Dotz Benzannulation Reactions

Since the original discovery of the Dotz benzannulation reaction in 1975 [21], a vast number of examples that define its scope and limit have been presented. Thorough comprehensive reviews that are dedicated to this reaction have appeared in the literature [la,b]. The scope, yield, selectivity, and operational aspects have 

1 Synthesis of Planar Chiral Aromatic Compounds The Dotz benzannulation reaction initially affords arene complexes, which are somewhat unstable and difficult to isolate. These complexes possess a chirality element that is lost upon decomplexation. The instability originates with the free phenol group, and a relatively stable complex that can easily be isolated using standard organic chemistry techniques is obtained if the free phenol is converted to an ester or silyl ether prior to isolation. Planar chiral arene/transition metal complexes have been used extensively for asymmetric synthesis [27]. 

59% (7 3 mixture, both isomers usefui for total synthesis) 

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A Dotz benzannulation reaction was utilized in the synthesis of the furo[2,3- >]furan core of aflatoxin B2 as illustrated below <06TL2299>. Synthesis of polynuclear aromatic compounds was achieved by using [5+5] cycloaddition of 2-alkynylarylcarbene complexes and enyne-aldehyde derivatives <06TL5303>. 

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. 

Fig. 2.24. Possible mechanism of the Dotz benzannulation reaction (R, R large, small substitutents H, alkyl, aryl).

Fig. 2.26. Synthesis of fredericamycin A utilizing a Dotz benzannulation reaction [268].

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]. 

Additional examples of Dotz benzannulation reactions are given in Table 2.17. Further examples have been reported (see, e.g., [269,270,340-344]). 

Table 2.17. Examples of the preparation of substituted phenols by use of the Dotz benzannulation reaction.

The formation of cycloheptadienones from alkoxy(cyclopropyl)carbene complexes and alkynes (Entry 5, Table 2.24) [388,389] proceeds essentially by the same mechanism as the Dotz benzannulation reaction (see Figure 2.32). The cyclopropyl group participates in the electrocyclic rearrangement as the equivalent of a vinyl group. 

A new chromahexatriene (118) route has been proposed for the mechanism of the Dotz benzannulation reaction between vinylcarbene complexes (117) and ethynes (Scheme 46). ... 

The Dotz benzannulation reaction, based on the alkyne cycloaddition to chromium carbene complexes, is the most important application of Fischer carbene complexes. Among the various Fischer carbene complexes, alkoxy and aminocarbene complexes of chromium undergo a novel inter- and intramolecular tandem alkyne insertion/ carbene annotation sequence to give 9H-carbazoles and nf/-benzo[fl]carbazoles. 

The mechanism of the Dotz benzannulation reaction has not been fully elucidated. The first step is the ratedetermining dissociation of one carbonyl ligand from the Fischer carbene complex, which is cis to the carbene moiety. Subsequently, the alkyne component coordinates to the coordinatively unsaturated carbene complex, and then it inserts into the metal-carbon bond. After the alkyne insertion, a vinylcarbene is formed that can lead to the product by two different pathways (Path A or Path b). ... 

P. Quayle and co-workers utilized the Dotz benzannulation reaction for the synthesis of diterpenoid quinones." The authors developed a novel synthetic approach to 12-O-methyl royleanone using a simple vinyl chromium carbene complex along with a disubstituted oxygenated acetylene. The bicyclic hydrazone was converted to the corresponding vinyllithium derivative by the Shapiro reaction and then functionalized to give the desired crude Fischer chromium carbene complex. The benzannulation took place in refluxing THF with excellent regioselectivity, and the natural product was obtained in 37% overall yield from the hydrazone. 

Related reactions Danheiser benzannulation, Dotz benzannulation reaction ... 

A prototypical example of the Dotz benzannulation reaction is shown in equation (15). 

A recent synthesis of this building block has been published by Eastham et al. in 2006 (48). Their key step is a Dotz benzannulation reaction and is shown in Scheme 2.10. The bromohydrin 66 was formed from dihydrofuran (50). Cobalt-mediated cyclization, followed by ozonolysis with reductive work-up yielded 68 after hydrazine formation. Reductive removal of the hydrazine function, followed by chromium-carbonyl formation gave the Dotz reaction precursor 69. This reacted with an alkyne in the Dotz reaction, and was then oxidized and hydrogenated 70). Pyrolysis gave the protected alcohol and the remaining free alcohol was protected as a triflate (—> 71). Reductive removal of the triflate and deprotection of the silyl ether yielded the desired 33 in 1.2% overall yield. 

The Dotz benzannulation reaction (DBR) is the reaction of an a,P unsaturated Fischer carbene with an alkyne to produce a highly substituted phenol. Alternatively, the DBR can be considered a metal templated 3 + 1 + 2 cycloaddition of an allylic carbine (3 carbon unit), carbon monoxide (1 carbon unit), and an alkyne (2 carbon unit). The initial product of the reaction is the arene chromium tricarbonyl complex of the phenol as in 4. These complexes are typically unstable in air such that workup and purification of the product lead to the complete loss of the metal. Chromium is the most often used metal for the benzannulation. Molybdinum, tungsten, and manganese have been used but usually give mixtures of products and require harsh reaction conditions. 

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