Synthesis of functionalized alkynes via palladium-catalyzed Sonogashira reactions

Article abstract of DOI:10.1016/j.tetlet.2015.12.086

A highly efficient protocol for the copper and phosphine free Sonogashira cross-coupling reactions of aryl iodides with terminal alkynes under aerobic conditions has been developed. Using 1 mol % of the palladium-bis(oxazoline) complex, Pd-BOX A, in the p

Full text of DOI:10.1016/j.tetlet.2015.12.086

Accepted Manuscript
Synthesis of functionalized alkynes via palladium-catalyzed Sonogashira reac-
tions
Mansur B. Ibrahim, Bassam El Ali, Imran Malik, Mohammed Fettouhi
PII:
S0040-4039(15)30501-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.12.086
TETL 47133
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
17 August 2015
19 December 2015
22 December 2015
Please cite this article as: Ibrahim, M.B., Ali, B.E., Malik, I., Fettouhi, M., Synthesis of functionalized alkynes via
palladium-catalyzed Sonogashira reactions, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.
2015.12.086
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`Synthesis of functionalized alkynes via palladium-catalyzed Sonogashira
reactions
Mansur B. Ibrahim, Bassam El Ali*, Imran Malik, Mohammed Fettouhi
Chemistry Department, King Fahd University of Petroleum & Minerals, Dhahran 31261,
Saudi Arabia
Abstract
A highly efficient protocol for the copper and phosphine free Sonogashira cross-coupling
reactions of aryl iodides with terminal alkynes under aerobic conditions has been developed.
Using 1 mol% of the palladium-bis(oxazoline) complex, Pd-BOX A, in the presence of KOH,
and a CH3CN-H2O solvent system allowed for the cross-coupling reactions to proceed at
room temperature or 60 °C. This new catalytic system was found to be highly active for the
cross-coupling reaction of aryl diiodo substrates with unactivated alkyl alkynes to produce
various symmetrical dialkynes, as well as for the cross-coupling of terminal dialkynes with
aryl iodides to generate symmetrical disubstituted internal alkynes.
Keywords: Palladium-bis(oxazoline), Sonogashira coupling, diiodobenzene, alkyl alkynes,
dialkynes
* Corresponding author. Tel.: +966 13 860 4491; Fax: +966 13 860 4277
E-mail address: belali@kfupm.edu.sa (B. El Ali).
1

The Sonogashira reaction of aryl halides with aryl and alkyl alkynes provides a powerful tool
for the construction of a carbon-carbon bond between acetylenes and alkenes/arenes.1-6 The
importance of alkynes is directly associated with their occurrence in a wide range of natural
products and other biologically active substances,7 and with their versatility as intermediates
for the production of materials for advanced engineering applications such as conducting
polymers, non-linear optical devices and liquid crystals.8-10 The development of methods for
incorporating carbon-carbon triple bonds into molecules remains an important area of
research.11
In general, the Sonogashira reaction, which represents the leading method for the production
of internal alkynes, is catalyzed by palladium complexes in combination with copper salts
and a large excess of an amine base.12 However, the presence of copper (I) co-catalysts can
result in the in situ formation of copper (I) acetylides leading to the oxidative homocoupling
of alkynes.12-14 To avoid homocoupling reactions, serious efforts have been made, including
the employment of new, active palladium complexes as catalysts. Other problems associated
with the copper free systems include the frequent requirement for high palladium catalysts
loadings, an excess amount of base and rigorously dried organic solvents.15,16
Through a comparison of available literature reports describing the use of phosphorous
ligands in copper-free Sonogashira reactions,17-19 it was found that there were only a
relatively limited number of studies on the use of palladium-nitrogen catalyst systems.20-24
Moreover, the reported dinitrogen catalyst systems utilize high temperature, a longer reaction
time, a relatively high palladium catalyst loading, phosphine ligands, copper as a co-catalyst,
or phase transfer agent.25-29 Furthermore, many of the reported phosphine and copper free
systems were limited to the coupling of aryl iodides with aryl alkynes.10,30
In a continuation of our research efforts on the use of palladium-BOX catalysts in cross-
coupling reactions,32,33 herein we report an efficient and mild catalytic system for the copper
and phosphine free Sonogashira coupling reactions of aryl iodides with aryl alkynes, alkyl
alkynes and dialkynes. In comparison with the reported dinitrogen palladium complexes and
our previous reports,32,33 palladium-BOX complexes are highly effective copper and
phosphine free catalysts for cross-coupling reactions of aryl iodides with various terminal
alkynes under mild reaction conditions. We also reported, for the first time, the synthesis of
1,3-bis(phenylethynyl)benzene (4ag), 6-phenylhex-5-ynenitrile (6ah), 6,6'-benzene-1,4-
diylbishex-5-ynenitrile (7gg), 1,4-bis(5-chloropent-1-yn-1-yl)benzene (7gh) and 1,4-bis(3,5-
2

dimethyl-1-hex-1-yn-3-ol)benzene (7go) as new materials prepared from the Sonogashira
cross-coupling reactions using palladium-BOX catalysts.
In order to determine the ideal conditions, several different experiments were performed at
room temperature under aerobic conditions using iodobenzene and phenylacetylene as model
substrates, while utilizing various palladium catalysts including Pd-BOX complexes32 (Table
1). The effect of varying the solvent was investigated using Pd-BOX-A (Figure 1). No
reaction was observed using water as the solvent (Table 1, entry 1) and only 10 % of product
was obtained in DMF (Table 1, entry 2). It was observed that there were gradual increases in
the yield when DMF-water mixtures were used as solvent (Table 1, entries 3 and 4). The
yield was severely decreased in acetonitrile (Table 1, entry 5). Remarkably, changing the
solvent system to CH3CN-H2O led to excellent isolated yields (Table 1, entries 6 and 7).
Other solvent systems such as CH3OH-H2O gave lower yields (Table 1, entry 8).
The presence of a base is essential for the palladium catalyzed Sonogashira cross-coupling
reaction.32-40 A control experiment in the absence of any base gave only a trace amount of
product (Table 1, entry 9). Various bases such as KOH, NaOH, K2CO3, Et3N (Table 1, entries
1-8, 10-20) were tested. Excellent yields were obtained with KOH and NaOH, (94% and 90%
respectively) (Table 1, entries 7 and 10). However, much lower yields were observed with
K2CO3 and Et3N (60% and 47% respectively) (Table 1, entries 11 and 12).
During the optimization of the reaction conditions, it was revealed that palladium
bis(oxazoline) complexes (Pd-Box A, B, C) (Figure 1, Table 1, entries 7, 13 and 14)32,33 all
provided excellent yields in comparison with commercially available palladium(II)
complexes and salts (Table 1, entries 16-20). Absence of the palladium catalyst gave no
coupling product (Table 1, entry 15), showing the crucial role of palladium in the cross-
coupling reaction.
It was found that the nature of the palladium complex had a pronounced impact on the
reaction. The use of Pd(OAc)2 (75%, Table 1, entry 17) gave slightly higher yields than PdCl2
(69%, Table 1, entry 16), PdCl2-Bipy (40%, Table 1, entry 18) and PdCl2-Phen (20%, Table
1, entry 19).
3

Table 1: Optimization of the reaction conditions for the palladium-catalyzed
Sonogashira coupling reaction of iodobenzene with phenylacetylene.a
I
[Pd]
+
Base, Solvent
1a
3aa
2a
Yield
(%)b
Entry
Pd Complex
Solvent
Base
1
2
Pd-BOX-A
Pd-BOX-A
Pd-BOX-A
Pd-BOX-A
Pd-BOX-A
Pd-BOX-A
Pd-BOX-A
Pd-BOX-A
Pd-BOX-A
Pd-BOX-A
Pd-BOX-A
Pd-BOX-A
Pd-BOX-B
Pd-BOX-C
-
H2O
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
-
Traces
10
DMF
3
DMF-H2O (3:1)
DMF-H2O (1:1)
CH3CN
27
4
35
5
Traces
80
6
CH3CN-H2O (3:1)
CH3CN-H2O (1:1)
CH3OH-H2O (1:1)
CH3CN-H2O (1:1)
CH3CN-H2O (1:1)
CH3CN-H2O (1:1)
CH3CN-H2O (1:1)
CH3CN-H2O (1:1)
CH3CN-H2O (1:1)
CH3CN-H2O (1:1)
CH3CN-H2O (1:1)
CH3CN-H2O (1:1)
CH3CN-H2O (1:1)
CH3CN-H2O (1:1)
CH3CN-H2O (1:1)
7
94
8
15
9
Traces
90
10
11
12
13
14
15
16
17
18c
19d
20
NaOH
K2CO3
Et3N
60
47
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
90
93
Traces
69
PdCl2
Pd(OAc)2
PdCl2-Bipy
PdCl2-Phen
PdCl2(PPh3)2
75
40
20
43
a. Reaction Conditions: Pd-catalyst (1 mol%), iodobenzene (1.0 mmol),
phenylacetylene (1.5 mmol), base (2.0 mmol), solvent (4 ml), r.t., 2 h.
b. Isolated yield.
c. PdCl2-Bipy = (2, 2’-bipyridine)dichloridopalladium(II).
4

d. PdCl2-Phen = (1, 10-phenanthroline)dichoridopalladium(II).
H3C
O2N
O
O
O
O
O
O
N
N
N
N
N
N
Pd
Pd
Pd
Cl
Cl
Br
Br
AcO OAc
Pd-BOX-A
Pd-BOX-B
Pd-BOX-C
Figure 1. Palladium-BOX complexes used in the Sonogashira coupling reactions
Under the optimized reaction conditions (1 mol% Pd-BOX-A, 2 equiv. KOH, 1:1 CH3CN-
H2O, R.T.), we then screened a range of aryl iodides with an array of structurally and
electronically different aryl alkynes (Table 2). With respect to the aryl iodides, both activated
and deactivated aryl iodides reacted smoothly with alkynes bearing electron withdrawing and
electron donating substituents and the cross-coupling products were obtained in excellent
yields. The coupling of phenylacetylene with deactivated aryl iodides (Table 2, entries 2-5)
afforded the internal acetylenes in high yields within 1 h. The coupling reactions of activated
aryl iodides such as 4-iodoanisole (Table 2, entry 6) and 4-iodoaniline (Table 2, entry 7) were
complete within 3 h. The coupling of iodobenzene with activated aryl alkynes (Table 2,
entries 8-10) afforded high yields of internal acetylenes within 3 h. The synthesis of 4,4’-
diaminodiphenylacetylene was achieved in high yield from the reaction of 4-iodoaniline with
4-ethynylaniline (Table 2, entry 11).
Table 2. Sonogashira coupling reactions of aryl iodides with aryl alkynes catalyzed
by Pd-BOX-A.a
I
Pd-BOX-A
R
R'
+
KOH, CH3CN-H2O
rt
R
R'
3aa-fe
1a-f
2a-e
R
1a-f
R’
2a-e
Time
(h)
Yield (%)b
3aa-fe
Entry
5

H
1a
H
2a
94
3aa
1
2
2
1
1
1
1
3
3
3
3
3
4
NO2
1b
H
2a
98
3ba
CH3CO
H
2a
96
3ca
3
1c
CN
1d
H
2a
97
3da
4
CN
1d
CHO
2b
98
3db
5
CH3O
1e
H
2a
91
3ea
6
NH2
1f
H
2a
90
3fa
7
H
1a
CH3
2c
93
3ac
8
H
1a
CF3
2d
88
3ad
9
H
1a
NH2
2e
96
3ae
10
NH2
1f
NH2
2e
88
3fe
11
a. Reaction Conditions: Pd-BOX-A (1 mol%), aryl iodide (1.0 mmol), alkyne (1.5 mmol),
KOH (2.0 mmol), CH3CN (2 mL), H2O (2 mL), rt.
b. Isolated yield.
Bis(phenyl ethynyl)-benzene (BPEB) derivatives have been commonly recognized as
important components of liquid crystals for electronic displays42-43 and have been applied in
the production of note book computer screens, mobile phones, flat screen monitors and LCD
televisions. BPEBs are characterized by a high clearing and melting point, as well as large
optical anisotropy values.44-46 Our new catalyst system was successfully applied to the
synthesis of BPEB’s (Table 3). 1,3 and 1,4-Bis(phenylethynyl)-benzenes were obtained from
the reactions of aryl iodides with 1,3- and 1,4-diethynyl benzenes, respectively (Table 3).
Complete conversions were observed after 1-3 h (Table 3, entries 1-4), depending on the
nature of the substituent. The desired cross-coupling products were isolated in excellent
yields. It is worth noting that the reactions were conducted at room temperature and the
palladium catalysts showed particular air and moisture stability. This phosphine free catalytic
6

system represents a significant advantage, specifically when the reactions were conducted in
air. Moreover, the reactions were conducted in the absence of copper; therefore, no homo-
coupling of the alkyne products were detected.
Table 3. Sonogashira coupling reaction of aryl iodides with dialkynes. Synthesis of
bis(phenyl ethynyl)-benzene derivatives (BPEBs).
R
I
Pd-BOX-A
+
R
KOH, CH3CN-H2O
R
rt
2f-g
4
1a, c
R
1a,c
Aryl dialkyne
2f-g
Time
(h)
Yield (%)b
4
Entry
90
4af
1
2
3
4
H
1a
3
3
1
2
2f
89
4ag
H
1a
2g
97
4cf
CH3CO
1c
2f
97
4cg
CH3CO
1c
2g
a. Reaction Conditions: Pd-BOX-A (1 mol%), aryl iodide (1.1 mmol), alkyne (0.5 mmol),
KOH (2.0 mmol), CH3CN (2 mL), H2O (2 mL), rt.
b. Isolated yield.
The Sonogashira cross-coupling reactions of aryl iodides with alkyl alkynes using palladium-
phosphine catalysts have been widely studied.2,5,18 On the other hand, there are only a few
reports on the copper and phosphine free Sonogashira cross-coupling of aryl iodides with
alkyl alkynes,14,31,47 however, in some studies low yields of products were observed at high
temperatures.2 Interestingly, the Pd-BOX complexes were highly active in the cross-coupling
reactions of aryl iodides with alkyl alkynes at 60 oC. For instance, the coupling reactions of 4-
iodoacetophenone with various alkyl alkynes was achieved to give the expected internal
acetylenes in excellent yield (Table 4, entries 1-6). The reactions were found to be unaffected
by the alkyl chain lengths, however, phenyl substituted alkyl alkynes were more reactive
7

(Table 4, entries 4-5). In fact, 4-iodobenzonitrile reacted with 1-hexyne in a similar manner
(Table 4, entry 6). Iodobenzene also reacted efficiently with alkyl alkynes and substituted
alkyl alkynes to produce the alkyl alkynes in high yields (Table 4, entries 7-14). Interesting
examples were the cross-coupling reactions of trimethylsilyl acetylene (Table 4, entry 11)
and triphenyl silyl acetylene (Table 4, entry 12). These reactions led predominantly to the
corresponding aryl silyl acetylenes indicating that the new catalytic system containing Pd-
BOX were highly effective in the coupling reactions of aryl iodides with silyl acetylenes.4,48
Similarly, a silyloxy acetylene was very reactive; however, the silyloxy group was
hydrolyzed under the reaction conditions to give the corresponding alkynol (Table 4, entry
13). The cross-coupling reaction of iodobenzene with a terminal alkynol was also successful,
giving the desired product in 87 % yield (Table 4, entry 14).
Table 4. Sonogashira coupling reactions of aryl iodide with alkyl alkyne catalyzed by
Pd-BOX-A.a
Pd-BOX-A
R
R
+
I
KOH, CH3CN-H2O
60 oC
'
R'
R
6
5a-m
1a,c,d
Yield
(%)b
6
R
1a,c,d
Alkyl alkyne
5a-n
Time
(h)
Entry
95
6ca
1
2
3
CH3CO
3
3
5a
5b
5c
1c
96
6cb
CH3CO
1c
90
6cc
CH3CO
3
2
1c
98
6cd
4
5
CH3CO
1c
5d
CH3CO
96
6ce
2
1c
5e
5f
5f
CN
1d
93
6df
6
7
3
4
H
1a
80
6af
8

Cl
H
1a
95
6ag
8
9
4
4
5g
5h
CN
H
1a
90
6ah
92
6ai
10
11
H
1a
4
4
5i
Si
93
6aj
H
1a
5j
SiPh3
H
1a
95
6ak
12
4
4
5k
OSi
90
6al
13c
H
1a
5l
OH
87
6am
14
H
1a
4
5m
a. Reaction Conditions: Pd-BOX-A (1 mol%), aryl iodide (1.0 mmol), alkyl alkyne (1.5 mmol),
KOH (2.0 mmol), CH3CN (2 mL), H2O (2 mL), 60 oC.
b. Isolated yield.
c. The hydrolyzed product was obtained:
d. aryl iodide (1.1 mmol), alkyl alkyne (0.5 mmol)
Interestingly, the terminal dialkyl alkyne, octa-1,7-diyne, coupled smoothly with 4-
iodoacetophenone to afford the corresponding internal dialkynyl ketone in excellent yield
(equation 1).
O
Pd-BOX-A
(1 mol %)
I
O
+
KOH (2.0 mmol)
CH3CN (2 mL)
H2O (2 mL)
O
60o C, 6 h
1c (1.1 mmol)
5n (0.50 mmol)
6cn (95 %)
Eq. 1
We further studied the Sonogashira cross-coupling reaction of diiodobenzene with aryl and
alkyl alkynes. Remarkably, the reaction proceeded successfully to give new internal alkynes
in excellent yields (Table 5). The reactions of 1,4-diiodobenzene with phenylacetylene or 4-
ethynyl aniline (Table 5, entries 1 and 2) successfully yielded the corresponding
bis(phenylethynyl)-benzene derivatives. Similarly, the reaction of 1,4-diiodobenzne with
9

various alkyl alkynes gave the corresponding symmetrically disubstituted alkynyl benzenes in
excellent yields (Table 5, entries 3-7). Alkynols and alkyndiols represent important building
blocks for the synthesis of a wide variety of industrially and pharmaceutically important
heterocycles.49 Representative dialkyndiols, 4,4’-benzene-1,4-diylbisbut-3-yn-1-ol (Table 5,
entry 6)50 and 1,1’-benzene-1,4-diylbis-(3,4-dimethylpent-1-yn-3-ol) (Table 5, entry 7)50,
were successfully synthesized from the coupling of 1,4-diiodobenzene with 1-
trimethylsiloxy-3-butyne and 3,5-dimethylhex-1-yn-3-ol, respectively.
Table 5. Sonogashira coupling reaction of 1,4-diiodobenzene with aryl and alkyl
alkynes.a
Pd-BOX-A
R
I
+
R
I
R
KOH, CH3CN-H2O
60 oC
1g
2
7
Alkyne
2
Yield (%)b
7
Entry
95
7ga
1
2
2a
2e
96
7ge
H2N
96
7gf
3
4
5f
CN
95
7gh
5h
96
7gg
Cl
5
6
5g
OSi
90
7gl
5l
OH
93
7go
7
5o
a. Reaction Conditions: Pd-BOX-A (1 mol%), 1,4-diiodobenzene (0.5 mmol),
alkyne (1.5 mmol), KOH (2.0 mmol), CH3CN (2 mL), H2O (2 mL), 60 oC, 12 h.
b. Isolated yield.
10

In conclusion, we have developed a highly efficient protocol for the synthesis of various
internal alkynes from the Sonogashira cross-coupling reaction of aryl halides with a wide
range of aryl and alkyl alkynes based on palladium-bis(oxazoline) complexes. This new
copper and phosphine free catalytic system provides a significant advantage in terms of
activity, selectivity, and tolerance to various functional groups on both the aryl halide and the
alkyne.
Acknowledgements
This project was funded by the National Plan for Science, Technology and Innovation
(MARIFAH) - King Abdulaziz City for Science and Technology - through the Science &
Technology Unit at King Fahd University of Petroleum & Minerals (KFUPM), the Kingdom
of Saudi Arabia, award number (11-PET1665-04).
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31. General procedure for Sonogashira coupling reaction
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50. Analytical and Spectroscopic Data of New Compounds: 1,3-Bis(phenylethynyl)benzene
1
(4ag): Brown solid; Yield 89 %; H NMR (500 MHz, CDCl3) δ (ppm): 7.70-7.64 (m,
13
1H), 7.52-7.42 (m, 6H), 7.34-7.32 (m, 7H), C NMR (125 MHz, CDCl3) δ (ppm):134.6,
131.6, 131.2, 128.4, 128.3, 88.5, GC-MS m/z 278 (M+1) Anal. Calc. for C22H14, (278.35):
C, 94.93; H, 5.07. Found: C, 95.01.61; H, 5.01; 6-phenylhex-5-ynenitrile (6ah): Yellow
oil; Yield 90 %; 1H NMR (500 MHz, CDCl3) δ (ppm): 7.34-7.32 (m, 2H), 7.24 – 7.22 (m,
3H), 2.53 (t, J = 6.7 Hz, 2H), 2.49 (t, J = 7.3 Hz, 2H), 1.89 (m, 2H); 13C NMR (125 MHz,
CDCl3) δ (ppm):131.5, 128.2, 127.9, 123.1, 119.1, 86.8, 82.3, 24.6, 18.5, 16.1, GC-MS
m/z 169 (M+1) Anal. Calc. for C12H11N (169.08): C, 85.17; H, 6.55; N, 8.28. Found: C,
85.21; H, 6.62; N, 8.73; 6, 6'-Benzene-1,4-diylbishex-5-ynenitrile (7gg):Yellow oil,
Yield 95 %; 1H NMR (500 MHz, CDCl3) δ (ppm): 7.29 (s, 4H), 2.59 (t, J = 6.7 Hz, 4H),
2.53 (t, J = 7.3 Hz, 4H), 1.94 (m, 4H); 13C NMR (125 MHz, CDCl3) δ (ppm):132.2,
123.5, 119.8, 89.4, 82.8, 25.2, 19.3, 16.9; IR (KBr, vcm-1) 2953, 2246, 1919, 1672, 1505,
1446, 1296, 1215, 1056, 838; GC-MS m/z 260 (M+). Anal. Calc. for C18H16N2 (260.13):
C, 83.04; H, 6.19; N, 10.76. Found: C, 83.24; H, 6.23; N, 10.92; 1,4-Bis(5-chloropent-1-
1
yn-1-yl)benzene (7gh): Yellow oil, Yield 96 %; H NMR (500 MHz, CDCl3) δ (ppm):
7.24 (s, 4H), 4.0 (t, J = 6.4 Hz, 4H), 2.54 (t, J = 6.7 Hz, 4H), 1.98 (m, 4H); 13C NMR (125
MHz, CDCl3) δ (ppm):131.3, 122.9, 89.7, 81.2, 43.7, 31.3, 16.9; IR (CH2Cl2, vcm-1)
2947, 2230, 1915, 1706, 1501, 1437, 1283, 1064; GC-MS m/z 279 (M+) Anal. Calc. for
C16H16Cl2 (279.21): C, 68.83; H, 5.78. Found: C, 68.51; H, 5.43; 1,4-Bis(3,5-dimethyl-1-
1
hex-1-yn-3-ol)benzene (7go): Yellow viscous oil, Yield 93 %; H NMR (500 MHz,
CDCl3) δ (ppm): 7.31 (s, 4H), 1.98 (m, 2H), 1.67 (d, J = 6.2 Hz, 4H), 1.55 (s, 6H); 1.03
(d, J = 4.6 Hz, 12H), 13C NMR (125 MHz, CDCl3) δ (ppm):131.4, 122.6, 95.0, 83.1,
68.5, 51.9, 30.9, 25.2, 24.2; IR (CH2Cl2, vcm-1) 3373, 2953, 2225, 1910, 1658, 1457,
1367, 1153, 926, 834; GC-MS m/z 326 (M+) Anal. Calc. for C22H30O2, (326.22): C,
80.94; H, 9.26. Found: C, 80.61; H, 9.33.
13

Synthesis of functionalized alkynes via palladium-catalyzed Sonogashira
reactions
Mansur B. Ibrahim, Bassam El Ali*, Imran Malik, Mohammed Fettouhi
Graphical Abstract
O
O
O
N
N
I
Pd
Cl
Cl
O
+
KOH, CH CN-H O
3
2
95%
O
14