Thermal Benzannulations

There are only a few reactions in which substituted benzenes are constructed in one step and with predictable regioselectivity. Carbene-complex-mediated benzannulations are one of these. Because of the scarcity of reliable benzannulation reactions, the use of carbene complexes for this purpose has become one of the most valuable synthetic applications of these organometallic reagents. 

Recent calculations [329] suggest that the first reaction step of the Dotz benzannulation reaction may not necessarily be the thermal cleavage of one carbonyl ligand. 

The choice of the solvent is critical, and both non-coordinating solvents or polar aprotic solvents such as DMF can lead to intractable product mixtures. Solvent effects and side-reactions in chromium carbene benzannulation reactions have been thoroughly investigated [207,333,334]. 

Aryl(dialkylamino)carbene chromium complexes do not yield aminonaphthols upon treatment with alkynes, but form indene derivatives. Vinyl(dialkylamino)car-bene complexes, however, react with alkynes to yield aminophenols as the main products if solvents of low nucleophilicity are used [335]. (2-Amino-1-vinyl)carbene complexes do not undergo benzannulation when treated with alkynes, but form cyclopentadienes or heterocycles instead [251]. 

The Dotz benzannulation reaction yields either arene chromium tricarbonyl complexes or the decomplexed phenols, depending on the work-up conditions. Because of the instability of hydroxy-substituted arene chromium tricarbonyl complexes, yields of the latter tend to be low. High yields of arene complexes can, however, be obtained by in situ silylation of the crude product of the benzannulation reaction [336]. Oxidative work-up yields either decomplexed phenols or the corresponding quinones. Treatment of the benzannulation products with phosphines also leads to decomplexed phenols [272]. 

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The thermal benzannulation of Group 6 carbene complexes with alkynes (the Dotz reaction) is highly developed and has been used extensively in synthesis [90,91]. It is thought to proceed through a chromium vinylketene intermediate generated by sequential insertion of the alkyne followed by carbon monoxide into the chromium-carbene-carbon double bond [92]. The realization that photodriven CO insertion into Z-dienylcarbene complexes should generate the same vinylketene intermediate led to the development of a photochemical variant of the Dotz reaction (Table 14). 

The thermal benzannulation is a well-elaborated synthetic technique that provides direct access to Cr(CO)3-activated, densely substituted arenes. While it is possible to obtain the free... 

Kawasaki [113] (Scheme 57). The enyne intermediate 150, which is formed by Sonogashira coupling, undergoes a thermal benzannulation in the sense of a [4 + 2]-cycloaddition followed by rearrangement to the aromatic system. 

An additional benzannulation over the C6-C7 bond of the oxaquadricyclane also allows this thermal rearrangement to the 3-benzoxepin system.133... 

Several examples of [5C+1S] cycloaddition reactions have been described involving in all cases a 1,3,5-metalahexatriene carbene complex as the C5-syn-thon and a CO or an isocyanide as the Cl-synthon. Thus,Merlic et al. described the photochemically driven benzannulation of dienylcarbene complexes to produce ortho alkoxyphenol derivatives when the reaction is performed under an atmosphere of CO, or ortho alkoxyanilines when the reaction is thermally performed in the presence of an isonitrile [111] (Scheme 63). In related works, Barluenga et al. carried out analogous reactions under thermal conditions [36a, c, 47a]. Interestingly, the dienylcarbene complexes are obtained in a first step by a [2+2] or a [3S+2C] process (see Sects. 2.3 and 2.5.1). Further reaction of these complexes with CO or an isonitrile leads to highly functionalised aromatic compounds (Scheme 63). 

The first and rate-determining step involves carbon monoxide dissociation from the initial pentacarbonyl carbene complex A to yield the coordinatively unsaturated tetracarbonyl carbene complex B (Scheme 3). The decarbonyla-tion and consequently the benzannulation reaction may be induced thermally, photochemically [2], sonochemically [3], or even under microwave-assisted conditions [4]. A detailed kinetic study by Dotz et al. proved that the initial reaction step proceeds via a reversible dissociative mechanism [5]. More recently, density functional studies on the preactivation scenario by Sola et al. tried to propose alkyne addition as the first step [6],but it was shown that this... 

Exo-alkylidene oxacycloalkylidene complexes such as chromium 2-oxacy-clopentylidene 30 are reluctant to react thermally with alkynes. Nevertheless, benzannulation can be achieved under photochemical conditions (for a detailed... 

Merlic developed a new variation of the thermally induced benzannulation reaction. The dienylcarbene complex 132 was reacted with isonitrile to give an orf/zo-alkoxyaniline derivative 135 [76] (Scheme 56). This annulation product is regiocomplementary to those reported from photochemical reaction of chromium dienyl(amino)carbene complexes. The metathesis of the isocyanide with the dienylcarbene complex 132 generates a chromium-complexed di-enylketenimine intermediate 133 which undergoes electrocyclisation. Final tau-tomerisation and demetalation afford the orf/zo-alkoxyaniline 135. 

This photodriven benzannulation was used in the synthesis of indolocar-bazoles (Eq. 22) [96] and calphostins (Eq. 23) [97]. The thermal insertion of isonitriles into these same classes of carbenes provided a complementary approach to similar benzannulations [98-100]. Manganese alkoxycarbene complexes underwent both inter- [101] and intramolecular [102] photodriven benzannulation reactions with alkynes (Eqs. 24 and 25). 

The ability of (Z)-l,2,4-heptatrien-6-ynes (enyne-allenes) and the benzannulated derivatives to undergo cyclization reactions under mild thermal conditions to produce biradicals has been the main focus of their chemical reactivities [1-5]. With the development of many synthetic methods for these highly conjugated allenes, a variety of biradicals are readily accessible for subsequent chemical transformations. Cyclization of the enyne-allene 1 could occur either via the C2-C7 pathway (Myers-Saito cyclization) leading to the a,3-didehydrotoluene/naphthalene biradical 2 [6-10] or via the C2-C6 pathway (Schmittel cyclization) producing the fulvene/benzofulvene biradical 3 [11] (Scheme 20.1). 

A new method for the benzannulation of indole involving the thermal cyclization of 3-buta-l,3-dienylindoles (560 and 561) was described for the synthesis of 3-methoxycarbazole alkaloids 562 (538-540). Contrary to earlier benzannulation procedures, this method involves the ring closure of a 3-buta-l,3-dienylindole without the loss of the methoxy group at the 3-position of the carbazole nucleus. The 3-buta-l,3-dienylindole required for this method was obtained by Sakamoto s procedure (538,539) starting from l-acetyl-2-methoxy-l,2-dihydroindole-3-one by... 

Carbene complexes undergo benzannulation under photochemical conditions with carbon monoxide to give the indolocarbazoles via a ketene intermediate, or aminobenzannulation with /t-butyl isonitrile under thermal conditions via a ketenimine (Equation (77) Table 3) <1997TL6787, 2001T5199>. 

The photochemical protocol may be the method of choice in cases where the thermal reaction fails. This is true for exo-alkylidene oxacyclopentylidene chromium complexes such as 62, which are inert under thermal conditions but undergo a photoinduced benzannulation with, for example, 3-hexyne to give benzofuran 63 (Scheme 24) [61]. 

A complementary access to extended indole and carbazole systems is based on the thermal intramolecular benzannulation of ortfio-al kyn ylan i 1 i nocarbene complexes or on a photo-induced benzannulation of phenylpyrrolylcarbene complexes. The first example involves an intramolecular access to the carbazole skeleton. Refluxing a solution of orflio-alkyn yl phen yl amino carbene complex 109 in acetonitrile gave a 63 % yield of benzocarbazole 110. Less strongly coordinating solvents (TBME, THF, or di-n-butyl ether) or other substituents less bulky than 2,4,6-trimethylphenyl (for example, phenyl or 4-methylphenyl) led to a considerably reduced yield (Scheme 39) [83]. 

Heteroatom-stabilized carbene complexes of type 1, first discovered by E.O. Fischer in 1964 [1], nowadays belong to the best investigated classes of transition metal compounds. Such complexes are coordinatively saturated, intensely colored solids = 350-400 nm), which exhibit a sufficient stability for normal preparative use. Especially chromium carbene complexes (2) enjoy increasing importance in organic synthesis, and it must be added that thermal reactions such as benzannulations (i.e. the Ddtz reaction), cyclopropanations and additions to a,j8-unsatu-rated complexes clearly predominate [2J. 

Related benzannnlation reactions are also observed using isocyanides in place of carbon monoxide. It should be noted that the regiochemistry is opposite to that previously described. Reaction of complex (24) with t-butylisocyanide under thermal conditions produced naphthalene (25) used in total synthesis of the calphostins (Scheme 51). Benzannulations... 

Collomb, D., Deshayes, C., and Doutheau, A., Synthesis of functionalized phenolic derivatives via the benzannulation of dienylketenes formed by a thermal Wolff rearrangement of a-diazo-P-keto compounds. Tetrahedron, 52, 6665, 1996. 

The competition of benzannulation and pentannulation significantly depends on the donor ability of the carbene ligand. Substitution of alkoxy for amino groups in the carbene ligand increases the thermal stability of the metal-carbonyl bond which hampers both the primary decarbonylation and the CO incorporation into the final product. As a consequence, annulation of chromium amino(aryl)carbenes requires elevated temperatures (> 90°C) and affords cyclopentannulation products (indenes). A-Acylation e.g. by Boc) reduces the donor properties of the amino substituent and thus favours again the... 

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