Benzannulation functionality

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... 

The fact that pentacarbonyl carbene complexes react with enynes in a chemo-selective and regiospecific way at the alkyne functionality was successfully applied in the total synthesis of vitamins of the Kj and K2 series [58]. Oxidation of the intermediate tricarbonyl(dihydrovitamin K) chromium complexes with silver oxide afforded the desired naphthoquinone-based vitamin K compounds 65. Compared to customary strategies, the benzannulation reaction proved to be superior as it avoids conditions favouring (E)/(Z)-isomerisation within the allylic side chain. The basic representative vitamin K3 (menadione) 66 was synthesised in a straightforward manner from pentacarbonyl carbene complex 1 and propyne (Scheme 38). 

Nanaomycin A 103 and deoxyfrenolicin 108 are members of a group of naphthoquinone antibiotics based on the isochroman skeleton. The therapeutic potential of these natural products has attracted considerable attention, and different approaches towards their synthesis have been reported [65,66]. The key step in the total synthesis of racemic nanaomycin A 103 is the chemo-and regioselective benzannulation reaction of carbene complex 101 and allylacety-lene 100 to give allyl-substituted naphthoquinone 102 after oxidative workup in 52% yield [65] (Scheme 47). The allyl functionality is crucial for a subsequent intramolecular alkoxycarbonylation to build up the isochroman structure. However, modest yields and the long sequence required to introduce the... 

Benzannulated NHPs are straightforwardly accessible from AUV-disubsti luted o-phenylenediamines either via base-induced condensation with substituted dichlorophosphines [25] or PC13 [26], or via transamination with tris(dialkylamino) phosphines [13, 14, 27], respectively. An analogous NH-substituted derivative was obtained in low yield via transamination of o-phcnylcncdiaminc with ethoxy-bis(diethylamino)phosphine [28], and condensation of o-phenylenediamine with excess tris(diethylamino)phosphine furnished a l,3-bis(phosphino)-substituted heterocycle [29], Intermediates with one or two NH functions were detectable by spectroscopy but could not be isolated in pure form under these conditions. However, 2-chloro-benzo-l,3,2-diazaphospholene and the corresponding 1-phenyl derivative were prepared in acceptable yield via condensation of PC13 with o-phenylenediamine under microwave irradiation [30], or with A-phenyl-o-phenylenediamine under reflux [27], respectively, in the absence of additional base. The formation of tetrameric benzo-NHPs during transamination of A-alkyl-o-phenylenediamines with P(NMe2)3 has already been mentioned (cf. the section entitled 1,3,2-Diazaphospholes and 1,3,2-Diazaphospholides ). 

A nucleophilic attack on the acetylenic ketone functionality of golfomycin A (184) was proposed as a potential pathway to form the benzannulated enyne-allene 185 (Scheme 20.38) [71]. Subsequent biradical formation has been postulated as a possible mechanism to account for its DNA-cleaving properties and antitumor activity. 

Key words Dotz reaction, benzannulation, Fischer carbene complexes, reaction mechanism, density functional theory... 

The compatibility with different functional groups, the remarkable regio-and stereoselectivity, and the development of asymmetric procedures have made benzannulation an attractive methodology for the synthesis of natural products with densely functionalized quinoid or fused phenolic substructures [13-20], Some pertinent examples are the syntheses of vitamins K and E [17], and the production of anthracyclinones or naphtoquinone antibiotics [13, 14a, 15, 21]. 

A new benzannulation methodology was developed in order to overcome the limitations of electrocyclic ring closure of divinylindoles. The cyclization is achieved via an allene-mediated electrocyclic reaction of 2,3-difunctionalized indoles. This method is more efficient for the synthesis of highly substituted 2-methyl carbazole alkaloids (559). The 3-alkenyl-2-propargylindole 557, a precursor for the allene intermediate, was prepared from 2-formylindole over several steps using simple functional group transformations (536,537) (Scheme 5.20). 

Electrophilic functional groups in ortho-position to the carbon-magnesium bond allow two sequential alkylations. Starting from ort/io-iodobenzyl chloride 104, the benzannulated heterocycles 105 and 106 are obtained after the reaction with appropriate electrophiles (Scheme 8) . ... 

The palladium catalyzed benzannulation reaction, described by Yamamoto, was successfully extended to the synthesis of condensed pyranone derivatives. The precursor to the cyclization underwent the benzannulation spontaneously under the applied Sonogashira coupling conditions (8.40.) on formation, to give the desired dibenzo />,ri pyranone. The functionalities tolerated in the process include unsaturated bonds and polar functional groups, such as hydroxyl.52... 

Chromium carbene complexes containing chromenes undergo benzannulation reactions with acetylenes to give 3//-naphtho[2.1 -//]ehmmcncs as products (Equation 12 163—> 164). The intermediate naphthols are air sensitive and are best trapped by protecting groups or further functionalization <2006JA11044>. 

The Fischer carbene complex 518 undergoes a benzannulation reaction with 1-hexyne to furnish the highly substituted chroman 519 (Equation 213) <1998TL2851>. Treatment of the same complex with various functionalized alkynes provides tricyclic chromans <1998SL61>. 

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 Chromium-Templated Carbene Benzannulation Approach to Densely Functionalized Arenes (Dotz Reaction)... 

Recently, Barluenga et al. have introduced some electron-deficient dialkylamino carbene complexes that bear a carboxylic functionality at the vinyl moiety and undergo exclusively the benzannulation process [34]. 

The benzannulation reaction tolerates a range of alkyl and aryl allcynes, which may bear additional functionalities. The simultaneous presence of two bulky substituents directly attached to the C=C bond, as for example in bis(trimethylsilyl)ethyne, however, blocks the final electrocyclization and causes the reaction to stop at the vinyl ketene stage [44]. Neither very electron-rich nor very electron-poor allcynes can undergo benzannulation. Strongly electron-deficient allcynes such as hexafluorobut-2-yne cannot adequately compete with car-... 

The benzannulation approach has been applied to aromatic molecules of biological interest. Alkynes bearing porphyrin (for example 37) [51a, 51b], ferrocene (for example 39) [51c], and carbohydrate functionalities [51d, 51e] have been incorporated into the (hydro)quinone skeleton, as demonstrated for porphyrinyl and ferrocenyl naphthoquinones 38 and 40 (Scheme 18). 

The scope and value of the benzannulation reaction is further increased by the substitution pattern of the arene ring, which can be modified by the incorporation of allcynes bearing additional functional groups such as silyl, stannyl, or boryl substituents. These functional groups have been used in various palladium-catalyzed (cross)-coupling reactions [63, 64]. Further structural elaboration may be based on benzannulation followed by nucleophilic aromatic addition [63b]. 

The benzannulation technique is also applicable to the benzene homologation and functionalization of annulenes, as well to a quadruple arene modification of dendritic cores. The reaction of chromium carbene functionalized l,6-methano[10]annulene 82 with 3-hexyne under standard conditions afforded a fair yield of the benzannulation product 83 after protection and oxidative work-up (Scheme 32) [75]. The chromium complex 84 evidently partly survived the oxidation conditions using Feln a syn-stereochemistry with respect to the Cr(CO)3 fragment and the methano bridge was suggested on the basis of NMR data, which is in contrast to the preferred formation of anti-annulation products bearing cydophane skeletons [75b]. 

The benzannulation of naphthyl carbene complexes may be used as a direct route to functionalized phenanthrenes (Scheme 34) [37a]. While it is obvious that 1-naphthyl carbene complexes such as 87 lead to phenanthrenes 88 (see also Section 8.3.2, Scheme 19), chromium 2-naphthylcarbenes 89 offer two alternatives for annulation, giving either phenan-threne or anthracene derivatives. Generally, angular benzannulation affording phenanthrenes 90 is favored over linear benzannulation to give anthracene derivatives 91. A rationale for this regiopreference is the higher electron density at C-l compared with that at... 

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