Aqueous Sonogashira coupling of aryl halides with 1-alkynes under mild conditions: Use of surfactants in cross-coupling reactions

Article abstract of DOI:10.1039/c5ra00505a

Aqueous Sonogashira coupling between lipophilic terminal alkynes and aryl bromides or iodides gave moderate to high yields at 40°C using readily available and inexpensive surfactants (2.0 w/v% in water) such as SDS and CTAB. The catalyst precursor was 2 m

Full text of DOI:10.1039/c5ra00505a

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Aqueous Sonogashira coupling of aryl halides with
1-alkynes under mild conditions: use of surfactants
Cite this: RSC Adv., 2015, 5, 18960
in cross-coupling reactions†
Gina M. Roberts, Wenya Lu and L. Keith Woo*
Aqueous Sonogashira coupling between lipophilic terminal alkynes and aryl bromides or iodides gave
ꢀ
moderate to high yields at 40 C using readily available and inexpensive surfactants (2.0 w/v% in water)
3 2 2
such as SDS and CTAB. The catalyst precursor was 2 mol% Pd(PPh ) Cl , and included a 5 mol% Cu(I)
co-catalyst for aryl iodide substrates. Aryl-bromide reagents were found to be inhibited by iodide and
Cu(I). Studies under Cu(I)-free conditions reveal two competing pathways. A deprotonation pathway
gives rise to the traditional Sonogashira product (3), while a carbopalladation pathway produces enyne, 5.
The surfactant solution (SDS or CTAB) can be recycled up to three times for coupling between 1-octyne
and 1-iodonapthalene in the presence of CuI before the yields decrease.
Received 9th January 2015
Accepted 6th February 2015
DOI: 10.1039/c5ra00505a
www.rsc.org/advances
approaches include the use of biphasic water-organic solvent
systems; water-miscible organic co-solvents; phase transfer
Introduction
The biological and environmental hazards and resulting costly catalysts; and substrates or ligands with polar moieties (e.g.
processing and disposal of traditional organic solvents have sulfonates, quaternary amines, hydroxyls, and sugars).
1a–e
stimulated demands for more benign reaction media.
As a However, these methods still depend on organic solvents and
result, substantial effort has been directed towards developing can reduce substrate scope. Alternatively, a simple strategy is
new catalysis technology in non-traditional media such the use of surfactants to create micelles with an organic interior
2
3a–i
as ‘solvent-free’ conditions, ionic liquids,
supercritical or pocket that can entrain organic substrates in water. Even
3e,4a–f
3e,5a–c
6a–l

uids,
uorous solvents,
and water.
Industrial though the core of a micelle is largely hydrophobic, the interior
criteria for these technologies to be adopted as a reliable green can have regions of varying polarity, allowing incorporation of
9a–c
approach include adherence to the ‘twelve principles of green reagents that are both polar and nonpolar.
chemistry’, a low value for the ‘E-factor’, and economically
Studies on the scope of surfactant inuence on aqueous
7a–c
competitive production costs. Under these constraints, water metal-mediated reactions have been limited, largely due to the
stands out as a particularly attractive alternative, due to its
abundance, low expense, and nontoxic properties.
The versatility and utility of cross-coupling reactions in
8a–d
synthetic chemistry are well documented.
Traditional
coupling conditions employ a variety of organic solvents with
physical characteristics that match the needs of the desired
reaction. Limiting the reaction medium to water introduces
solubility and reactivity complications for catalysts and organic
reagents. For some reactions, such as the Diels–Alder cycload-
dition, aqueous solubility is a minimal concern because rates
and yields are enhanced by hydrophobic effects encountered by
6j,l
the nonpolar reagents in water.
However, most metal-
mediated cross-coupling reactions require additional methods
to solubilize reagents and improve reactivity in water. Common
Department of Chemistry, Iowa State University, Ames, Iowa 50011-3111, USA. E-mail:
kwoo@iastate.edu
Fig.
1 Representative surfactants, ligands and palladium catalyst
11b,c
†
Electronic supplementary information (ESI) available: Tables on effects of
employed in Lipshutz's work.
1
surfactant concentration and pH on yields; H NMR spectra, GC, and MS
characterization data for coupling products. See DOI: 10.1039/c5ra00505a
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common belief that surfactants are relatively interchangea- Table 1 Surfactant screening for the Sonogashira coupling of aryl
a
6h,9b,10a–m
halides with 1-octyne
ble.
Within the last decade, the development of versatile,
three-component designer surfactants derived from vitamin E
10g,k,11a–d
(Fig. 1) has been pioneered by Lipshutz.
These “green”
surfactants have proven to be very useful for Pd-catalyzed cross
couplings and Ru-catalyzed metathesis, providing a noticeable
decrease in reaction temperature and time.
To explore the inuence of surfactants on Pd-catalyzed cross
couplings, we turned our attention to a systematic study of the
12a–d
Sonogashira reaction
using commercially available surfac-
b
tants. However, only a few examples of aqueous Sonogashira
reactions are reported, with even fewer that incorporate sur-
% yield 3
c
Entry
R
X
Surfactant
(CuI)
(No CuI)
10b,d,h,i,l,11b,13
factants.
Herein, we explore the inuence of inex-
pensive, commercially available surfactants on the Sonogashira
cross-coupling reaction and provide additional insight on the
catalytic cycle, inuence of Cu(I) salts, and the recyclability of
the surfactant solution.
1
2
3
4
5
6
7
8
9
CN
CN
CN
CN
OMe
OMe
OMe
OMe
CN
I
I
I
I
I
I
I
I
Br
Br
Br
Br
Na cholate
CTAB
SDS
Triton X-100
Na cholate
CTAB
Quant.
97
Quant.
Quant.
74
92
85
68
24
48
57
61
58
30
38
30
29
42
57
55
44
SDS
Results and discussion
Triton X-100
Na cholate
CTAB
SDS
Triton X-100
In this study, we employed four common, inexpensive surfac-
tants (Fig. 2), sodium cholate (critical micelle concentration,
CMC, 0.388–0.603% w/v%), cetyl trimethylammonium bromide 12
1
1
0
1
CN
CN
CN
20
16
32
(
0
CTAB; CMC 0.32 w/v%), sodium dodecylsulfate (SDS; CMC
.173–0.230 w/v%), and Triton X-100 (CMC 0.0155 w/v%).
a
Reaction conditions: 0.08 mmol aryl halide, 0.1 mmol 1-octyne,
0.24 mmol piperidine, 2.0 mol% Pd(PPh ) Cl , 0.8 mL surfactant in
9a,14
3
2
2
ꢀ
b
1
H
2
5
O, 40 C, 4 h. Average H NMR yields for duplicate runs (ꢁ3).
For convenience and economics, air-stable Pd(PPh ) Cl was
3
2
2
c
mol% CuI.
selected as the catalyst for this modication of the Sonogashira
coupling. This catalyst also provided an additional benchmark
due to its ubiquitous use in Cu(I) co-catalyzed couplings.
Furthermore, complexes such as PdCl
2
, Na
2
PdCl
4
, and Pd(OAc)
2
of sodium cholate and Triton X-100 led us to focus on the more
in the absence of phosphine ligands were not effective catalysts effective surfactants, SDS and CTAB, in subsequent studies.
for coupling under the conditions used herein.
Within this initial screening, it was also found that copper
iodide strongly hindered the coupling of 4-bromobenzonitrile
and octyne with all four surfactants. Moreover, reactions with
the electron-rich 4-bromoanisole provided no coupling product
within 4 h. Aryl chlorides, such as p-nitrophenyl chloride, were
generally unreactive and not examined further.
Variation of the concentration of the surfactant for both SDS
and CTAB indicated that a 2.0 w/v% solution of each surfactant
provided optimal yields (Tables S1–S2†). Product yields were
greatly reduced at lower surfactant concentrations, albeit still
above the CMC, possibly due to an inadequate quantity of
micelles to sufficiently solubilize the organic reagents. CTAB is
not soluble at concentrations higher than 2.0 w/v% at room
temperature. However, SDS is soluble at room temperature,
even at concentrations of 8.0 w/v%, although concentrations
this high did not improve coupling activity.
Surfactant screening
Initial screening of surfactants for the coupling of 1-octyne with
an electron decient aryl iodide, 4-iodobenzonitrile, indicated
that each surfactant was able to facilitate quantitative coupling
when using a concentration of 2.0 w/v%, as long as CuI was
present (Table 1). When the aryl halide was switched to the more
electron rich 4-iodoanisole, differences between the efficacy of
the surfactants emerged. Lower coupling yields in the presence
Effect of base on Sonogashira coupling
In addition to surfactants, a variety of bases were also screened
using SDS and CTAB in the presence and absence of CuI (Table
S3†). Addition of base aids in proton abstraction during alky-
nylation of the metal center (either Cu or Pd) and facilitates the
12b,d,15
elimination of product from the Pd center.
soluble inorganic bases such as K CO , NaOAc, and Cs
resulted in low to no coupling product. However, NEt
Overall, water-
2
3
2
CO
3
Fig. 2 Surfactants used in this work.
3
,
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piperidine and pyrrolidine enabled coupling in high yields. Due Table 3 Sonogashira coupling of various aryl-Br in the presence of
a
SDS and CTAB
to improvement of yields and ease of handling, piperidine was
selected as the base of choice for this study. Since the properties
of the head group (carboxylate, sulfate, amine, etc.) of a
surfactant can affect pH, possibly altering the efficacy of the
base, the pH of the Sonogashira reaction conditions was
monitored (Table S4†). A 2.0 w/v% solution of each surfactant
had different pH values before addition of the Sonogashira
reagents. However, once piperidine was added to the solution,
ꢀ
the pH changed to ꢂ11.0 at 40 C and remained constant
throughout the reaction, regardless of the surfactant.
b
%
yield 3
Functional group tolerance of Sonogashira coupling in the
presence of surfactant
c
Entry
R
Surfactant (No CuBr) (CuBr) Yield 4a (mmol)
1
2
3
4
5
6
CN
CN
NO
NO
CHO
CHO
Napthyl SDS
Napthyl CTAB
Me
Me
SDS
CTAB
SDS
CTAB
SDS
CTAB
67
63
64
74
67
63
68
67
23
45
22
35
29
41
8
20
8
9
4
10
8
10
7
14
20
9
17
12
8
10
15
9
13
6
As shown in Table 2, the optimized aerobic reaction conditions
for the Sonogashira coupling of aryl iodides with 1-octyne was
2
2
Table 2 Sonogashira coupling of various aryl-I in the presence of SDS
d
a
7
8
and CTAB
d
9
SDS
CTAB
SDS
1
1
1
0
1
2
OMe
OMe
CTAB
9
8
a
Reaction conditions: 0.08 mmol aryl halide, 0.10 mmol 1-octyne,
.24 mmol piperidine, 2.0 mol% Pd(PPh Cl , 0.80 mL surfactant
O), 40 C, 20 h. Average H NMR yields for duplicate
0
3
)
2
2
ꢀ
b
1
(2.0 w/v% in H
2
c
d
runs (ꢁ3). Yield of 4a in mmol for reactions containing CuBr. Aryl-
Br is 1-bromonapthalene.
b
c,d
e
Entry
R
CuX
Surfactant
% yield 3
Yield 4a
general and tolerant of a range of functionalities on the aryl
substrate. Both electron decient and electron rich p-substitu-
ents afforded high yields of coupled product. When using aryl
bromide substrates, moderate yields were also obtained (Table
1
2
3
4
5
6
7
8
9
CN
CN
CN
CN
CuI
CuBr
CuI
CuBr
CuI
CuBr
CuI
CuBr
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuBr
CuI
CuBr
CuI
CuBr
CuI
CuBr
CuI
CuI
CTAB
CTAB
SDS
97 (57)
12
12
11
10
9
10
10
9
14
18
17
13
18
17
16
17
18
18
13
13
16
12
10
9
Quant. (57)
Quant. (61)
Quant. (61)
Quant. (68)
97 (68)
Quant. (60)
90 (60)
91 (75)
92 (74)
96 (61)
Quant. (60)
89 (50)
87 (57)
97 (50)
93 (50)
90 (34)
94 (34)
92 (50)
88 (50)
81 (39)
80 (39)
SDS
CF
CF
CF
CF
3
CTAB
CTAB
SDS
SDS
CTAB
SDS
CTAB
SDS
CTAB
SDS
CTAB
CTAB
SDS
3
9
, entries 1–8), except for electron rich aryl bromides (entries
–12). While coupling was achieved with either aryl-iodides or
3
3
3
bromides, the reaction conditions were distinctly different for
these two types of halide reagents. Both CuI and CuBr increased
product yield in the coupling of aryl-iodide compounds with
NO
NO
Ac
2
2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
1-octyne, but strongly inhibited coupling of aryl-bromides,
Ac
despite the choice of surfactant or base (Tables 1, 2 and S3†).
This inhibitory effect of Cu(I) with less active aryl-halides was
noted earlier, resulting in development of alternative copper-
CO
CO
2
Me
Me
2
OMe
OMe
OMe
OMe
Me
Me
Me
Me
Napthyl
Napthyl
10d,11b,16a–f
free Sonogashira conditions.
Inhibition has been
reported to be a result of Cu(I)-catalyzed homocoupling (Glaser
coupling) of terminal alkynes, which requires oxygen to
SDS
CTAB
CTAB
SDS
SDS
CTAB
SDS
17,18
proceed.
In all of our reactions, under aerobic conditions, a
secondary diyne product was present, resulting from the
homocoupling of the alkyne (vide infra).
f
f
97 (63)
Quant. (41)
Cu(I) salt and iodide inhibition on Sonogashira coupling of
aryl bromide reagents
a
Reaction conditions: 0.08 mmol aryl halide, 0.10 mmol 1-octyne,
ꢀ
0
.24 mmol piperidine, 2.0 mol% Pd(PPh
3
)
2
Cl
2
, 40 C, 0.80 mL
b
surfactant (2.0 w/v% in H O). Rxns 1–14 ran 4 h, rxns 15–24 ran 5 h.
2
Further exploration showed that CuI was more inhibiting than
CuBr in aryl bromide reactions (Table 4). Moreover, the coupling
of 1-iodonapthalene and 4-bromobenzonitrile was assessed in
c
1
d
Average H NMR yields for duplicate runs (ꢁ3). Parenthetical
e
f
value is Cu(I)-free yield. Yield is reported in mmol. Aryl-I is
-iodonapthalene.
1
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Table 4 Effect of salt on Sonogashira coupling of aryl halides with 1-
a
octyne
c
%
yield 3
b
Entry
Aryl-X
Salt (0.2 M)
None
SDS
CTAB
1
2
3
4
5
6
7
8
9
1-Iodonapthalene
1-Iodonapthalene
1-Iodonapthalene
1-Iodonapthalene
1-Iodonapthalene
1-Iodonapthalene
4-Bromobenzonitrile
4-Bromobenzonitrile
4-Bromobenzonitrile
4-Bromobenzonitrile
4-Bromobenzonitrile
4-Bromobenzonitrile
19
86
88
26
24
22
67
0
29
64
62
47
45
86
86
45
43
39
63
10
41
62
61
24
d
CuI
CuBr
d
KCl
KBr
KI
None
d
CuI
d
CuBr
1
1
1
0
1
2
KCl
KBr
KI
a
Reaction conditions: 0.08 mmol aryl halide, 0.1 mmol 1-octyne,
ꢀ
0
.24 mmol piperidine, 2.0 mol% Pd(PPh
3
)
2
Cl
2
, 40 C, 0.80 mL
b
surfactant (2.0 w/v% in H O; 0.2 M in Salt). Rxn 1–6 ran 4 h, rxn
2
c
1
7
–12 ran 20 h. Average H NMR yields for duplicate runs (ꢁ3).
d
5
mol% CuX was used, SDS and CTAB solutions contained no salt.
Fig. 3 Effect of potassium halide salts on coupling of 4-bromo-
benzonitrile with 1-octyne. Reaction conditions: 0.08 mmol aryl
the presence of various potassium halide salts. These studies
halide, 0.1 mmol 1-octyne, 0.24 mmol piperidine, 2 mol% Pd(PPh
3
)
2
-
ꢀ
demonstrate that the 4-bromobenzonitrile reactions were Cl , 0.80 mL, surfactant solution (2.0 w/v% in water), 40 C, 20 h;
2
1
strongly inhibited by iodide. Even at a concentration of 0.05 M, average H NMR yields for duplicate runs (ꢁ3). Top: with SDS; bottom:
with CTAB.
KI lowered coupling product yield by 23% and 34% in both SDS
and CTAB respectively (Fig. 3). The reduction in Sonogashira
coupling is most likely due to competitive iodide binding to Pd,
possibly hindering the oxidative addition of the aryl bromide.
The recyclability of the surfactant solution for Sonogashira
Recycling of aqueous surfactant solution
coupling was assessed for 1-iodonapthalene and 1-octyne
Formation of an enyne product
(Fig. 4). A typical 1.0 mL scale coupling reaction between
-iodonapthalene and 1-octyne was conducted in a 1.7 mL
microcentrifuge tube. Aer 4 h, 200 mL of EtOAc was added to the
1
Coupling of phenylacetylene with aryl iodide was explored to
determine if Cu(I) could be eliminated by using a more reactive
alkyne substrate. When coupling excess phenylacetylene to
tube. The mixture was thoroughly agitated and centrifuged at
10 000 rpm for 2 min to separate the organic reagents from the
4
-iodoanisole, conversions were high to quantitative using
either SDS or CTAB as the surfactant, both with and without CuI
Table 5). However, in the absence of CuI a signicant amount
surfactant solution. This EtOAc wash, centrifugation, and sepa-
ration was done a total of three times. The aqueous surfactant
layer was removed and reused in another coupling reaction
between 1-iodonapthalene and 1-octyne. Fig. 4 illustrates that
over 3 reaction cycles, yields of coupling product remained
relatively constant, but decreased with subsequent cycles. Reuse
of the CTAB solution caused the surfactant to precipitate over
time, contributing to the subsequent lowering of yields.
(
of an enyne side product (5) was observed (Table 5). This side
product was previously observed by Djakovitch et al. and
proposed to originate from the insertion of phenylacetylene 2
into the initial Sonogashira product 3 under thermal or
palladium-catalyzed conditions (vide infra). In contrast, the
analogous enyne product, that could result from using 1-octyne
as the alkyne, was never detected under any of our reaction
conditions. When CuI was present, 5 was not detected. Instead,
16b
Product purication
quantitative Sonogashira products were produced and all excess To illustrate the ease of product purication and surfactant
4
b
phenylacetylene was converted to 1,4-diphenylbuta-1,3-diyne,
according to GC analysis.
removal, both the aryl iodide and bromide reactions were scaled
up ten-fold (Table 6). In addition to employing the optimized
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Table 5 Cu(I)-free Sonogashira coupling of aryl-halides and phenyl- eluted with the Sonogashira product during ash column
a
acetylene in the presence of SDS and CTAB
chromatography, even when using neat hexane as the eluent.
Mechanistic considerations
Copper(I) co-catalyzed Sonogashira reactions are commonly
agreed to have three fundamental steps, (1) oxidative addition of
the aryl halide to Pd(0), (2) transmetallation of the acetylide
moiety from Cu(I) to the Pd center, and (3) subsequent reductive
12d
elimination of the alkyne product (Fig. 5a). The key benet of
Cu is facilitating the formation of the Pd-acetylide, which occurs
through the formation of a Cu-acetylide intermediate (G).
However, the Cu-acetylide is also active for homocoupling under
aerobic conditions that leads to a diyne product, 4, a side-reaction
that would divert the alkyne substrate from forming the desired
Sonogashira product. In our aryl iodide system, this homocou-
pling process was not detrimental to the formation of the desired
product, 3. Moreover, homocoupling was not the cause of
reduced yields in the aryl bromide reactions. In these cases, the
formation of diyne, 4a, was low (<20 mmol) in all reactions
involving aryl bromides. The low yield in aryl bromide reactions
was also not caused by Cu-catalyzed oligomerization of 1-octyne.
No oligomers were detected in these reactions and a substantial
amount of 1-octyne remained at the end of the reaction.
b,c
b,c
Entry
Surfactant
Ratio 1a : 2b
% yield 3b
% yield 5
1
2
3
4
5
6
7
8
SDS
SDS
SDS
SDS
CTAB
CTAB
CTAB
CTAB
1 : 5
1 : 2
1 : 1
2 : 1
1 : 5
1 : 2
1 : 1
2 : 1
58 (Quant.)
75 (92)
39 (0)
19 (0)
8 (0)
72 (82)
50 (71)
8 (0)
61 (Quant.)
75 (Quant.)
65 (84)
39 (0)
21 (0)
10 (0)
6 (0)
68 (83)
a
Reaction conditions: 0.24 mmol piperidine, 2.0 mol% Pd(PPh
3
)
2
Cl
ꢀ
2
0 C, 0.80 mL surfactant (2.0 w/v% in H O), 4 h. Average H NMR
c
2
,
b
1
4
yields for duplicate runs (ꢁ3). Parenthetical value is yield in
In seeking to improve the yields of the aryl bromide reactions,
we examined the role of the alkyne substrate by varying its
amount and rate of addition (Table 7). When 1-octyne was the
limiting reagent in reactions with 1-bromonaphthalene, the
yield of product 3r was quantitative, based upon the loading of
the alkyne. As the amount of 1-octyne was increased, the yield of
presence of 5 mol% CuI, homocoupling product yield not determined.
3r decreased. However, if the alkyne was added in smaller
aliquots throughout the duration of the reaction, the yield of 3r
was signicantly improved (78%, Table 7, entry 4) as compared
to a reaction with the same loading of 1-octyne added entirely at
the beginning of the reaction (51%, Table 7, entry 3). This alkyne
0
inhibition is consistent with coordination to Pd L
2
(A), forming a
2
0
0
(
h -RC^CR )Pd L
2
complex that is less electron rich, further
decreasing the extent of oxidative addition of the aryl halide to
19
the Pd center. In support of this alkyne inhibition, 1,4-
diphenylbuta-1,3-diyne, 4b, was added to the coupling of 1-bro-
Fig. 4 Recycling of aqueous surfactant solution for the Sonogashira monapthalene and 1-octyne. For the reactions with 20 mmol
coupling between 1-iodonapthalene and 1-octyne. Each cycle was
heated at 40 C for 4 h.
(
5
25 mol%) diyne, the yield of product 3r was reduced to 51% and
3% for CTAB and SDS respectively (Table 7, entries 6 and 8).
ꢀ
Two mechanisms have been proposed for the copper-free
Sonogashira coupling: a ‘deprotonation mechanism’ and a
carbopalladation mechanism’ (Fig. 5 steps c and d, respec-
conditions developed above, all reagents were added under
argon and the aqueous surfactant solution was sparged with
argon for 30 min before addition to the reaction vessel.
Reducing the atmospheric oxygen lowered or eliminated the
formation of the homocoupling product, 4, in Cu(I) co-catalyzed
reactions and gave an increase in isolated yield for aryl-bromide
reactions. The alkyne product was easily extracted from the
aqueous surfactant solution using hexanes or ethyl acetate.
Passing the extracted solution through a plug of silica gel
eliminated trace surfactant contamination and residual cata-
lyst. Purication difficulties arose when the homocoupling
product was also present. The diyne products (4a and 4b) co-
‘
tively). Recently, a number of experimental and computational
studies indicate that the latter is more feasible than the former.
M ˚a rtensson et al. argued against the carbopalladation mecha-
nism because isolated intermediates such as F do produce
product 3 and intermediate A in the presence or absence of
16a
NEt
3
.
Additionally, a computational study for the ambient-
temperature coupling of iodobenzene and phenylacetylene
catalyzed by Pd(PPh ) produced a calculated energy barrier of
3 2
ꢃ1
4
0.4 kcal mol for the pyrrolidine-assisted b-H elimination
from intermediate F to form product 3. However, the depro-
20
tonation mechanism does not explain the formation of the side
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a
Table 6 Isolated Sonogashira coupling yields for aryl-I and aryl-Br substrates
Entry
1
Aryl halide
Alkyne
Surfactant
CTAB
CuI (5 mol%)
Product (% yield)
—
45 (3a)
2
3
4
1a
1a
1a
2a
2b
CTAB
CTAB
CTAB
CuI
—
92 (3a)
54 (3b)
96 (3b)
CuI
5
1a
CTAB
CuI
94 (3c)
6
2a
SDS
CuI
91 (3d)
7
8
1b
1b
2b
2c
SDS
SDS
CuI
CuI
96 (3e)
94 (3f)
9
2a
SDS
—
61 (3g)
10
11
12
1c
1c
1c
2a
2b
2b
SDS
SDS
SDS
CuI
—
CuI
96 (3g)
72 (3h)
97 (3h)
13
14
15
16
2a
2b
2a
2b
CTAB
CTAB
CTAB
CTAB
CuI
CuI
—
91 (3i)
98 (3j)
77 (3k)
81 (3l)
1d
1e
—
1
7
2a
SDS
—
79 (3m)
1
1
8
9
1f
1f
2b
2c
SDS
SDS
—
—
87 (3n)
80 (3o)
2
0
1
2a
2b
SDS
SDS
—
—
74 (3p)
79 (3q)
2
1g
2
2
2a
CTAB
—
63 (3r)
2
2
3
4
1h
1h
2b
2c
CTAB
CTAB
—
—
76 (3s)
66 (3t)
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Table 6 (Contd.)
Entry
Aryl halide
Alkyne
Surfactant
SDS
CuI (5 mol%)
Product (% yield)
2
5
2a
—
67 (3u)
a
Condition: 0.8 mmol aryl halide, 1.0 mmol alkyne, 3.0 mmol piperidine, 2 mol% Pd(PPh
3
)
2
Cl
2
, 5 mol% CuI if indicated, 8.0 mL surfactant
ꢀ
(2.0 w/v% in water), 40 C, under Ar, 5 h for aryl-I and 20 h for aryl-Br reactions.
product, 5. We conrmed that under our conditions diphenyl- the surfactant structure, and expanding the scope to other
acetylene does not form an enyne product with phenylacetylene, catalytic reactions.
indicating that product 5 is not due to alkyne addition to
product 3. More likely, 5 may be formed by the reaction of
Experimental
16a
intermediate F with excess alkyne.
Thus, under Cu(I)-free
conditions both mechanisms appear to be competing. When General considerations
alkyne coordinates to Pd to form intermediate C, the pathway
Surfactants, aryl halides, alkynes, bases and copper salts were
can undergo base assisted deprotonation to form Pd-acetylide,
D, or syn addition form intermediate F. Excess phenyl-
acetylene further favors the formation of product 5 from F.
When Cu(I) is present, the transmetallation step is so fast that
intermediate C may not form in high enough concentration,
disfavoring the pathway to 5.
purchased commercially ($97% purity) and used without further
purication. Bis(triphenylphosphine)dichloropalladium(II) was
prepared and characterized according to a literature procedure.
21
Surfactant solutions were prepared using deionized water. All
NMR-scale reactions were performed in 1.7 mL microcentrifuge
tubes from Corning Incorporated and were shaken with an
Eppendorf Thermomixer R for the time and temperature indi-
cated. Preparative scale reactions were performed in 20 mL glass
scintillation vials, sealed with a cap containing a Poly-Seal cone
Summary
Our work has shown that inexpensive, commercially available
surfactants such as SDS and CTAB are effective in the aqueous-
phase Sonogashira coupling for various aryl iodide and
bromide substrates with alkynes, providing a substantial
improvement of product yields achieved in neat water at the
1
liner. H NMR spectra were obtained using a Varian MR400 MHz
NMR. Mass spectra were collected on a Waters GCT GC-MS.
NMR scale procedure for the Sonogashira reaction
same temperature. Under the surfactant conditions described A suspension of 47 mg (67 mmol) Pd(PPh ) Cl was made with
3
2
2
above, both the deprotonation and carbopalladation mecha- 1.0 mL of piperidine in a 20 mL glass vial. If indicated, 168 mmol
nisms appear to be active. The deprotonation mechanism forms of CuX (X ¼ I or Br) was also included in this suspension. The
the desired Sonogashira product, but in the presence of excess suspension was sonicated until homogeneous and clear
phenylacetylene, the enyne product (5) derived from a carbo- (30 min), resulting in a bright yellow Pd solution in the absence
palladation pathway, is observed as a side-product. Copper(I) of Cu(I) and a dark green Pd solution with Cu. A 1.7 mL
salts and excess alkyne inhibit aryl bromide reactions. Conse- microcentrifuge tube was charged with 0.08 mmol aryl halide
quently, aryl bromide reactions benet from slow addition of the and 0.1 mmol alkyne, and 0.8 mL of aqueous surfactant solu-
alkyne reagent under Cu-free conditions.
Overall, use of a surfactant enhances reactivity in water and solution was added. This resulted in 0.24 mmol of piperidine,
thus minimizes the need for organic solvents. However, 1.6 mmol (2 mol%) of Pd(PPh Cl and 4.0 mmol (5 mol%) CuX
tion (2.0 w/v%). Finally, 24 mL of the sonicated base/catalyst
3
)
2
2
contaminated water is still a waste material if it cannot be per reaction. The tube was sealed, thoroughly mixed, and
ꢀ
recovered from the organic reagents and reused, detracting shaken at 1100 rpm and 40 C for the time indicated. Aer
from its green benets. Both SDS and CTAB solutions proved reaction completion, the mixture was cooled to ambient
recyclable, maintaining moderate to high yields for coupling of temperature, and 50 mL of a standard solution (400 mg mesi-
1
-iodonapthalene and 1-octyne. The efficacy and recyclability of tylene diluted to 10 mL with CDCl ) was added. The samples
3
these surfactant solutions as reaction media demonstrates that were extracted with neat CDCl3 (2 ꢄ 0.4 mL). To facilitate
these conditions are a good foundation for further modica- separation of the organic and water layers, the tubes were
tions, including utilizing a more reactive Pd-complex, varying centrifuged at 1200 rpm for 2 min aer each extraction. The
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Table 7 Influence of alkyne and diyne (4b) on coupling in Cu-free
a
aryl-bromide reactions
b
Entry
1h : 2a
4b (mol%)
Surfactant
% yield 3r
c,d
1
2
3
4
5
6
7
8
1 : 0.7
1 : 1
—
—
—
—
—
25
—
25
CTAB
CTAB
CTAB
CTAB
CTAB
CTAB
SDS
Quant. (67)
56
51
78
67
51
68
53
1 : 1.7e
1 : 1.7
1 : 1.3
1 : 1.3
1 : 1.3
1 : 1.3
SDS
a
Reaction conditions: 0.08 mmol aryl halide, 0.24 mmol piperidine,
ꢀ
2
.0 mol% Pd(PPh
3
)
2
Cl
2
, 40 C, 0.80 mL surfactant (2.0 w/v% in water).
b
1
c
Average H NMR yields for duplicate runs (ꢁ3). % yield based
d
upon the loading of 1-octyne, 0.05 mmol. Parenthetical value is
conversion of 1-bromonapthalene. 0.07 mmol 1-octyne added at
e
t ¼ 0 h and 8 h.
ꢀ
and stirred while gently heating at 40 C for the time indicated.
Aer reaction completion, all volatiles were removed under
reduced pressure, and the aqueous solution was extracted with
EtOAc (3 ꢄ 5 mL). The combined EtOAc extracts were washed
with saturated NaCl (3 ꢄ 5 mL), dried with MgSO
4
, ltered, and
all solvent was removed under reduced pressure. The crude
product was puried via ash column chromatography using
hexane or hexane/EtOAc as the eluent. Product purity was
Fig. 5 Proposed mechanism of the Sonogashira coupling in the
presence of piperidine, with and without a Cu(I) co-catalyst; (a) tradi-
1
determined via H NMR and GC-MS analysis. Characterization
tional Cu(I) co-catalyzed Sonogashira; (b) catalytic cycle for Cu(I) data for all coupling products matched literature values.
including formation of diyne, 4; (c) Cu(I)-free coupling via deproto-
nation mechanism; (d) Cu(I)-free carbopalladation cycle forming
product 5.
22
1
-Methoxy-4-(oct-1-yn-1-yl)benzene (3a). Clear oil, 161 mg,
1
9
2
1
2%; H NMR (400 MHz, CDCl
3
) d (ppm): 7.34 (d, J ¼ 8.8 Hz,
H), 6.82 (d, J ¼ 8.8 Hz, 2H), 3.81 (s, 3H), 2.39 (t, J ¼ 6.6 Hz, 2H),
.63–1.54 (m, 2H), 1.50–1.41 (m, 2H), 1.37–1.29 (m, 4H), 0.91 (t,
+
extracts were combined and passed through a plug of Al
2
O
3
and J ¼ 6.0 Hz, 3H); EI-MS: m/z (rel. intensity%) 216.1 (M , 52), 201.1
1
MgSO , into a NMR tube. Yields were determined by H NMR. (5), 187.1 (27), 173.1 (48), 158.1 (34), 145.1 (100), 130.0 (17),
4
Each reaction was performed in duplicate.
121.1 (25), 115.1 (22), 102.0 (23), 91.1 (14).
22
1
-Methoxy-4-(phenylethynyl)benzene (3b).
White solid,
1
Preparative scale procedure for the Sonogashira reaction
162 mg, 96%; H NMR (400 MHz, CDCl
3
) d (ppm): 7.54–7.51 (m,
2
H), 7.48 (d, J ¼ 9.0 Hz, 2H), 7.37–7.30 (m, 3H), 6.89 (d, J ¼ 9.0
The indicated aqueous surfactant solution (2.0 w/v%) was
sparged with Ar for 30 min. During this time, a suspension of
+
Hz, 2H), 3.84 (s, 3H); EI-MS: m/z (rel. intensity%) 208.1 (M ,
00), 193.1 (40), 165.1 (23), 139.1 (8), 115.1 (2), 104.0 (3).
1
3 2 2
47 mg (67 mmol) Pd(PPh ) Cl was made in 1.0 mL of piperidine
2
3
1
-(Cyclohex-1-en-1-ylethynyl)-4-methoxybenzene (3c). Clear
in a 20 mL glass vial. If indicated, 168 mmol of CuX (X ¼ I; 32 mg
or Br; 24 mg) was also included in this suspension. The
suspension was sonicated until the mixture became homoge-
neous and clear (30 min), resulting in a bright yellow solution in
the absence of Cu(I) and a dark green solution with Cu. Under Ar,
a 20 mL glass vial was charged with a stir bar, 0.8 mmol aryl
halide, 1.0 mmol alkyne, and 8.0 mL of the sparged aqueous
surfactant solution, and 0.24 mL of the sonicated catalyst solu-
tion. The vial was briey purged with Ar (5 min), sealed with a cap
1
oil, 155 mg, 94%; H NMR (400 MHz, CDCl
8
3
MS: m/z (rel. intensity%) 212.2 (M , 100), 197.2 (11), 184.2 (23),
1
3
) d (ppm): 7.36 (d, J ¼
.8 Hz, 2H), 6.83 (d, J ¼ 8.8 Hz, 2H), 6.21–6.18 (m, 1H), 3.81 (m,
H), 2.26–2.20 (m, 2H), 2.18–2.12 (m, 2H), 1.73–1.56 (m, 4H); EI-
+
69.2 (13), 153.1 (8), 141.1 (12), 132.1 (8), 121.1 (2), 115.1 (10).
2
2
1
-Methyl-4-(oct-1-yn-1-yl)benzene (3d). Clear oil, 151 mg,
1
9
2
1%; H NMR (400 MHz, CDCl
3
) d (ppm): 7.29 (d, J ¼ 8.0 Hz,
H), 7.09 (d, J ¼ 8.0 Hz, 2H), 2.41 (t, J ¼ 7.0 Hz, 2H), 2.34 (s, 3H),
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1
.67–1.58 (m, 2H), 1.48–1.44 (m, 2H), 1.36–1.28 (m, 4H), 0.92 (t, (78), 188.1 (63), 172.1 (22), 156.1 (53), 142.1 (70), 130.1 (100),
+
J ¼ 5.6 Hz, 3H); EI-MS: m/z (rel. intensity%) 200.2 (M , 33), 185.2 115.1 (63), 102.0 (32), 95.1 (28), 89.0 (18).
22
(3), 171.2 (13), 157.1 (45), 143.1 (33), 129.1 (100), 115.1 (23),
1-Nitro-4-(phenylethynyl)benzene (3n). Yellow solid, 152
1
105.1 (21), 91.1 (10).
mg, 87%; H NMR (400 MHz, CDCl ) d (ppm): 8.30 (d, J ¼ 9.2 Hz,
3
22
1
-Methyl-4-(phenylethynyl)benzene (3e). White solid, 149 2H), 8.16 (d, J ¼ 9.2 Hz, 2H), 7.60–7.55 (m, 2H), 7.47–7.43
1
3
mg, 96%; H NMR (400 MHz, CDCl ) d (ppm): 7.55–7.52 (m, 2H), (m, 3H); EI-MS: m/z (rel. intensity%) 206.1 (85), 178.1 (100),
7
2
1
.44 (d, J ¼ 8.0 Hz, 2H), 7.38–7.32 (m, 3H), 7.16 (d, J ¼ 8.0 Hz, 152.1 (10), 129.0 (87), 115.0 (2), 101.0 (12), 89.0 (5), 75.0 (15).
+
25
H), 2.38 (s, 3H); EI-MS: m/z (rel. intensity%) 192.2 (M , 100),
1-(Cyclohex-1-en-1-ylethynyl)-4-nitrobenzene (3o). Yellow
1
76.1 (2), 165.1 (10), 152.1 (2), 139.1 (4), 115.1 (2), 96.1 (2).
3
solid, 142 mg, 80%; H NMR (400 MHz, CDCl ) d (ppm): 8.17
24
1
-(Cyclohex-1-en-1-ylethynyl)-4-methylbenzene (3f). Clear (d, J ¼ 8.8 Hz, 2H), 7.52 (d, J ¼ 8.8 Hz, 2H), 6.32–6.29 (m, 1H),
1
oil, 153 mg, 94%; H NMR (400 MHz, CDCl ) d (ppm): 7.32 (d, 2.29–2.15 (m, 4H), 1.73–1.61 (m, 4H); EI-MS: m/z (rel.
3
+
J ¼ 8.0 Hz, 2H), 7.10 (d, J ¼ 8.0 Hz, 2H), 6.23–6.18 (m, 1H), 2.34 intensity%) 227.1 (M , 100), 235.2 (20), 212.1 (11), 199.1 (13),
(s, 3H), 2.26–2.20 (m, 2H), 2.18–2.10 (m, 2H), 1.70–1.56 (m, 4H); 180.1 (32), 165.1 (60), 152.1 (50), 139.1 (19), 127.1 (9), 115.1 (15),
+
EI-MS: m/z (rel. intensity%) 196.2 (M , 100), 181.1 (52), 165.1 102.1 (6), 98.0 (2), 89 (8).
42), 153.1 (23), 139.1 (13), 128.1 (8), 115.1 (8), 105.1 (7), 89.1 (7). 1-(Oct-1-yn-1-yl)-4-(triuoromethyl)benzene
26
(
(3p).
Pale
2
2
1
1
-(4-(Oct-1-yn-1-yl)phenyl)ethan-1-one (3g). Yellow oil, 178 yellow oil, 146 mg, 74%; H NMR (400 MHz, CDCl ) d (ppm): 7.54
3
1
mg, 96%; H NMR (400 MHz, CDCl
3
) d (ppm): 7.87 (d, J ¼ 8.4 Hz, (d, J ¼ 8.0 Hz, 2H), 7.48 (d, J ¼ 8.0 Hz, 2H), 2.43 (t, J ¼ 7.0 Hz, 2H),
2
1
H), 7.46 (d, J ¼ 8.4 Hz, 2H), 2.60 (s, 3H), 2.44 (t, J ¼ 7.2 Hz, 2H), 1.67–1.58 (m, 2H), 1.45–1.43 (m, 2H), 1.33–1.29 (m, 4H), 0.90 (t, J
+
.65–1.59 (m, 4H), 1.50–1.44 (m, 2H), 1.38–1.31 (m, 4H), 0.90 (t, ¼ 6.6 Hz, 3H); EI-MS: m/z (rel. intensity%) 254.3 (M , 48), 235.2
+
J ¼ 6.8 Hz, 3H); EI-MS: m/z (rel. intensity%) 228.2 (M , 54), 213.1 (20), 225.2 (78), 211.2 (100), 197.2 (48), 183.1 (84), 170.1 (30),
(100), 199.1 (12), 185.1 (32), 171.1 (12), 157.1 (24), 143.1 (28), 159.1 (48), 1511 (10), 143.2 (15), 129.1 (52), 115.1 (22), 95.1 (15).
23
1
29.1 (60), 114.1 (30).
1-(Phenylethynyl)-4-(triuoromethyl)benzene (3q).
Light
) d (ppm):
) d (ppm): 7.95 (d, J ¼ 8.4 7.67–7.60 (m, 4H), 7.57–7.54 (m, 2H), 7.40–7.36 (m, 3H); EI-MS:
22
1
1
-(4-(Phenylethynyl)phenyl)ethan-1-one (3h). White solid, yellow solid, 151 mg, 79%; H NMR (400 MHz, CDCl
3
1
174 mg, 97%; H NMR (400 MHz, CDCl
3
+
Hz, 2H), 7.62 (d, J ¼ 8.4 Hz, 2H), 7.59–7.54 (m, 2H), 7.40–7.36 m/z (rel. intensity%) 246.0 (M , 100), 227.1 (58), 219.1 (3), 207.1
+
(m, 3H), 2.63 (s, 3H); EI-MS: m/z (rel. intensity%) 220.1 (M , 65), (5), 196.1 (30), 185.0 (1), 176.1 (35), 169.0 (4), 157.1 (1), 151.1 (7),
2
05.1 (100), 176.1 (35), 151.1 (15), 126.1 (3), 102.5 (6), 88.0 (8).
Methyl 4-(oct-1-yn-1-yl)benzoate (3i). White solid, 178 mg,
144.0 (2), 123.0 (12), 113.5 (3), 98.0 (29).
22
27
1-(Oct-1-yn-1-yl)naphthalene (3r). Clear oil, 115 mg, 63%;
1
1
9
2
1
1%; H NMR (400 MHz, CDCl
3
) d (ppm): 7.96 (d, J ¼ 8.8 Hz,
H NMR (400 MHz, CDCl
3
) d (ppm): 8.36 (d, J ¼ 8.4 Hz, 1H), 7.85
H), 7.45 (d, J ¼ 8.8 Hz, 2H), 3.92 (s, 3H), 2.43 (t, J ¼ 7.0 Hz, 2H), (d, J ¼ 8.8 Hz, 2H), 7.79 (d, J ¼ 8.4 Hz, 1H), 7.64 (d, J ¼ 7.2 Hz,
.65–1.60 (m, 2H), 1.50–1.44 (m, 2H), 1.37–1.30 (m, 4H), 0.92 (t, 1H), 7.60–7.48 (m, 2H), 7.45–7.38 (m, 1H), 2.58 (t, J ¼ 7.0 Hz,
+
J ¼ 6.8 Hz, 3H); EI-MS: m/z (rel. intensity%) 224.2 (M , 50), 229.1 2H), 1.78–1.67 (m, 2H), 1.61–1.55 (m, 2H), 1.42–1.35 (m, 4H),
+
(
(
2), 215.1 (43), 201.1 (58), 183.1 (18), 173.1 (35), 149.1 (21), 143.1 0.95 (t, J ¼ 7.2 Hz, 3H); EI-MS: m/z (rel. intensity%) 236.2 (M ,
53), 129.1 (100), 115.1 (41), 105.1 (8), 95.1 (12), 91.1 (18). 62), 221.2 (2), 207.1 (23), 193.1 (33), 178.1 (34), 165.1 (100), 152.1
22
Methyl 4-(phenylethynyl)benzoate (3j). White solid, 177 (24), 141.1 (10), 128.1 (3), 115.1 (5).
1
27
mg, 98%; H NMR (400 MHz, CDCl ) d (ppm): 8.03 (d, J ¼ 8.3 Hz,
1-(Phenylethynyl)naphthalene (3s). White solid, 133 mg,
3
1
2
H), 7.60 (d, J ¼ 8.3 Hz, 2H), 7.57–7.54 (m, 2H), 7.39–7.36 76%; H NMR (400 MHz, CDCl
3
) d (ppm): 8.45 (d, J ¼ 8.4 Hz,
(
2
1
m 3H), 3.94 (s, 3H); EI-MS: m/z (rel. intensity%) 236.1 (95), 1H), 7.88 (t, J ¼ 8.4 Hz, 2H), 7.79 (d, J ¼ 8.0 Hz, 1H), 7.69–7.36
+
05.1 (100), 191.1 (1), 176.1 (39), 163.1 (1), 151.1 (15), 137.0 (2), (m, 8H); EI-MS: m/z (rel. intensity%) 228.1 (M , 100), 213.1 (2),
26.1 (3), 111.0 (1), 102.5 (4), 98.0 (2), 88.0 (7). 202.1 (32), 187.1 (6), 176.1 (5), 163.1 (3), 150.1 (7), 139.1 (1),
2
2
4
-(Oct-1-yn-1-yl)benzonitrile (3k). Pale yellow oil, 136 mg, 126.0 (3), 113.0 (36), 101.0 (18).
1
26
7
2
7%; H NMR (400 MHz, CDCl ) d (ppm): 7.57 (d, J ¼ 8.0 Hz,
1-(Cyclohex-1-en-1-ylethynyl)naphthalene (3t). Clear oil,
3
1
H), 7.46 (d, J ¼ 8.0 Hz, 2H), 2.43 (t, J ¼ 7.2 Hz, 2H), 1.66–1.57 119 mg, 66%; H NMR (400 MHz, CDCl ) d (ppm): 8.34 (d, J ¼ 8.4
3
(
3
(
m, 2H), 1.50–1.41 (m, 2H), 1.37–1.29 (m, 4H), 0.91 (t, J ¼ 6.6 Hz, Hz, 1H), 7.84 (d, J ¼ 8.0 Hz, 1H), 7.79 (d, J ¼ 8.0 Hz, 1H), 7.64
+
H); EI-MS: m/z (rel. intensity%) 211.2 (M , 28), 196.1 (1), 182.1 (d, J ¼ 7.2 Hz, 1H), 7.58–7.49 (m, 2H), 7.48–7.40 (m, 1H), 6.35 (s,
52), 168.1 (100), 154.1 (56), 140.1 (70), 127.1 (28), 116.1 (26), 1H), 2.36 (m, 2H), 2.22 (m, 2H), 1.79–1.64 (m, 4H); EI-MS: m/z
+
1
01.1 (2), 95.1 (11).
(rel. intensity%) 232.1 (M , 100), 217.1 (15), 203.1 (32), 189.1
2
2
4
-(Phenylethynyl)benzonitrile (3l). White solid, 135 mg, (12), 176.1 (10), 165.1 (11), 152.1 (15), 141.1 (1), 126.0 (2), 108.0
1
8
7
1%; H NMR (400 MHz, CDCl
3
) d (ppm): 7.70–7.59 (m, 4H), (3), 101.0 (7), 94.5 (3).
28
.59–7.52 (m, 2H), 7.43–7.36 (m, 3H); EI-MS: m/z (rel.
4-(Oct-1-yn-1-yl)benzaldehyde (3u). Clear oil, 11 mg, 67%;
+
1
intensity%) 203.1 (M , 100), 176.1 (4), 164.1 (1), 151.1 (2), 137.0
H NMR (400 MHz, CDCl ) d (ppm): 9.99 (s, 1H), 7.80 (d, J ¼ 8.3
3
(1), 126.0 (1), 111.0 (1), 101.5 (2), 88.0 (2).
Hz, 2H), 7.53 (d, J ¼ 8.3 Hz, 2H), 2.44 (t, J ¼ 6.8 Hz, 2H), 1.68–
2
2
1
-Nitro-4-(oct-1-yn-1-yl)benzene (3m). Yellow oil, 143 mg, 1.58 (m, 2H), 1.50–1.42 (m, 2H), 1.37–1.30 (m 4H), 0.91 (t, J ¼ 7.3
1
+
7
2
9%; H NMR (400 MHz, CDCl
3
) d (ppm): 8.16 (d, J ¼ 8.0 Hz, Hz, 3H); EI-MS: m/z (rel. intensity%) 214.2 (M , 33), 119.2 (1),
H), 7.52 (d, J ¼ 8.0 Hz, 2H), 2.45 (t, J ¼ 7.2 Hz, 2H), 1.67–1.58 185.1 (23), 171.1 (31), 157.1 (21), 143.1 (63), 129.1 (100), 115.1
(
3
m, 2H), 1.51–1.43 (m, 2H), 1.38–1.31 (m, 4H), 0.90 (t, J ¼ 6.6 Hz, (74), 102.1 (5), 95.1 (10), 91.1 (22).
+
H); EI-MS: m/z (rel. intensity%) 231.1 (M , 32), 215.1 (3), 202.1
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Procedure for recyclability study
made with 1.0 mL of piperidine in a 20 mL glass vial. The
suspension was sonicated until homogeneous and clear (30 m),
resulting in a bright yellow Pd solution. Under Ar, a 20 mL-glass
vial was charged with a stir bar, 195 mg (0.8 mmol) 4-iodoani-
sole, 0.5 mL (4.5 mmol) phenylacetylene, 8.0 mL of the sparged
CTAB solution, and 0.24 mL of the sonicated catalyst solution.
The vial was briey purged with Ar (5 min), sealed with a cap
A suspension of 47 mg (67 mmol) of Pd(PPh ) Cl and 32 mg CuI
3
2
2
was made with 1.0 mL of piperidine in a 20 mL glass vial. The
suspension was sonicated until the mixture became homoge-
neous, green, and translucent (30 min). A 1.7 mL microcentrifuge
tube was charged with 0.08 mmol 1-iodonapthalene, 0.1 mmol 1-
octyne, and 0.8 mL of aqueous surfactant solution (2.0 w/v%).
Finally, 24 mL of the sonicated base/catalyst solution was added.
This resulted in 0.24 mmol of piperidine, 1.6 mmol (2 mol%) of
Pd(PPh ) Cl and 4.0 mmol (5 mol%) CuI per reaction. The tube
ꢀ
and stirred while heated at 40 C for 24 h. At reaction comple-
tion, all volatiles were removed under reduced pressure, and the
aqueous solution was extracted with EtOAc (3 ꢄ 5 mL). The
combined EtOAc extracts were washed with saturated NaCl (3 ꢄ
3
2
2
ꢀ
was sealed, thoroughly mixed and shaken at 1100 rpm and 40 C
for 4 h. At reaction completion, the mixture was cooled to ambient
temperature and extracted with EtOAc (3 ꢄ 200 mL). To assist
separation of the organic and water layers, the tubes were
centrifuged at 1200 rpm for 2 min aer each extraction. The
extracts were combined, washed with saturated NaCl (3 ꢄ 0.5 mL),
and all volatiles removed under reduced pressure. The crude
product was puried via a short column of silica gel using hexanes
as the eluent. To the extracted surfactant solution another aliquot
of reagents and catalyst/piperidine solution were added. The
subsequent solution was treated for the same temperature and
time as before. This procedure was repeated 5 times.
5
mL) and all solvent was removed under reduced pressure. The
crude product was puried via ash column chromatography
using hexane. Product purity was determined via NMR and GC-
MS analysis.
(
Z)-(4-(4-Methoxyphenyl)but-3-en-1-yne-1,3-diyl)dibenzene
16e
1
(
3
5). Yellow solid, 210 mg, 85%; H NMR (400 MHz, CDCl )
NMR (400 MHz, CDCl ): 8.02 (d, J ¼ 9.2 Hz, 2H), 7.78 (d, J ¼ 8.0
3
Hz, 2H), 7.59–7.55 (m, 2H), 7.43–7.32 (m, 6H), 7.18 (s, 1H), 6.96
(
3
2
d, J ¼ 8.8 Hz, 2H), 3.87 (s, 3H); EI-MS: m/z (rel. intensity%)
+
10.2 (M , 100), 295.2 (31), 279.2 (19), 265.1 (23), 252.1 (18),
39.1 (9), 202.1 (8), 189.1 (14), 165.1 (10).
Acknowledgements
Preparative scale procedure for the synthesis of diyne (4)
We thank the U.S. Department of Energy (award DESC0002142)
and NSF (ERC award EEC-0813570 to the Center for Bio-
renewable Chemicals, CBiRC, at Iowa State University) for
partial support of this work.
3 2 2
A suspension of 47 mg (67 mmol) of Pd(PPh ) Cl and 32 mg CuI
was made with 1.0 mL of piperidine in a 20 mL glass vial. The
suspension was sonicated until homogeneous, translucent, and
green in color (30 min). A 25 mL round bottom ask was
charged with 0.80 mmol of aryl halide, 1.0 mmol of alkyne, and
8
.0 mL of aqueous CTAB (2.0 w/v%). Subsequently, 240 mL of the
Notes and references
sonicated catalyst solution was added. The reaction was stirred
at 40 C for 12 h without exclusion of oxygen. Aer reaction
completion, all volatiles were removed under reduced pressure,
and the aqueous solution was extracted with EtOAc (3 ꢄ 5 mL).
The combined EtOAc extracts were washed with saturated NaCl
ꢀ
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(
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The crude product was redissolved in hexane and residual
2 3
catalyst was removed by passing through a plug of neutral Al O
and silica gel. Removal of hexane under vacuum afforded pure
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3
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1
Hexadeca-7,9-diyne (4a). Clear oil: 77 mg, 69%; H NMR
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1
400 MHz, CDCl ): d 2.24 (t, J ¼ 7.0 Hz, 4H), 1.56–1.47 (m, 4H),
3
.42–1.34 (m, 4H), 1.29 (ddd, J ¼ 10.2, 8.7, 2.5 Hz, 8H), 0.89 (t,
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1
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(
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An aqueous CTAB solution (2.0 w/v%) was sparged with Ar for 30
m. While sparging, a suspension of 47 mg Pd(PPh ) Cl was
3 2 2
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