Optimized Sonogashira Protocols

Research will be limited to:
- Reaction: Sonogashira cross-coupling
- Substrates: Terminal Alkynes, Aryl Halides
- Catalysis: Copper-free, Palladium Catalyst
- Scope: Suppress Glaser Homocoupling

Strategy: The objective is to identify optimized protocols for copper-free Sonogashira coupling that specifically address the suppression of Glaser homocoupling, which is a common side reaction when oxygen is present or when copper is used. I will focus on the selection of amine bases (e.g., DIPA, TEA, DABCO) and palladium catalyst systems (e.g., Pd(PPh3)4, Pd(OAc)2 with bulky phosphines) that facilitate the reaction without copper. Additionally, I will look for literature regarding degassing techniques (freeze-pump-thaw vs. argon sparging) and scale-up considerations for these specific conditions.
Queries:
- copper-free Sonogashira coupling aryl halides terminal alkynes amine base selection
- suppress Glaser homocoupling Sonogashira copper-free palladium catalyst
- optimized protocol copper-free Sonogashira coupling scale-up degassing
- palladium-catalyzed Sonogashira coupling without copper amine base effect homocoupling
- Sonogashira cross-coupling terminal alkynes aryl halides copper-free mechanism inhibition of Glaser

Executing 5 concurrent searches:
- copper-free Sonogashira coupling aryl halides terminal alkynes amine base selection
- suppress Glaser homocoupling Sonogashira copper-free palladium catalyst
- optimized protocol copper-free Sonogashira coupling scale-up degassing
- palladium-catalyzed Sonogashira coupling without copper amine base effect homocoupling
- Sonogashira cross-coupling terminal alkynes aryl halides copper-free mechanism inhibition of Glaser

Found 8 papers. Key excerpts:

Copper-free Sonogashira cross-coupling reactions: an overview. — Fatemeh Mohajer et al., 2021

The Sonogashira reaction is unquestionably among the most competent and efficient reactions widely used in organic synthesis. This named reaction has proved useful in many areas of organic synthesis, including the synthesis of pharmaceuticals, heterocycles, natural products, organic compounds, complex molecules having biological activities, nanomaterials, and many more materials that we use in our daily lives. 1 The Sonogashira reaction is among the most prominent methods for sp 2 -carbon–sp-carbon bond formation extensively used in organic synthesis. The original reaction includes the coupling of a terminal alkyne with an alkyl halide in the presence of a palladium species as a catalyst, a copper complex as a co-catalyst, and a phosphine or amine as a base. A considerable efficiency is afforded under ordinary conditions through this unique combination of reagents ( Scheme 1 ). 2,3 The significance of the present work lies in the issues that arise in the presence of Cu in the Sonogashira reaction, 4 some of which are environmentally friendly, 5,6 or solid-supported Pd catalysts. 7
For the first time, this cross-coupling reaction was outlined by Kenkichi Sonogashira et al. in 1975, then rapidly developed using various catalysts, additives, and ligands under different conditions. 8 Since then, the Sonogashira reaction has been regularly employed in the total syntheses of all manners of natural products 9 and compounds of biological activities, 10,11 e.g. , isocoumarins, α-pyrons and indoles, 12–15 arylbenzofurans, 15 dendrimers, 16 conjugated polymers, and nanostructures. 17 Because of its high efficiency as well as milder operational conditions, this reaction is now drawing the attention of synthetic chemists even more than before. 11
The Sonogashira reaction is often performed in the presence of a Pd compound besides CuI as the co-catalyst in different solvents. 18–21 This cross-coupling reaction can also be conducted in aqueous solutions 22 to provide the feasibility of biological screening of products in a direct manner. Although striking developments have been achieved and extensive attempts have been made, the mechanism for the palladium-copper catalyzed Sonogashira reaction has not been thoroughly inferred. Nonetheless, a plausible mechanism for the reaction has been

proposed. As depicted in Scheme 2 , the reaction probably proceeds through Pd–Cu catalytic cycles.
Therefore, the active complex, i.e. , Pd(0)L 2, which is obtained in situ via reduction of the Pd( ii ) species, first catalyzes the rapid step, i.e. , oxidative addition of the vinyl or aryl halide (R–X). Upon another connection with the copper co-catalytic cycle, the RPd(–C
Created by potrace 1.16, written by Peter Selinger 2001-2019
CR')L 2 species is attained through a transmetalation reaction that one may consider it as the rate-determining step in the proposed mechanism. Next, as predicted for a catalyzed reaction, the desired coupled alkyne is derived through a reductive elimination reaction to reproduce the catalyst, as predicted for a catalyzed reaction. The rate of the oxidative addition of the vinyl or aryl halide widely depends upon the electronic properties of the R–X bond so that electron-withdrawing groups tend to activate the R–X bond by increasing its electron density in the order of X = I ≥ OTf ≥ Br > Cl.
Quite a few Pd( ii ) compounds have been prepared and successfully tested to affect the Sonogashira cross-coupling reaction. 23–26 However, one can consider Palladium's use without Cu and/or phosphine -

or amines- co-catalysts as bases as advanced development in the organic synthesis. The Sonogashira reactions are preferred to be conducted without copper and/or phosphines as the Glaser by-products formed before the homo-coupling reaction of alkynes are undesirable, 9,12–14 and copper is essentially toxic. The design and synthesis of heterogeneous palladium-containing catalysts in order to develop Sonogashira cross-coupling reactions free of Cu and/or phosphine has therefore drawn huge attention in the last decade.
Sonogashira–Hagihara cross-coupling of a terminal alkyne with an aryl halide in the presence of Cu and catalyzed by Cd provides an easy method for the synthesis of a variety of unsymmetrical alkynes as well as enynes with biological activities. The standard reaction proceeds through catalysis by a Pd complex, which is usually Pd(PPh 3 ) 4 , in the presence of CuI and also some tertiary amine in various solvents. 27 A copper acetylide is formed upon the reaction of CuI with the alkyne. The resulting copper acetylide is then arylated in the presence of TMEDA or pyridine to form tolans (and benzofurans, indoles, and phthalides resulting due to subsequent heterocyclizations). The reaction is indeed a Stevens–Castro coupling reaction which dates back to 1963. 28
In 1975, three different research groups working separately managed to arylate terminal acetylenes catalyzed by Pd complexes. 29–31 Heck 30 and Cassar 29 carried out the arylation reaction without Cu that is, under the Heck conditions. On the other hand, Sonogashira and co-workers 31 described a Stevens–Castro cross-coupling reaction catalyzed by Pd. The latter has become the chief method to achieve the arylation or vinylation of a terminal alkyne (the Sonogashira cross-coupling reaction). Subsequently, couplings solely catalyzed by Pd complexes with Cu absent were reported, and reaction conditions were adjusted for relatively mild reactions exclusively catalyzed by Cu complexes.
The introduction of a reaction catalyzed by palladium that results in the coupling between terminal acetylenes and aromatic/heterocyclic rings by Sonogashira and

Recent progress in copper-free Sonogashira-Hagihara cross-couplings in water — Julia Struwe et al., 2023

Over the past five decades, a number of transition metal-catalyzed cross-coupling reactions have surfaced as an indispensable toolbox for molecular chemists, finding a wide range of applications in particular in the agrochemical and pharmaceutical industries. 1 , 2 , 3 , 4 , 5 , 6 , 7 Specifically, palladium-catalyzed cross-coupling reactions have matured to become highly effective methods for efficient C‒C bond formations. Since the first procedures in the 1970s, 8 , 9 , 10 , 11 significant progress was achieved because of the ligand design that has resulted in a wide range of applications. The enormous impact of these broadly applicable C‒C bond-forming reactions was recognized with the chemistry Nobel Prize to R. F. Heck, E.i. Negishi, and A. Suzuki in 2010. 2 , 12 , 13 , 14 Among the developed cross-couplings, the Sonogashira-Hagihara reaction has shown to be a powerful procedure to construct valuable internal alkynes, predominantly using palladium catalysts and copper as a co-catalyst. 15 , 16 , 17 , 18 , 19 , 20 Additionally, several copper-free procedures have been developed. 6 , 21 Further illustrating the impact of the transformation in biological active compounds or intermediates, the Sonogashira-Hagihara reaction is also often exploited in their synthesis ( Figure 1 A). 22
Until recently, polar aprotic solvents were the reaction media of choice for such transformations, mostly because of the rather high polarity required to promote the transformations in solution. Traditionally, many of the reported Sonogashira-Hagihara reactions were conducted in organic solvents, such as N -methylpyrrolidone (NMP), N , N -dimethylformamide (DMF), or tetrahydrofuran (THF), using amine bases, with the reaction being typically performed at elevated reaction temperatures ( Figure 1 B). However, such solvents often come with liabilities. DMF, NMP, or N , N -dimethylacetamide are, for example, reprotoxic, 23 and have been the subject of tremendous efforts in the last 15 years for their substitution. In addition, organic solvents are critical contributors to the environmental footprint, as demonstrated in several reports. 23 , 24 , 25 During the last decade, examples of transformations

in water or aqueous surfactant solutions have emerged and given rise to more environmentally benign reactions, following the 12 principles of green chemistry. 26 , 27 As a result of the current requirements on sustainability and the development of green reactions, 28 many efficient and environmentally benign approaches in aqueous media have recently been developed in both academic laboratories and in the pharmaceutical industry, leading to greener, safer, and easier to handle alternatives, 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 among those also Sonogashira-Hagihara cross-couplings in micellar regime ( Figure 1 C). Water is a highly desirable reaction medium. Its safety properties (non-toxic and non-flammable) render it a highly suitable solvent. The major drawback of an aqueous reaction medium is the general low solubility of organic starting materials and reagents in water. However, a solution to this challenge resurfaced a few years ago, through the use of surfactants, such as polyoxyethanyl-α-tocopheryl sebacate (PTS) or TPGS-750-M. These detergents organize themselves in micelles because of the hydrophobic effect. In these structures, the unfavored interaction between the hydrophobic moieties and the aqueous and thus polar reaction medium is minimized by exposing the polar head groups of the amphiphiles to the water. Thereby, lipophilic compartmentation is achieved by forming stable, but likewise dynamic micelles. Organic compounds as well as transition metal catalysts can migrate easily in the lipophilic interior of the micelles, or at their hydrophilic interface. Such a process facilitates the (partial) “solubilization” of organic compounds within their supramolecular structure. The hydrophobic effect of micelles can facilitate and enhance organometallic processes in aqueous reaction media, which is termed micellar catalysis. Likewise, these structures can prevent the decomposition of sensitive intermediates as reported for oxidations, reductions, and C‒C forming processes ( Figure 2 ). 38 , 39
Furthermore, in many examples, the use of micellar catalysis instead of conventional homogeneous catalysis in an organic solvent resulted in milder conditions with lower reaction temperatures and lower catalyst loading. Frequently, the reaction rate was strongly enhanced as well by

the use of surfactants. In contrast with the long-prevalent theory that this can be explained by increased local concentrations, recent computations propose that the underlaying principle for the increased reaction rates is a reduced loss in entropy. The lower energy barrier is believed to be a consequence of the localization of the reactants in the internal surface of the micelles and in line with that a reduced degree of freedom at the two-dimensional surface. 40 Because of the great prominence of these C‒C bond-forming reactions, 41 many of the reports on reactions in water deal with cross-coupling reactions such as Suzuki-Miyaura reactions, 42 , 43 , 44 , 45 , 46 , 47 and with the versatile Sonogashira-Hagihara reaction by homogenous and heterogeneous catalysis. 48 In this account, we aim to illustrate the current developments of copper-free Sonogashira-Hagihara couplings using water as a sustainable reaction medium and to shed light on hurdles and solutions toward green and efficient transformations with the aid of key surfactants often used in organic synthesis ( Figure 3 ).
Most frequently used procedures rely on a palladium/copper bimetallic catalyst system to allow for the transformation of aryl (pseudo)halides with terminal alkynes in organic reaction media at elevated reaction temperatures. The less reactive aryl bromides and chlorides tend to require harsher conditions and a specific ligand. While the use of a mixed reaction media containing an organic solvent and water was also established, 49 , 50 , 51 , 52 , 53 the use of water as the sole reaction medium was associated with considerable limitations, with significant constraints on the substrates and the catalyst to ensure solubility in the reaction medium, with very exceptional cases performing in a robust manner. 54 , 55 , 56 Attempts to achieve the efficient construction of the internal alkyne moiety using aryl bromides in water with pyrrolidine as base thus required harsh reaction conditions with temperatures of 120°C. 57 Lipshutz et al. overcame reliably this limitation, when they reported on an unprecedented palladium-catalyzed Sonogashira-Hagihara cross-coupling of aryl bromides 1 under copper-free conditions 58 , 59 and in the absence of any organic solvent to furnish alkyne 3 ( Scheme 1 A). 60 Essential for the success for

Solid-Supported Palladium Catalysts in Sonogashira Reactions: Recent Developments — Diego A. Alonso et al., 2018

1. IntroductionThe palladium-catalyzed Csp2-Csp coupling reaction between aryl or alkenyl halides or triflates and terminal alkynes is the most important method to prepare arylalkynes and conjugated enynes, which are precursors for natural products, pharmaceuticals, and molecular organic materials (Scheme 1) [1]. The pioneering works of Heck [2] and Cassar [3] in 1975, using phosphine-palladium catalysts at temperatures up to 100 °C, were improved in the same year by Sonogashira and Hagihara, reporting that the addition of a catalytic amount of copper(I) accelerates the reaction, thus enabling to achieve the alkynylation at room temperature [4]. Therefore, the Sonogashira–Hagihara protocol (more often simply known as Sonogashira reaction) became the most popular procedure for the alkynylation of aryl or alkenyl halides [1,5,6]. It is interesting to note that many of the recent developments about new catalytic systems able to carry out this reaction are intended to be “copper-free” processes, to avoid undesirable Glaser-type alkyne homocoupling [7] and to diminish environmental contamination, these processes however still being termed as “Sonogashira reactions”.From an economical, as well as an environmental, point of view, recovering and reusing the expensive palladium catalyst results particularly interesting. The obvious way of recovering the catalyst would be anchoring the catalytic species to a solid support, which would allow its easy separation after the reaction completion just by simple filtration, this topic being considered nowadays a fast-moving research field [8,9,10,11,12]. The present review shows recent developments in the Sonogashira reaction carried out by using solid-supported palladium catalysts and reported from 2012 till the beginning of 2018 [13]. The review has been divided considering the different types of supports for the palladium species. It is necessary to note that, although in many cases the real catalyst is unknown, palladium (0) nanoparticles (PdNPs) are generally considered to be the active catalytic species, most of the palladium complexes being just precursors. 2. Organic Polymer-Supported Palladium CatalystsOrganic polymers

have been the oldest recoverable supports for palladium species acting as catalyst in Sonogashira reactions, and still many new palladium-containing organic polymers able to catalyze this cross-coupling reaction appear. It is interesting to note that almost all these new catalysts can perform the reaction in a copper-free fashion (Scheme 2).Polystyrene-divinylbenzene resin beads have been the most frequently employed organic supports for anchoring palladium complexes. Thus, PdNPs supported on a crosslinked polystyrene 1 (Figure 1) were used as catalyst in the copper-free Sonogashira coupling of phenylacetylene with aryl iodides, bromides and chlorides (Scheme 2), the addition of tetra-n-butylammonium bromide (TBAB) as nanoparticle stabilizer being necessary in the case of aryl chlorides [14]. The catalyst was recovered by filtration and reused up to five times in the model reaction between iodobenzene and phenylacetylene obtaining recycling yields ranging from 88% to 72%. Other case is the phenyldithiocarbazate Pd(II) complex 2 (Figure 1), which catalyzes the copper-free coupling of aryl iodides and bromides, in pyridine as base and at room temperature under neat conditions (Scheme 2) [15]. The supported catalyst has been reused up to five times in the reaction between iodobenzene and phenylacetylene almost keeping the same yield (from 99% to 95%). In addition, no additional solvent has been used when the 1,2,4-triazine-functionalized polystyrene resin-supported Pd(II) complex 3 (Figure 1) has been employed as catalyst using triethylamine or piperidine as base, the aryl chloride derivatives affording lower detected yields and almost no decreasing in the final yield being detected after reusing it five times [16]. In addition, the polystyrene-Pd(II)-furfural complex 4 (Figure 1) has presented catalytic activity in the C-C bond forming reactions, such as the Sonogashira coupling of aryl iodides, bromides and even chlorides with phenylacetylene, although chlorobenzene showed low conversion and activated aryl chlorides gave moderate yields working

at higher temperatures in longer reaction times [17]. The recyclability of this catalyst was studied, but in a Suzuki cross-coupling reaction, keeping its reactivity after five runs.Biphosphinite PCP-pincer palladium complex 5 (Figure 2), based on Merrifield resin, was prepared and characterized [18]. This supported species has been employed as catalyst in the cross-coupling of aryl iodides, bromides and chlorides with phenylacetylene, the addition TBAB additive being necessary in the case of aryl chlorides. The recyclability of the catalyst was not checked in the Sonogashira process but in a Heck reaction, showing the necessity of increasing the reaction time to achieve similar final yields after ten runs. In addition, a recent example of the use of a supported Pd-NHC complex as catalyst is the Merrifield resin-anchored species 6, obtained from the corresponding supported imidazolium chlorides by treatment with palladium(II) acetate (Figure 2) [19]. This catalyst has been used in the copper- and solvent-free coupling of different aryl bromides and two aryl chlorides with terminal acetylenes, these last halides affording low yields. The recyclability of the catalyst was assayed in the coupling of bromobenzene with phenylacetylene for five consecutive runs, observing a certain decrease in the final yield (from 95% to 75%). It is interesting to note that a related supported catalyst with a shorter spacer has also been prepared showing a lower performance, indicating the importance of achieving accessibility to active catalytic sites. Moreover, the aminocarbene palladium complex with polystyrene support 7 has been used as catalyst in the typical copper-cocatalyzed Sonogashira coupling of aryl iodides and bromides with monosubstituted alkynes (Figure 2) [20]. Recycling experiments were conducted, and it was possible to reuse the catalyst up to eight times, although considerable palladium leaching minimized by the addition of triphenylphosphine was observed. The synthetic absorbent resin DIAION HP20 (a styrene-divinylbenzene copolymer) has been used to support palladium(II) acetate, using this material as catalyst for the coupling or ary

Mechanism of copper-free Sonogashira reaction operates through palladium-palladium transmetallation — Martin Gazvoda et al., 2018

Introduction Over recent decades, palladium-catalysed cross-coupling reactions have gained an enormous power in the art of synthetic organic chemistry by providing a fundamental tool for the formation of a carbon–carbon bond in many relevant academic and industrial applications 1 – 5 . In the array of cross-couplings, the reaction between aryl or vinyl halides and terminal alkynes has become the most general, reliable, and effective method to prepare substituted alkynes (Fig.  1 a) 1 , 4 , 6 – 14 . It is known as the Sonogashira reaction—less often, as the Sonogashira–Hagihara reaction. Industrial applications of the Sonogashira reaction are well documented 4 , 9 . There are two main characteristically distinct protocols for Pd-catalysed alkynylations differing profoundly in the use of co-catalysts. The original Sonogashira reaction requires a copper(I) salt as a co-catalyst in combination with the palladium source. Although beneficial for the effectiveness, the usage of copper as a co-catalyst in Pd/Cu catalysed Sonogashira reaction entails several drawbacks including the application of environmentally unfriendly reagents, the formation of undesirable alkyne homocoupling side products, and the necessity of strict oxygen exclusion in the reaction mixture 8 . Efforts to overcome these unsought circumstances have led to amazing developments in the field of Cu-free Sonogashira reaction, also known as the Heck–Cassar coupling or Heck alkynylation. Fig. 1 The Sonogashira reaction. a General representation of Pd/Cu catalysed and Cu-free Sonogashira reaction. b Textbook mechanism for the Pd/Cu catalysed Sonogashira cross-coupling reaction that is synergistically catalysed by Pd and Cu. c Textbook mechanism for Cu-free Sonogashira reaction. d Our mechanistic proposal for Cu-free Sonogashira reaction. OA oxidative addition, TM transmetallation, RE reductive elimination ( cis – trans isomerization steps are omitted for clarity) According to the consensus mechanism depicted in Fig.  1b , the Pd/Cu catalysed Sonogashira reaction comprises oxidative addition, transmetallation and reductive elimination, and proceeds along two synergistically operating catalytic cycles 15 . In

Cycle A, the Pd 0 species undergoes oxidative addition of the C( sp 2 )–X (X = halide) bond of aryl or vinyl halide to provide Pd II complex A . Ligand X is then replaced by the acetylene group of a copper acetylide reagent in the transmetallation step to generate σ-alkynylpalladium(II) species B . The copper acetylide reagent is produced from the acetylene substrate in the second reaction sequence shown in Cycle B. Finally, species B undergoes reductive elimination releasing acetylene derivative and regenerating the starting Pd 0 species. Although some specifics of the transmetallation step and Cycle B are not fully established, the mechanism of the Pd/Cu catalysed Sonogashira reaction from Fig.  1b is generally accepted in the chemical community 1 , 2 , 6 , 8 , 10 , 13 , 14 , 16 – 18 . With some modifications, the oxidative addition–transmetallation–reductive elimination cycle is common to other palladium-catalysed cross-couplings, such as the Suzuki–Miyaura, Stille–Migita–Kosugi, Negishi, Kumada–Tamao–Corriu, and Hiyama–Denmark reactions, where the auxiliary metal, i.e. boron, tin, zinc, magnesium, and silicon, respectively, is essential to assist the transmetallation 1 , 16 . Although the first report on the Cu-free Sonogashira reaction dates more than 4 decades ago 19 , 20 , its mechanism remains elusive. It was tentatively proposed by the group of Soheili in 2003 to consist of the oxidative addition and the reductive elimination steps, as depicted in Fig.  1c 21 . It has been argued that the Cu-free variant cannot build on a transmetallation process. Instead, the formation of B was proposed to take place through a reversible π-coordination of the alkyne reagent to complex A into η 2 -alkyne–palladium intermediate C and subsequent base mediated deprotonation of the terminal acetylenic proton. Although great deal of experimental and theoretical effort has been undertaken in support of this mechanism 22 – 31 , numerous questions are still open and

the proposed model remains unconfirmed. Adversely, recent thorough computational investigations revealed a relatively high activation barrier for the formation of π-complex C from the acetylene and the oxidative adduct A , for example, refs. 26 , 27 , 31 . In contrast to the currently accepted mechanism, we hypothesize that the Cu-free Sonogashira reaction proceeds through a tandem Pd/Pd double-cycle shown in Fig.  1d . This pathway is practically identical to the Pd/Cu catalysed mechanism from Fig.  1b , but the role of the copper co-catalyst is taken by a Pd complex. This concept stems from our recent endeavour in the field 32 . The experimental evidence and computational investigation presented in this study convincingly support the operation of a general tandem Pd/Pd cycle in the coupling of aryl halides and terminal alkynes under various conditions. Results Model reactions and conditions To genuinely map out the pathway of the Cu-free Sonogashira mechanism, it is essential to identify pertinent model reactions and conditions. For the experimental analysis, we tentatively selected 4-iodotoluene ( 1 ) and phenylacetylene ( 2 ) as archetypal substrates, and triphenylphosphine-based palladium pre-catalysts. Triphenylphosphine, along with other bulky phosphines, is a widely used ligand, with [Pd 0 (PPh 3 ) 4 ] and trans -[Pd II (PPh 3 ) 2 Cl 2 ] being the most common catalyst precursors for the Sonogashira reaction 1 . It is well documented that the choice of the catalysts precursor is highly specific to the selection of base, solvent, and reaction temperature, prompting us to consider two discrete reaction conditions shown in Fig.  2a , which were taken directly from literature. Reaction a employs [Pd 0 (PPh 3 ) 4 ] as a Pd 0 pre-catalyst, N , N -dimethylformamide (DMF) as a polar solvent and sodium methoxide as a base 19 , complementary, for Reaction b we selected trans -[Pd II Cl 2 (PPh 3 ) 2 ] as a Pd II pre-catalyst with pyrrolidine base in apolar dichloromethane 27 . Both reactions were run at

Designing Homogeneous Copper-Free Sonogashira Reaction through a Prism of Pd–Pd Transmetalation — Bruno A. Martek et al., 2020

Although the palladium catalyzed
C–C bond formation between aryl or vinyl halides and terminal
alkynes by Heck 1 and Cassar 2 evolved into the most effective tool for the synthesis
of disubstituted alkynes, it is the copper cocatalyzed variant that
has mostly entered industrial applications ( Scheme 1 ). 3 , 4 Scheme 1 General Representation
of Pd-Catalyzed and Copper Cocatalyzed Alkynylation
Reaction This is exemplified by the
synthesis of many Food and Drug Administration
(FDA) approved active pharmaceutical ingredients (APIs), 3a , 3d including Terbinafine (Sandoz, squalene epoxide inhibitor), 5 Ponatinib (Ariad Pharmaceuticals, tyrosine-kinase
inhibitor), 6 Tazarotene (Allergan, receptor-selective
retinoid), 7 and Eniluracil (GlaxoSmithKline,
dihydropyrimidine dehydrogenase inactivator). 8 As reported by Sonogashira et al., 9 alkynylation
in the presence of copper salts proceeds under much milder conditions. 3 , 4 , 10 Copper additives, however, promote
Glaser–Hay 11 competitive homocoupling
of alkyne and interfere with some functional groups potentially present
in the coupling partners like azide, amine, and alkyne. During the
isolation process, removal of copper cocatalyst may complicate the
workup and purification, especially in the synthesis of APIs. 12 , 13 When it comes to a bulk industrial process, recovery of the precious
metal from spent catalysts is more challenging for the copper cocatalyzed
than the copper-free process. 14 , 15 Although homogeneous
copper-free alkynylation has witnessed tremendous improvements, it
mostly benefited from development of novel ligands 3 , 4 , 10b , 16 and technologies.
Aqueous micellar catalysis developed by the groups of Lipshutz, 17 and Sparr and Parmentier 18 is a notable example of the latter. Contrary to a
previous belief, it has been recently postulated
by us 19 , 20 and others 21 that
the mechanism of copper-free alkynyl

ation operates through a process
that resembles copper cocatalyzed variant, but the role of copper
is played by palladium ( Scheme 2 ). It builds on transmetalation (TM) between two distinct
palladium species, oxidative addition (OA) intermediate A that is generated within Pd1-Cycle , and acetylide B from the Pd2-Cycle . Ideally for the productive
alkynylation, the concentrations of both reactive intermediates in
the reaction mixture are kept equimolar throughout the process. Increasingly
favorable formation of A over B from the
single (pre)catalyst decelerates or even terminates the cross-coupling
and promotes undesired homocoupling side reaction into biaryls instead.
Likewise, acetylide B as a (pre)catalyst sink potentially
leads to 1,3-diyne and/or enyne byproducts. This condition, however,
is rather difficult to meet rationally by introducing a single palladium
source/ligand combination that has so far been exclusively applied
for the copper-free alkynylation. 3 , 4 Scheme 2 General
Representation of Bicyclic Mechanism of Copper-Free Alkynylation
That Is Synergistically Catalyzed by Two Pd Species Based on the mechanistic rationale, herein we present
a novel concept
for the design of palladium catalyzed copper-free alkynylation. It
features simultaneous introduction of two different palladium (pre)catalysts
into the reaction mixture, one tuned to facilitate oxidative addition
to aryl halide in Pd1-Cycle , and another one to activate
terminal alkyne in Pd2-Cycle . Initially, we
selected (PhCN) 2 PdCl 2 as a
source of palladium to operate in the Pd1-Cycle and
set a brief screening ( vide infra ) through a selection
of commercially available phosphine-based ligands shown in Table 1 . These Pd/ligand
combinations have already proven to promote the formation of catalytically
active Pd 0 species, subsequent oxidative addition, and
reductive elimination (RE) in a range of cross-couplings.

3 , 4 , 10b , 16d , 22 Table 1 Phosphine
Ligand Evaluation in Model
Alkynylation Reaction a a NMR yields are
reported as determined
from at least two consecutive runs. To build on Pd2-Cycle , we decided
to avoid the
phosphine-based palladium complexes. Although their ability to activate
terminal alkynes into acetylides of type B is well-established, 10b , 23 the propensity of phosphines to dissociate and exchange 24 could lead to undesired scrambling between the
reactive palladium species from both cycles, leading to uncontrolled
side reactions or even termination of the process. Instead, we selected
N-heterocyclic carbene (NHC) ligand of a pyridine (Py) functionalized
mesoionic (MIC) structure (PyMIC), 19 , 25 possessing
coordination abilities to a metal beyond phosphines and even NHCs. B -like NHC acetylide Pd 2+ complexes are well-documented, 26 and their formation is also evident from many
Pd-NHC promoted copper-free and copper cocatalyzed alkynylations. 27 All of the above applies to the Pd-PyMIC complex ( Table 1 )
that has proven to have an exceptional stability, promoting copper-free
alkynylation in hot water under aerobic conditions. 19 For the test reaction, we selected 4-bromotoluene
( 1a , 1 equiv) and phenylacetylene ( 2a , 1.4
equiv) as the
model substrates ( Table 1 ). The reaction conditions employed (PhCN) 2 PdCl 2 (2 mol %), phosphine ligand L (4 mol %), Pd-PyMIC (1 mol %), and 1,4-diazabicyclo[2.2.2]octane (DABCO, 1.4 equiv)
as a base in acetonitrile at room temperature. We aimed to design
the reaction conditions that would enable cross-coupling at room temperature
(22 °C). By screening through the ligands L , only
Cata CX ium A ( L7 ) provided reasonable
conversion to

Copper-Free One-Pot Sonogashira-Type Coupling for the Efficient Preparation of Symmetric Diarylalkyne Ligands for Metal-Organic Cages** — Marc Lehr et al., 2021

Introduction

     Palladium-catalyzed cross-coupling reactions are powerful synthetic methods for carbon−carbon bond formation in modern organic chemistry.1 In particular, Sonogashira cross-coupling reactions2 have been used extensively for the synthesis of diarylalkynes in natural products,3 conjugated oligomers/polymers in materials science4 and ligands/building blocks5 in coordination chemistry and supramolecular chemistry due to their typically high yields and tolerance of a wide range of functional groups.

     Symmetric diarylalkynes find application in diverse fields since they are precursors in the synthesis of hexaarylbenzene derivatives,6 building blocks for light-emitting materials,7 and inorganic heterocycles8 as well as building blocks in supramolecular architectures.5b, 5c, 5f However, their preparation is typically a multi-step synthesis (black route, Scheme 1), often involving long reaction times and multiple purification steps, resulting in overall lower yields and making scale-up for applications difficult.7 Glaser coupling9 can also take place in the presence of the copper co-catalyst with traces of oxygen, leading to side-product formation2a, 10 and difficult purifications. As a result, one-pot cross-coupling methods using a variety of acetylene sources (e. g. gaseous acetylene,11 calcium carbide,12 propiolic acid13 and silyl-protected alkynes14) as well as copper-free Sonogashira-type couplings12, 13, 14b, 15 (e. g. replacing the copper co-catalyst and amine with tetrabutylammonium fluoride (TBAF)15a, 15b) have been developed to overcome these problems, respectively.




              Scheme 1Open in figure viewerPowerPoint




                 Multi-step synthesis of diarylacetylenes via sequential Sonogashira cross-coupling reactions (black) and the copper-free one-pot Sonogashira method (blue) in this work.




     Ligand synthesis is a bottleneck for the self-assembly and application of metal-organic cages5g-5m due to multi-step syntheses and challenging purifications. Diarylalkyne-based ligands are appealing given their potential synthesis via a one-pot procedure and further functionalisation via the alkyne functionality, e. g. through post-assembly modification.5c However, most one-pot Sonogashira couplings have been reported for symmetric carbocyclic rather than heterocyclic diarylalkynes with limited examples including those based on thiophene11, 12, 14b, 14c and pyridine12, 14 derivatives.

     We report the efficient synthesis of symmetric diarylalkyne ligands 1 a–c and 2 b–c for metal-organic cages 3 a–c and 4 a–b (Figure 1) via a copper-free one-pot procedure using trimethylsilylacetylene as the acetylene source and TBAF functioning as a base, activator, and deprotection reagent (blue route, Scheme 1). In addition to significantly reducing the synthetic burden from a 3 step synthesis with a long overall reaction time to a single 3-hour step, the ligands were prepared in high isolated yields (32–92 %) for a one-pot procedure. The proof-of-principle for large-scale ligand synthesis was also demonstrated. Thus, this method enables rapid access to ligands for metal

-organic cages from suitable aryl halide building blocks and this will facilitate the discovery of new cages as well as the translation of cages to applications.

              Figure 1Open in figure viewerPowerPoint


                 Symmetric heterocyclic diarylalkyne ligands synthesized using the copper-free one-pot Sonogashira-type coupling and their respective Co4L6 metal-organic cages.

Results and Discussion

     We recently reported that the synthesis of ligand 1 a16 could be reduced from three to two steps using TBAF for the in situ deprotection of the TMS-protected alkyne (first step in black route, Scheme 2).5f However, the Glaser by-product was also obtained in the final Sonogashira coupling using copper(I) iodide in some instances. Mori15a and Li15b reported copper- and amine-free Sonogashira couplings between terminal alkynes and aryl halides, including aryl chlorides, with short reaction times and good to excellent yields using TBAF as an activator. It is proposed that the TBAF activates and stabilizes the Pd(0) species, deprotonates the alkyne, and acts as a phase-transfer catalyst.15b Therefore, we envisaged TBAF could play the role of not only a deprotection reagent but also an activator and base in a one-pot procedure while preventing the formation of Glaser by-products.

Room-Temperature, Copper-Free, and Amine-Free Sonogashira Reaction in a Green Solvent: Synthesis of Tetraalkynylated Anthracenes and In Vitro Assessment of Their Cytotoxic Potentials. — Khadimul Islam et al., 2023

Organic semiconducting materials based
on polyethynylated anthracene 1 have attracted
global attention due to their
versatile applications in solar cells, 1e , 2 organic light-emitting
diodes (OLEDs), 1b organic field-effect
transistors (OFETs), 1f , 1h devices based on nanowires, 3 sensors, 4 liquid-crystal
displays, 5 and organic fluorescence. 1g The fluorescence efficiency and the electronic
properties of the molecules depend on the geometry of the molecules. 1d The rigid polycyclic aromatic hydrocarbons (PAHs) 1d , 6 exhibit high fluorescence efficiency, which can be controlled by
the addition of substituents like amino, 7 amino acid ester, 8 aryl, 7 carboxylic acid, 9 and hetero
atoms. 1d , 7 Addition of polyethynylated units to the
PAHs enhances the π-conjugation, which helps to decrease the
band gap, lowering the torsional barrier and enhancing the thermal
stability, which are favorable for the fabrication of such compounds
in optoelectronic devices. 1d The polyalkynylated
unit can be introduced to the PAHs by the Sonogashira reaction. The
Sonogashira reaction is vital in organic synthetic chemistry for the
synthesis of various organic compounds like natural products, 10 pharmaceutical molecules, 11 biologically active complexes, 12 heterocycles, 13 and organic materials. 1d
In 1975, Sonogashira, Hagihara, and Tohda
reported a cross-coupling
reaction by employing Pd(PPh 3 ) 2 Cl 2 as the catalyst, CuI as the cocatalyst, and amine as the base, which
was later modified using various catalysts, additives, and numerous
ligands under different conditions. 1c , 1d , 12 , 14 Traditionally, in the
Sonogashira reaction, Cu(I) coordinates with alkyne to enhance the
acidity of the terminal acetylenic proton, assisting in the formation
of the acetylide Cu(I), which is involved in the transmetallation
step in the catalytic cycle when the alkyne unit is transferred to
Pd that subsequently couples with the ary

l moiety to form the product
via reductive elimination. 1d However, the
presence of copper salts can sometimes have deleterious effects on
catalysis, 15 which include but are not
limited to participation in the Glasser homocoupling of two terminal
alkynes to form dialkynes, 1d , 12 , 15a inhibition of the activity of the Pd catalyst, 15a and oxidation of unsaturated Pd(0) species to halide-bridged
dinuclear Pd(I) complexes that accelerate polymerization 16 of the alkyne. Rightly, a lot of research emphasis
is devoted to the development of copper-free and preferably amine-free
Sonogashira catalytic systems. 12 , 15 , 17
There are reports that demonstrate that Pd and Cu together
are
no longer required as catalysts for Sonogashira reaction; instead,
simply Pd has proven to be adequate when correctly complexed with
state-of-the-art ligands in the absence of any amine additives. 12 , 15a , 17c − 17e , 18 In 2003, Buchwald demonstrated
a copper-free and amine-free Sonogashira reaction catalyzed by Pd(CH 3 CN) 2 Cl 2 (1 mol %) and X-Phos-type ligand
(2 mol %) in the presence of Cs 2 CO 3 (2 equiv)
in CH 3 CN at 70–95 °C. 15a Lim and coworkers reported a copper-free and amine-free Sonogashira
reaction by employing Pd(CH 3 CN) 2 Cl 2 (1 mol %) in combination with Cy*Phine (2 mol %) using Cs 2 CO 3 (2 equiv) as the base in CH 3 CN at 90 °C
for 6 h. Very recently, Mak and coworkers had investigated the reaction
mechanism for the same. 17c , 18b It is thus evident
that while there are a few studies on copper-free and amine-free Sonogashira
systems, reports that accomplish these very important reactions at
room temperature are very rare. 12 , 19
The waste of
chemical industries is mainly from solvents, which
is about 80–90% of the total mass process. 20 The choice of solvent is very crucial

in Pd-catalyzed cross-coupling
reactions owing to the stability of the catalyst, selectivity, and
rate of the reaction. 21 As per the literature,
more than 40% of the reports on Heck–Casser–Sonogashira
reactions have been performed in N , N -dimethylformamide (DMF) solvent, which generates toxic dimethylamine
and highly genotoxic nitrosamine. 22 Other
solvents like tetrahydrofuran (THF), 1,4-dioxane, dimethoxyethane
(DME), dimethyl sulfoxide (DMSO), and trimethylamine (TEA) also have
been used in the Sonogashira reaction. 22b Triethyl amine is a malodorous substance, highly toxic, and exhibits
bioaccumulation potential. 23 Exposure to
amine vapors for 0.5 h to several hours may cause glaucopsia, blur
the vision, and make one see halos around lights. 24 Unfortunately, all other solvents have the same drawbacks
like DMF, which are a threat to the environment, the human body, and
the ecosystem. 24 Recently, green solvents
like dimethylisosorbide, γ-valerolactone, cyrene, tert -butyl acetate ( t BuOAc), anisole, N -octylpyrrolidone (NOP), N -cyclohexylpyrrolidone
(NCP), N -benzylpyrrolidone (NBnP), and N -hydroxyethylpyrrolidone (HEP) have been reported in the Sonogashira
reaction. 22b − 22e
A brief survey of the literature above clearly indicates that
development
of copper-free and amine-free Sonogashira catalytic systems in green
solvents at room temperature is still a challenge that is unaddressed.
In particular, 2-methyl tetrahydrofuran (2-MeTHF) that is readily
obtained from renewable biomass cellulose, bagasse, corncobs, and
agricultural waste 25 has not been explored
to date. 22 From the context of PAHs, it
would thus be valuable to have a Son

Palladium-Catalyzed Mizoroki-Heck and Copper-Free Sonogashira Coupling Reactions in Water Using Thermoresponsive Polymer Micelles. — Noriyuki Suzuki et al., 2021

The development of environmentally benign processes that enable organic syntheses to achieve the United Nations Sustainable Development Goals (SDGs) is an urgent subject. Transition metal-catalyzed chemical transformations are broadly utilized for producing fine chemicals; however, most catalytic reactions require organic solvents, which consequently results in an increase in the E-factor [ 1 ]. Conducting catalytic reactions in water is attractive to chemists who want to develop environmentally benign processes. In fact, many examples of palladium-catalyzed reactions conducted in water (or “on water”) have been reported over the past few decades [ 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 ]. The addition of surfactants to aqueous reaction mixtures causes the formation of oil/water ( o / w ) emulsions such that the organic reactions proceed in the micelle core. It is known that some chemical reactions can be accelerated in micellular systems [ 14 , 15 , 16 , 17 ]; however, organic reactions in o / w emulsions often require extraction processes using organic solvents to separate the products. Reducing the amount of the extraction solvent is an important subject for decreasing the E-factor of a process. Extraction processes might be more efficient if micelle formation can be “turned off” upon completion of the reaction. We envision that a thermoresponsive polymer micelle could be utilized for this purpose ( Figure 1 ).
Poly( N -isopropylacrylamide) (PNIPAAm), which shows a lower critical solution temperature (LCST) at 32 °C in water, is known to be a thermoresponsive polymer and its applications in fields such as drug delivery systems and smart therapeutic materials have been studied extensively [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ]. Thermoresponsive micelles that consist of PNIPAAm blocks have been vastly investigated, as has their utilization for therapeutic purposes [ 26 , 27 , 28 , 29 , 30 ]. For organic synthetic methods, there have also been many reports in which PNIPAAm was applied for organic reactions, as well as transition metal-catalyzed reactions. Many of these studies involve the use of a cross-linked PNIPAAm gel [ 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 ,

41 , 42 , 43 ]; however, examples of thermoresponsive micelles applied for organic synthesis are still rare [ 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 ]. We previously reported the utilization of PNIPAAm block copolymers that form thermoresponsive micelles in water for organic synthesis. These micelles form at a temperature above 40 °C and dissociate at room temperature. We have tethered organocatalysts such as L-proline on the PNIPAAm block copolymers and demonstrated asymmetric cross-aldol reactions in water [ 44 , 46 , 47 ]. O’Reilly and coworkers also reported the use of PNIPAAm-based copolymer micelles bearing L-proline for asymmetric reactions in water [ 48 ]. We recently reported palladium-catalyzed Mizoroki–Heck reactions in water using these thermoresponsive polymer micelles [ 45 ] and showed that these reactions gave the products in high yields and with a good extraction efficiency. In the previous study, we reported that more efficient extraction was observed for aqueous solutions of the diblock copolymer poly( N -isopropylacrylamide)- b -poly(sodium 4-styrenesulfonate) (PNIPAAm- b -PSSNa, NS ) compared to PNIPAAm -b -PEG, although the E-factor was still no less than 20. The extraction of more products from the aqueous reaction mixture with less organic solvent usage is important for elucidating an improved E-factor. Furthermore, the turnover number (TON) of palladium catalysts (2 mol %) was no more than 50, and reuse of the aqueous catalyst solutions was not achieved. Herein, we wish to report that Mizoroki–Heck reactions proceed in water using thermoresponsive micelles with a palladium catalyst 1 bearing 2,9-diphenyl-1,10-phenanthroline as a ligand. The TON reached 7800 due to high catalytic activity of 1 . In this study, we employ a new system of three diblock copolymers ( NA , DS and DA ), and examine the reactions with these copolymers as well as the extraction efficiency from the aqueous solutions ( Figure 2 ). We

also report palladium-catalyzed Sonogashira coupling reactions using these copolymers in water.
The preparation of copolymers was conducted under an argon atmosphere using standard Schlenk techniques unless otherwise mentioned. N -Isopropyl acrylamide (NIPAAm) was purchased from Kanto Chemical Co., Inc. and recrystallized from hexane/toluene prior to use. 2,2′-Azobis(isobutyronitrile) (AIBN), and dimethylacetamide (DMA) were purchased from Kanto Chemical Co., Inc. and used without further purification. Sodium dodecyl sulfate (SDS) and 4,4′-azobis(4-cyanovaleric acid) (V-501) were purchased from FUJIFILM Wako Pure Chemical Corporation and were used as received. N , N -Diethylacrylamide was purchased from Tokyo Chemical Industry Co., Ltd. and was distilled prior to use. Styrene was purchased from Tokyo Chemical Industry Co., Ltd., distilled, and kept under argon. Sodium 4-styrenesulfonate, 2-acrylamido-2-methylpropanesulfonic acid, dichlorobis(triphenylphosphine)palladium, 2,9-diphenyl-1,10-phenanthroline, iodobenzene, n -butyl acrylate, diisopropylethylamine, and α-methylstyrene were purchased from Tokyo Chemical Industry Co., Ltd. and were used as received. Other aryl halides, alkenes, ethynylarenes, and palladium catalysts were purchased and used as received. XPhos and Triton X-100 were purchased from Sigma-Aldrich Co. LLC. and used without further purification.
Palladium complex 1 was prepared from 2,9-diphenyl-1,10-phenanthroline and dichlorobis(acetonitrile)palladium according to the literature [ 52 ]. RAFT agent 2a and 2b were prepared according to the reported method in the literature [ 53 , 54 ]. Triethylammonium hypophosphite was prepared from triethylamine and hypophosphinic acid in toluene. The dib