Unsymmetrical coupling of 1-chloroalkynes and terminal alkynes under experimental Sonogashira conditions

Article abstract of DOI:10.1055/s-0033-1339891

The coupling of a 1-chloroalkyne and a terminal alkyne to furnish a 1,3-butadiyne under experimental Sonogashira conditions is investigated. Through competition experiments, it is found that 1-chloroalkynes provide cross-coupling products as efficiently (or slightly better) in comparison with iodobenzenes, and almost as effectively as vinyl bromides. Yet, in regard to the degree of conversion into various products, chloroalkynes are the most reactive of all the substrates examined under the explored conditions. Optimized conditions for this cross-coupling reaction are presented. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1339891

LETTER
▌2715
lUettner symmetrical Coupling of 1-Chloroalkynes and Terminal Alkynes under
Experimental Sonogashira Conditions
Chloroalkyne Coupling Partners in Palladium-Catalyzed Reactions
Mikkel Andreas Christensen, Morten Rimmen, Mogens Brøndsted Nielsen*
Department of Chemistry, University of Copenhagen, Universitetsparken 5, 2100 Copenhagen Ø, Denmark
Fax +4535320212; E-mail: mbn@kiku.dk
Received: 23.08.2013; Accepted: 05.09.2013
substrates.7 In particular, we wanted to establish the re-
Abstract: The coupling of a 1-chloroalkyne and a terminal alkyne
activity of chloroalkynes in comparison to traditional
to furnish a 1,3-butadiyne under experimental Sonogashira condi-
Sonogashira substrates.
tions is investigated. Through competition experiments, it is found
that 1-chloroalkynes provide cross-coupling products as efficiently
(or slightly better) in comparison with iodobenzenes, and almost as
effectively as vinyl bromides. Yet, in regard to the degree of con-
simple method for generating chloroalkynes by treating a
version into various products, chloroalkynes are the most reactive
of all the substrates examined under the explored conditions. Opti-
Chloroalkynes are attractive substrates as they are rela-
tively easily accessed. For example, we have developed a
trimethylsilyl-protected alkyne precursor with silver
nitrate (AgNO3) and trichloroisocyanuric acid.8
mized conditions for this cross-coupling reaction are presented.
First, we investigated the reactivity of the known chloro-
alkyne 18 toward different alkynes under Sonogashira
conditions using diisopropylamine as the base (Scheme 1
and Table 1). Using different terminal alkynes (2.5–3.0
mol equiv) provided the corresponding butadiynes 2–5 in
good yields (see Table 1) and in short reaction times (2–3
h). The only isolated by-products were the symmetrical
diynes resulting from homocoupling of the terminal al-
kynes. When using only one molar equivalent of terminal
alkyne, reduced, but still reasonable, yields were ob-
tained.
Key words: alkynes, catalysis, copper, cross-coupling, palladium
1-Haloalkynes are precursors for the synthesis of unsym-
metrical 1,3-butadiynes. The first use of haloalkynes for
the formation of diynes was reported in 1954 by Black and
co-workers,1 who showed that iodoalkynes underwent
coupling with alkynyl Grignard reagents in the presence
of copper(I) chloride (CuCl) or cobalt(II) chloride
(CoCl2). In 1955, Cadiot and Chodkiewicz2 discovered
that bromoalkynes and terminal alkynes could be coupled
to give a diyne using a copper(I) catalyst and an amine
base. The first examples of coupling of chloroalkynes un-
der similar conditions were reported 15 years later,3 but
with diyne products being obtained in various yields. In
the 1990s, the coupling of haloalkynes and terminal al-
kynes was further refined by the addition of a palladium
co-catalyst, usually resulting in improved yields.4 Alami
and Ferri4e reported the palladium-catalyzed coupling of a
chloroalkyne and a terminal alkyne, but the unsymmetri-
cal 1,3-butadiyne was, however, obtained in rather low
yield (20–30%). Subsequently, Nishihara et al.5 devel-
oped a convenient route to unsymmetrical diynes by sub-
jecting a chloroalkyne and a trimethylsilyl-protected
alkyne to copper(I) chloride in N,N-dimethylformamide at
80 °C for 48 hours, in the absence of an amine base. They
found that addition of a palladium catalyst decreased the
yields on account of homocoupling of the chloroalkynes.
One disadvantage of the method was the need to heat the
reaction mixture for a long time, and for this reason, we
became interested in investigating, in more detail, the
scope of palladium-catalyzed cross-couplings of chloro-
alkynes and terminal alkynes under room-temperature
Sonogashira conditions6 [PdCl2(PPh3)2, CuI, amine],
which have proven so useful with aryl or vinyl halides as
R
R
Cl
PdCl2(PPh3)2, CuI
i-Pr2NH, THF
NC
NC
2 (R = SiMe3)
3 (R = Ph)
1
4 (R = 4-MeOC6H4)
5 (R = 4-O2NC6H4)
Scheme 1 Synthesis of unsymmetrical butadiynes
Table 1 Coupling of Chloroalkyne 1 with Different Terminal
Alkynes under Sonogashira Conditions
Entry
R
Alkyne
equiv
Time
Product
(yield)
1
2
3
4
5
6
7
8
SiMe3
3
2 h
2 h
2 h
2 h
3 h
3 h
3 h
3 h
2 (75%)
2 (44%)
3 (72%)
3 (44%)
4 (58%)
4 (39%)
5 (58%)
5 (35%)
SiMe3
1
Ph
3
Ph
1
4-MeOC6H4
4-MeOC6H4
4-O2NC6H4
4-O2NC6H4
3
1
2.5
1
SYNLETT 2013, 24, 2715–2719
Advanced online publication: 16.10.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1339891; Art ID: ST-2013-D0815-L
© Georg Thieme Verlag Stuttgart · New York

2716
M. A. Christensen et al.
LETTER
Having established that the chloroalkyne 1 undergoes pal- Supporting Information). In addition to the product 11,
ladium-catalyzed cross-couplings, our next objective was 1,2-diphenylethyne (12) was also formed, corresponding
to establish its reactivity in comparison to aryl halides. For to a reductive cross-coupling of 8 and iodobenzene. With
this goal we turned to competition experiments9 in which respect to GC–MS evaluation of the contents of the mix-
an approximate 1:1:1 mixture of chloroalkyne, aryl ha- tures, it should be noted that both the bromobenzene and
lide, and terminal alkyne was subjected to Sonogashira iodobenzene starting materials gave lower intensities than
conditions. We used trimethylsilylacetylene as the termi- expected from reference mixtures with compounds bal-
nal alkyne in an amount that corresponded roughly to one anced out in known ratios (see the Supporting Informa-
equivalent. The reaction mixtures, after a standard wash- tion). Moreover, some of these aryl halides were lost in
ing procedure, were analyzed by GC–MS in order to es- the intermediate work-up procedure (during evaporation
tablish the product ratios. First, a competition experiment of solvents), but this is not relevant for the ratios provided
between chloroalkyne 1 and 4-bromobenzonitrile (6) was in Table 2 and in the subsequent Tables, that only show
conducted (Scheme 2). After two hours, the mixture (fol- relative product distributions [in this regard ignoring the
lowing work-up by extraction9) was analyzed by GC–MS 1,4-bis(trimethylsilyl)buta-1,3-diyne product], and not in-
(see the Supporting Information). Apart from some buta- cluding unreacted starting materials.
diyne generated by homocoupling of trimethylsilylacety-
lene (indicating that it was present in some excess), only
SiMe3
the diyne cross-coupling product 2 was formed. A signal
due to unreacted 4-bromobenzonitrile was observed,
while no signals corresponding to unreacted chloroalkyne
1 or the cross-coupling product 7 were evident.
Ph
9
Cl
SiMe3
SiMe3
Ph
Ph
8
PdCl2(PPh3)2, CuI
10
SiMe3
Ph
Cl
i-Pr2NH, THF
Ph
X
X = Br or I
Ph
SiMe3
11
12
NC
NC
PdCl2(PPh3)2, CuI
Ph
2 (formed)
1
6
SiMe3
i-Pr2NH, THF
Ph
Br
Scheme 3 Competition experiments. Reagents and conditions:
PdCl2(PPh3)2 (5 mol%), CuI (5 mol%), 2 h, r.t. For product ratios, see
Table 2.
NC
NC
7 (not formed)
Scheme 2 Competition experiment. Reagents and conditions:
PdCl2(PPh3)2 (5 mol%), CuI (5 mol%), 2 h, r.t.
Table 2 Outcomes of the Competition Experiments (cf. Scheme 3);
Product Distributions Based on GC–MS Analysis
Next, we studied the reactivity of the parent chloroethy-
nylbenzene 88 in comparison to bromo- and iodobenzene
(Scheme 3). The conversions after two hours of reaction
are shown in Table 2. GC–MS analysis (see the Support-
ing Information) revealed that, in the presence of bromo-
benzene, the chloroalkyne underwent conversion into the
butadiyne cross-coupling product 9 (but unreacted chloro-
alkyne was also present after 2 h), while the product 10
was not formed from bromobenzene (Table 2, entry 1).
Thus again, this experiment signals the higher reactivity
of a chloroalkyne in comparison to bromobenzene. In ad-
dition, we identified a product in substantial amount,
which we assigned as the butadiyne 11. Formation of this
product can be explained by a reductive homocoupling of
two chloroalkynes, as previously reported for the coupling
of bromo- and iodoalkynes.4c,d,10 Using instead iodoben-
zene as the competing coupling partner, we found from
two independent experiments (Table 2, entries 2 and 3)
that the products 9 and 10 formed in almost equal
amounts. To verify the accuracy of the method, a mixture
of 9 and 10, prepared from the pure compounds, was ana-
lyzed by 1H NMR spectroscopy and GC–MS; both meth-
ods gave similar ratios between the two species (see the
Entry
Ph–X
9 (%)
10 (%)
11 (%)
12 (%)
1
2
3
Ph–Br
Ph–I
61
34
35
0
33
31
39
14
14
0
19
20
Ph–I
The different reactivities of the chloroalkyne and aryl bro-
mide functionalities should allow for selective coupling
reactions. Subjecting compound 13 and trimethylsi-
lylacetylene to Sonogashira conditions furnished the
diyne product 14 in an isolated yield of 63% (Scheme 4).
GC–MS analysis of the crude reaction mixture also re-
vealed the presence of by-products 15 and 16, but only in
minor quantities.
Vinyl bromides are usually more reactive than iodoben-
zenes in the Sonogashira coupling,7 and are hence also ex-
pected to be more reactive than chloroalkynes. A
competition experiment between the bromostyrene 17 and
the chloroalkyne 8 was performed (Scheme 5 and Table
3), the outcome of which revealed a ratio (1.2–1.3) be-
tween cross-coupling products 18 and 9 in favor of enyne
Synlett 2013, 24, 2715–2719
© Georg Thieme Verlag Stuttgart · New York

LETTER
Chloroalkyne Coupling Partners in Palladium-Catalyzed Reactions
2717
SiMe3
Table 3 Outcomes of the Competition Experiments (cf. Scheme 5;
Two Independent Experiments); Product Distributions Based on GC–
MS Analysis
Cl
SiMe3
PdCl2(PPh3)2, CuI
Entry
9 (%)
18 (%)
11 (%)
19 (%)
Br
Br
i-Pr2NH, THF
14
13
1
2
28
33
36
39
14
15
22
13
63%
Br
SiMe3
Next, we studied the influence of having an alkyl group
instead of an aryl group on the chloroalkyne. Scheme 6
and Table 4 show the results of competition experiments
between 1-chloro-1-octyne (20) and aryl halides. It was
evident that 20 was significantly more reactive than bro-
mobenzene (product 21 was formed almost exclusively,
Table 4, entries 1 and 2). In comparison to iodobenzene,
more of the cross-coupled product was obtained from 20,
as revealed by the ratio between products 10 and 21 of ap-
proximately 1.4 (Table 4, entries 3 and 4). Again it is note-
worthy that while both halobenzene substrates were
observed by GC–MS after two hours of reaction, no signal
from the chloroalkyne 20 was evident.
Me3Si
Br
15
16
GC–MS ratio: 14/15/16 93:5:2
Scheme 4 Selective cross-coupling reaction
18, from two independent experiments. Yet, when com-
paring GC–MS and NMR ratios of a preformed mixture of
the two compounds, it seems that GC–MS overestimates
the content of 18 (see the Supporting Information) (by a
factor of ca. 1.2 relative to the ratio found by NMR). Tak-
ing this uncertainty in the method into account, the yield
of 9 was comparable to that of 18. Again the reductive ho-
mocoupling product 11 of the chloroalkyne was observed,
along with the enyne 19 corresponding to reductive cross-
coupling of the chloroalkyne and bromostyrene sub-
strates. It is also noteworthy that no chloroalkyne starting
material 8 was observed by GC–MS, while some bromo-
styrene 17 remained. Although the chloroalkyne may
have been lost during work-up (evaporation under re-
duced pressure), GC–MS showed a higher intensity of the
products originating from the chloroalkyne than those de-
rived from the bromostyrene, and it thus seems that the
chloroalkyne is more readily converted into different
products under the explored conditions.
SiMe3
C6H13
21
Cl
SiMe3
SiMe3
C6H13
Ph
10
20
PdCl2(PPh3)2, CuI
C6H13
i-Pr2NH, THF
Ph
X
X = Br or I
C6H13
22
23
C6H13
Ph
Scheme 6 Competition experiments. Reagents and conditions:
PdCl2(PPh3)2 (5 mol%), CuI (5 mol%), 2 h, r.t. For product ratios, see
Table 4.
SiMe3
Table 4 Outcomes of the Competition Experiments (cf. Scheme 6);
Product Distributions Based on GC–MS Analysis
Ph
9
SiMe3
Entry
Ph–X
21 (%)
67
10 (%)
0.5
0
22 (%)
32.5
20
23 (%)
Cl
1
2
3
4
Br
Br
I
0
0
SiMe3
Ph
Ph
Ph
8
80
PdCl2(PPh3)2, CuI
18
11
Ph
Br
i-Pr2NH, THF
34
25
6
35
31
I
33
23
13
Ph
17
Ph
In order to diminish formation of the homocoupling prod-
uct from two chloroalkynes, we screened the effect of in-
creasing the copper-to-palladium ratio on the reaction
between chloroalkyne 8 and trimethylsilylacetylene. The
GC–MS product ratios (9:11) under different conditions
are listed in Table 5. The validity of the GC–MS ratios
Ph
19
Scheme 5 Competition experiment. Reagents and conditions:
PdCl2(PPh3)2 (5 mol%), CuI (5 mol%), 2 h, r.t. Compounds 18 and 19
were formed as cis/trans mixtures.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2715–2719

2718
M. A. Christensen et al.
LETTER
was ascertained by analyzing two mixtures with known
amounts of the two products (see the Supporting Informa-
tion). The results showed that by using a higher cop-
per:palladium ratio, the yield of the desired cross-
coupling product 9 was increased (Table 5, entries 1 vs 2
and 3 vs 4). When using three molar equivalents of the ter-
minal alkyne (Table 5, entry 4), the yield increased to
91%. Further, we found that using tetrakis(triphenylphos-
phine)palladium(0) [Pd(PPh3)4] as the palladium catalyst
instead of bis(triphenylphosphine)palladium(II) dichlo-
ride [PdCl2(PPh3)2] had little influence on the product ra-
tio, but the reaction time was increased significantly
(Table 5, entry 5). It seemed that the prolonged reaction
time was due to the additional triphenylphosphine (Ph3P)
ligands. As previously recognized for Sonogashira cou-
plings,11 this is likely due to the larger equilibrium content
of catalytically inactive tris(triphenylphosphine)palladi-
um(0) species at the expense of the catalytically active
bis(triphenylphosphine)palladium(0) [Pd(PPh3)2] species
for the oxidative addition step. Indeed, when repeating the
reaction with bis(triphenylphosphine)palladium(II) di-
chloride plus two molar equivalents of triphenylphos-
phine (relative to the Pd catalyst), no conversion was
observed according to TLC analysis after two hours,
while a parallel reaction without the additional triphe-
nylphosphine seemed to be complete after this period. Ac-
cording to TLC, it took more than 17 hours for the
reaction with added triphenylphosphine to go to comple-
tion (Table 5, entry 6). The ratio between 9 and 11 was,
however, slightly more beneficial for 9 than that obtained
in entry 3. We also tested the influence of leaving out ei-
ther of the two catalysts. Thus, in the absence of a palladi-
um catalyst, only starting material was observed by GC–
MS after 120 hours (Table 5, entry 7). When copper(I) io-
dide was omitted, some conversion was observed with the
bis(triphenylphosphine)palladium(II) dichloride catalyst,
but the reaction proceeded very slowly; after 120 hours,
GC–MS analysis provided a ratio between starting mate-
rial 8 and product 9 of 66:34. Using tetrakis(triphe-
nylphosphine)palladium(0) instead (and no CuI), less than
1% conversion was observed after 120 hours. Overall,
these experiments show that for optimal coupling condi-
tions both the palladium and copper sources should be
present. Thus, palladium plays an active role in the reac-
tion mechanism, although we cannot say whether the
mechanism strictly follows the conventional Sonogashira
mechanism.
Table 5 Optimization of the Conditions for the Reaction between 8
and Trimethylsilylacetylene; Product Distributions from GC–MS
Analysis
Entry
Pd cat.
CuI
Alkyne
Time
(h)
9
(%)
11
(%)
(mol%)a (mol%) (equiv)
1
2
3
4
5
6
7
5
5
10
5
1
1
3
3
3
3
3
3
3
61
75
81
91
77
87
0
39
25
19
9
1
5
3
1
10
5
3
5b
5c
0
24
24
120
23
13
0
5
5
a Pd cat. = PdCl2(PPh3)2 unless otherwise stated.
b Pd cat. = Pd(PPh3)4.
c PdCl2(PPh3)2 + PPh3 (2 equiv).
tablish which substrates provide Sonogashira cross-cou-
pling products most readily under similar experimental
conditions, which is particularly important when aiming
at selective cross-coupling reactions on multifunctional
molecules, but this does not imply that the investigated
substrates necessarily follow the exact same mechanism
of coupling.
Acknowledgment
The University of Copenhagen is gratefully acknowledged for fi-
nancial support. We thank Mr. Dennis Larsen for recording HRMS
spectra.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
m
t
iornat
References
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In conclusion, chloroalkynes readily undergo cross-cou-
pling reactions with terminal alkynes under experimental
Sonogashira conditions. From competition experiments,
we can place chloroalkynes in the following sequence
when it comes to furnishing the cross-coupling product:
vinyl bromide ≥ chloroalkyne ≥ aryl iodide >> aryl bro-
mide. However, when it comes to general reactivity, with
conversions not only providing the desired cross-coupling
product, chloroalkynes seem to be the most reactive sub-
strates under the explored conditions. Finally, it should be
emphasized that our primary aim in this work was to es-
Synlett 2013, 24, 2715–2719
© Georg Thieme Verlag Stuttgart · New York

LETTER
Chloroalkyne Coupling Partners in Palladium-Catalyzed Reactions
2719
(9) Competition Experiments; General Procedure
The chloroalkyne (0.7 mmol) and the appropriate aryl or
vinyl halide (0.7 mmol) were dissolved in THF (10 mL) and
diisopropylamine (2 mL). To this solution was added
PdCl2(PPh3)2 (26 mg, 0.037 mmol), CuI (7 mg, 0.04 mmol),
and trimethylsilylacetylene (ca. 72 mg, ca. 0.7 mmol). After
stirring the mixture at r.t. for 2 h, sat. aq NH4Cl solution (25
mL) was added, and the mixture was extracted with CH2Cl2
(50 mL), washed with brine (25 mL), dried over Na2SO4,
filtered and concentrated under reduced pressure. The
residue was analyzed by GC–MS.
(10) Weng, Y.; Cheng, B.; He, C.; Lei, A. Angew. Chem. Int. Ed.
2012, 51, 9547.
(11) Amatore, C.; Jutand, A. Acc. Chem. Res. 2000, 33, 314.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2715–2719

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