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Synlett 2021; 32(06): 616-620
DOI: 10.1055/a-1290-8469
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A Palladium-Free Sonogashira Coupling Protocol Employing an In Situ Prepared Copper/Chelating 1,2,3-Triazolylidene System

Efstathios Tonis
a   Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, 15771 Athens, Greece
,
Felix Stein
b   Institut für Chemie und Biochemie, Anorganische Chemie, Freie Universität Berlin, Fabeckstraße 34/36, 14195 Berlin, Germany
,
Ioannis K. Stamatopoulos
a   Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, 15771 Athens, Greece
,
Jessica Stubbe
b   Institut für Chemie und Biochemie, Anorganische Chemie, Freie Universität Berlin, Fabeckstraße 34/36, 14195 Berlin, Germany
,
Athanasios Zarkadoulas
a   Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, 15771 Athens, Greece
,
Biprajit Sarkar∗
b   Institut für Chemie und Biochemie, Anorganische Chemie, Freie Universität Berlin, Fabeckstraße 34/36, 14195 Berlin, Germany
c   Chair of Inorganic Coordination Chemistry, Institute of Inorganic Chemistry, University of Stuttgart, Pfaffenwaldring 55, 70569 Stuttgart, Germany
,
Georgios C. Vougioukalakis∗
a   Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, 15771 Athens, Greece
› Author Affiliations

This work was supported by the Hellenic Foundation for Research and Innovation under the ‘First Call for H.F.R.I. Research Projects to support Faculty members and Researchers and the procurement of high-cost research equipment grant’ (H.F.R.I., Grant Number: 16 – Acronym: SUSTAIN). The contribution of the European Cooperation in Science and Technology (COST, Grant Number CA15106; C–H Activation in Organic Synthesis – CHAOS) is also gratefully acknowledged. Financial support from a joint DAAD-IKY project (funded by DAAD through funds from the Bundesministerium für Bildung und Forschung - BMBF) is also acknowledged.
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Corrected by:

Erratum - Synthesis and Structural Stability of α-Helical Gold(I)-MetallopeptidesySynlett 2021; 32(04): e4-e4
DOI: 10.1055/s-0040-1706620

Abstract

A new, palladium-free Sonogashira coupling reaction protocol using a catalytic system that comprises a simple, cheap, widely available copper salt and a chelating 1,2,3-triazolylidene ligand precursor is reported. This protocol provides the desired coupling products in moderate to very good yields.


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Key words

Sonogashira coupling - palladium-free - copper - sustainability - 1,2,3-triazolylidenes

The Sonogashira coupling reaction is a metal-catalyzed cross-coupling transformation widely used in organic synthesis to form Csp2–Csp bonds, through the coupling of aryl or vinyl halides with terminal alkynes, affording conjugated acetylenic compounds.[1] In 1975, two protocols were independently reported by Cassar,[2] and Dieck and Heck,[3] who used palladium catalysis for the conversion of monosubstituted acetylenes into aryl- or vinyl-substituted acetylene derivatives, through their reaction with the corresponding organohalides. In the same year, Sonogashira, Tohda, and Hagihara reported an analogous, but more efficient protocol, in which the reaction was materialized in the presence of copper(I) iodide as co-catalyst under mild conditions.[4]

The Sonogashira reaction has many applications in diverse areas of organic chemistry and materials synthesis. For example, in the synthesis of natural products it is used for the preparation of compounds containing conjugated enynes or enediynes.[5] Sonogashira coupling protocols combined with reduction transformations lead to alkaloids, polyketides, or polycyclic xanthones, whereas couplings affording substituted alkynes followed by regioselective heteroannulations are employed to synthesize indoles, oxyindoles, furans, benzofurans, or isoquinolinones.[5] Moreover, it is widely used in the synthesis of pharmaceuticals and compounds with biological activity,[6] nonlinear optical materials and molecular electronics,[7] polymeric and dendrimeric materials,[8] macrocycles with acetylene links,[9] as well as polyalkynylated molecules.[10]

Sonogashira coupling protocols initially used palladium phosphine complexes as catalysts for the oxidative addition–transmetalation–reductive elimination steps, copper salts as co-catalysts (towards efficient acetylide formation), and organic amines as bases.[3] [4] Later on, phosphine ligands were replaced by N-heterocyclic carbenes (NHCs), among others, given that the properties of NHCs can be easily adjusted on-demand, both sterically and electronically, and, also, because the bond between the metal and the NHC is in general stronger than the metal–phosphorus bond.[11] Nowadays, well-defined, palladium-based tailor-designed complexes, bearing either phosphine or NHC ligands, are attracting the interest of the organic and the organometallic community in this regard.[12]

Alternative, Pd-free protocols for the Sonogashira reaction have been also developed, mostly due to the fact that Pd catalysts have low sustainability and are expensive.[13] These protocols include nonconventional Pd-free couplings employing Cu-, Fe-, or Ni-based complexes as catalysts,[14`] [b] [c] transition-metal-free, microwave-assisted Sonogashira reactions, using water as the solvent together with a phase-transfer agent,[15] photoinduced Sonogashira approaches,[16] or even catalytic protocols involving metal nanoparticles.[17] Recently, in the framework of our interest in sustainable catalysis,[18] [19] [20] [21] [22] [23] some of us reported the development of a Pd-free Sonogashira protocol using a catalytic system comprising the widely available CuSO4·5H2Ο and a cheap, commercially available NHC precursor salt.[24] This system can successfully employ a wide variety of terminal alkynes (electron-poor aryl, electron-rich aryl, or alkyl) with either electron-poor or electron-rich aryl iodides.

With the same mindset, we decided to explore the potential of another sustainable Sonogashira reaction protocol, employing an in situ generated, chelating 1,2,3-triazolylidene instead of an NHC. Along these lines, herein we report the development of a new, user-friendly protocol for the Pd-free Sonogashira coupling reaction. This protocol requires a simple experimental setup and can be easily followed in any synthetic laboratory. After screening a number of low-cost, widely available copper sources, in combination with the in situ prepared chelating 1,2,3-triazolylidene (Trz*Ph,Ph)2CH2 (L, Figure [1]),[25] the most efficient catalytic system was found to be the one employing Cu(OAc)2. A number of electron-poor or electron-rich aryl iodides along with a variety of terminal alkynes were coupled with satisfactory results.

Zoom Image
Figure 1 The chelating 1,2,3-triazolylidene ligand precursor (Trz*Ph,Ph)2CH2 (L) utilized in the present work

Optimization experiments towards probing efficient and straightforward catalytic conditions not requiring the formation and isolation of well-defined copper-based complex(es) were initially performed. Our studies also aimed at increasing the sustainability and selectivity of the protocol in favor of the Sonogashira product, in comparison to the simultaneously formed Glaser coupling product, as well as at the decrease of our protocol’s cost. The coupling of p-iodonitrobenzene with phenylacetylene was chosen as the model reaction and all experiments were conducted under an inert atmosphere employing the chelating 1,2,3-triazolylidene ligand precursor (Trz*Ph,Ph)2CH2 (L, Figure [1]). Initially, we tested the catalytic activity of a wide variety of copper sources (Table [1]).

Table 1 Copper Source Optimization

Entry

Copper source

Product (%)a

 1

CuSO4 anhydrous

14

 2

CuCl2 anhydrous

90

 3

Cu(OAc)2·xH2O

86

 4

CuCl2·2H2O

81

 5

CuCO3·Cu(OH)2

74

 6

Cu2O

 –

 7

CuCl

84

 8

CuBr

80

 9

CuBr2

87

10

CuI(NO3)2·3H2O

80

11

[Cu(CH3CN)4]PF6

91

12

Cu(acac)2

89

13

Cu(OAc)

92

14

Cu(OAc)2

91

15

CuI

72

a Yields calculated by GC–MS analysis. Experimental conditions: Cu salt (20 mol%), ligand L (10 mol%), 1-iodo-4-nitrobenzene (0.167 mmol), phenyl­acetylene (0.2 mmol), K2CO3 (2 equiv), DMF (1 mL), 130 °C, 8 h.

Satisfactory catalytic activity is provided by both copper(I) and copper(II) sources, but we decided that the use of Cu(OAc)2 provided the best catalytic system, taking into account the stability, cost, toxicity, and availability of this copper source, besides, of course, its catalytic efficiency. The copper and ligand loading utilized are relatively low, in comparison with our developed NHC-based catalytic system, as well as with other published protocols.[24] [26]

After also testing some inorganic and organic bases (Table [2]), potassium carbonate was found to give the highest yield. Solvent optimization experiments were performed as well. DMF and PEG 350 are the solvents providing the best results. Despite the more sustainable nature of PEG 350, we decided that DMF is superior, due to difficulties and the bad reproducibility in the isolation of the product when using PEG 350. Finally, we concluded that 130 °C was the best temperature for the reaction and that 8 hours is the optimum reaction time, as prolonged reaction times did not improve the results, at least in the specific transformation.

Table 2 Reaction Optimizationa

Base

Solvent

Temp (°C)

Time (h)

Product (%)b

Cs2CO3

DMF

130

 8

56

KOH

DMF

130

 8

20

AcONa

DMF

130

 8

40

Et3N

DMF

130

 8

 0

K2CO3

toluene

130

 8

 9

K2CO3

p-cymene

130

 8

17

K2CO3

NMP

130

 8

 4

K2CO3

DMF

130

 8

86 (80)

K2CO3

diglyme

130

 8

56

K2CO3

1,4-dioxane

130

 8

 0

K2CO3

PEG 350

130

 8

82

K2CO3

DMF

 RT

 8

 0

K2CO3

DMF

 70

 8

10

K2CO3

DMF

100

 8

57

K2CO3

DMF

130

 2

21

K2CO3

DMF

130

 4

48

K2CO3

DMF

130

 6

77 (69)

K2CO3

DMF

130

10

85

K2CO3

DMF

130

14

86

a Reaction conditions: 1-iodo-4-nitrobenzene (0.167 mmol), phenylacetylene (0.2 mmol), Cu(OAc)2 (10 mol%), ligand L (5 mol%), base (2 equiv), solvent (1 mL).

b Yields calculated by GC–MS analysis; isolated yields are given in parentheses.

As mentioned above, one of the known byproducts of the Sonogashira reaction is the Glaser coupling product (coupling of two terminal alkynes/homocoupling).[24] [27] In our protocol discussed herein, the Glaser product is formed as well, however, in very low yields. Specifically, in all of the reactions conducted, the ratio of the Sonogashira coupling product vs the Glaser coupling product is below 5.3:1. Moreover, although p-iodonitrobenzene and phenylacetylene are known to provide both the corresponding Sonogashira and Glaser products, simply in the presence of some copper sources (albeit in low yields and in nonfavorable Sonogashira/Glaser ratios),[24] and this was confirmed in our present study, when we ran some blank tests only with Cu(OAc)2, the Sonogashira product yield obtained in this way is inferior to that of our optimized system (including L), even concerning this exceptional substrate case (Sonogashira/ homocoupling product yield was 38%/14% under otherwise identical to the substrate scope reaction conditions). Along these lines, only traces of the Sonogashira product were observed in the absence of ligand L in the coupling of p-iodoanisole with phenylacetylene. Finally, a blank experiment carried out in the coupling of phenylacetylene with p-iodonitrobenzene in the absence of a copper source did not provide any product.

After the optimum catalytic system and reaction conditions were determined, we studied our protocol’s substrate scope. As already shown in the optimization studies above, concerning p-iodonitrobenzene, aryl iodides bearing electron-withdrawing groups afford the desired cross-coupling product in very good isolated yields (3a, 3c, and 3e, Scheme [1]). Aryl iodides having no substituents (3f), heterocyclic rings (3d), or electron-donating substituents (3b) provide moderate to good isolated yields (Scheme [1]). Aryl bromides (bromobenzene, 4-bromobenzotrifluoride) and aryl chlorides (chlorobenzene) are not amenable to this protocol, as concerns their attempted coupling with phenylacetylene, providing very low yields of the desired cross-coupled products, or no product at all.

Zoom Image
Scheme 1 Aryl halide Sonogashira reaction scope. Reagents and conditions: Cu(OAc)2 (10 mol%), ligand L (5 mol%), aryl halide (1.0 equiv, 0.167 mmol), phenylacetylene (1.2 equiv, 0.2 mmol), K2CO3 (2 equiv), DMF (1 mL), 130 °C, 8 h. a 2× catalyst loading: Cu(OAc)2 (20 mol%), ligand (10 mol%) (with Cu(OAc)2 (10 mol%), ligand (5 mol%): 61% isolated yield).

We then investigated the substrate scope of our protocol with regards to the terminal alkynes. Given that the aryl halide scope study showed that electron-donating groups result in moderate to good yields, we only studied the coupling of aryl halides bearing electron-withdrawing groups (Scheme [2]). More specifically, both alkyl- and aryl-substituted terminal alkynes, bearing either electron-donating or electron-withdrawing groups on the phenyl ring, afforded good to very good isolated yields. This result suggests that the electronic characteristics of the aromatic terminal alkynes employed do not play a significant role in the outcome of the reaction, at least at the extent of the analogous influence shown by the electronic characteristics of the aryl halide.

Zoom Image
Scheme 2 Terminal alkyne Sonogashira reaction scope. Reagents and conditions: Cu(OAc)2 (10 mol%), ligand L (5 mol%), aryl halide (1.0 equiv, 0.167 mmol), terminal alkyne (1.2 equiv, 0.2 mmol), K2CO3 (2 equiv), DMF (1 mL), 130 °C, 8 h.

To probe the possible intervention of radical species in our catalytic protocol, we performed a reaction in the presence of a radical scavenger and another in the presence of a radical initiator. More specifically, utilization of one of the most widely used radical scavengers, 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO), afforded almost identical results with our typical protocol, revealing that the absence of radical species does not negatively affect the reaction’s yield. As radical initiator we used azobisisobutyronitrile (AIBN). Again, we did not observe any change in the reaction’s yield, thus excluding the presence of free radical species in the reaction. The mechanism we propose for this transformation is similar to those of analogous, copper-based catalytic systems, including copper acetylide formation, oxidative addition to the organohalide, and, eventually, reductive elimination of the cross-coupled product.[24] [28] [29] This Cu(I)/Cu(III) catalytic cycle[30] requires, in the present case, the in situ reduction of Cu(II) to Cu(I), which can take place by the solvent or the ligand.[24]

Finally, we decided to study the catalytic efficiency of a pre-formed, well-defined copper complex that could possibly form and function under the catalytic reaction conditions employed, in order to compare it with the in situ generated catalytic system. Several attempts were made to prepare such a complex: reactions of anhydrous copper(II) acetate or copper(II) triflate as the copper source, in the presence of the 1,2,3-triazolylidene (Trz*Ph,Ph)2CH2 (generated from L, Figure [1]) in various solvents of different polarity and coordinating ability (CH2Cl2, CH3OH, CH3CN, DMF, or THF), with different bases (anhydrous sodium acetate, sodium acetate trihydrate, anhydrous potassium carbonate, or potassium tert-butoxide) were all unsuccessful. Performing the complexation reactions at room temperature or under heating also did not yield a well-defined compound. Transmetalation of the 1,2,3-triazolylidene using silver(I) salts was unsuccessful as well. In all cases, the products of the reactions were inorganic salts of copper with carbonate, acetate, or triflate counteranions. To this end, dicopper(I)-dimesoionic carbene complex 4 (Figure [2]), that is, a binuclear complex with one bridging mesoionic dicarbene ligand and one bridging acetate, previously reported by some of us,[31] was alternatively used, as a well-defined catalyst possibly resembling our in situ prepared system. Although the Sonogashira coupling was successful (GC–MS yield using the well-defined complex 46% vs GC–MS yield using our protocol 91%), the results were significantly inferior compared to that of the in situ prepared system, as both the Sonogashira product yield and the Sonogashira/Glaser products ratio (3:2) were lower in the case of complex 4.

Zoom Image
Figure 2 Well-defined dicopper(I)-dimesoionic carbene complex 4 tested for its catalytic activity under the optimized conditions.

Summing up, herein we have reported the development of a user-friendly, sustainable protocol for the Pd-free Sonogashira coupling reaction.[32] Reaction conditions were optimized with regards to the copper source, the base, the solvent, the temperature, and the reaction time utilized. The final catalytic system was chosen on the basis of its efficiency, components stability, cost, toxicity, and availability. It is formed in situ and the necessary catalyst loading is relatively low, when compared to analogous systems. The reaction scope of the organohalides and the terminal alkynes amenable to this system was investigated by employing a variety of substrates. Aryl bromides and aryl chlorides are, in general, innocent bystanders. On the other hand, aryl iodides bearing electron-withdrawing groups provide very good isolated yields, while aryl iodides bearing electron-donating groups provide moderate to good yields. With regards to the various terminal alkynes studied, the results are very good with aryl-substituted terminal alkynes bearing either electron-withdrawing or electron-donating substituents. Alkyl-substituted terminal alkynes afford the desired product in moderate yields.


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Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-1290-8469.
  • Supporting Information

Corresponding Authors

Biprajit Sarkar
Chair of Inorganic Coordination Chemistry, Institute of Inorganic Chemistry, University of Stuttgart
Pfaffenwaldring 55, 70569 Stuttgart
Germany   

Georgios C. Vougioukalakis
Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens
15771 Athens
Greece   

Publication History

Received: 20 September 2020

Accepted after revision: 15 October 2020

Accepted Manuscript online:
15 October 2020

Article published online:
13 November 2020

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Zoom Image
Figure 1 The chelating 1,2,3-triazolylidene ligand precursor (Trz*Ph,Ph)2CH2 (L) utilized in the present work
Zoom Image
Scheme 1 Aryl halide Sonogashira reaction scope. Reagents and conditions: Cu(OAc)2 (10 mol%), ligand L (5 mol%), aryl halide (1.0 equiv, 0.167 mmol), phenylacetylene (1.2 equiv, 0.2 mmol), K2CO3 (2 equiv), DMF (1 mL), 130 °C, 8 h. a 2× catalyst loading: Cu(OAc)2 (20 mol%), ligand (10 mol%) (with Cu(OAc)2 (10 mol%), ligand (5 mol%): 61% isolated yield).
Zoom Image
Scheme 2 Terminal alkyne Sonogashira reaction scope. Reagents and conditions: Cu(OAc)2 (10 mol%), ligand L (5 mol%), aryl halide (1.0 equiv, 0.167 mmol), terminal alkyne (1.2 equiv, 0.2 mmol), K2CO3 (2 equiv), DMF (1 mL), 130 °C, 8 h.
Zoom Image
Figure 2 Well-defined dicopper(I)-dimesoionic carbene complex 4 tested for its catalytic activity under the optimized conditions.