Alkynes isocoumarins

A facUe synthesis of 3,4-disubstituted isocoumarins and their benzologues is based on the Pd-catalysed annulation of internal alkynes by 2-iodobenzoate esters (Scheme 27). Tri- and tetra- substituted pyran-2-ones are also available by this route <99JOC8770>. 3-Substituted isocoumarins result from the Pd-catalysed 6-endo-dig cyclisation of 2-ethynylbenzoic acids. The 5-exo-dig products, phthalides, are also formed when there is a terminal bulky group on the alkyne moiety <99S1145>. 

Several examples of intramolecular solvomercuration of arylalkynes have been reported (equations 81 to 83).200 The mercury moiety can be removed by protiodemetallation or converted to a variety of other functional groups. The use of a methyl ether as the nucleophilic functionality is noteworthy, as is the change in the regioselectivity (equation 82 versus equation 83). A bromocyclization related to equation (83) using a phenylethynylbenzoate ester also gives an isocoumarin derivative via 6-endo cyclization.201 Palladium-catalyzed cyclizations of 3,y-alkynic ketones or 2-methyl-3-alkyn-l-ols to form substituted furans are discussed in Chapter 1.4, Section 3.1.3 in this volume. 

Hydroxyisocoumarins are accessible from 3-hydroxybenzyl ketones using directed lithiation as the key step (95G 111) and isocoumarins have been prepared from 2-iodobenzoic acid and alkynes through a Pd-mediated annulation (95JOC3270, 3711). The cyclisation of tertiary alcohols derived from the reaction of o-cyanobenzyllithium with aldehydes and ketones yields 3,4-dihydroisocoumarins (95S1102). 

Terminal alkynes can be coupled with ortho-iodobenzoic acids, using a Pd/C-PPh3-CuI catalystic system to afford 3-substituted isocoumarins (Equation 327) <2005JOC4778>. Likewise, the copper(l) mediated coupling of ortho-iodobenzoic acid with ethynylbenzene under microwave irradiation forms 3-phenyl-isocoumarin in excellent yield (Equation 328) <2002SC1937>. 

Benzoic acids yield isocoumarins through a Rh-catalysed Cu-promoted oxidative coupling with internal alkynes. When a two-fold excess of alkyne is used with Ir catalysis,... 

Pyridopyrimidines and pyrimidines fused with five- or six-membered heterocycles can be prepared via the ring closure of intermediate ethynylpyrimidines, which are themselves obtained by the Pd-catalyzed cross-coupling of halopyrimidines with alkynic compounds (Scheme 34). ° ""° o-Alkynylanilines such as (51), which are made by Pd-catalyzed coupling reactions of alkynes with o-haloaniline precursors, are easily cyclized to the indoles in the presence of base (Scheme 35). " " Similar meth( s can be employed in the synthesis of isocoumarins," thienopyridines," furopy-ridines" and the marine alkaloid asptamine." ... 

Substituted isocoumarins 27 result from the reaction of 2-iodobenzoic acids with terminal alkynes in ethanol under combined Pd/Cu catalysis <05JOC4778> and a one-pot reaction between 2-formylbenzoic acid, substituted anilines and KCN in AcOH initiated by a Strecker reaction affords good yields of 3-amino-4-(arylamino)isocoumarins (Scheme 10) <05EJO817>. 

The most general route involves coupling an alkyne with ort/to-iodobenzoic acid or with methyl ortho-iodobenzoate." Both mono- (giving 3-substituted isocoumarins" ) and disubstituted alkynes will serve, allowing considerable flexibility for the construction of substituted isocoumarins. 

Replacing the Cul with ZnCl2 affords primarily isocoumarins [30]. The direct reaction of o-halobenzoic acids with copper acetylides also affords phthalides [22-24]. The reaction of (Z)-3-halopropenoic acid and terminal alkynes in the presence of a palladium catalyst and catalytic amounts of Cul provides a convenient synthesis of alkylidene butenolides (Eq. 8) [31,32]. 

Although ester groups do not normally participate in organopalladium reactions, o-halobenzoate esters react with internal alkynes in the presence of a palladium catalyst to produce good yields of isocoumarins (Eq. 36) [72,77,78]. 

Reaction of o-iodoaniline (33) with internal alkynes offers a good synthetic method of substituted indoles [13], A practical synthesis of psilocin was carried out by utilizing the reaction of the iodoaniline derivative 34 with internal alkyne to form an indole derivative as a key reaction [14], The thieno[3.2- ]pyrrole 37 was obtained by the reaction of 2-iodo-3-aminothiophene (35) with the alkyne 36 [15], These reactions of aryl iodides proceed in the absence of phosphine ligands. The isocoumarin 39 was obtained by the reaction of methyl o-iodobenzoate (38). Poor yield was obtained when the free acid was used [11]. 

Scheme 2.33 Isocoumarins by carbopalladation of internal alkynes terminated by esters [74].

Disubstituted isocoumarins arise from the copper(II)-catalyzed addition of o-halobenzoic acids to active internal alkynes (13JOC1660), rhodium(III)-mediated oxidative coupling ofbenzoic acids with disubsti-tuted alkynes (13T4454), palladium(II)-catalyzed tandem annulation reaction of o-alkynylbenzoates with methyl vinyl ketone (13T8626), and nickel(II)-promoted t-butyl isocyanide insertion in 2-(o-bromophenyl)-1-ethanones followed by hydrolysis (Scheme 69) (13SC3262). 

The decarbonylative addition of (thio)phthalic anhydrides to alkynes for the preparation of valuable (thio)isocoumarins is another application of nickel(O) catalysts for the formation of Ar-C(sp ) bonds (Scheme 22.14) [23a, b]. When the reaction is applied to thiophthalic anhydrides, benzothiophenes or thiochromanones can be prepared selectively in place of thioisocoumarins, depending on the reaction conditions employed [23h]. In related reactions, the nickel-catalyzed... 

The preparation of isocoumarins from the oxidative coupling of benzoic acids with alkynes in MeOH with oxidant AgOAc is catalysed by [Cp lrCl2]2 complex. Alkyl alkynes are more reactive than aryl alkynes. The DFT calculations of intermediates and transition states reveal that C-H activation occurs via an acetate-assisted meehanism, the C-H activation is not turnover limiting and the AgOAc oxidizes the reduced form of the catalyst via an Ir(I)-lr(ll)-Ir(IIl) sequence. ... 

Reactions with alkynes may lead to the formation of cyclized products. The reaction of iodobenzenes with two equivalents of an alkyne has been shown to give naphthalene derivatives in the presence of cobalt catalyst with a manganese reduc-tant. The process, shown in Scheme 15, is thought to involve oxidative addition of the aryliodide to cobalt followed by double alkyne insertion. The cobalt-catalysed annulation step probably involves an pathway. The cyclopentadienyl-rhodium-catalysed annulation of benzoic acids with alkynes has been used to form isocoumarin derivatives, such as (126). The process is thought to involve cyclorhodation at the ortho-position of a rhodium benzoate intermediate, followed by alkyne insertion to form a seven-membered rhodacycle and reductive elimination The silver-catalysed annulations of diphenylphosphine oxides with alkynes proceed in the absence of rhodium. Benzophosphole oxides such as (127), formed with diphenylethyne, are produced. Here, the proposed mechanism involves homolytic cleavage of the phosphorus-hydrogen bond to give a radical which can add to the alkyne and subsequently cyclize. ... 

Iodobenzoic acid can be subjected to Pd-C/CuI-mediated coupling reaction with terminal alkynes in the presence of Ph3 P and EtsN accompanied by cycUzation to give 3-substituted isocoumarins 35 [47]. 

In a metal-free modification, (2-ethoxycarbonyl)aryl alkynes 36 were cyclized to isocoumarins of type 37 promoted by TosOH under microwave irradiation [49]. 

Phthalic anhydrides can be reacted with various internal alkynes to give isocoumarins 41 on catalysis of Ni(COD)2 and co-catalysis of ZnCl2 and PMes [50] ... 

In this decarbonylative cycloaddition process, Ni(0) is thought to be responsible for CO elimination. Unsymmetrical substrates mostly lead to mixtures of regioisomeric isocoumarins terminal alkynes do not react due to their rapid Ni-induced oligomerization. Derivatives of maleic anhydride give rise to 2-pyrones. 

In 2007, Ueura et al. reported the first effective example for oxidative coupling of aromatic substrates with alkynes through C—H bond cleavage under rhodium catalysis [22]. Thus, benzoic acids 9 and 50 react with alkynes 2 efficiently in the presence of 0.5 mol % of [Cp RhCl2]2 and 2 equiv of Cu(OAc)2 H2O in o-xylene at 100 °C to afford the corresponding isocoumarins 51 as 1 1 coupling products (Scheme 25.26) [5,22]. Five years later, the same reaction was conducted using ruthenium catalysts in place ofRh [23]. 

A plausible mechanism for the 1 2 coupling of benzamide 89 with 2c is illustrated in Scheme 25.44. A 1 1 coupling intermediate A seems to be formed in a similar way to that for an isocoumarin 51 in Scheme 25.27. Then, coordination of the nitrogen of A to RhXs, directed C—H bond cleavage to form a rhodacycle B, alkyne insertion, and reductive elimination may take place to produce 90. 

In 2007, the Mlura group reported a Rh(III)-catalyzed oxidative coupling of benzoic acids with internal alkynes to the synthesis of isocoumarins via aromatic C-H activation (Scheme 6.24a) [38]. Importantly, the reaction of benzoic acids with alkynes takes place efficiently even with a reduced amount (5mol%) of Cu(0Ac)2-H20 under air (Scheme 6.24b) [5b]. The same group also developed the rhodium-catalyzed coupling of acrylic acids with alkynes to provide corresponding a-pyrone via vinylic C-H bond cleavage (Scheme 6.24c) [5c]. In 2015, Wen and coworkers described a Rh(III)-catalyzed synthesis of... 

In 2014, Liu and coworkers reported a Rh(III)-catalyzed annulation of O-benzoylhydroxylamines with internal alkynes to the preparation of isocoumarins... 

Scheme 6.26 Synthesis of isocoumarins from W,W-diethyl-0-benzoylhydroxylamine and alkynes.

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