Benzannulation 3+2 + 1 cycloadditions

Benzannulated azocines can be prepared starting from 4-phenyl-l,2.3-benzotriazine (16), flash-vacuum pyrolysis of which leads to 2-phenylbenzazete (17) (cf. Houben-Weyl. Vol. E16c, p 939), which is stable until about 40 °C and easily enters into cycloaddition reactions with dienes. With tetraphenylcyclopentadienone, a nonisolable adduct is formed which, by loss of carbon monoxide, gives an azabicyclo[4.2.0]octatriene derivative that isomerizes to the 1 -benzazocine 18.22... 

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]. 

In the same way as arylcarbene complexes, alkenylcarbene complexes typically react with alkynes to provide [3C+2S+1C0] Dotz cycloadducts (see Chap. ccChromium-Templated Benzannulation Reactions , p. 123 in this book). However, some isolated examples involving the formation of five-membered rings through [3C+2S] cycloaddition processes have been reported [71]. In this context, de Meijere et al. found that /J-donor-substituted alkenylcarbene complexes react with alkynes to give cyclopentene derivatives [71a]. This topic is also discussed in detail in Chap.ccThe Multifaceted Chemistry of Variously Substituted a,/J-Unsaturated Fischer Metalcarbenes , p. 21 of this book. 

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). 

Other examples of [2C+2S+1C0] cycloaddition reactions have been described by Herndon et al. by the use of chromium cyclopropyl(methoxy)carbenes. These complexes react with alkynes releasing ethene and forming cyclopenta-dienone derivatives, which evolve to cyclopentenone derivatives in the presence of chromium(O) and water [122] (Scheme 76). This reaction has been extended to intramolecular processes and also to the synthesis of some natural products [123]. These authors have also described another process involving a formal [2C+2S+1C0] cycloaddition reaction. Thus, the reaction of methyl and cyclo-propylcarbene complexes with phenylacetylene derivatives does not afford the expected benzannulated products, and several regioisomers of cyclopentenone derivatives are the only products isolated [124] (Scheme 76). 

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). 

Abstract The photoinduced reactions of metal carbene complexes, particularly Group 6 Fischer carbenes, are comprehensively presented in this chapter with a complete listing of published examples. A majority of these processes involve CO insertion to produce species that have ketene-like reactivity. Cyclo addition reactions presented include reaction with imines to form /1-lactams, with alkenes to form cyclobutanones, with aldehydes to form /1-lactones, and with azoarenes to form diazetidinones. Photoinduced benzannulation processes are included. Reactions involving nucleophilic attack to form esters, amino acids, peptides, allenes, acylated arenes, and aza-Cope rearrangement products are detailed. A number of photoinduced reactions of carbenes do not involve CO insertion. These include reactions with sulfur ylides and sulfilimines, cyclopropanation, 1,3-dipolar cycloadditions, and acyl migrations. 

Thiepin-1,1-dioxide undergoes a number of chromium(0) mediated [6jt + 4jt] cycloaddition reactions with a range of 1,3-dienes. The intermediate adduct undergoes a Ramberg-Backlund rearrangement to form new benzannulated products <96JOC7644>. 

Construction of isolated or benzannulated five-membered rings of NHPs can be accomplished by means of various condensation or cycloaddition reactions all of which involve interaction of an electrophilic Pj and a nucleophilic C2N2 building block. Salts containing 1,3,2-diazaphospholide anions or 1,3,2-diazaphospholenium cations can be directly accessed by some of these reactions but the products are in most cases neutral 1,3,2-diazaphospholes or NHP. A particularly concerted effort has been directed toward the synthesis of P-halogen-substituted NHP which are capable of undergoing further reactions via halide displacement or halide abstraction and serve thus as entry points for the preparation of a wide variety of neutral and cationic NHP derivatives. 1,3,2-Diazaphospholide anions are normally accessed by deprotonation of suitable iV-H-substituted precursors. 

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>. 

Treatment of the propargylic alcohol 144, readily prepared from condensation between benzophenone (143) and the lithium acetylide 101, with thionyl chloride promoted a sequence of reactions with an initial formation of the chlorosulfite 145 followed by an SNi reaction to produce in situ the chlorinated and the benzannulated enyne-allene 146 (Scheme 20.30) [62], A spontaneous Schmittel cyclization then generated the biradical 147, which in turn underwent a radical-radical coupling to form the formal [4+ 2]-cycloaddition product 148 and subsequently, after a prototropic rearrangement, 149. The chloride 149 is prone to hydrolysis to give the corresponding 11 H-bcnzo h fluoren-ll-ol 150 in 85% overall yield from 144. Several other llff-benzo[fc]fluoren-ll-ols were likewise synthesized from benzophenone derivatives. 

Scheme 20.31 Intramolecular [2 + 2]-versus [4 + 2]-cycloaddition reactions of benzannulated enyne-allenes.

The Dotz reaction was first reported2 for an aryl carbene of the type 8, and the resulting benzannulation may be summarized conveniently as shown in Scheme 3. The major product of the reaction is usually the naphthol 9, the result of a formal [3 + 2 + 1] cycloaddition.10 In cases where CO insertion does not take place, five-membered rings (10) may also be formed. 

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. 

Mai et al. reported a new benzannulation strategy for the synthesis of murrayafoline A (7) via anionic [4+2] cycloaddition of the furoindolone 650 (583,584). Using a literature procedure, Fischer indolization of 3-(2-phenylhydrazono)-dihydrofuran-2(3H)-one (648) afforded the furoindolone 649 (583). This was... 

An extensive review of 6 + 4-cycloaddition reactions has been published.287 The use of a precatalyst in the chromium(0)-promoted 6 + 4-cycloaddition reaction of cyclohepta-l,3,5-triene with acychc dienes ensures that only stoichiometric quantities of the metal are involved in the cycloaddition (Scheme 59).288 The first example of an aqueous 6 + 4-cycloaddition of tropone with the water-soluble diene -([l-D-glucopyranosyloxyjbuta-1,3-diene (152) yields 2-(glucopyranosyloxy)bicyclo-[4.4.1]undecanones (153) and (154) with exo selectivity (Scheme 60).289 A new benzannulation sequence is based on chromium(0)-promoted 671 + 47i-photo-cycload-dition of O/ -thicpin- l, 1 -dioxidc)tricarbonylchromium(O) in the presence of a diene followed by a Ramberg-Backlund rearrangement of the cycloadduct.290... 

Ramberg-Backlund rearrangement of fused dihydrothiepine 1,1-dioxides obtained via [6n+4n] cycloaddition (Section 13.03.5.2) led to benzannulated polycycles <1996JOC7644, 1999JA8237>. The rearrangement was conducted by the sequential treatment of dihydrothiepin 1,1-dioxides 102-106 with Bu OK and A-chlorosuccinimide (NCS) or. V-iodosiiccinimidc (NIS) at —105 °C, followed by the addition of another equivalent of the base (Scheme 13). The benzannulated product 111 was transformed to (-l-)-estradiol 112. 

In a new benzannulation procedure, the 4 + 2-cycloaddition of lithium ynolates (131) with (trialkylsilyl)vinylketenes (132) yields, via an intermediate 3-(oxido)dienyl-ketene (133), the highly substituted phenols (134), which can be converted to ben-zofurans and benzopyrans (Scheme 37).135 The reaction of buta-2,3-dienoate with vinylketenimine yields the expected Diels-Alder adduct together with an unexpected aniline formed by a competing 2 + 2-cycloaddition.136 The first example of a... 

Having sufficient amounts of these novel dienes in hand opens the field for further study. Cycloaddition of acetylenedicarboxylic acid dimethyl ester (ADDE) to [3]dendralene 7 in toluene first afforded the l l-adduct 43, which by a second addition of ADDE provided the expected 2 l-adduct 44. After this had been aromatized by treatment with DDQ to the naphthalene derivative 45, a double benzannulation could be carried out as described in Scheme 8 [13]. 

A palladium-catalyzed intramolecular benzannulation of bis-enynes 1135 proceeds chemoselectively to afford dihydroisocoumarins 1136 (Equation 441) <2002JOC2653>. A reaction sequence involving ruthenium-catalyzed yne-ene cross-metathesis of a polystyrene supported undecynoic acid ester followed by a Diels-Alder cycloaddition reaction with DMAD provides the basis for a combinatorial approach to dihydroisocoumarins featuring a variety of side chains at C-6 and C-8 <1999SL1879>. 

The benzannulation product may be viewed as a formal [3+2+1] cycloaddition product, in which the alkyne (C2 synthon) is connected to the carbon monoxide ligand (Cj unit) and the carbene carbon atom of the unsaturated carbene ligand (C3 building block), the / -carbon... 

Furthermore, the successful [3+2+1] cycloaddition of alkynes bearing a cyclopropane ring and a carbene complex unit has been reported. These benzannulations result in the formation of bimetallic naphthohydroquinone chromium tricarbonyl complexes [48]. Additionally, (non-strained) cyclic alkynes are potent reaction partners in the cycloaddition of chromium carbene complexes [49]. 

The C=C bond is distinctly more reactive towards the metal carbene than the C=C bond [50]. This distinction allows a benzannulation approach to vitamins K and E (see Section 8.6.1). Bis(alkynes) have been shown to participate in the [3+2+1] cycloaddition with either one or both of their triple bonds (see Section 8.5). 

Benzoindole 114 has been synthesized by a remarkable sequence, in which the benzannulation precursor 113 is pre-assembled starting from two different chromium carbenes. It is formed in a [3+2] cycloaddition, in which the acylamino carbene complex 111 acts as the dipolar component and the alkynylcarbene complex 112 serves as the dipolarophile. The resulting 3-pyrrolylcarbene complex 113 undergoes a photoinduced intramolecular benzannu-lation to give the benzoindole 114 [84a]. This strategy complements an approach towards carbazoles [84b], Isoindolines and 1,2,3,4-tetrahydroisoquinolines are accessible from the reaction of pentacarbonyl (a-methoxyethylidene) chromium with 7r,co-dialkynes bearing a nitrogen atom in the carbon ether [84c]. 

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. 

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... 

R.L. Danheiser and co-workers generated a key vinylketene intermediate via tandem Wolff rearrangement-ketene-alkyne cycloaddition to utilize it in a photochemical aromatic annulation reaction Danheiser benzannulation) for the total synthesis of the phenalenone diterpene salvilenone. ... 

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