Calcium carbide catalytically activated with tetra-: N -butyl ammonium fluoride for Sonogashira cross coupling reactions

Article abstract of DOI:10.1039/c7ob01334e

We report a novel method for the direct synthesis of mono- and bis-arylated alkynes utilizing catalytically activated CaC₂ as the alkyne component. This fluoride-activated cross coupling reaction provides advantages over existing methods regarding operational simplicity, use of readily available starting materials, and low cost.

Full text of DOI:10.1039/c7ob01334e

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ISSN 1477-0520
COMMUNICATION
Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
rsc.li/obc

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PAPER
Calcium Carbide Catalytically Activated with Tetra-n-butyl
Ammonium Fluoride for Sonogashira Cross Coupling Reactions
Abolfazl Hosseini,a Afsaneh Pilevar,a Eimear Hogan,a Boris Mogwitz,b Anne S. Schulze,c and Peter R.
Schreiner*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
We report a novel method for the direct synthesis of mono- and or chloride. Though the use of unprotected acetylides is of
bis-arylated alkynes utilizing catalytically activated CaC2 as the immense value for the preparation of terminal alkynes, such
alkyne component. This fluoride-activated cross coupling reaction procedures suffer from limitations including dry conditions and
provides advantages over existing methods regarding operational low temperatures.
simplicity, use of readily available starting materials, and low cost. Although acetylene gas may be viewed as the first choice for
the introduction of alkynyl moieties, its handling is
inconvenient.14
On the other hand, it was recently
Introduction
demonstrated that calcium carbide (CaC2) could be a suitable
substitute for acetylene gas, offering benefits including ease of
operation and safer handling than acetylene gas, and there is
increasing number of reports on the use of CaC2 in organic
synthesis.14-15 CaC2 has been successfully used for the
synthesis of symmetric diaryl ethynes using bromoarenes as
cheap starting materials.16 Iodoarenes and diiodoarenes also
react with CaC2 to yield the corresponding di-substituted
acetylenes and poly(p-phenylene ethynylene)s, respectively.17
CaC2 can be utilized in three-component reactions,18
alkynylation of tertiary amines,19 synthesis of acetylenic
alcohols, and enaminones.20
Terminal alkynes are versatile reagents utilized in synthetic
transformations including Sonogashira cross coupling,1 hydra-
tion,2 oxidative homocoupling,3 carbonylation reactions,4 and
many others.5 Numerous methods have been developed for
alkyne substitution, but direct mono-substitution of acetylene
has remained a challenge ever since the discovery of the Pd-
catalysed substitution of acetylene.6 The reaction of acetylene
with aryl iodides affords di-substituted acetylenes as the main
products even with
a
large excess of acetylene gas.7
Therefore, the synthesis of terminal alkynes is limited to the
use of protected acetylenes that require deprotection, making
the process costly.8 A direct method utilizing cheap reactants
is highly desirable,9 with acetylene being the preferred acety-
lide source.10 It was shown that the conversion of acetylene to
can be facilitated in solvents of low polarity but at the expense
of low yields; moreover, this method requires dry conditions
and no product was obtained in the presence of 5% of water.11
An alternative approach gave moderate yields of mono-
substituted acetylenes directly from acetylene, but it requires
a stream of acetylene gas and large amounts of solvent.12
Negishi et al. accomplished direct synthesis of terminal alkynes
using ethynylzinc chlorides and bromides13 generated in situ by
the reaction of ethynyl-magnesium halides with zinc bromide
Scheme 1 Use of an acetylide “ate”-complex from CaC2 as reagent and
TBAF•3H2O as catalyst in ethynylation and Sonogashira reactions.
Results and discussion
The challenge in working with sluggish CaC2 lies in its catalytic
activation. Recently, we have developed a novel method for
the activation of CaC2 using catalytic tetra-n-butyl ammonium
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Table 2 Optimization of the number of the calcium carbide / water ratio.a
fluoride (TBAF) in DMSO and used it for the synthesis of pro-
pargylic alcohols.21 Fluoride activation of CaC2 is thought to
generate a highly nucleophilic acetylide “ate”-complex that
may also be used for a variety of other transformations. As
this method is rather convenient, we decided to extend our
approach to Sonogashira cross coupling reactions (Scheme 1).
TBAF promotes the Sonogashira cross coupling reaction
without addition of amines;22 this approach is also effective for
C–H substitution of heterocycles.23 TBAF also facilitates
decarboxylative cross-coupling of alkynyl carboxylic acids with
aryl halides.24
CaC2, Pd(OAc)2 (5 mol%)
PPh3 (20 mol%), CuI (10 mol%)
Ph Br
+
Ph
Ph
Ph
TBAF•3H2O (1 equiv)
H2O, DMSO, 65 °C, 24 h
1a
2a
3a
Entry
CaC2 (mmol)
0.68
H2O (mmol)b
Yield (%)b
2a:3a
1:5
1
2
1.5
1.5
2
63
75
60
75
72
65
1.36
1:5
3
1.36
1:7
4
2.7
1.5
2.5
1.5
1:2
5
6d
2.7
1:1
Table 1 Optimization of the reaction conditions for the Pd-catalyzed cross coupling of
phenyl bromide with CaC2/TBAF.a
2.7
1:100
CaC2 (1.36 mmol), [Pd] (5 mol%)
Ligand (20 mol%)
aConditions: 1a (0.5 mmol), Pd(OAc)2 (5 mol%), PPh3 (20 mol%), CuI (10 mol%),
TBAF•3H2O (1 equiv), CaC2, H2O, DMSO (3 mL), 24 h. bWater from TBAF•3H2O
and added water. cDetermined via GC analysis. dReaction at 90 °C.
Ph Br
+
Ph
Ph
Ph
CuI (10 mol%), TBAF 3 H2O
DMSO, temp, 24h
1a
2a
3a
Pd(PPh3)2Cl2 (#3) provided only low conversion to both mono
(8%) and di-substituted products (16%) and addition of PPh3 as
a ligand did not affect the outcome much unless the amount of
TBAF was increased to 1 equiv (#6). At 65 °C the results were
similar, while conversion was low at r.t. (#7, 8). Various phos-
phine ligands (Figure 1) have been tested (#9–13), however,
the simplest and cheapest phosphine ligand (PPh3) afforded
the best result. Only low conversion was observed for the
much less reactive chlorobenzene using either palladium ace-
tate or chloride under identical conditions (#15–18). 1,4-Di-
phenylbuta-1,3-diyne, a common side product, was observed
at most in trace amounts. It was suggested that the addition
of small amounts of water can speed up reactions CaC2.18, 20
Previously21 we found that the H2O:CaC2 ratio is crucial for the
reaction. The current working hypothesis incolves the reac-
tions of trace amounts of water with calcium carbide, thereby,
breaking down the polymeric structure of CaC2 into smaller
particles,18 which are more readily activated with TBAF•3H2O
to form the corresponding ate-complex as illustrated in
Scheme 1. Therefore, we examined the effect of water (taking
into account that a small amount of water is introduced via
TBAF•3H2O). To facilitate optimization of the experimental
TBAF
Yield
(%)b
trace
trace
24
Entry
[Pd]
Ligand
T / °C
2a:3a
(equiv)
1c
2c
3c
0.1
0.5
0.5
0.1
0.5
1
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)2Cl2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd/C
–
120
120
120
120
120
120
65
–
–
–
–
1:2
1:100
1:3
1:100
1:5
–
4
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L1
L1
L1
L1
L1
4
5
12
6
77
7
1
75
8
1
rt
trace
6
9
1
65
2:1
–
10
11
12
13
14
15e
16e
17e
18e
1
65
<1
1
65
<1
–
1
65
66
1:100
4:1
3:1
–
1
65
5
1
65
7
1
Pd(OAc)2
Pd(OAc)2
PdCl2
65
trace
17
1
120
65
1:100
–
1
trace
19
1
PdCl2
120
1:100
aReaction conditions: 1a (0.5 mmol), Pd catalyst (5 mol %), CuI (10 mol%), TBAF•3
H2O, CaC2 (1.36 mmol), DMSO (3 mL), 24 h. bVia GC analysis. cReaction carried out conditions we first targeted the synthesis of the di-substituted
without additional ligand. eReaction performed using chlorobenzene as substrate.
product. The reaction proceeds smoothly in the presence of 3
equiv of water and results in good conversion (Table 2, #1).
Increasing the amount of CaC2 to 2.7 equiv increased the total
conversion 75% (#2). Employing larger amounts of water low-
ered the conversion (#3).
A simultaneous increase of both CaC2 and water furnished the
expected products with about the same conversions albeit
Fig. 1 Ligands used in the screening reactions.
with an increase in 2a (#4, 5). These results indicate that the
H2O:CaC2 ratio significantly affects selectivity and a molar ratio
A Pd-catalysed reaction of bromobenzene was examined to
test the suitability of CaC2/TBAF in Sonogashira reactions. The
reaction of bromobenzene with CaC2 using 0.1 equiv of
TBAF•3H2O and 5 mol% Pd(OAc)2 without additional ligand in
DMSO at 120 °C afforded the phenyl acetylene only in trace
amounts and no di-substituted product was detected (Table 1,
#1); a larger amount of TBAF did not show improvement (#2).
of 1.1:1 of water to CaC2 was chosen for optimization. A de-
crease in total conversion was observed at 90 °C although the
selectivity for 3a significantly increased. The role of solvent is
important for CaC2 activation and for Sonogashira reactions.16,
18
Therefore, a number of solvents (as well as copper sources)
were examined (Table 3). Less polar solvents like THF and
toluene gave the product 3a in low yields (Table 3, #1, 2).
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Table 3 Effects of solvents and copper catalysts on bromobenzene cross-coupling.a
alkynes 3a–e (Table 4) in good yields. The mono-coupled
product 2 was only a side reaction in 12–21% yield under these
CaC2 (1.35 mmol), Pd(OAc)2 (5 mol%)
PPh3 (20 mol%), [Cu]
conditions.
Ph Br
+
Ph
Ph
Ph
Table 4 One-pot synthesis of symmetrical bis-aryl ethynes.a
TBAF•3H2O (1 equiv)
Solvent, 65 °C
1a
2a
3a
CaC2, Pd(OAc)2, PPh3
Cu(acac)2, TBAF•3H2O
Ph Br
+
Ph
Ph
Ph
Entry
Solvent
THF
[Cu]
Yield (%)b
2a:3a
1:100
1:100
1:30
1:5
DMSO, 65 °C
1a-e
2a-e
3a-e
1
2
CuI
CuI
17
31
60
69
87
83
97
97
9
Toluene
1,4-Dioxane
NMP
3
CuI
Entry
1
Arylbromide
Yield (%)
2:3
4
CuI
83
ndb
5
DMSO
CuCl
1:8
6
DMSO
CuBr
1:3
7
DMSO
Cu(acac)2
Cu(acac)2
Cu(acac)2
1:100
1:100
2:1
2
3
90
94
nd
8c
9d
DMSO
DMSO
aConditions: 1a (0.5 mmol), CaC2 (1.36 mmol), TBAF•3H2O (1 equiv), Pd(OAc)2 (5
mol%), [Cu] (10 mol%), PPh3 (20 mol%), solvent (3 mL), 24 h, at 65 °C. bVia GC
analysis. c5 mol% of Cu(acac)2 used. dReaction at rt.
1:3
4
5
71
67
nd
In 1,4-dioxane and NMP the conversions are lower than in
DMSO (#3, 4). It has been reported that catalytic amounts of
copper(I) co-catalyst shorten the reaction times in Sonogashira
1:5
25
reactions;6, this is superior to Cassar’s procedure that re-
quires temperatures up to 100 °C using Pd(0) as the sole cata-
lyst.10 Although Cu(II) is a good catalyst for Glaser coupling of
alkynes, it has been shown that Cu(II) also efficiently catalyses
Sonogashira reactions when TBAF is used as a promoter.26
Indeed, Cu(II) species are suggested to be converted to Cu(0)
nanoparticles in the presence of reducing agents; with small
amounts of oxygen these nanoparticles are oxidized to adapt a
Cu2O shell.27 Such Cu@Cu2O core−shell nanoparꢀcles have
been suggested to be stabilized by TBA salts and have shown
excellent catalytic activity in coupling reactions.28 Cu2O nano-
particles apparently are effective catalyst in the presence of
TBAF or TBABr.29 While both CuCl and CuBr promote the reac-
tion, Cu(acac)2 was the best affording 3a in 97% at 65 °C (Table
3, #5–7). The reaction still proceeds well when the catalyst
loading was decreased to 5 mol%, providing 3a in 96% over the
course of 24 h (#8). Significant reduced conversion was ob-
served when the reaction was conducted at r.t. (#9). In anal-
ogy to earlier proposals, we reasoned that Cu(acac)2 would be
reduced in the presence of TBAF to yield Cu particles with a
Cu2O shell that is responsible for the observed catalytic activ-
ity. Disproportionation of the acetylide “ate”-complex at ele-
vated temperatures leads to low concentration of available
acetylide that favours the formation of the di-substituted
product (Table 3, #9).30
aConditions: Method A: 1 (0.5 mmol), CaC2 (1.36 mmol), TBAF•3 H2O (1 equiv),
Pd(OAc)2 (5 mol%), Cu(acac)2 (5 mol%), PPh3 (20 mol%), DMSO (3 mL), 24 h, at 65
°C. bNot determined.
The ratio of the mono- (2) to di-coupled product (3) increases
with increasing electron-donating ability of the substituent.
Bromoarenes bearing methoxy and isopropyl groups afforded
significant amounts of the valuable mono products. This find-
ing encouraged further exploration of this reaction toward
acetylene mono-substitution. We reasoned that an appropri-
ate H2O:CaC2 ratio would favour mono-substitution, and the
optimized conditions were applied to the synthesis of phenyla-
cetylene with various H2O:CaC2 ratio (Table 5). The results
demonstrate that increasing the amounts of water and CaC2
suppress the formation of di-coupled product 3a at 65 °C;
higher temperatures resulted in lower conversions (Table 5, #
1, 2). A molar H2O:CaC2 ratio of 1.3:1 turned out to be the
best. Conversion decreased dramatically when P(t-Bu)3 was
used (#7); only traces of the desired product were observed
when Pd(dppe)2NO3 was used instead of palladium acetate
(#8). Performing the reaction at 50 ᵒC led to significant de-
crease in the yield (#9). Surprisingly, the yield improved when
40 mol% of PPh3 used, indicating stabilizing effect of PPh3 be-
yond simple formation of the palladium complex (#10).31 The
reaction improved when water and TBAF were slowly added
(Table 6, #3). Other ways of adding PPh3, TBAF, and water did
not lead to improvement (#5–10), and the conditions of #4
(Table 6) were chosen for all reactions.
Although CuI gave a somewhat higher mono-substitution se-
lectivity, GC analysis of the reaction using CuI after 3 and 24 h
(Table 3, #7) showed that there is little increase in yield (72%
after 3 h, with a mono:di ratio of 1:5), while with Cu(acac)2 the
reaction was much faster and afforded a mono:di ratio of 1:3
after 3 h that progressed to 96% yield after 24 h at 5 mol%
loading. Using Bu4NF, the Sonogashira coupling of a variety of
aryl bromides with CaC2 gave the corresponding symmetric
The reaction was also performed on 2 g scale and afforded
85% of diphenylacetylene 3a according to the conditions
described in Table 4; the procedure was added to the SI. The
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Reagents / Catalystsb
PPh3 (mol%) H2O (mmol) TBAF (equiv)
reaction of 4-bromoanisole was also carried out at this scale
and the result was similar to that reported in Table 7.
Entry
Yield (%)c 2a:3a
1d
2e
3 f
4
–
–
7
–
–
66
76
67
92
89
38
81
63
41
79
9:5
1:2
3:1
3:1
2:1
5:1
2:1
3:1
6:1
1:1
Table 5 Effect of calcium carbide / water molar ratios on the selectivity of the So-
nogashira cross-coupling reaction.a
7
–
3.5
2.8
2.8
2.8
3.34
2.23
4.45
2.8
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.75
10
15
7.5
10
10
10
10
CaC2,Pd(OAc)2 (5 mol%)
PPh3 (20 mol%), Cu(acac)2 (5 mol%)
5
Ph Br
+
Ph
Ph
Ph
6
TBAF•3H2O (1 equiv), H2O, DMSO
1a
2a
3a
7
8
Entry
CaC2 (mmol)
H2O (mmol)b
T / °C
65
Yield (%)c
88
2a:3a
17:10
58:10
4:5
9
1
2
5.3
5.3
5.3
5.3
4
7
7
10
100
65
54
aReaction conditions: Schlenk tube: 1a (0.5 mmol), CaC2, TBAF•3 H2O, Pd(OAc)2 (5
3
5.4
8.7
5.7
12.5
7
86
mol%), Cu(acac)2 (5 mol%), PPh3, DMSO (3 mL), 24 h. Syringe pump: DMSO (0.3
b
4
65
91
1:2
mL), THF (0.2 mL), TBAF•3 H2O, PPh3, addition was performed during 3 h. The
5
65
75
7:10
1:1
same amounts of PPh3, water and TBAF were added to Schlenk tube unless indi-
cated otherwise. c Via GC analysis. d Schlenk tube: PPh3 (20 mol%), without addi-
6
10.6
5.3
5.3
5.3
5.3
65
100
28
e
7d
8e
9
65
5:1
tional water and TBAF (1 equiv). Schlenk tube: PPh3 (40 mol%), without addi-
tional water and TBAF (1 equiv). f Schlenk tube: PPh3 (20 mol%), water (3.5 mmol)
7
65
trace
3
–
and TBAF (0.5 equiv).
7
50
–
10f
7
50
29
5:1
Table 7 Synthesis of mono-substituted aryl ethynes.a
aConditions: 1a (0.5 mmol), CaC2, TBAF•3 H2O, Pd(OAc)2 (5 mol%), Cu(acac)2 (5
mol%), PPh3 (20 mol%), DMSO (3 mL), 24 h. bWater from TBAF•3H2O and added
water. cVia GC analysis. dP(t-Bu)3. ePd(dppe)2NO3. f40% of PPh3 used.
CaC2, Pd(OAc)2, PPh3
Cu(acac)2, TBAF•3H2O
Ar Br
+
Ar
Ar
Ar
DMSO, 90 °C
1c-j
2c-j
3c-j
Although the optimized reaction conditions afforded good
results for the parent substrate, other aryl bromides gave low
conversions in some cases. A minor modification provided a
competent alternative as outlined in Method B. This protocol
was employed for catalytic cross-coupling reactions of elec-
tron-rich bromoarenes (Table 7); 4-methoxybromobenzene
gave the mono-substituted product in moderate yield (Table 7,
entry 1).
Entry
Aryl bromide
Yield of 2 (%)
2:3
1
2
66
2:1
1:1
65
Table 6 Preferential mono-substitution Sonogashira cross coupling reaction through
3
4
5
57
28
52
4:1
ndb
nd
slow addition of activating reagents.a
Pd(OAc)2 (5 mol%), PPh3
Cu(acac)2 (5 mol%), TBAF•3H2O
Ph Br
+
Ph
Ph
Ph
CaC2 (5.3 mmol), H2O
DMSO, 65 °C
1a
2a
3a
6
57
nd
7c
55d
90
nd
8c,e
3:1
aConditions: Method B: Schlenk tube: 1 (0.5 mmol), CaC2 (11.4 mmol), TBAF•3
H2O (0.5 equiv), Pd(OAc)2 (5 mol%), Cu(acac)2 (5 mol%), PPh3 (0.2 equiv), DMSO
(3 mL), water (50 µL), 90 °C, 24 h. Syringe pump: DMSO (0.5 mL), TBAF•3 H2O (0.5
equiv), PPh3 (0.2 equiv), water (50 µL), addition over 3 h. bNot determined.
cMethod C: 1 (0.25 mmol), CaC2 (7.8 mmol), TBAF•3 H2O (0.75 equiv), Pd(OAc)2 (5
mol%), Cu(acac)2 (5 mol%), PPh3 (0.4 equiv), DMSO (3 mL), 35 °C, 24 h. dNMR
yield. eReaction with 1 mmol of starting material.
1-Bromonaphthalene gave the desired product in 35% yield
along with an interesting by-product that was isolated and
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identified by NMR as the enynes 4a and 4b with a cis:trans solution onto a silicon chip followed by freeze-drying. The
ratio of 5:1 possibly through triple bond activation via Cu(I) particle morphology was analysed by SEM showing that the
complexation followed by dimerization (Scheme S1).9 Bro- copper nanoparticles form non-uniform rods. In the case of
moarenes substituted with isopropyl, methyl, phenyl, and N,N- palladium, monodisperse amorphous spherical nanoparticles
dimethylamine gave the mono-products 2e–h in up to 57% were obtained. Further insight into the elemental composition
yield. As expected, with iodoarenes the reaction was per- was obtained from Energy Dispersive Spectroscopy (EDS) to
formed simply in one-pot without the need for a syringe pump identify the composition of each samples embedded within
to furnish the desired mono-substituted products in good the organic stabilizers. Interestingly, EDS analysis suggested
yields (Table 7, #7, 8). 3,5-Dimethyliodobenzene afforded 55% that copper nanoparticles are surrounded by DMSO while the
of the mono-product. 4-Ethynyl-1,2-dimethoxybenzene could palladium nanoparticles are stabilized by the phosphine lig-
be obtained in good yield that is comparable to its two step ands. 31P NMR analysis showed that contrary to palladium,
synthesis of via silyl protected acetylene.32
there is no need for phosphine for the reduction of copper (II)
In order to elucidate the role of nanoparticles in our reaction, with DMSO acting as a capping and reducing agent.36 In fact,
the reaction conducted in the absence of copper salt using PPh3 essentially remained untouched when Cu nanoparticles
10% of TBAF was monitored by analyzing the samples with formed, whereas Pd(II) species react with PPh3 as a reducing
GC/MS and (appropriately prepared) TEM. The results show agent to afford PPh3O and the Pd(0); this process is aided by
that no product was observed after 4 h and that the sample extra amounts of PPh3 (Figure 4 and 5)..
does not contain Pd nanoparticles. However, the reaction It has been reported that electron-rich phosphine ligands can
immediately started when we increased the amount of TBAF significantly improve the efficiency of cross-coupling reac-
to one equivalent, and simultaneous analysis of the tions;1 however, they are highly prone to oxidation.37 This
appropriately prepared sample by TEM showed the presence implies that phosphine oxidation by water competes with the
of Pd nanoparticles. Therefore, we reasoned that the Pd desired reduction of Pd(II) to Pd(0) and prevents the formation
nanoparticles are likely to be involved in the catalysis as well. of Pd nanoparticles. Competitive phosphine oxidation is evi-
Although the role of TBAF is not fully understood, it has been dent from using P(t-Bu)3 as the yield of reaction decreases to
suggested that Pd nanoparticles form from the reaction of 28% when the amount of water rises (Table 1, entry 12 and
PdCl2 with TBAF,33 exhibiting enhanced catalytic activity.34 The Table 5, entry 7). This could be the reason that why some of
reduction of Pd(II) to Pd(0) with phosphine ligands is established active phosphine ligands are not effective in this
accelerated in the presence of F–, which makes it possible to system (Figure 1).
generate palladium and copper nanoparticles without the
addition of reducing agents.35
PPh3
PPh3O
Cu NP
Fig. 2 Scanning electron micrographs image and EDX spectrum of copper nano-
particles generated under the conditions identical to those of Table 4.
Fig. 4 31P NMR (DMSO-d6) investigation of triphenylphosphine and the corresponding
phosphine-stabilized nanoparticles.
The formation of palladium nanoparticles stabilized by
triphenylphosphine was also investigated using 31P NMR spec-
troscopy. As we mentioned above, TBAF facilitates the for-
mation of Pd(0) using PPh3 as reducing agent. However, the
resulting active Pd(PPh3)4 complex is not stable and easily dis-
sociates38 and could further oxidized the free PPh3 ligands and
Fig. 3 Scanning electron micrographs and EDX spectrum of palladium nanoparti-
cles generated under the conditions identical to those of Table 4.
affords non-coordinating P(O)Ph3.39 This could be readily con-
firmed by 31P NMR of Pd(PPh3)4. The 31P NMR spectra show a
3
On the other hand, it has been shown that phosphine ligands
strong peak at 28.97 ppm in CDCl3 assigned to P(O)Ph3.
coordinate to palladium nanoparticles to produce stabilized
monodisperse palladium nanoparticles.31
Negishi et al. reported that Pd(PPh3)4 acts as a pre-catalysts for
cross coupling reactions and an 14-electron species, with
The possible formation of palladium and copper nanoparticles
“Pd(PPh3)2” as the actual catalyst undergoing oxidative addi-
tion with organic halides.40
were investigated distinctly using TBAF and PPh3 in DMSO at
65 °C. The samples were prepared by placing a drop of this
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Organic & Biomolecular Chemistry
Fig. 7 TEM image of palladium nanoparticles and particle size distribution histo-
gram calculated from TEM.
We investigated the stabilization effect of phosphine ligands
on palladium nanoparticles (Figure 5). It is known that the co-
ordination of phosphine ligands on palladium induces a down-
field shift in the 31P NMR. According to the previous reports
we reasoned that the peak at 20.0 ppm and both at 23.2 and
23.6 result from Pd(PPh3)3 and Pd(PPh3)2. The peak at 29.0
ppm corresponds to P(O)Ph3 produced from oxidation of PPh3.
Finally, we assigned the peak at 33.1 ppm to PPh3 coordinated
on the Pd nanoparticles.
Conclusions
We have developed cheap, simple, mono- and bis-substitution
protocols for bromoarenes utilizing CaC2 as the acetylide
source. 31P NMR studies confirm that Pd(II) were reduced in
the presence of PPh3 to produce the active Pd(0) species that
are stabilized with PPh3; Cu(I) salts were employed as co-
catalysts as these accelerate the coupling reactions. SEM and
TEM analyses reveal the presence of Pd(0) and Cu(0)
nanoparticles as the actual catalysts; these are stabilized by
the phosphine ligands.
To the best of our knowledge, this is the first report on the use
of bromoarenes for the direct formation of aryl-substituted
acetylenes utilizing CaC2 as the acetylide source. For mono-
substituted aryl acetylenes, this route represents operational
and cost improvements over the two step synthesis of termi-
nal alkynes by eliminating the need for protection-deprotec-
tion of acetylene. The reaction benefits from slow addition of
reagents that reduces di-substitution. Increased mono-func-
tionalization was achieved for iodoarenes with product yields
comparable with established (but more expensive) two-step
methods.
Fig. 5 31P NMR (CDCl3) investigation of triphenylphosphine-stabilized palladium nano-
particles.
Experiment
General information
All chemicals were purchased from Aldrich, Alfa Aesar, Fluo-
rochem and Acros Organics in reagent grade or better quality
and used without further purification. All reactions were car-
ried out under an argon atmosphere in a Schlenk tube. Anhy-
drous solvents (dioxane, NMP, THF and Toluene) were dried
before use. DMSO was dried using molecular sieves (3 Å). The
water content was determined to be 12.5 ppm using Karl
Fischer titration. Analytical thin-layer chromatography (TLC)
was performed on plastic-backed silica gel 60 coated with a
fluorescence indicator. Visualization of TLC plate was per-
formed by UV (254 nm) or permanganate/ phosphomolybdic
acid stains. Flash column chromatography was conducted us-
Fig. 6 TEM image of copper nanoparticles and particle size distribution histogram
calculated from TEM.
Transmission electronic microscopy (TEM) measurements re-
veal the formation of nanoparticles with average particle sizes
of 2.5 and 2.3 nm for copper and palladium nanoparticles,
respectively. The TEM images indicate that the Cu nanoparti-
cles are non-uniform whereas the Pd nanoparticles are spheri-
cal (Figures 6 and 7).
1
ing Merck silica gel 60 (0.040–0.063 mm). H and 13C spectra
were measured with Bruker spectrometer Avance II 200 Hz (AV
200), Avance II 400 MHz (AV 400) and Avance III 600 MHz (AV
600), using TMS as the internal standard. Chemical shifts are
reported in parts per million (ppm). The progress of reactions
was monitored by GC-MS analyses with a Quadrupol-MS HP
MSD 5971(EI) and HP 5890A GC equipped with a J & W Scien-
tific fused silica GC column (30 m × 0.250 mm, 0.25 micron
DB–5MS stationary phase: 5% phenyl and 95% methyl silicone)
using He (4.6 grade) as carrier gas; T-program standard 60–250
°C (15 °C/min heating rate), injector and transfer line 250 °C.
Calcium carbide (Acros Organics, 97%) was powdered using
6 | Org. Biomol. Chem., 2017, 00, 1-7
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Paper
mortar and pestle. TBAF•3 H2O was used as 0.5 M stock solu- 1,2-Bis(4-methoxyphenyl)acetylene (3c).43 1H NMR (400 MHz,
tion in DMSO.
CDCl3) δ 7.44 (d, J = 8.8 Hz, 4H), 6.86 (d, J = 8.9 Hz, 4H), 3.81 (s,
6H); 13C NMR (101 MHz, CDCl3) δ 159.4, 132.9, 115.7, 114, 88,
55.3.
1,2-Bis(2-naphthyl)acetylene (3d).44 1H NMR (400 MHz, CDCl3)
δ 8.63 (d, J = 8.3 Hz, 2H), 7.90 – 7.95 (m, 6H), 7.52 – 7.70 (m,
6H); 13C NMR (101 MHz, CDCl3) δ. 133.3, 130.6, 128.9, 128.4,
126.9, 126.5, 126.3, 125.4, 121.1, 92.4.
1,2-Bis(4-isopropylphenyl)acetylene (3e).45 1H NMR (400 MHz,
CDCl3) δ 7.45 (d, J = 8.3 Hz, 4H), 7.20 (d, J = 8.1 Hz, 4H), 2.91
(sept, J = 6.8 Hz, 2H), 1.25 (d, J = 6.9 Hz, 12H); 13C NMR (101
MHz, CDCl3) δ 149.1, 131.6, 126.5, 120.8, 88.8, 34.1, 23.8.
1-ethynyl-4-methoxybenzene (2c).46 1H NMR (400 MHz, CDCl3)
δ 7.44 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.9 Hz, 2H), 3.81 (s, 3H),
3.01 (s, 1H). 13C NMR (101 MHz, CDCl3) δ 159.9, 133.6, 114.2,
113.9, 83.7, 75.8, 55.3.
1-ethynylnaphthalene (2d).47 1H NMR (400 MHz, CDCl3) δ 8.36
(d, J = 8.3 Hz, 1H), 7.83 (d, J = 8.3 Hz, 2H), 7.73 (d, J = 7.1 Hz,
1H), 7.54 (m, 2H), 7.40 (t, J = 8.3, 1H), 3.46 (s, 1H). 13C NMR
(101 MHz, CDCl3) δ 133.5, 133.1, 131.3, 129.3, 128.3, 127.0,
126.5, 126.1, 125.1, 119.8, 82.0, 81.8.
1-Ethynyl-4-isopropylbenzene (2e).48 1H NMR (400 MHz,
CDCl3) δ 7.35 (d, J = 8.3 Hz, 2H), 7.11 (d, J = 8.0 Hz, 2H), 2.95 (s,
1H), 2.83 (sept, J = 6.9 Hz, 1H), 1.17 (d, J = 6.9 Hz, 6H). 13C NMR
(101 MHz, CDCl3) δ 149.8, 132.1, 126.5, 119.4, 83.9, 76.4, 34.1,
23.8.
1-ethynyl-4-methylbenzene (2f).46 1H NMR (400 MHz, CDCl3) δ
7.38 (d, J = 8.1 Hz, 2H), 7.12 (d, J = 7.9 Hz, 2H), 3.02 (s, 1H),
2.35 (s, 3H); 13CNMR (100 MHz, CDCl3) δ 139.0, 132.0, 129.1,
119.1, 83.9, 76.4, 21.5.
4-Ethynyl-1,1-biphenyl (2g).49 1H NMR (400 MHz, CDCl3) δ 7.59
– 7.56 (m, 6H), 7.46 – 7.42 (m, 2H), 7.38 – 7.34 (m, 1H), 3.12 (s,
1H); 13C NMR (101 MHz, CDCl3) δ 141.6, 140.3, 132.6, 128.9,
127.7, 127.1, 127.0, 121.0, 83.6, 77.8.
4-Ethynyl-N,N-dimethylaniline (2h).50 1H NMR (200 MHz,
CDCl3) δ 7.36 (d, J = 8.9 Hz, 2H), 6.61 (d, J = 8.9 Hz, 2H), 2.97 (s,
1H), 2.96 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 150.4, 133.2,
111.7, 108.7, 84.9, 74.8, 40.1.
General procedures
Method A: An oven-dried Schlenk tube equipped with a mag-
netic stir bar under argon atmosphere was charged with
Pd(OAc)2 (5.6 mg, 0.025 mmol), Cu(acac)2 (6.6 mg, 0.025
mmol), PPh3 (27 mg, 0.1 mmol) and DMSO (3 mL) and the solu-
tion was purged with argon (5 min). Then TBAF stock solution
(0.5 mmol, 1 mL), calcium carbide (0.09 g, 1.36 mmol) and
arylbromide (0.5 mmol) were successively added to the solu-
tion. The mixture was stirred at 65 °C for 24 h. The reaction
was allowed to reach room temperature and quenched with
an aqueous ammonium chloride solution (5%), extracted with
diethyl ether and washed with brine. The organic layer was
dried over Na2SO4, concentrated in vacuo, and the crude prod-
uct was purified by column chromatography to give the de-
sired product.
Method B: An oven-dried Schlenk tube equipped with a mag-
netic stir bar under argon atmosphere was charged with
Pd(OAc)2 (5.6 mg, 0.025 mmol), Cu(acac)2 (6.6 mg, 0.025
mmol), PPh3 (27 mg, 0.1 mmol) and DMSO (3 mL) and the solu-
tion was purged with argon (5 min). Then TBAF stock solution
(0.25 mmol, 0.5 mL), calcium carbide (0.76 g, 11.4 mmol), wa-
ter (50 µL) and arylbromide (0.5 mmol) were successively
added to the solution. A solution of DMSO (0.5 mL), TBAF stock
solution (0.25 mmol, 0.5 mL), PPh3 (27 mg, 0.1 mmol) and wa-
ter (50 µL) was prepared and added to the aforementioned
mixture via syringe pump at a rate of 0.3 mL/h at 90 °C for 24
h. The reaction was allowed to reach room temperature and
quenched with aqueous ammonium chloride solution (5%),
extracted with diethyl ether and washed with brine. The or-
ganic layer was dried over Na2SO4, concentrated in vacuo, and
the crude product was purified by column chromatography to
give the desired product.
Method C: An oven-dried Schlenk tube equipped with a mag-
netic stir bar under argon atmosphere was charged with
Pd(OAc)2 (2.8 mg, 0.0125 mmol), Cu(acac)2 (3.3 mg, 0.0125
mmol), PPh3 (27 mg, 0.1 mmol) and DMSO (3 mL) and the solu-
tion was purged with argon (5 min). Then TBAF stock solution
(0.19 mmol, 380 µL), calcium carbide (0.52 g, 7.8 mmol) and
aryl iodide (0.25 mmol) were successively added to the solu-
tion. The mixture was stirred at 35 °C for 24 h. The reaction
was quenched with an aqueous ammonium chloride solution
(5%), extracted with diethyl ether and washed with brine. The
organic layer was dried over Na2SO4, concentrated in vacuo,
and the crude product was purified by column chromatog-
raphy to give the desired product.
3,4-Dimethoxyphenylacetylene (2i).51 1H NMR (400 MHz,
CDCl3) δ 7.10 (dd, J = 8.3, 1.9 Hz, 1H), 6.99 (d, J = 1.9 Hz, 1H),
6.80 (d, J = 8.3 Hz, 1H), 3.89 (s, 3H), 3.87 (s, 3H), 3.00 (s, 1H).
13C NMR (101 MHz, CDCl3) δ 149.9, 148.6, 125.5, 114.8, 114.2,
111.0, 83.8, 75.6, 55.9.
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