Benzannulation

Due to its chemo- and regioselectivity, tolerance of functional groups and mild conditions the benzannulation reaction has been applied as a key step in the total synthesis of various natural products such as vitamins, antibiotics and steroids. 

In the presence of an excess of small alkynes the typical [3+2+1 jbenzannulation has to compete with a [2+2+1+lj (two-alkyne) annulation resulting from two consecutive alkyne insertion steps. The selectivity for this variant is increased for an intramolecular reaction. Diynyl-arylcarbene complexes 31 and 32, in which the carbene moiety is tethered by an appropriate spacer to two alkyne functionalities, are formed in a chemoselective Diels-Alder reaction of the more electron-deficient bond in the triyne carbene precursor complexes 35 and 36 with Danishefsky s diene a final thermal two-alkyne annulation affords the steroid skeleton 33. The sequence can be performed as a one-pot procedure in yields of 30% 

Cyclotrimerization of substituted alkynes catalyzed by various transition metal complexes to produce benzene derivatives is a well-known reaction. As a recent example. 

Yokota et al. reported quantitative cyclotrimerization of symmetrie internal alkynes using a complieated eatalyst system of Pd(II)/chlorohydroquinone/NPMoV under oxygen [54]. In addition, regiocontrol to produce a single isomer is one problem inherent in cyclotrimerization of substituted alkynes, and many attempts to achieve regioselective cyclization have been carried out with partial success. 

Perez and co-workers reported a novel Pd-catalyzed cyclotrimerization of cycloalkynes. They generated highly strained cyclohexyne (181) by the treatment of 2-trimethylsilylcyclohexenyl triflate (180) with CsF in the presence of Pd(PPhs)4. Cyclotrimerization of cyclohexyne (181) occurred rapidly as soon as it was generated, and they obtained dodecahydrotriphenylene (182) in 62% yield [55], 

The reaction has many synthetic applications. 4-Substituted anisole 189 was obtained from 2-methoxyenyne 188 using Pd(PPh3)4 and additional P(o-Tol)3, and the product was converted to 4-methoxyacetophenone 190 [58]. The intramolecular reaction is useful for the synthesis of various phane derivatives. Several oxaparacyclophanes 192 have been prepared from 191 using Pd(PPh3)4 and additional ligands in DMSO in good yields [59]. 

In the second type [4 + 2] addition, the conjugated diynes 202 are used as the partner of the enynes 183, and the arylalkynes 204 are obtained by the path as shown by 203. The other expected isomers 206 via 205 are not formed [63]. 

Danheiser and co-workers have used the modified Danheiser benzannuiation for the synthesis of the marine carbazole alkaloid hyellazole. The required diazoketone was prepared from the A/-Boc derivative of 3-acetylindole using a diazo transfer reaction. The diazoketone was irradiated in the presence of the alkyne to afford the desired carbazole annulation product in 56% yield. Finally, in order to install the phenyl group of hyellazole at Cl, the phenolic hydroxyl group was converted to the corresponding triflate and a Stiiie cross-coupiing was performed. 

The use of substituted alkoxyacetylenes in synthesis is fairly limited due to the lack of simple, general methods for their preparation. However, silyloxyacetylenes are easier to make and can be prepared from esters in a one-pot operation. In the laboratory of C.J. Kowalski, research has shown that silyloxyacetylenes could be successfully used in the Danheiser benzannuiation. This modification was used in the total synthesis of A-6-tetrahydrocannabinol. 

During the total synthesis of (-)-cylindrocyclophane F, A.B. Smith et al. used the Danheiser benzannuiation to construct the advanced aromatic intermediate for an olefin metathesis dimerization reaction. The starting material triisopropylsilyloxyalkyne was synthesized from the corresponding ethyl ester using the Kowalski two-step chain homologation.  

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Benzannulated furans are coordinated preferentially at the aromatic ring (Ti -mode). 

Volume 78 of Advances in Heterocyclic Chemistry contains four contributions. A. P. Sadimenko of Fort Hare University of South Africa has covered organometal-lic compounds of furan, thiophene, and their benzannulated derivatives. This constitutes the first installment of a projected series on the organometallic chemistry of heteroaromatic ligands, a subject of great fundamental and technical importance that has exploded in the 1990s. 

An interesting case of the benzannulated B, N complex is species 58 (X = C1) (00AGE948), prepared from [(OC)Os(PPh3)2Cl(BCl2)] and 8-aminoquinoline. It reacts with tetra- -butyl ammonium iodide and forms 58 (X = I). 

Organometallic Compounds of Chalcogenoazoles and Their Benzannulated Derivatives... 

The three different benzoxepins are simply assigned by the position of the oxygen 1 -benzoxepin, 2-benzoxepin, 3-benzoxepin. Among the four possible dibenzoxepins only dibenz[6,d]oxepin and dibenz[6,/]oxepin are of importance whereas the two other isomers are only of theoretical interest because they contain unfavorable o-quinoid structures. Benzannulation across all of the C-C double bonds leads to tribenz[6,rf,/]oxepin. 

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

The dehydrohalogenation reaction has been extended to benzannulated oxepins. Elimination of hydrogen bromide from 3-bromo-4-phenyl-2,3-dihydro-l-benzoxepin with 1,5-diazabicyclo-[4.3.0]non-5-ene gives 4-phenyl-1-benzoxepins 15a15 and 15b16 in low yield. 

According to the Hantzsch-Widman system, the seven-membered unsaturated hcterocyclc with one sulfur atom is named thiepin (1). The three different benzothiepins are assigned by the position of sulfur 1-benzothiepin (2), 2-benzothiepin (3) and 3-benzothiepin (4). Of the four possible dibenzothiepins only dibenzo[6,r/]thiepin (5) and dibenzo[A,/]thiepin (6) are of importance for synthesis, while the other two isomers, which contain unfavorable o-quinoid structures, exist mainly as the stable dihydro compounds, i.c. 5,7-dihydrodibenzo[c,t ]thiepin (7) and 6,1 l-dihydrodibenzo[6,c ]thiepin (8). Benzannulation over all double bonds results in tri-benzo[6,(7,/]thiepin (9). 

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... 

Some benzannulated azocine systems can be obtained via Beckmann rearrangement of the corresponding benzocycloheptatrienone oxime derivatives.27... 

While benzannulated azocines have been prepared in good yield using a halogenation/ dehyd-rohalogenation method,2" monocyclic azocines are generated by this procedure only in very low yields. 

Monocyclic 2-methoxyazocines 1 (see Section 1.1.1.1.1.) can be hydrolyzed to the corresponding lactams with anhydrous hydrogen bromide, but only in low yield. NMR spectroscopy reveals that, in contrast to the benzannulated systems (vide supra), the products mainly exist as their bicyclic tautomers 3.28... 

To date, the chemistry of 1,3-diazocines is poorly understood. Neither the parent system 1, nor simple benzannulated derivatives, have been described.1... 

The 1,2,4-triazole derivative 1 reacts in the presence of aluminum trichloride to provide the benzannulated 1,3-diazocine 2.6... 

Diazocines can formally exist in two bond-isomeric forms. Hitherto, however, it has not been possible to prepare the parent system 1 only benzannulated systems are known. Moreover, many of the systems originally claimed as benzannulated 1,4-diazocines were subsequently identified as the rearranged isoindolobenzimidazoles (see Section 1.4.1.1.1.). 

The benzo-fused derivative 8 of l,4-dimethyTl,4-dihydro-l,4-diazocine can be prepared by gas phase thermolysis of the cyclobutene derivative 7,31 a reaction that can be reversed photo-chemically. In contrast to the parent system, the heterocyclic ring of the benzannulated compound displays no aromatic character. 

The unsubstituted parent 1,5-diazocine (1) is hitherto unknown. Benzannulated systems, however, have been prepared, particularly dibenzo f>,/][l, 5]diazocine and its derivatives which have been intensively investigated due to their pharmacological properties. So far, all compounds synthesized show no evidence for delocalization of the 7t-electrons. One special review on the chemistry of 1,5-diazocines is available.1... 

Table 3. Benzannulated 1,5-Diazocines by the Condensation of Anthranilic Acid Derivatives...

To date there is no synthesis of the parent system or of simple benzannulated 1,2,5-triazocine derivatives. It is very likely that the 1,2,5-triazocine system exists preferentially as the valence isomeric triazapentalene betaine.7... 

Different derivatives of the benzannulated azonine can also be prepared via the generation of an anion, generated from 8 with methyllithium.14 ... 

Because of the strongly electron-withdrawing character of the Cr(CO)5 unit, the reaction with alkynes to hydroquinone and phenol derivatives [35-37] (Dotz reaction) is possible according to Scheme 6 (see also Chap. 4 Chromium -templated Benzannulation Reactions ). 

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). 

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