A systematic study on the Cadiot-Chodkiewicz cross coupling reaction for the selective and efficient synthesis of hetero-diynes

Article abstract of DOI:10.1039/c6ra07308e

Mild reaction conditions for the Cadiot-Chodkiewicz cross coupling process have been developed for the highly selective and efficient synthesis of unsymmetrical diynes. The most abundant, economic, environmentally friendly, green solvent, water was employed as the sole reaction medium in combination with a minimal amount (5 equiv.) of piperidine base. The reported new reaction conditions provide operational simplicity, high selectivity for hetero coupling (>97%), use of water, and low basicity of the reaction medium compared to commonly used highly basic conditions, i.e., 30-70% amine in water or 100% piperidine. Various sensitive functional groups were found to be highly compatible with the developed low basic reaction conditions. This study supports the fact that the Cadiot-Chodkiewicz cross coupling can be a greener reaction, has a very broad substrate scope, but has always been employed in non-green highly basic conditions and with limited substrate scope.

Full text of DOI:10.1039/c6ra07308e

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A systematic study on the Cadiot–Chodkiewicz
cross coupling reaction for the selective and
efficient synthesis of hetero-diynes†
Cite this: RSC Adv., 2016, 6, 54449
*
Bhavani Shankar Chinta and Beeraiah Baire
Mild reaction conditions for the Cadiot–Chodkiewicz cross coupling process have been developed for the
highly selective and efficient synthesis of unsymmetrical diynes. The most abundant, economic,
environmentally friendly, green solvent, water was employed as the sole reaction medium in
combination with a minimal amount (5 equiv.) of piperidine base. The reported new reaction conditions
provide operational simplicity, high selectivity for hetero coupling (>97%), use of water, and low basicity
of the reaction medium compared to commonly used highly basic conditions, i.e., 30–70% amine in
water or 100% piperidine. Various sensitive functional groups were found to be highly compatible with
the developed low basic reaction conditions. This study supports the fact that the Cadiot–Chodkiewicz
cross coupling can be a greener reaction, has a very broad substrate scope, but has always been
employed in non-green highly basic conditions and with limited substrate scope.
Received 20th March 2016
Accepted 29th May 2016
DOI: 10.1039/c6ra07308e
www.rsc.org/advances
reaction, a copper-catalyzed process between terminal alkynes
and haloalkynes (Scheme 1).8
Introduction
However, though the reaction is successful in many situa-
tions,9–11 there are still some disadvantages, such as (a) poor
selectivity for heterocoupling (b) basicity of the reaction
medium is very high (70% to 100%) and (c) conditions are not
very general for divergent substrates. Various modications
have been reported to help in suppressing the formation of the
unwanted homocoupled products but they use costly reagents
like Pd-catalysts along with Cu and they are very substrate
specic etc. In this context, our aim was to develop economic,
environmentally friendly, operationally simple and yet highly
selective reaction conditions for the Cadiot–Chodkiewicz cross
coupling. Here in we report a systematic study on the Cadiot–
Water is a nontoxic, non-ammable, economic and green
solvent, possessing unique properties.1 Many natural and bio-
logical transformations have been carried out in water.2 The
unique properties of water make it highly appealing for
biomimetic synthetic chemistry. Water as a solvent to promote
organic transformations has been largely explored in the past
two decades due to its fascinating advantages over traditional
organic solvents, such as relative abundance, low cost, and non-
toxicity.3 The pioneering work of Breslow4 and Sharpless5
inspired the development of catalysis and green protocols in
water for the synthesis of highly functionalized and biologically
important compounds. Despite these advantages, most of the
organic transformations are incompatible with water since
most of the organic compounds do not dissolve in water and
solubility is generally considered a prerequisite for reactivity.
The 1,3-diynes (symmetric and unsymmetrical) and polyynes
are very important in synthetic organic and materials chemistry.
These are the common structural motifs of a large variety of
biologically active natural products6 and supramolecular
materials.7 The synthesis of unsymmetrical diynes is more
challenging and important as compared to symmetrical diynes
in terms of selectivity and applications. The most commonly
used procedure for the preparation of unsymmetrical diynes
and polyynes is the Cadiot–Chodkiewicz cross-coupling
Department of Chemistry, Institute of Technology Madras, Chennai – 600036, India.
E-mail: beeru@iitm.ac.in
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c6ra07308e
Scheme 1 Reaction conditions in (a) classical Cadiot–Chodkiewicz
cross coupling and (b) this work.
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Chodkiewicz reaction, which resulted in the development of detected. We next carried out this reaction in highly polar
reaction conditions with water as the sole solvent and 5 equiv- solvents like MeOH, EtOAc, CH3CN, and THF (Table 1, entries
alents of piperidine base, for the highly synthesis of unsym- 7–10 respectively). These solvents with the exception of CH3CN
metrical diynes.
(77%) resulted in a very selective cross coupling reaction but in
relatively less yields (52–63%). When hexane, a nonpolar solvent
was employed (entry 11), cross coupling was quick and efficient
(70%) but gave 5% of homo-coupled diol 3. These observations
and outcomes clearly indicate that, there is no need to use the
amine base as solvent or in excess amounts during the Cadiot–
Chodkiewicz coupling and this reaction can be equally efficient
and selective in common organic solvents with few equivalents
of amine.
Results and discussion
Initially, we screened divergently polarized organic solvents and
water for the reaction (Table 1). We have chosen bromopro-
pargyl alcohol 1 and phenyl acetylene as substrates, piperidine
(5 equivalents) as base, CuCl (0.1 eq.) as catalyst and 0 ꢀC
temperature as reaction conditions for this study.
We next carried out this reaction in normal water as well as
distilled water to make the process more environmentally
benign and economic. To our delight the reaction was highly
selective and efficient (82%) for the formation of heterodiyne 2
(Table 1, entries 12 & 13), as compared to any organic solvent.
Furthermore, even trace amount of 3 was not detected. We next
changed the amount of CuCl employing water as the solvent. In
case of 5 mol% (entry 14) the yield of the 2 was reduced on the
other hand 20 mol% (entry 15) was equally efficient as 10 mol%
but gave 5% of homodimer 3. When we increased the amount of
water (entries 16 & 17) from 4 mL to 7 mL, with 5 equivalents of
piperidine and 10 mol% of CuCl, the yield of the 2 was reduced
(76%), whereas with 10 mL water, reaction was a bit slow and
low yielding along with 3% of 3. Hence, among all the solvents
screened acetonitrile, chloroform, 1,2-DCE and water were
found to be selective and efficient for cross coupling product.
Next screening study for various amine bases was carried out
in water and 1,2-DCE by keeping the amount of base as 5
equivalents. When water was employed as the solvent
(Table 2A), all the four amine bases screened, such as pyridine,
When the reaction was carried out in freshly degassed neat
piperidine as in the literature12 (Table 1, entry 1), the cross
coupled diyne 2 was formed in 63% yield along with 13% of
homodiyne 3. Keeping this outcome as the reference, we next
studied various solvents. In dichloromethane (CH2Cl2), with 5
equivalents of piperidine (Table 1, entry 2), the reaction was
quicker (15 min) and selective (68%) towards 2, as there was no
detection of 3. Acetone was equally good for the formation of 2
but gave about 10% of homodimer 3. Various chlorinated
solvents such as CHCl3 (79% of 2), 1,2-dichloroethane (1,2-DCE,
82% of 2), and 1,2-dichlorobenzene (1,2-DCB, 72% of 2) were
screened (Table 1, entries 4–6). All of them were found to be
highly selective and efficient for the formation of unsymmet-
rical diyne 2. It is surprising and noteworthy that, in case of all
the chlorinated solvents screened, no trace of the 3 was
Table 1 Solvent screening for Cadiot–Chodkiewicz reaction
i
nBuNH2, Pr2NH and Et3N underwent the coupling reaction in
about 15–30 min. But, the process was less efficient (57–77%
yields of 2) and less selective (6–12% of homo-diynol 3) towards
heterodiyne 2 (entries 2–5) compared to piperidine (entry 1).
Similar results were observed when the same amines were
screened in 1,2-DCE as the solvent (Table 2B). Hence piperidine
was found to be the best amine for the Cadiot–Chodkiewicz
cross coupling reaction irrespective of the nature of the solvent
used.
Aer nding out the best solvent (water) and best amine
(piperidine) then we wished to determine the optimal amount
of piperidine base required to synthesize hetero-diynes selec-
tively and efficiently. According to the currently existing and
well accepted mechanism for Cadiot–Chodkiewicz coupling
reaction, at least in one equivalent of base is required. But in the
literature, amine is always used either as the solvent or in large
excess i.e. at least 20 equivalents. However, use of excess amine
base is not adherable and affordable. Hence, we have under-
taken this task to reduce the equivalents of amine required for
better reaction conditions.
S. No
Solvent
Time (min)
Yield of 2b (%)
1
2
3
4
5
6
7
8
Piperidine
CH2Cl2
Acetone
CHCl3
1,2-DCE
1,2-DCB
MeOH
EtOAc
CH3CN
THF
Hexane
Waterh
Distilled water
Water
Water
Water
30
15
15
15
15
15
15
30
15
30
15
15
15
15
15
15
25
63 (13)c
68
68 (10)c
79
82
72
63
54
77
52
9
10
11
12
13
14d
15e
16f
17g
70 (5)c
82
82
78
82 (5)
76
78 (3)
Water
a
Accordingly, we carried out the reaction in water as well as
All the reactions were carried out with 0.2 mmol of 1 and 0.22 mmol of
b
phenyl acetylene. Isolated yields aer column chromatography. 1,2-DCE employing piperidine in variable amounts as shown in
c
d
Numbers in paranthesis are isolated yields of homodimer 3. CuCl
Table 3A and B. When 1 equiv., of piperidine was employed
(Table 3A, entry 1) in water, the reaction was relatively slower (1
h) than with 5 equiv., (Table 3A, entry 4) and resulted in the
was in 5 mol%. e CuCl was in 20 mol%. f 7 mL of water was used. 10
mL of water was used. h Normal water from tap.
g
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Table 2 Amine screening for Cadiot–Chodkiewicz reaction in water Table 3 Optimization study for amount of piperidine in water and 1,2-
and 1,2-DCEa
DCEa
A
A
Time
(min)
Yield of 2b
(%)
Dimmer 3b
(%)
S. No
Solvent
Amine
Piperidine
S. No Solvent equiv.
Time (h) 2b (%) 3b (%) rsm 1b (%)
1
2
3
4
5
Water
Water
Water
Water
Water
Piperidine
Et3N
15
60
70
60
90
82
57
66
77
65
—
12
7
7
6
1c
2c
3c
4c
5
Water
Water
Water
Water
Water
Water
1.0
3.0
4.0
5.0
7.0
1
65
72
80
82
78
81
7
5
—
—
8
10
—
—
—
—
—
iPr2NH
nBuNH2
Pyridine
1/4
1/4
1/4
1/4
1/4
B
6
10.0
3
Time
(min)
Yield of 2b
(%)
Dimmer 3b
(%)
B
S. No
Solvent
Amine
Piperidine
S. No Solvent equiv.
Time (h) 2b (%) 3b (%) rsm 1b (%)
1
2
3
4
5
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
Piperidine
Et3N
15
15
15
15
15
82
63
45
34
23
—
10
25
25
30
iPr2NH
nBuNH2
Pyridine
1d
2d
3c
4c
5c
6c
1,2-DCE 0.2
1,2-DCE 0.5
1,2-DCE 1.0
1,2-DCE 3.0
1,2-DCE 4.0
1,2-DCE 5.0
5
5
3
1/4
1/4
1/4
37
59
62
78
80
82
15
12
12
25
10
5
—
—
—
ꢁ2%
a
Conditions: all the reactions were carried out with 0.2 mmol of 1 and
0.22 mmol of phenyl acetylene, either in degassed water or 1,2-DCE (2
mL/0.1 mmol of 1). b Isolated yields aer column chromatography.
—
—
a
Conditions: all the reactions were carried out with 0.2 mmol of 1 and
0.22 mmol of phenyl acetylene, either in degassed water or 1,2-DCE (2
b
c
mL/0.1 mmol of 1). Isolated yields aer column chromatography.
0
ꢀC only. d 0 ꢀC / RT.
formation of 65% of 2, and 7% of 3, along with 10% of
unreacted bromoalcohol 1.13 In case of 3 equiv., of piperidine
(entry 2), the reaction took only 15 min to yield 72% of cross
diyne 2 and 5% of homodiyne 3, without any le over starting
bromide 1. Surprisingly, 4 equivalents of piperidine afforded 2
as the sole product in 80% isolated yield (entry 3). Surprisingly,
increasing amount of piperidine to 7 and 10 equivalents (Table
3A, entries 5 and 6) afforded 3 in comparable yields to 5 equiv.,
but there was a variable amount of homodimer 3 observed. In
continuation, this study was also performed in 1,2-DCE. With 1
equivalent or less amount of piperidine (Table 3B, entries 1–3),
the cross coupling was slow (3–5 h, at RT) and less efficient (37–
62%) for 2. In these cases, there was always a considerable
amount (5–25%) of unreacted bromide 1 and formation of
homo dimer 3 (up to 12–15%) was observed. On the other hand,
3 equivalents of piperidine (entry 4), gave 78% yield of 2 and
ꢁ2% of homo dimer 3 within 15 min. Similar to water, 4 equiv.
of piperidine in 1,2-DCE (Table 3B, entry 5) resulted in 80% of 2
various terminal alkynes and alkynylbromides for the synthesis
of structurally divergent heterodiynes. Initially we screened
diversely functionalized alkynes keeping the bromide 1 as the
coupling partner. Many sensitive functional groups like
primary, secondary, tertiary alcohols, amines, OTs and OBn, are
compatible under the developed reaction conditions and gave
excellent yields of corresponding heterodiynes 4–11, within 15
min and without any traces of homo diynes. Similar alkyne
substrates (functional groups) were reported to give very poor
yields under classical Cadiot–Chodkiewicz coupling reaction
conditions.14 All these divergently functionalized diyne units
can be useful synthons for materials possessing excellent elec-
tronic and optical properties. When highly non polar groups are
present on alkynes, such as OTBS ether and long chain alkyls, 3–
5% of homodimer 3 was typically observed though corre-
sponding heterodiynes 12–15 were isolated in good yields (69–
91%). But when highly hydrophobic TMS-acetylene was
employed as an alkyne partner there was no formation of cross
product 16, homo product 3 was isolated instead in 87% yield.
This may be due to the poor solubility of TMS-acetylene in water.
To compare the solvent effect i.e., water vs. organic solvents,
on reactivity and selectivity, we have also carried out the Cadiot–
ꢀ
as the sole product in 15 min at 0 C. The results and obser-
vations from Table 3A and B, clearly sets the lowest limit for the
amount of piperidine as 5 equivalents for the quicker, selective,
and efficient formation of heterodiynes, both in water as well as
in organic solvents (1,2-DCE).
So the best conditions found for the Cadiot–Chodkiewicz
cross coupling are water as the solvent, 0 ꢀC as the temperature,
and 5 equivalents of piperidine as the base. With an optimized
reaction condition in hand, we next performed scope studies for
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Chodkiewicz coupling of most of the above substrates in
Scheme 2, in 1,2-DCE as shown in Scheme 3. Interestingly, all
the substrates afforded good yields of corresponding cross
diynes 4–10, 12, 13 & 16 but with relatively lesser selectivity, i.e.
variable amounts (3–14%) of homo-coupled product 3 was
always observed for all the substrates. Surprisingly and contrary
to the outcome in water, coupling of TMS-acetylene with 1 gave
excellent yield (83%) of cross diyne 16 and only 5% of homo
diyne 3 was detected. These observations proved that water is
the best solvent to perform the Cadiot–Chodkiewicz coupling
Scheme 4 Scope study for functionalized alkynyl bromides in water.
reaction for a majority of substrates including long chain
alkynes, with the exception of highly hydrophobic trialkylsilyl
acetylenes (1,2-DCE would be a best solvent for them).
In continuation we have also studied the compatibility of
variously functionalized alkynyl bromides with the optimized
reaction conditions by employing the propargylic alcohol 17 as
an alkyne partner (Scheme 4). All the substrates were found to
undergo the coupling reaction smoothly in water and resulted
in the formation of corresponding cross coupled diynes 18–23
in 65–87% yields along with 3–5% of homo coupling product 24.
In the literature it is found that the bromoalkynes have been
employed more frequently in the Cadiot–Chodkiewicz coupling
reaction and give better yields than their corresponding iodo-
and chloro-counter parts because of their milder reactivity.
Hence, aer studying the reactivity and substrate scope for
various alkynyl bromides, we next turned our attention to
observe the reactivity of various alkynyl iodides under our
optimized reaction conditions.
Structurally divergent terminal alkynes underwent smooth
cross coupling reaction with both the iodocyclohexyl-
propargylic alcohol and iodo-phenylacetylene to afford
moderate to good yields of corresponding hetero-diynes 5–7, 9 &
25–30 (Scheme 5). Next we performed a scope study for various
functionalized iodoacetylenes employing 17 as an alkyne
partner (Scheme 6). In all cases the reaction was smooth and
afforded corresponding hetero-diynes 19, 20, 22, & 23 in good
yields along with variable amounts of homodiyne 24. These
Scheme 2 Scope study for functionalized alkynes in water for the
synthesis of structurally divergent heterodiynes. Conditions: all the
reactions were carried out with 1 equiv. of 1 and 1.1 equiv. of alkynes,
0.1 equiv. of CuCl, 2 mL of degassed water for 0.1 mmol of 1 and 4
b
equiv. of degassed piperidine; all the yields are after column chro-
c
matography; numbers in paranthesis are isolated yields of homo-
dimer 3.
Scheme 3 Scope study for various alkynes in 1,2-DCE. Conditions: all
the reactions were carried out with 1 equiv. of 1 and 1.1 equiv. of
alkynes, 0.1 equiv. of CuCl, 2 mL of degassed 1,2-DCE for 0.1 mmol of 1
b
and 4 equiv. of degassed piperidine; all the yields are after column
c
chromatography;
numbers in paranthesis are isolated yields of
homodimer 3.
Scheme 5 Testing various alkynyl iodides in water.
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against various sensitive functional groups, structurally diver-
sied terminal alkynes as well as alkynyl bromides and iodides.
The importance of the conditions has also been described by
the efficient and selective synthesis of triynes and tetraynes.
This study shows that the Cadiot–Chodkiewicz coupling can
actually be a greener reaction, has broad scope and can be
performed without the use of costly catalysts, highly basic
conditions, in contrary to what has been shown so far in the
literature.
Scheme 6 Scope study for various alkynyl iodides.
Experimental section
Reactions were monitored by thin-layer chromatography
(TLC) carried out on Merck silica plates using UV light and
anisaldehyde or potassium permanganate stains for visual-
ization. Column chromatography was performed on silica
gel (60–120 mesh) using hexanes and ethyl acetate as
eluents. NMR data were recorded on 400 and 500 MHz
spectrometers. 13C and 1H chemical shis in NMR spectra
were referenced relative to signals of CDCl3 (d 7.263 ppm for
1H and 77.16 ppm for 13C). Chemical shis d and coupling
constants J are given in ppm (parts per million) and Hz
(hertz), respectively. Multiplicities were given as: s (singlet);
d (doublet); t (triplet); q (quartet); dd (doublets of doublet) or
m (multiplets). HRMS were recorded by electron spray ioni-
zation (ESI) method on a Q-TOF Micro with lock spray
source. Known compounds data have been compared with
the reported data, and references were given appropriately.
Characterization data for new compounds are given below.
1H and 13C (proton decoupled) NMR spectra for all new
compounds are given in the ESI.† Reagents were purchased
from chemical companies.
Scheme 7 Extension to triynes and tetraynes. Reaction conditions:
CuCl (10 mol%); piperidine (5 eq.), 0 ꢀC; water, 30 min.
experimental results and observations from Schemes 5 & 6,
supports the fact that alkynyl iodides can also be employed as
suitable partners during the Cadiot–Chodkiewicz cross
coupling under our developed reaction conditions, as efficiently
as their bromo-counterparts.
Finally, aer nding a very good substrate scope for the
newly developed, greener reaction conditions for the Cadiot–
Chodkiewicz coupling, we aimed to extend it further for
triynes and tetraynes as well (Scheme 7). As anticipated
triynes 30 & 31 were efficiently (68% & 85%) and selectively
prepared under standard conditions from the reaction
between alkynyl bromides 1 & 32 and diyne 33. The tetrayne
34 was also synthesized in moderate yield (61%) from two
diyne units 33 & 35 and found to be stable under reaction
conditions. Quite surprisingly there was no formation of
homodimers.
General experimental procedure for synthesis of
unsymmetrical diynes
To a solution of an alkyne (1 equiv.), and alkynyl bromide (1.1
equiv.) in freshly degassed amine (piperidine) (5 equiv.) and
water or organic solvent like 1,2-DCE (4 mL/0.1 mmol) at 0 C
ꢀ
under nitrogen atmosphere, was added CuCl (0.1 equiv.), and
the reaction mixture was stirred either at 0 ꢀC or at room
temperature for few minutes to several hours. Reaction mixture
was diluted with EtOAc (10 mL/0.1 mmol), saturated with aq.
NH4Cl (10 mL), and extracted with ethyl acetate (3 Â 10 mL).
The combined organic layer was washed with brine (10 mL) and
dried over MgSO4. Evaporation of the solvent and purication of
the crude mixture by ash column chromatography gave the
corresponding unsymmetrical diyne.
Conclusions
In conclusion, we have performed a systematic study on Cadiot–
Chodkiewicz cross coupling reaction to develop greener, highly
selective and efficient reaction conditions for the synthesis of
unsymmetrical diynes. The most abundant, most economic and
universal solvent water has been employed as the sole reaction
Acknowledgements
medium in combination with 5 equivalents of piperidine base. This work was supported by Indian Institute of Technology
These conditions offered operational simplicity, very less or no Madras, Chennai, through CHY/13-14/622/NFSC/BEER grant.
byproducts, use of green solvent water, and use of minimal BSC thanks IIT Madras for HTRA fellowship. We thank Mr
base. The compatibility of these reaction conditions was tested Ramkumar for single crystal X-ray analysis.
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