Dotz reaction, chromium-carbene complex

The coupling reaction of an a ,/3-unsaturated chromium carbene complex, e.g. 1, and an alkyne 2, through coordination to the chromium center, is called the Dotz reaction. The initial product is the chromium tricarbonyl complex of a hydroquinone derivative 3, which can easily be converted to a free hydroquinone or quinone. 

The synthetic value of the Dotz reaction has for example been demonstrated by the synthesis of vitamin Ki(20) 10 (simplified structure). This natural product has been prepared synthetically from the chromium carbene complex 8 and the alkyne 9 in two steps the second step being the oxidative decomplexation to yield the free product 10 ... 

The reaction of alkoxyarylcarbene complexes with alkynes mainly affords Dotz benzannulated [3C+2S+1C0] cycloadducts. However, uncommon reaction pathways of some alkoxyarylcarbene complexes in their reaction with alkynes leading to indene derivatives in a formal [3C+2S] cycloaddition process have been reported. For example, the reaction of methoxy(2,6-dimethylphenyl)chromium carbene complex with 1,2-diphenylacetylene at 100 °C gives rise to an unusual indene derivative where a sigmatropic 1,5-methyl shift is observed [60]. Moreover, a related (4-hydroxy-2,6-dimethylphenyl)carbene complex reacts in benzene at 100 °C with 3-hexyne to produce an indene derivative. However, the expected Dotz cycloadduct is obtained when the solvent is changed to acetonitrile [61] (Scheme 19). Also, Dotz et al. have shown that the introduction of an isocyanide ligand into the coordination sphere of the metal induces the preferential formation of indene derivatives [62]. 

At this point the catalytic process developed by Dotz et al. using diazoalkanes and electron-rich dienes in the presence of catalytic amounts of pentacar-bonyl(r]2-ds-cyclooctene)chromium should be mentioned. This reaction leads to cyclopentene derivatives in a process which can be considered as a formal [4S+1C] cycloaddition reaction. A Fischer-type non-heteroatom-stabilised chromium carbene complex has been observed as an intermediate in this reaction [23a]. 

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. 

Fischer-type chromium carbene complexes of furans underwent Dotz benzannulation with alkynes to provide trisubstituted benzo [, ]furan derivatives. An example used in the synthesis of isodityrosine is depicted in Equation (39) <2005JOC7422>. The efficiency of the reaction could be improved by ultrasound sonication <19990L1721>. 

The stereoselectivity of the Buchi-Paterno reaction between 3-hydroxy-2,3-dihydrofuran and benzophenone was found to be influenced by solvent, temperature and steric effect <06TL2527>. A Dotz benzannulation involving a dihydrofuran chromium carbene complex and an alkyne was employed to form the aflatoxin skeleton, providing the annulated product as the only regioisomer <06TL2299>. Cycloaddition involving 2,3-dihydrofuran, 1-aminoanthraquinone and salicy aldehyde was catalyzed by... 

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. 

Dotz, K. H., Tomuschat, P. Annulation reactions of chromium carbene complexes scope, selectivity and recent developments. Chem. Soc. Rev. 1999, 28, 187-198. 

In the Dotz reaction, an unsaturated chromium carbene complex is combined with an alkyne to give a substituted phenol. The unsaturated group may be an alkenyl, cycloalkenyl, or aryl group. There is almost always a methoxy or other alkoxy group attached to the carbene. 

Chromium carbene complexes undergo other reactions, too. The mechanisms of these reactions consist of steps ([2 + 2] cycloadditions, electrocyclic reactions) that are similar to those seen in the mechanism of the Dotz reaction. 

Fischer-type chromium carbene complexes with 1-ethoxycyclopropylalkynyl substituents at the carbene carbon, e.g. 25, on reaction with dimethylamine and subsequent conversion of the resulting vinylcarbene with alkynes surprisingly did not give phenol derivatives, as would be expected from the known Dotz reaction, but gave cyclopenta[ )]pyrans, e.g. 26. The reaction is interpreted as a double alkyne-insertion/CO-insertion sequence with formation of a trienylketene intermediate, which undergoes intramolecular hetero-Diels-Alder cycloaddition and dimethylamine elimination. ... 

A comprehensive treatment of the benzannulation of Fischer carbene complexes with alkynes is not possible in this review, and thus instead the material presented here will hopefully serve to give the reader an overview of its scope and limitations. The first report of this reaction was in 1975 by Dotz in which he describes the formation of the naphthol chromium tricarbonyl complex (236) from the reaction of the phenyl chromium complex (la) with diphenylacetylene. In the intervening years over 100 papers have been published describing various aspects of this reaction.The reaction of the generic cartene complex (233 Scheme 34) with alkynes will serve to focus the organization of the scope and limitations of the benzaimulation reaction. The issues to be considered are (i) the regioselectivity with unsymmetri-cal alkynes (ii) possible mechanisms (iii) applications in natural product syntheses (iv) the effect of substitution on the aryl or alkenyl substituent of the carbene carbon (v) functionality on the alkyne (vi) effects of the solvent and the concentration of the alkyne (vii) tandem applications with other reactions of carbene complexes (viii) reactions where aromatization is blocked (cyclohexadienone annulation) (ix) annulation of aryl versus alkenyl carbene complexes (x) the effect of the ligands L on the metal (xi) the effect of the ancilliary substituent RX and (xii) reactions with —C X functionality. 

C. A. Merlic made use of this procedure in a benzannulation reaction leading to ortho-substituted phenols. Note that the photochemical method perfectly complements the Dotz-reaction which gives p-alkoxyphenols from chromium carbene complexes and alkynes. 

The [3+2+1] cycloaddition of an a, 3-unsaturated or aryl carbene complex of chromium, an alkyne, and carbon monoxide, that is named the Dotz benzannulation, is a useful method for the synthesis of a phenol or naphthol derivative, although this reaction requires a stoichiometric amount of the chromium carbene complex of chromium [35]. A mechanism of this reaction is shown in Scheme 21.31. When unsymmetrical alleynes are used, the regioselectivity is determined in the alkyne insertion step by the steric effect. 

Harrity and co-workers described the application of 2-substituted 1-alkynylboronic esters in the Dotz cycloaddition of Fisher chromium carbene complexes, affording in a highly regioselective fashion a novel class of hydroxy-naphthyl boron pinacolates (entry 18, Table 1.3) [217]. These reaction products also provided, upon treatment with ceric ammonium nitrate, the corresponding quinone boronic esters. 

The unsaturated substituent in the carbene complex 1 often is aromatic or heteroaromatic, but can also be olefinic. The reaction conditions of the Dotz procedure are mild various functional groups are tolerated. Yields are often high. The use of chromium hexacarbonyl is disadvantageous, since this compound is considered to be carcinogenic however to date it cannot be replaced by a less toxic compound. Of particular interest is the benzo-anellation procedure for the synthesis of anthra-cyclinones, which are potentially cytostatic agents. ... 

Aryl- and alkenylcarbene complexes are known to react with alkynes through a [3C+2S+1C0] cycloaddition reaction to produce benzannulated compounds. This reaction, known as the Dotz reaction , is widely reviewed in Chap. Chromium-Templated Benzannulation Reactions , p. 123 of this book. However, simple alkyl-substituted carbene complexes react with excess of an alkyne (or with diynes) to produce a different benzannulated product which incorporates in its structure two molecules of the alkyne, a carbon monoxide ligand and the carbene carbon [128]. As referred to before, this [2S+2SH-1C+1C0] cycloaddition reaction can be carried out with diyne derivatives, showing these reactions give better yields than the corresponding intermolecular version (Scheme 80). 

A similar tandem Dotz-Mitsunobu reaction has been reported starting from a l,6-methano[10]annulene carbene complex, but no conclusion could be reached on the influence of the chiral information regarding the stereoselective course of the reaction since the chromium fragment could not be kept coordinated to the benzannulation product [47]. 

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). 

Among the synthetically useful reactions of Fischer carbenes, the benzannulations are certainly the most prominent. In particular, the so-called Dotz reaction, first reported by Dotz in 1975 [3], is an efficient synthetic method that starting from aryl- or alkenyl-substituted alkoxycarbene complexes of chromium affords p-alkoxyphcnol derivatives by successive insertion of the alkyne and one CO ligand in an a,/Tunsaturated carbene, and subsequent electrocyclic ring closure (see Figure 1). 

Density functional calculations on the Dotz reaction leading from chromium carbene (75) with acetylene to give the phenol (78) suggested a new mechanism involving the formation of a chromahexatriene complex (77) from the initially formed vinylallyl-idene complex (76). " Complex (77) then collapses to the phenol complex (78). 

Heinrich Dotz, from the Kekule-Institut (a predestined name ) of the University of Bonn, is another famous chemist who has given his name to a reaction. Coming from E. O. Fischer s school, he advantageously exploited his serendipitous discovery of the very rich reactivity of Fischer-type carbene complexes in synthesizing polycydic arene derivatives. This chromium-templated carbene benzannulation approach to densely functionalized arenes (Dotz reaction) is the subject of the chapter (No. 8) that he has co-authored with J. Stendel Jr. 

The first carbene compound to be well characterized was prepared in 1966 and was one of many Fischer-Type Carbene Complexes to be reported (see equation 7). Fischer carbenes are characterized by heteroatom substituents at the carbene carbon, stabilization by a low-valent metal center, and a partial positive charge at the carbene carbon. In contrast, Schrock-Type Carbene Complexes, or alkylidenes," that have alkyl substituents, are found on metal centers in higher oxidation states, and are nucleophihc at carbon. Many Fischer carbenes are known for chromium, whereas chromium alkylidenes are much less common. Monohalocarbenes of chromium, for example, (OC)5Cr=C(F)NEt2, have also been extensively investigated." Two carbene reactions of note for their application to organic synthesis are the cycloaddition of alkenes with carbene complexes and the reaction of aromatic carbenes with aUcynes to yield complexed naphthols (the Dotz reaction ). ... 

Generally, arene(alkoxy)carbene chromium complexes react with aryl-, alkyl-, terminal or internal alkynes in ethers or acetonitrile to yield 4-alkoxy-l-naphthols, with the more hindered substituent ortho to the hydroxyl group . Upon treatment with alkynes, aryl(dialkylamino)carbene chromium complexes do not yield aminonaphthols, but they form indene derivatives . Vinyl(dialkylamino)carbene complexes, however, react with alkynes to yield aminophenols as the main products The solvent is one of the many factors that affects this type of reaction, for which the most important is the polarity and/or coordinating ability of the solvent. The Dotz benzannulation reaction yields either arene chromium tricarbonyl complexes or the decomplexed phenols, depending on the work-up conditions. Oxidative work-up yields either decomplexed phenols or the corresponding quinones. 

In a general illustration of the Dotz reaction a terminal or internal alkyne reacts with a carbene 123 and one carbonyl ligand at a [Cr(CO)3] template in a formal [3 + 2+1] cycloaddition reaction producing a chromium-complexed naphthol (124) under mild reaction conditions via the vinylketene intermediate 125 (see Scheme 57). Terminal alkynes (R1C = CR2 R HjR H) react with total regioselectivity, while the regiocontrol in the reaction course of internal alkynes... 

---