Carbonylative Sonogashira Reactions

Abstract

The Sonogashira reaction is generally known as a coupling reaction of terminal alkynes with aryl or vinyl halides. This reaction was first reported by Sonogashira and Hagihara in 1975. Today the Sonogashira coupling reaction is one of most powerful processes for C–C bond formation, especially for the synthesis of substituted alkynes. From the reaction mechanism aspect, a transmetalation step was included between the palladium center and the in situ-formed organocopper intermediate.

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The Sonogashira reaction is generally known as a coupling reaction of terminal alkynes with aryl or vinyl halides. This reaction was first reported by Sonogashira and Hagihara in 1975 (Scheme 5.1) [1]. Today the Sonogashira coupling reaction is one of most powerful processes for C–C bond formation, especially for the synthesis of substituted alkynes [2–4]. From the reaction mechanism aspect, a transmetalation step was included between the palladium center and the in situ-formed organocopper intermediate.

Scheme 5.1

Palladium-catalyzed Sonogashira coupling reaction

If the Sonogashira reaction is carried out in a CO atmosphere, the reactions are called Carbonylative Sonogashira Reactions, which will give alkynone as an interesting structural motif found in numerous biologically active molecules [5–7]. Notably, this class of compounds plays a crucial role in the synthesis of natural products [8–12] and as key intermediates for the efficient formation of several heterocycles [13–15]. Traditionally, alkynones have been synthesized by transition metal catalyzed cross-coupling reactions of acid chlorides and terminal alkynes (Scheme 5.2) [16–24]. However, the stability of the respective acid chlorides is limited and a lack of functional tolerance is another problem of this methodology. Without a doubt, carbonylative Sonogashira coupling of corresponding terminal alkynes and aryl halides represents the most straightforward way to set up alkynones.

Scheme 5.2

Selected synthesis and applications of alkynones

The first palladium-catalyzed carbonylative Sonogashira coupling was reported in 1981 by Kobayashi and Tanaka [25]. Aryl, heterocyclic, and vinylic halides reacted with CO and terminal acetylenes at 120 °C and 80 bar in the presence of NEt₃ and a catalytic amount of a palladium(II) complex to form alkynones in a 46–93 % yield (Scheme 5.3). Remarkably, aryl bromides and aliphatic alkynes were also included in the range of substrates. But NEt₃ was used as a solvent for this transformation and a relatively high pressure of CO was needed.

Scheme 5.3

First Pd-catalyzed carbonylative Sonogashira coupling of organic halides

Interestingly, in 1991 Alper and Huang described another type of palladium-catalyzed carbonylative Sonogashira coupling of aryl iodides with benzyl acetylenes. Here, furanones were isolated as the terminal products and not the predicted alkynones [26]. In the presence of Pd(OAc)₂/PPh₃, aryl iodides and benzyl acetylenes were transformed into furanones in 33–88 % yields (Scheme 5.4). Palladium-catalyzed carbonylative Sonogashira coupling reactions of iodobenzene and 2-methyl-3-butyn-2-ol under biphasic conditions to furanones were also described by Kiji and colleagues [27].

Scheme 5.4

Pd-catalyzed carbonylation of benzyl acetylenes to fuanones

In 1991 Ortar and colleagues published a general procedure for the carbonylative Sonogashira couplings of vinyl triflates with terminal acetylenes [28]. Various alkynyl ketones were produced in moderate to good yields (Scheme 5.5). However, this methodology failed in the case of activated alkynes or aryl triflates.

Scheme 5.5

Pd-catalyzed carbonylative Sonogashira coupling of vinyl triflates with 1-alkynes

The catalytic ability of dimeric palladium hydroxide in carbonylative Sonogashira coupling was demonstrated by Alper and his team in 1994 [29]. In this report, terminal alkynes and alkynols were coupled with aryl iodides in the presence of carbon monoxide in moderate to good yields (Scheme 5.6). In 1995 Cacchi and colleagues presented a general methodology for 5-(2-acylethynyl)-3′,5′-di-O-acetyl-2′-deoxyuridines synthesis [30]. In the presence of a palladium-catalyst, the corresponding alkynones were synthesized from aryl iodides and alkynes (Scheme 5.7).

Scheme 5.6

Dimeric palladium hydroxide-catalyzed carbonylative Sonogashira coupling

Scheme 5.7

Pd-catalyzed carbonylative Sonogashira coupling of aryl iodides

The carbonylative Sonogashira reaction of iodonium salts with terminal alkynes was described by Kang and colleagues [31]. Both palladium/copper and palladium-catalyst systems alone could be used and various alkynones were synthesized in moderate to good yield in aqueous media (Scheme 5.8). Interestingly, a catalytic amount of CuI could also catalyze the reaction, and gave the corresponding alkynones in good yields.

Scheme 5.8

Pd-catalyzed carbonylative Sonogashira coupling of iodonium salts with and without Cu co-catalysts

Another example of carbonylative Sonogashira coupling reactions with iodinium iodide and 1-alkynes was published by Ma and colleagues in 2001 [32]. Under mild conditions, iodine-substituted alkynones were produced in good yields (Scheme 5.9). Both aromatic, aliphatic and heterocyclic terminal acetylenes can be applied as their substrates.

Scheme 5.9

Pd-catalyzed carbonylative Sonogashira coupling of iodinium iodide

An interesting room temperature carbonylation using a palladium/copper-catalyst system was published by Mori and Ahmed in 2003 [33–35]. As shown in Scheme 5.10, various aromatic alkynones were produced in moderate to good yields using aqueous ammonia as a base. Surprisingly, no competitive amination reaction occurred. This methodology was further exploited by Bishop’s group to generate pyrazoles [35].

Scheme 5.10

Carbonylative room temperature Sonogashira reaction in aqueous ammonia

Water as a green solvent has been successfully applied as a reaction medium for palladium-catalyzed carbonylative Sonogashira reactions (Scheme 5.11) [36]. Instead of using alkynes, activated acetylenes stibanes can also be applied as coupling partners in carbonylations. An example is the palladium-catalyzed carbonylative Sonogashira coupling of alkynyl stibanes with aryl iodides that was published by Kakusawa and Kurita in 2006 [37]. The reaction was carried out under 1 bar of CO in DMAc using 5 mol% of Pd(OAc)₂ and 20 mol% of PPh₃. Alkynones were obtained in good yields along with a small amount of non-carbonylative coupling products (Scheme 5.12). However, this side reaction can be completely suppressed by increasing the CO pressure to 20 bar.

Scheme 5.11

Pd-catalyzed carbonylative Sonogashira coupling in water

Scheme 5.12

Pd-catalyzed carbonylative Sonogashira coupling of ethynyl stibane with aryl iodides

The use of ionic liquids and flow chemistry technologies attract increasing attention. Consequently, these novel tools have also been successfully used in carbonylative Sonogashira reactions by Ryu and colleagues [38, 39]. Various alkynones were synthesized in moderate to good yields at a low pressure of CO in n-butyl methyl imidazolium hexafluorophosphate. The microreactor-based flow system was compared with typical batch conditions, and higher yields could be achieved with flow system (Scheme 5.13).

Scheme 5.13

Pd-catalyzed carbonylative Sonogashira reaction in ionic liquids

In 2006 Chen and his colleagues described a convenient, effective method for the carbonylative Sonogashira coupling of aryl iodides with ethynyl ferrocene under one atmosphere of CO [40]. Various aryl ferrocenylethynyl ketones have been synthesized in a 62–88 % yield (Scheme 5.14). Unexpectedly, strongly activated aryl iodides (4-Ac, 4-NO₂) and iodopyridine gave no desired carbonylation product. However, this methodology was also applied to a two-step synthesis of ferrocenyl pyrazole and pyrimidine derivatives by Skoda–Foldes and co-worker [41]. In 2009, this group reported on another protocol for the synthesis of ferrocenylethynyl ketones in water [42].

Scheme 5.14

Pd-catalyzed carbonylative Sonogashira coupling of ethynyl ferrocene with aryl iodides

The use of phosphites, e.g., P(OPh)₃ as a ligand in palladium-catalyzed carbonylative Sonogashira coupling, was first reported by Trzeciak and colleagues [43]. Using the defined complex PdCl₂[P(OPh)₃]₂ as a catalyst, alkynones were produced in low to moderate yields at 1 bar of CO (Scheme 5.15). When the reaction was conducted in an ionic liquid, the catalyst could be reused in four consecutive catalytic runs with high activity. Notably, benzyl bromide was reported as a substrate for the first time, but 2 equivalents of acetylenes were required for this system.

Scheme 5.15

PdCl₂[P(OPh)₃]₂-catalyzed carbonylative Sonogashira coupling of aryl iodides with alkynes

Kondo and Iizuka presented a palladium-catalyzed “CO-free” method for alkynone synthesis, which applies stoichiometric amounts of Mo(CO)₆ as a CO source [44]. The reaction was carried out at room temperature, and PtBu₃ was found to be an essential ligand under these conditions. When strong electron-withdrawing substituted aryl iodides were used as substrates in this protocol, the corresponding alkynones were produced in good to excellent yields (Scheme 5.16). Again, a one-pot synthesis of pyrazoles via condensation of corresponding alkynones with hydrazine was also conducted and the corresponding products were obtained in good yields at room temperature.

Scheme 5.16

Pd-catalyzed carbonylative Sonogashira coupling reaction with Mo(CO)₆ as a CO source

In 2008, Xia and Chen described a recyclable phosphine-free catalyst system for alkynone synthesis [45]. Using palladium on charcoal (Pd/C) and NEt₃, the carbonylative Sonogashira coupling of aryl iodides with alkynes was smoothly carried out and the desired products were isolated in moderate to excellent yields (Scheme 5.17).

Scheme 5.17

Pd/C-catalyzed carbonylative Sonogashira reaction of aryl iodides

Later on, the same group presented an unusual variation of the palladium-catalyzed carbonylative Sonogashira coupling reaction [46]. Here, a magnetically separable palladium-catalyst was synthesized by combining palladium nanoparticles and superparamagnetic Fe₃O₄ nanoparticles in a KBH₄ solution. This catalyst proved to be effective for the carbonylation reaction of aryl iodides with alkynes under phosphine-free conditions. Because of the magnetic behavior of Fe₃O₄, the catalyst could be reused with sustained selectivity and activity. Various alkynones have been synthesized in good to excellent yields (Scheme 5.18).

Scheme 5.18

Pd/Fe₃O₄-catalyzed carbonylative Sonogashira coupling of aryl iodides

Another approach applying a heterogeneous palladium-catalyst was recently published by Cai and colleagues. They disclosed the MCM-41-supported bidentate phosphine palladium complex [MCM-41-2p-Pd(0)] as a polymer-supported palladium-catalyst [47]. Terminal alkynes were converted with aryl iodides under 1 bar CO to give alkynones in good to high yields (Scheme 5.19). Noteworthy is the fact that the use of a polymer as support in a Sonogashira coupling reaction was already reported by Takahashi and colleagues in 2008. The products can be released from the polymer by adding acid [48].

Scheme 5.19

[MCM-41-Pd]-catalyzed carbonylative Sonogashira coupling reaction of aryl iodides

So far, basically all methodology developments in this area have focused on the use of expensive and easy-to-activate aryl iodides. Thus it was interesting that in 2010 Beller’s group discovered a general and convenient palladium-catalyzed carbonylative Sonogashira coupling of aryl bromides [49]. The key to the success was the application of BuPAd₂ as a ligand in the presence of K₂CO₃. Alkynones have been generated in moderate to good yields from the corresponding aryl bromides and terminal alkynes (Scheme 5.20). The one-pot synthesis of isoxazolines and pyrazoles was also successful.

Scheme 5.20

Pd-catalyzed carbonylative Sonogashira coupling of aryl bromides

Since aryl triflates can easily be generated from corresponding phenols, Beller also developed a palladium-catalyzed carbonylative Sonogashira coupling of aryl triflates in 2010 [50]. This is the first carbonylative Sonogashira protocol that can apply aryl triflates as substrates. Various alkynones were produced in moderate to good yields under low pressure of CO (Scheme 5.21). A one-pot synthesis of enaminones was also achieved by running the reaction in the presence of primary amines.

Scheme 5.21

Pd-catalyzed carbonylative Sonogashira coupling of aryl triflates

Taking the advantages of anilines, Beller and his colleagues developed the first general and efficient methodology for carbonylative Sonogashira reaction of anilines [51]. This transformation proceeded under mild reaction conditions, and no base was needed. Both aromatic and aliphatic alkynes are suitable starting materials, and 30 different kinds of alkynones were produced in moderate to excellent yields (Scheme 5.22).

Scheme 5.22

Palladium-catalyzed Sonogashira carbonylation of anilines

They also extended their methodologies to benzyl chlorides [52]. Applying an unusual Pd(PPh₃)₂Cl₂/P(OPh)₃ catalyst system, eight different alkynones are produced in moderate to good yields (45–80 %) by the carbonylation of benzyl chlorides and alkynes. Benzyl acetylene gave the corresponding furanones in moderate a yield (45–68 %) via palladium-catalyzed domino double carbonylation reactions. Based on this work, the carbonylative synthesis of furanones from aryl bromides and aryl triflates were developed as well [53]. The generality of this methodology was proved by more than 30 examples that proceeded good yields (Scheme 5.23). Notably, the straightforward synthesis of permethylated BE-23372M, a kinase inhibitor, was achieved. Later on, they found that the carbonylation of aryl iodides with benzylacetylenes could even be carried out at room temperature under 1 bar of CO [54].

Scheme 5.23

Palladium-catalyzed furanones synthesis

Ryu and colleagues described the synthesis of alkyl alkynyl ketones via the Pd/light-induced carbonylative Sonogashira coupling of iodoalkanes with terminal alkynes [55]. Using xenon light, in the presence of a catalytic amount of PdCl₂(PPh₃)₂ and NEt₃, alkynones were produced in good yields (Scheme 5.24). This represents the first examples for Sonogashira carbonylations of alkyl iodides [56].

Scheme 5.24

Pd-catalyzed carbonylative Sonogashira coupling of iodoalkanes using xenon light

Despite all the synthetic developments, relatively little detailed mechanistic work has been performed on Sonogashira carbonylations until the present. The generally accepted mechanism is shown in Scheme 5.25. The typical reaction begins with the oxidative addition of ArX to a palladium(0) complex to form an aryl palladium(II) intermediate. The subsequent insertion of CO leads to the respective palladium acyl complex. Transmetallation, and finally reductive elimination, releases the product and a new catalytic cycle can be started. Notably, all species passing through the cycle are believed to be in a reversible equilibrium.

Scheme 5.25

Proposed reaction mechanism for carbonylation Sonogashira reaction

Besides the intermolecular Sonogashira carbonylation reactions, intramolecular Sonogashira carbonylations offer various possibilities for the preparation of interesting heterocycles. Typically, in these reactions 2-halophenols and 2-haloanilines or their derivatives are used with terminal alkynes. As early as 1990, Chiusoli and colleagues reported on the palladium-catalyzed synthesis of indoxyl derivatives (Scheme 5.26) [57].

Scheme 5.26

Pd-catalyzed carbonylative synthesis of indoxyls

Shortly afterwards, Torii and co-worker reported a novel methodology for the synthesis of quinolines [58, 59]. Here, quinolines were produced in good yields via palladium-catalyzed carbonylation of 2-haloaniline with terminal alkynes in the presence of CO (Scheme 5.27).

Scheme 5.27

Pd-catalyzed carbonylative synthesis of quinolines

When the amino group of the 2-haloaniline substrate is primary, the cyclization proceeded without problem. But using alkylated anilines under the same conditions, the yield of the corresponding cyclization product decreased dramatically. A similar methodology was reported by Kalinin and colleagues in 1992, using PdCl₂(dppf) as a palladium precursor [60]. This cyclization was applied to synthesize the quinolone substructure of BILN 2061, a serin protease inhibitor [61, 62]. That same year, Chiusoli and colleagues published an interesting methodology for indenone synthesis [63]. The sequential oxidative addition of ortho-alkoxycarbonylmethylene or alkylamido-methylene-substituted aryl iodides, CO insertion, reductive coupling with terminal alkynes, nucleophilic attack by the activated methylene group, and protonation with metal elimination, afford the indenones high yields in a one-pot process (Scheme 5.28).

Scheme 5.28

Pd-catalyzed carbonylative synthesis of indenones

In 2000 Yang and Miao reported a novel method for the preparation of flavones [64]. Various flavones are easily synthesized via palladium-catalyzed carbonylative annulation of iodophenol acetates with terminal acetylenes in high yields (Scheme 5.29). This novel reaction provides the possibility of a combinatorial synthesis of flavones on solid supports.

Scheme 5.29

Pd-catalyzed carbonylative synthesis of flavones

More recently, Capretta and Awuah described a microwave-assisted, one-pot palladium-catalyzed carbonylative Sonogashira annulation reaction [65]. Various flavones have been produced in moderate to good yields (Scheme 5.30). Alper and Yang reported another example of carbonylations of o-iodophenols with terminal acetylenes to obtain flavones. Their reaction proceeded under 1 bar of CO in ionic liquids based on phosphonium salt (PSIL102, C₁₄H₂₉(C₆H₁₃)₃)P⁺Br⁻) [66]. It should be noted that by using PSIL102 as an ionic liquid, no phosphine ligand was required (Scheme 5.31).

Scheme 5.30

Pd-catalyzed carbonylative synthesis of flavones

Scheme 5.31

Pd-catalyzed carbonylative synthesis of flavones in PSIL102

Elegant synthetic applications of carbonylative Sonogashira reactions were described by Müller and his group. For example, in 2005 they succeeded in producing palladium-catalyzed one-pot, four-component carbonylations for the synthesis of meridianins [67], which are natural and biologically activated compounds (Scheme 5.32).

Scheme 5.32

Pd-catalyzed carbonylative synthesis of meridianins

In 2008 Bhanage’s team reported on a copper-catalyzed carbonylative Sonogashira reaction of aryl iodides [68]. In this procedure, copper bis(2,2,6,6-tetramethyl-3,5-heptanedionate) [Cu(TMHD)₂] was used as the catalyst for this transformation and using NEt₃ as a base. Alkynones were produced in good yields (Scheme 5.33). A nickel-catalyzed carbonylation of allyl halides and acetylenes was reported on by Moretó and colleagues [69]. Cyclopentane skeletons were produced in high yields and with controlled stereochemistry.

Scheme 5.33

Copper-catalyzed carbonylative Sonogashira reaction

In this chapter, we have discussed the carbonylative Sonogashira reaction of organohalides and their synthetic applications. Palladium-catalysts are still the main catalysts in this area. From the mechanism point of view, the same as the contents of Chap. 4, transmetalation is involved in the case of in situ formation of alkynylcopper intermediate. But the mechanism is different if a palladium-catalyst is the sole catalyst, which should be similar to the contents that will be discussed in the next chapter.