(OAc)2–PPh3
Pd(OAc)2–PPh3
Pd(OAc)2–PPh3
Pd(OAc)2–PPh3
Pd(OAc)2–PPh3
Pd(OAc)2–PPh3
Pd(OAc)2–PPh3
Pd(OAc)2–PPh3
Et2NH
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
Toluene
1:3
1:3
1:3
1:3
1:3
1:3
1:3
1:3
1:3
3
pyridine
4
DIEA–DMAPe
DIEA–DMAP
DIEA–DMAP
DIEA–DMAP
DIEA–DMAP
DIEA–DMAP
DIEA–DMAP
5
6
THF
7
DMSO
8
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
9
10
aReaction conditions: 2-iodophenol (1 mmol), 3-hexyne (2 mmol), base (2–4 mmol), Mo(CO)6 (0.5 mmol), Pd(OAc)2 (5 mol%, 0.05 mmol), and PPh3
(20 mol%, 0.2 mmol) in solvent (1 mL) under microwave irradiation to 60 °C for 10 min and then to a certain temperature for 30–60 min.
bYield of 3a and 4a.
1
cDetermined by H NMR.
dStarting materials were recovered.
eDiisopropylethylamine (DIEA), 4-dimethylaminopyridine (DMAP).
wish to describe the first example of microwave-accelerated,
palladium-catalyzed intermolecular carbonylative cyclization,
resulting in chromen-2-one derivatives (eq. [1]).
The reaction of 3-hexyne (2a) and 2-iodophenol (1) was
chosen as a model reaction. On the basis of the knowledge
gained from previous findings (8), DMF was initially em-
ployed as the solvent as well as a CO source. The reaction
was run on a 1 mmol scale, using 5 mol% Pd(OAc)2 as the
catalyst, 20 mol% PPh3 as the ligand, 2 equiv. of alkyne,
and 1 equiv. of diethyl amine (DIEA) in 5 mL of DMF at
180 °C for 30 min under microwave irradiation. However,
the reaction did not give the corresponding carbonylation
product under these conditions. The addition of 0.5 equiv. of
Mo(CO)6 to the above reaction resulted in the formation of
3,4-diethyl-chromen-2-one (3a) and 2,3-diethyl-chromen-4-
one (4a) in 18% and 36% isolated yields, respectively (eq. [2]).
Thus, the effects of varying the base, solvent, reaction tem-
perature, and reaction time on the model reaction were then
examined.
Of particular interest is the fact that some chromen-2-one
derivatives possess remarkable biological activity, including
anticancer and HIV-1-specific reverse transcriptase inhibitor
properties (13). They are also very useful precursors of other
heterocyclic compounds (14). Of the various routes to their
preparation (15), the methodology presented herein is one of
the most straightforward and efficient ways to afford such
compounds, with small reaction scales and short reaction
times.
Results and discussion
Initial studies were focused on examining the feasibility of
the microwave-accelerated, intermolecular carbonylative
cyclization reaction, and optimizing reaction conditions that
could be applied to a variety of alkynes and 2-iodophenol.
Table 1 shows the results of the model reaction under dif-
ferent conditions. It was found that Mo(CO)6 was not active
itself as an efficient catalyst in the model reaction under mi-
R1
O
Pd(OAc)2/PPh3, Mo(CO)6
I
R1
R2
R2
and (or)
R1
R2
[1]
+
DIEA, DMAP, 1,4-dioxane
MW: 160 °C , 30 min
OH
O
O
O
1
2
3
4
R1, R2 = H, alkyl or aryl
O
Et
O
Et
Et
Et
O
Pd(OAc)2/PPh3, Mo(CO)6
I
OH
[2]
+
+
Et
Et
DIEA, DMF, MW: 180 °C, 30 min
O
3a
18%
4a
36%
1
2a
© 2005 NRC Canada

828
Can. J. Chem. Vol. 83, 2005
crowave irradiation (Table 1, entry 1), while Pd(OAc)2 with
4 equiv. of PPh3 worked very well in most cases (Table 1,
entries 2–10). It can be concluded from Table 1 that the re-
action is significantly influenced by the solvent and base
employed. For example, when N-ethyldiisopropylamine
(DIEA) and 4-(dimethylamino)pyridine (DMAP) were used
as a co-base, the reaction gave the carbonylation products in
60% isolated yield in 1,4-dioxane (Table 1, entry 4). Other
solvents, such as toluene, THF, and DMSO can be employed
as the solvent for the reaction, but none appears to be as
good as 1,4-dioxane (Table 1, entries 5–7). In addition to
DIEA–DMAP, we have examined other bases, such as di-
ethyl amine and pyridine, for the reaction (Table 1, entries 2
and 3). The results show that both of them are inferior to
DIEA–DMAP. The use of inorganic bases (K2CO3 or
KOAc) resulted in the formation of a complicated mixture;
therefore, they were ruled out for further investigation.
kynes, in principle, they might also give two regioisomers
(Scheme 1). However, during the insertion of the alkyne into
the aryl–palladium bond, route a is much more favorable
than route b because of the interaction of the bigger alkyl
group (compare with H) with the palladium species
(Scheme 1). Therefore, chromen-2-one 8, rather than 9, was
formed as a sole product in the reaction.
The formation of two regioisomers in the reaction of in-
ternal alkynes could be rationalized according to Scheme 2.
The reaction may start from the oxidative addition of 2-
iodophenol to Pd(0) to form an arylpalladium complex 10,
and then both CO and the internal alkyne insert subsequently
to the aryl–Pd bond to form complexes 11 and 12, respec-
tively. Depending on the rate difference of the insertion and
(or) the stabilities of 11 and 12, the reaction exhibits
regioselectivity and eventually affords chromenones 3 and 4
in different ratios (Scheme 2).
The reaction temperature is another critical factor for the
carbonylative cyclization, with the best result being attained
at 160 °C. Variations of the temperature from this value have
been proven to be detrimental to the reaction. For example,
increasing the temperature to 180 and 200 °C gave only 60%
and 55% yields, respectively (Table 1, entries 8 and 10). De-
creasing the temperature to less than 150 °C did not give any
carbonylation product because Mo(CO)6 could not thermally
decompose to generate carbon monoxide at this temperature
(16).
We did not rigorously examine the effect of the CO source
on the reaction. In principle, any compounds that could lib-
erate CO under the above conditions might be used as a CO
source in the reaction. However, compared with Cr(CO)6,
Fe(CO)5, Co2(CO)8, and Ni(CO)4, Mo(CO)6 was found to be
the best choice for the present reaction.
Conclusions
In summary, this research has resulted in the first example
of microwave-accelerated, palladium-catalyzed intermolecu-
lar carbonylative cyclization of 2-iodophenol and alkynes
with the solid molybdenum hexacarbonyl as an efficient
source of carbon monoxide. The methodology presented
here is attractive because of the short reaction time, the ex-
perimental simplicity, and the fact that no external carbon
monoxide needs to be added.
Experimental section
General methods
Unless otherwise noted, materials were purchased from
commercial suppliers and used without further purification.
Solvents and liquid organic bases were freshly distilled ac-
cording to the known procedures (16). Column chromatogra-
phy was performed using 200–300 mesh silica gel. IR was
recorded on a PerkinElmer PE-983 IR spectrometer as KBr
film with absorption in cm–1. 1H NMR spectra were re-
corded on Varian Mercury 400 (400 MHz) spectrometers.
Chemical shifts are reported in ppm from TMS with the sol-
vent resonance as the internal standard (CDCl3: δ 7.24). Data
are reported as follows: chemical shift, multiplicity (singlet
(s), doublet (d), triplet (t), quartet (q), broad (br), multiplet
(m)), coupling constants (Hz). 13C NMR spectra were re-
corded on Varian Mercury 400 (100 MHz) with complete
proton decoupling spectrophotometers (CDCl3: δ 77.7).
All experiments were performed in a Smith Synthesizer
producing controlled irradiation at 2450 MHz with a power
of 0–300 W.
Thus, the final optimized reaction conditions for the
microwave-accelerated carbonylative cyclization of 2-
iodophenol and 3-hexyne with Mo(CO)6 as the CO source
have been determined to be 1 mmol of 2-iodophenol,
2 equiv. of 3-hexyne, 0.5 equiv. of Mo(CO)6, 5 mol%
Pd(OAc)2, 20 mol% PPh3 in the presence of 1 equiv. of
DIEA, and 1 equiv. of DMAP in 1–1.5 mL of 1,4-dioxane
under microwave irradiation at 160 °C for 30 min. Using
these reaction conditions, reactions of a variety of internal
and terminal alkynes with 2-iodophenol were studied, and
the results are summarized in Table 2.
Internal and terminal alkynes can be successfully em-
ployed in the microwave-accelerated, palladium-catalyzed
carbonylative cyclization reactions with 2-iodophenol using
Mo(CO)6 as a solid carbon monoxide source, to give the cor-
responding chromenone derivatives in good isolated yields
(Table 2). The regioselectivity of this reaction depends on
the substrate employed. The terminal alkynes reacted with 2-
iodophenol to exclusively afford the chromen-2-one deriva-
tives in pretty good yields (Table 2, entries 3–7). Mixtures of
regioisomers were obtained with modest regioselectivity
when internal alkynes were applied in the reaction (Table 2,
entries 1 and 2). Both the regioselectivity and the yield of
the reactions of internal alkynes are affected by the steric
bulk of the alkyl substituent. Increasing the size of the alkyl
group from ethyl to propyl resulted in an increase in the
regioselectivity (Table 2, entries 1 and 2), but a decrease in
the yield of the reaction. For the reactions of terminal al-
Typical procedure for the microwave-accelerated,
palladium-catalyzed carbonylative cyclization
A 2.0–5.0 mL process vial was charged with 2-iodophenol
(1 mmol) and Pd(OAc)2 (0.05 mmol), PPh3 (0.2 mmol),
Mo(CO)6 (0.5 mmol), alkyne (2 mmol), DIEA (1 mmol),
DMAP (1 mmol), and dry 1,4-dioxane (1.0 mL). The vial
was immediately capped with a Teflon septum under N2 and
irradiated with microwaves to 60 °C for 10 min, then to
160 °C for another 30 min. After cooling, the reaction mix-
ture was filtered through a short Celite pad, and the solvent
© 2005 NRC Canada

Cao and Xiao
829
Table 2. Microwave-accelerated, palladium-catalyzed carbonylative cyclization reactions of alkynes with 2-
iodophenol using Mo(CO)6 as the CO source (eq. [1]).a
Alkyne
Entry
Product
3:4b
Yield (%)
O
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
1:3
74
1
2
O
O
3a
O
2a
4a
O
C3H7
C3H7
C3H7
C3H7
O
C3H7
C3H7
1:4
69
2b
O
O
3b
4b
C3H7
C3H7
71
76
63
3
4
5
2c
2d
O
3c
O
O
C4H9
C4H9
O
3d
C5H11
C5H11
C6H13
C6H5
2e
O
3e
O
C6H13
69
6
7
2f
O
O
3f
C6H5
78
2g
O
3g
O
aReaction conditions: 2-iodophenol (1 mmol), alkyne (2 mmol), DIEA (1 mmol), DMAP (1 mmol), Mo(CO)6 (0.5 mmol), Pd(OAc)2
(5 mol%, 0.05 mmol), and PPh3 (20 mol%, 0.2 mmol) in 1,4-dioxane (1 mL) under microwave irradiation at 160 °C for 30–60 min.
1
bDetermined by H NMR (17).
1
was removed under reduced pressure. The residue was puri-
fied by silica gel flash chromatography to give the desired
pure products.
4a: IR (cm–1): 1639. H NMR (CDCl3) δ: 8.21–8.19 (d, J =
8 Hz, 3/4H), 7.63–7.61 (m, 2 × 1/4H), 7.40–7.33 (m, 3/4H),
2.76–2.73 (m, 2 × 3/4H), 2.61–2.55 (m, 2 × 3/4H), 1.36–
1.34 (m, 3 × 3/4H), 1.15–1.12 (m, 3 × 3/4H). 13C NMR δ:
177.1, 156.1, 132.3, 124.8, 124.7, 116.9, 26.5, 22.8, 14.8,
10.9, 10.5. MS m/z (rel. intensity): 202 (26, M+).
3,4-Diethyl-chromen-2-one (3a) and 2,3-diethyl-
chromen-4-one (4a) (18)
Yellow oil; a mixture of regioisomers with a ratio of 1:3.
3a: IR (cm–1): 1710. 1H NMR (CDCl3) δ: 7.61 (d, J =
8.0 Hz, 1/4H), 7.44 (m, 1/4H), 7.26–7.32 (m, 2 × 1/4H), 2.85
(q, J = 7.5 Hz, 2 × 1/4H), 2.67 (q, J = 7.5 Hz, 2 × 1/4H),
1.28 (t, J = 8.0 Hz, 3 × 1/4H), 1.19 (t, J = 8.0 Hz, 3 × 1/4H).
3,4-Dipropyl-chromen-2-one (3b) and 2,3-dipropyl-
chromen-4-one (4b) (18)
White solid; a mixture of regioisomers with a ratio of 1:4.
3b: IR (cm–1): 1716. 1H NMR (CDCl3) δ: 7.59 (d, J =
© 2005 NRC Canada

830
Can. J. Chem. Vol. 83, 2005
Scheme 1.
R
Pd(PPh3)nI
OH
5
Favor
Disfavor
H
b
a
R
H
Pd(PPh3)nI
R
Pd(PPh3)nI
OH
OH
6
7
R
R
O
O
O
O
8
9
Scheme 2.
O
R
Pd(PPh3)nI
OH
R
CO
Fast
R
R
Pd(PPh3)nI
Pd(PPh3)nI
Slow
OH
OH
11
10
12
CO
R
R
R
O
R
O
R
R
O
O
3
4
8.0 Hz, 1/5H), 7.45 (d, J = 8.0 Hz, 1H), 7.25–7.32 (m, 2 ×
1/5H), 2.79 (m, 2 × 1/5H), 2.61 (m, 2 × 1/5H), 1.55–1.70
(m, 4 × 1/5H), 1.11 (t, J = 7.6 Hz, 3 × 1/5H), 1.03 (t, J =
7.6 Hz, 3 × 1/5H). 4b: IR (cm–1): 1639. 1H NMR (CDCl3) δ:
8.18–8.20 (d, J = 8.0 Hz, 1 × 4/5H), 7.56–7.60 (m, 2 ×
4/5H), 7.34–7.37 (m, 1 × 4/5H), 2.63–2.71 (m, 2 × 4/5H),
2.50–2.59 (m, 2 × 4/5H), 1.77–1.81 (m, 2 × 4/5H, CH2),
1.51–1.61 (m, 2 × 4/5H), 0.98–1.12 (m, 6 × 4/5H). 13C
NMR δ: 177.8, 155.8, 132.9, 126.3, 125.7, 124.4, 124.3,
116.8, 26.5, 22.8, 22.4, 20.9, 14.3, 14.2. MS m/z (rel. inten-
sity): 230 (2.5, M+).
4-Propyl-chromen-2-one (3c) (19)
1
Colorless oil. IR (cm–1): 1720. H NMR (CDCl3) δ: 7.53–
7.66 (m, 2H), 7.27–7.36 (m, 2H), 6.30 (s, 1H), 2.74–2.78
(m, 2H), 1.73–1.78 (m, 2H), 1.05–1.09 (t, 3H). MS m/z (rel.
intensity): 189 (22, M+ + 1).
4-Butyl-chromen-2-one (3d) (20)
1
Yellow solid. IR (cm–1): 1731. H NMR (CDCl3) δ: 7.28–
7.66 (m, 4H), 6.29 (s, 1H), 2.24–2.80 (m, 2H), 1.66–1.74
(m, 2H), 1.45–1.50 (m, 2H), 0.93–0.99 (m, 3H). MS m/z
(rel. intensity): 202 (2, M+).
© 2005 NRC Canada

Cao and Xiao
831
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1
Yellow solid. IR (cm–1): 1717. H NMR (CDCl3) δ: 7.30–
7.65 (m, 4H), 6.30 (s, 1H), 2.77 (t, J = 8.0 Hz, 2H), 1.69–
1.73 (m, 2H), 1.38–1.44 (m, 4H), 0.93 (t, J = 8.0 Hz, 3H).
13C NMR δ: 161.9, 156.3, 153.7, 131.6, 124.3, 119.3, 117.3,
113.2, 31.7, 31.5, 29.7, 27.8, 22.4, 13.9. MS m/z (rel. inten-
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Brown oil. IR (cm–1): 1655. H NMR (CDCl3) δ: 7.36–
1
8.20 (m, 4H, ArH), 6.18 (s, 1H, =CH), 2.62 (t, J = 8.0 Hz,
2H), 1.70–1.74 (m, 2H, CH2), 1.30–1.42 (m, 6H, 3CH2),
0.90 (t, J = 8.0 Hz, 3H). 13C NMR δ: 162.6, 156.4, 153.8,
133.4, 125.6, 124.7, 119.8, 117.9, 110.8, 34.3, 31.4, 29.7,
28.6, 22.5, 14.0. MS m/z (rel. intensity): 230 (2, M+).
4-Phenyl-chromen-2-one (3g) (19)
Colorless oil. IR (cm–1): 1645. H NMR (CDCl3) δ: 7.42–
1
8.26 (m, 9H), 6.85 (s, 1H). MS m/z (rel. intensity): 222 (100,
M+).
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Acknowledgments
We are grateful to the National Key Project for Basic Re-
search of China (2004CCA00100), the Natural Science
Foundation of China (20472021), the Hubei Province Sci-
ence Fund for Distinguished Young Scholar (2004ABB011),
and Central China Normal University, for the financial sup-
port of this research.
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