Copper-free Sonogashira coupling of acid chlorides with terminal alkynes in the presence of a reusable palladium catalyst: An improved synthesis of 3-iodochromenones (= 3-iodo-4H-1-benzopyran-4-ones)

Article abstract of DOI:10.1002/hlca.200890032

Pd/C is used as an efficient catalyst for the copper-free Sonogashira coupling of acid chlorides and terminal alkynes to afford ynones in high yields (Tables 1 and 3). Cyclization of (2-methoxyaryl)-substituted ynones induced by I₂/ammonium cer

Full text of DOI:10.1002/hlca.200890032

Helvetica Chimica Acta – Vol. 91 (2008)
259
Copper-Free Sonogashira Coupling of Acid Chlorides with Terminal Alkynes
in the Presence of a Reusable Palladium Catalyst: An Improved Synthesis of
3-Iodochromenones (¼ 3-Iodo-4H-1-benzopyran-4-ones)
by Pravin R. Likhar*, M. S. Subhas, Moumita Roy, Sarabindu Roy, and M. Lakshmi Kantam
Inorganic and Physical Chemistry Division, Indian Institute of Chemical Technology, Hyderabad,
500007, India
(fax: þ 91-40-27160921; e-mail:plikhar@iict.res.in)
Pd/C is used as an efficient catalyst for the copper-free Sonogashira coupling of acid chlorides and
terminal alkynes to afford ynones in high yields (Tables 1 and 3). Cyclization of (2-methoxyaryl)-
substituted ynones induced by I2/ammonium cerium(IV) nitrate (CAN) at room temperature gave 3-
iodochromenones (¼ 3-iodo-4H-1-benzopyran-4-ones) in excellent yield (Table 4).
Introduction. – Ynones are important synthetic targets for the preparation of
heterocyclic derivatives such as pyrroles [1], furans [2], furanones [3], pyrazoles [4],
isoxazoles [5], pyrimidines [6], quinolines [7], and iodochromones [8], etc. Ynones are
generally synthesized via coupling of carboxylic acid chlorides and alkynes by using
palladium and copper catalysts under homogeneous conditions [9]. Despite the
synthetic elegance, all of these homogeneous catalytic protocols suffer from the loss of
the precious palladium catalyst at the end of the reaction. Further, the use of a copper
co-catalyst facilitates the homocoupling of alkynes, which in turn makes the separation
of the products more tedious. So it is highly desirable to develop a copper-free reusable
catalytic system for the coupling of acid chlorides with alkynes.
Recently Pd/C has received considerable attention in organic synthesis for its
availability, low cost, heterogeneous nature, and ease of handling [10]. It was effectively
used in numerous CꢀC bond forming reactions. Buoyed with the literature reports
[10], we wish to examine the catalytic activity of Pd/C in the coupling of alkynes with
acid chlorides.
Results and Discussion. – Initially we studied the coupling of benzoyl chloride (1a)
and ethynylbenzene (2a) in the presence of 1 mol-% of Pd/C catalyst under different
conditions (Table 1). It was evident from Table 1 that the maximum formation of
product 3aa was observed when dry toluene was used as solvent in the presence of
triethylamine as base. By lowering the catalyst amount from 1 mol-% to 0.1 mol-%,
good to moderate yields were obtained after a longer reaction time (Table 1, Entries 10
and 11). Even at room temperature, Pd/C afforded 48% of 3aa within 8 h (Table 1,
Entry 9). To widen the scope of this catalytic protocol, several other alkynes and acid
chlorides were allowed to react under the optimized conditions. The results are
summarized in Table 2.
From Table 2, it can be observed that aromatic acid chlorides with electron-
withdrawing groups reacted more sluggishly than the aromatic acid chlorides with
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Helvetica Chimica Acta – Vol. 91 (2008)
Table 1. Optimization of Reaction Conditions for the Coupling of Ethynylbenzene and Benzoyl Chloridea)
Entry
Solvent
Base
Time [h]
Temperature [8]
Yieldb) [%]
1
2
3
4
5
6
7
8
9
dry toluene
dry toluene
dry toluene
dry toluene
dry toluene
dry THF
dry DMF
MeCN
dry toluene
dry toluene
dry toluene
Et3N
2
5
2
3
2
4
5
5
8
5
8
110
110
110
110
110
80
100
90
r.t.
96
20
80
30
68
70
53
42
NaOAc
iPr2EtN
Pyridine
DABCOc)
Et3N
Et3N
Et3N
Et3N
Et3N
48
78d)
57e)
10
11
110
110
Et3N
a) Reaction conditions:Alkyne (1 mmol), acid chloride (1.2 mmol), Pd/C (1 mol-%) (10 wt-% Pd/
charcoal), base (2 mmol), N2 atmosphere. b) GC Yield, with tridecane as internal standard.
c) DABCO ¼ 1,4-Diazabicyclo[2.2.2]octane. d) Pd/C (0.5 mol-%). e) Pd/C (0.1 mol-%).
electron-donating groups (Table 2, Entry 4). Also an a,b-unsaturated acid chloride or
cyclic aliphatic acid chloride reacted smoothly to afford the respective ynone in high
yield (Table 2, Entries 3 and 10). In case of a heterocyclic acid chloride, the coupling
product was obtained in good yield (Table 2, Entry 9). The reaction of aliphatic alkynes
provided relatively lower yields than that of aromatic alkynes (Table 2, Entries 12 and
15).
For any heterogeneous catalyst, it is important to know its ease of separation and
possible reusability. In this coupling reaction, the Pd/C catalyst was separated by a
simple filtration, washed with a copious amount of toluene and water, followed by
acetone, and then air-dried. The recovered catalyst was charged in the next cycle. The
yield of product decreased from 96 to 67% after the 6th cycle (Table 3). When the Pd-
content of the catalyst after the 6th cycle was analyzed by atomic absorption
spectroscopy (AAS), an almost 15% decrease in Pd-content was noticed. This
nonreversible leaching phenomenon was already observed in case of Pd/C [11].
The 2,3-diarylchromenones (¼2,3-diaryl-4H-1-benzopyran-4-ones) are known to
be antihypertensive and anti-inflammatory agents as well as COX-2 inhibitors [12]. The
3-iodochromenones can be used as a precursor for the synthesis of 2,3-diarylchrome-
nones. Iodochromenones are potential intermediates in the synthesis of bioactive
molecules [13]. Recently, Larock and co-workers have shown that iodine monochloride
(ICl) induced cyclization of heteroatom-substituted alkynones into various 3-iodo-
chromenones and analogues [8]. ICl is highly moisture- and light-sensitive. To develop
an easy and alternative methodology, it is necessary to have stable and safe reagent
systems. When molecular iodine (I2) was used in place of ICl for the cyclization of a (2-

Helvetica Chimica Acta – Vol. 91 (2008)
261
Table 2. Coupling of Acid Chlorides with Alkynes in the Presence of Pd/C Catalysta)
Entry Acid chloride RC(¼O)Cl Alkyne R’ꢀC ꢁ CꢀH Product
Time Yieldc)
RC(¼O)ꢀC ꢁ CꢀR’b) [h]
[%]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
1a; R ¼ Ph
2a; R’ ¼ Ph
3aa
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
2
2
2.5
4
3
2
3
2
2.5
2.5
2
3.5
3
2.5
3
2
92
90
91
65
95
89
90
82
78
83
90
72
90
85
60
89
1b; R ¼ 4-MeꢀC6H4
2a
1c; R ¼ PhꢀCH¼CH
2a
2a
2a
2a
2a
2a
2a
2a
1d; R ¼ 4-NO2ꢀC6H4
1e; R ¼ 4-ClꢀC6H4
1f; R ¼ 4-MeOꢀC6H4
1g; R ¼ 2-MeOꢀC6H4
1h; R ¼ 4-tBuꢀC6H4
1i; R ¼ furan-2-yl
1j; R ¼ cyclohexyl
3ja
3ab
3ac
1a
1a
1a
1g
1g
1g
2b; R’ ¼ 4-MeꢀC6H4
2c; R’ ¼ hexyl
2d; R’ ¼ 4-MeOꢀC6H4 3ad
2b
2c
2d
3gb
3gc
3gd
a) Reaction conditions:Terminal alkyne (1 mmol), acid chloride (1.2 mmol), Et 3N (2 mmol), dry
toluene (2 ml), Pd/C (1 mol-%) (10 wt-% Pd/charcoal), 1108, N2. b) All the products were characterized
by 1H-NMR and mass spectrometry. c) Yield of isolated pure product.
Table 3. Reusability of the Pd/Catalyst in the Coupling of Ethynylbenzene (2a) and Benzoyl Chloride
(1a)a)
1st cycle
2nd cycle
3rd cycle
4th cycle
5th cycle
6th cycle
Time [h]
2
96
2
90
2.5
83
3
78
4
72
6
67
Yieldb) [%]
a) Reaction conditions:Ethynylbenzene ( 2a; 3 mmol), benzoyl chloride (1a; 3.6 mmol), Et3N (6 mmol),
dry toluene (6 ml), 1108, N2. b) GC Yield, with tridecane internal standard.
methoxyaryl)-substituted alkynone, no iodochromenone product formation was
observed [8]. It is believed that for the facile formation of 3-iodochromenone, it is
essential to generate the iodine cation on the CꢁC bond of the ynone (iodonium
intermediate) via activation of I2. A literature search on the activation of I2 revealed
ammonium cerium(IV) nitrate (CAN) as an efficient and convenient activator for I2 in
the iodination of ketones, aromatic compounds, uracil derivatives, enones, and flavones
[14].
When 3ga was treated with I2/CAN, we obtained 97% of 4a (Table 4, Entry 1).
Consequently, several other substituted alkynones were treated with I2/CAN, and the
results are summarized in Table 4. It was observed that aliphatic substituted ynones
needed a longer reaction time than aromatic substituted ynones (Table 4, Entry 3).
In conclusion, we have developed a heterogeneous protocol for the coupling of acid
chlorides and alkynes. The catalyst can be easily separated and reused for several cycles

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Table 4. Synthesis of 3-Iodochromenones 4 with the I2/CAN Systema)
Entry
R
Alkynone
Time [min]
Productb)
Yieldc) [%]
1
2
3
4
Ph
3ga
3gb
3gc
3gd
15
15
30
15
4a
4b
4c
4d
97
95
91
98
4-MeꢀC6H4
hexyl
4-MeOꢀC6H4
a) Reaction conditions:Ynone (0.3 mmol), I (0.36 mmol), CAN (0.33 mmol), MeCN (3 ml), at r.t.
2
b) All the products were characterized by 1H-NMR and mass spectrometry. c) Yield after isolation.
of reactions. We have also developed a mild and highly efficient I2/CAN system for the
iodocyclization of (2-methoxyaryl)-substituted ynones.
We wish to thank CSIR and UGC, New Delhi, for financial assistance.
Experimental Part
1. General. The 10% Pd/C was purchased from SRL, India. All other reactants were commercially
available and used without purification. Toluene was distilled over sodium benzophenone. GC:
Shimadzu GC 2010, ZB-5 capillary column. IR Spectra: Perkin-Elmer FT spectrophotometer; n˜ in cmꢀ1
.
NMR Spectra: Bruker Avance-300 and Varian Gemini-200 spectrometers; chemical shifts d in ppm rel. to
SiMe4 as internal standard, coupling constants J in Hz.
2. Ynones: General Procedure. In an oven-dried vessel, a mixture of alkyne (1 mmol), Et3N
(2 mmol), 10% Pd/C (1 mol-%, 10 mg), and dry toluene (1 ml) was stirred for 10 min under N2. Next, the
acid chloride (1.2 mmol) in dry toluene (1 ml) was added dropwise to the mixture within 2 min. The
mixture was stirred at 1108 under N2, and the progress of the reaction was monitored by GC. After
completion, the catalyst was separated by filtration, and to the filtrate, H2O (20 ml) was added. The
mixture was extracted with AcOEt (3 ꢂ 20 ml), the combined org. phase dried (MgSO4), and the solvent
evaporated. The crude product was purified by column chromatography (CC) (silica gel, hexane/AcOEt
9 :1): pure ynone. The ynones were characterized by 1H-NMR and MS and compared with literature
data. The spectral data of some representative products are given below.
1
1,3-Diphenylprop-2-yn-1-one (3aa) [9c]: H-NMR (200 MHz, CDCl3):7.35 – 7.72 ( m, 8 H); 8.15 –
8.24 (m, 2 H). EI-MS:206 (82, Mþ), 178 (100), 129 (76).
1
1-(4-Nitrophenyl)-3-phenylprop-2-yn-1-one (3da) [9c]: H-NMR (300 MHz, CDCl3):7.42 – 7.56 ( m,
3 H); 7.68 – 7.72 (m, 2 H); 8.37 (s, 4 H). EI-MS:251 (20, Mþ), 223 (8), 129 (100).
1-(Furan-2-yl)-3-phenylprop-2-yn-1-one (3ia) [9c]: 1H-NMR (300 MHz, CDCl3):6.55 – 6.60 ( m,
1 H); 7.34 – 7.49 (m, 4 H); 7.60 – 7.69 (m, 3 H). EI-MS:196 (65, Mþ), 168 (68), 139 (88), 129 (100), 101
(10), 74 (50).
1-Cyclohexyl-3-phenylprop-2-yn-1-one (3ja) [9c]: 1H-NMR (300 MHz, CDCl3):1.14 – 2.13 ( m,
10 H); 2.38 – 2.54 (m, 1 H); 7.31 – 7.46 (m, 3 H); 7.52 – 7.62 (m, 2 H). EI-MS:212(2, Mþ), 130 (8), 129
(100), 102 (20), 75 (18), 55 (70).
3-(4-Methoxyphenyl)-1-phenylprop-2-yn-1-one (3ad) [9b]: 1H-NMR (300 MHz, CDCl3):3.85 ( s,
3 H); 6.90 (d, J ¼ 9.0, 2 H); 7.49 (t, J ¼ 7.6, 2 H); 7.55 – 7.65 (m, 3 H); 8.18 (d, J ¼ 8.3, 2 H). EI-MS:236
(57, Mþ), 208 (32), 165 (20), 159 (100), 144 (12).

Helvetica Chimica Acta – Vol. 91 (2008)
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1-(2-Methoxyphenyl)non-2-yn-1-one (3gc):IR (neat):2928, 2856, 2210, 1647, 1627, 1596, 1485, 1462,
1298, 1240, 1022, 755. 1H-NMR (200 MHz, CDCl3):0.91 ( t, J ¼ 6.8, 3 H); 1.29 – 1.37 (m, 4 H); 1.41 – 1.52
(m, 2 H); 1.59 – 1.69 (m, 2 H); 2.44 (t, J ¼ 6.8, 2 H); 3.91 (s, 3 H); 6.92 – 7.01 (m, 2 H); 7.42 – 7.49 (m, 1 H);
7.95 (dd, J ¼ 7.5, 1.5, 1 H). 13C-NMR (CDCl3, 75 MHz):13.97; 19.22; 22.50; 27.90; 28.58; 31.22; 55.78;
81.80; 95.29; 112.15; 120.09; 126.90; 132.78; 134.59; 159.65; 177.09. EI-MS:244 (25, Mþ), 187 (80), 174
(100), 173 (67), 135 (84), 121 (71), 115 (34), 91 (22), 77 (47). Anal. calc. for C16H20O2 (244.33):C 78.65,
H 8.25; found:C 78.79, H 8.15.
3. 3-Iodochromenones: General Procedure. In an oven-dried reaction tube, a mixture of ynone
(0.3 mmol), I2 (0.36 mmol), CAN (0.33 mmol), and MeCN (3 ml) was stirred at r.t., and the progress of
reaction was monitored by TLC. To the mixture, sat. aq. Na2S2O3 soln. (3 ml) and then sat. NaCl soln.
(20 ml) was added. The mixture was extracted with AcOEt (3 ꢂ 10 ml), the combined org. layer dried
(MgSO4), and the solvent evaporated. The residue was purified by CC (silica gel, hexane/AcOEt 9 :1):
pure iodochromenone. All the reported iodochromenones were identified by comparison with their
published spectral data.
3-Iodo-2-phenyl-4H-1-benzopyran-4-one (4a) [8]: 1H-NMR (200 MHz, CDCl3):7.39 – 7.58 ( m, 5 H);
7.64 – 7.82 (m, 3 H); 8.23 – 8.33 (m, 1 H). EI-MS:348 (100, Mþ), 221 (65), 165 (67), 121 (35).
3-Iodo-2-(4-methylphenyl)-4H-1-benzopyran-4-one (4b): 1H-NMR (200 MHz, CDCl3):2.48 ( s, 3 H);
7.23 – 7.35 (m, 2 H); 7.37 – 7.50 (m, 2 H); 7.62 – 7.75 (m, 3 H); 8.27 (d, J ¼ 7.8, 1 H). EI-MS:362 (100, Mþ),
235 (36).
2-Hexyl-3-iodo-4H-1-benzopyran-4-one (4c):IR (neat):2954, 2927, 2857, 1650, 1611, 1559, 1353,
1
1112, 758. H-NMR (300 MHz, CDCl3):0.92 ( t, J ¼ 6.8, 3 H); 1.29 – 1.53 (m, 6 H); 1.74 – 1.85 (m, 2 H);
3.03 (t, J ¼ 7.6, 2 H); 7.36 – 7.43 (m, 2 H); 7.61 – 7.68 (m, 1 H); 8.20 (dd, J ¼ 8.3, 2.3, 1 H). 13C-NMR
(CDCl3, 75 MHz):14.05; 22.43; 26.97; 28.68; 31.48; 38.63; 88.35; 117.39; 120.06; 125.39; 126.43; 133.77;
155.44; 169.11; 173.85. EI-MS:356 (15, Mþ), 229 (18), 159 (26), 131 (88), 121 (100), 95 (32), 69 (20).
Anal. calc. for C15H17IO2 (356.20):C 50.58, H 4.81; found:C 50.60, H 4.74.
3-Iodo-2-(4-methoxyphenyl)-4H-1-benzopyran-4-one (4d): 1H-NMR (200 MHz, CDCl3):3.90 ( s,
3 H); 6.95 – 7.04 (m, 2 H); 7.37 – 7.50 (m, 2 H); 7.63 – 7.82 (m, 3 H); 8.22 – 8.30 (m, 1 H). EI-MS:378 (100,
Mþ), 251 (24).
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