Bis-annelations

Bis-annelations. Danishefsky et al. have shown that this reagent can be used to effect bis-annelation. The product of addition of (1) to an enamine of a ketone, for example cyclohexanone, gives, after ketalization, the product (2). 

Steroid Synthesis. -The challenge of total synthesis has produced further new solutions. A series of papers reports an interesting new approach to the steroid nucleus and illustrates its versatility. An early asymmetric induction plays an important part in this route. A new bis-annelation procedure has been applied to a synthesis of D-homo-oestrone. The carbon atoms of rings a and b are supplied by 6-viny -a-picoline which contains in a masked form the functionality necessary for annelation. 

This alcohol can also be dehydrogenated, and the reaction is catalyzed by Cu/Zn alloy, yielding the l,7-octadien-3-one, a very useful bis-annelation reagent. This compound enables the simple synthesis of important intermediates in steroid chemistry, as outlined in Equation 9. 

Methyl-6-aminobenzoselenazole when treated with 3-penten-2-one gave by a simple Doebner-Miller type reaction the 2,7,8-trimethylselenazoloquinoline 43 in 18.6% yield, that is the angular product and not the linearly annelated one was formed. Its structure was confirmed by the coupling constant in proton NMR (71JHC693). Selenazoloquinoline 43 can be converted via the 6-methylpyridium salt in the reaction with 4-dimethylaminobenzaldehyde to 2,6-dimethyl-7,9-bis(l-(4-dimethylaminophenyl)-2-ethenyl)selenazolo[5,4-/]quinolinium iodide 44 (Ar = 4-dimethylaminophenyl). This dye exhibited two absorption maxima between 500 and 600 nm (72MI2). 

As an extension of this reaction the intramolecular cycloaddition of 5-propynyloxycycloalkanepyrimidines was studied. It was found that bi-and tricyclic annelated pyridine derivatives are formed by expulsion of either X-CH2-CN and/or HCN, respectively. A marked selectivity in the product formation was observed, depending on the size of the cycloalkane ring. With cyclohexapyrimidines a mixture of A and B is formed, while with the cycloheptapyrimidine derivative exclusive formation of the tricyclic compound B takes place (92T1643, 92T1657) (Scheme 39a). 

Double intramolecular /zcfcro-Diels-Alder reaction of 1,3-diynil-bis-a,)S-unsaturated hydrazones 139 and 140 is a good example of a thermal multiple Diels-Alder reaction and is a particularly attractive route to annelated pyridines [123]. The initial cycloadduct readily aromatizes by the loss of dimethylamine (Scheme 2.52) under thermal reaction conditions. 

Poly(l,4-naphthylenevinylene) (106) is accessible via the Wessling polymerization procedure. Lenz, Karasz, Wegner et al. have published the synthesis of PNV 106, starting from l,4-bis(chloromethyl)naphthalene [127, 128]. The poly(l,4-naphthylenevinylene) (106) displays an optical absorption energy of 2.05 eV, slightly red-shifted by about 0,3 eV relative to the parent PPV 60-system, due to the electronic effect of the annelated benzene ring. 

A general synthesis of dibenzo-annelated dithieno[3,Z-b Z, 3 - thiophene 18 has been reported from bis(o-hydro-xyl)diacetylenes. This cyclization constructs a fused tricyclic skeleton in one pot. The subsequent dechalconization with copper powder produces a series of thiophene and selenophene-based heterocenes (Scheme 64) <20050L5301>. 

Pyridine- and pyran-fused benzothiepin-SS-dioxide derivatives of types 74 and 75 (X = SO2) have been prepared by standard annelation procedures from the benzothiepin ketone derivatives. A number of the bis-fused derivatives showed good anti-cancer and moderate anti-HIV activity <00ZN(B)417>. 

An interesting application of a 1,2-disubstituted cyclopropanol in a seven-membered ring-annelation methodology has been developed by Cha et al. [82], The cyclopropanol 124, obtained from methyl 1-cyclopentenecarboxylate (123) and 4-(triisopropylsilyloxy)-butylmagnesium chloride, was converted to a 1,2-dialkenylcyclopropanol bis-silyl ether, which, by a subsequent facile Cope rearrangement, afforded the cycloheptadiene-anne-lated cyclopentane derivative 125 in 32% overall yield (Scheme 11.32). 

This reaction has been successfully applied to cyclopentenone annelation onto cycloalkenes. By modifying Danheiser s protocol [15], alkynyl-substituted bi-cyclo[n.l.0]alkanol derivatives are prepared by the reaction of gem-lithio-bromocyclopropanes 27 with alkynylborons, as shown in Scheme 10. 

The interesting bis(spirocyclohexane)-annelated bisspirocyclopropanated bicyclopropylidene 82 was prepared by dimerization of the cyclopropylidenoid generated from the dibromide 81 under the conditions discussed above [31]. 

Bicyclopropylidenes with two larger rings annelated at both cyclopropyl moieties are sufficiently well documented (Table 1). But compounds in which the larger ring bridges the two ends of a bicyclopropylidene are usually more highly strained and, as a consequence, not as easily accessible. The first such compounds 89 and 91 were obtained by Diels-Alder reaction of the bis(cyclo-propenyl) derivative 90 with dimethyl acetylenedicarboxylate (DMAD) and te-... 

Nickel(0)-catalyzed [2-1-2] cycloaddition of cyclobutene to bicyclopropylidene (1) gave rise to the bis(spirocyclopropane)-annelated bicyclo [2.2.0]hexane derivative 232, the main product was 1,5-cyclooctadiene (233), formed by dimerization of cyclobutene with subsequent rearrangement (Scheme 54) [8,144]. 

The observation that the bis-alkyne 5 was more stable that the enyne 13 led us to believe that the non-annelated bis-alkyne 19 might be a stable molecule. Our preliminary experiment to synthesize 19 was similar to the method used by Krebs. Unfortunately, dehydrobromination of the dibromide 2()3 3 with an excess of KO-t-Bu only gave an unseparable mixture of 21.3 jg therefore no direct support for the formation of 19 as an intermediate. 

In 1984, Giibble et al. reported for the first time a novel l,10-bis-(6-methyl-5H-benzo[fc]carbazol-ll-yl)decane (469) which has potential bifunctional nucleic acid intercalating properties (406). To function as anti-tumor active drugs, one of the most important cytostatic mechanisms of action of coplanar annelated polycyclic compounds is their intercalation with DNA (405). Ten years later, Kucklander et al. studied a series of 5H-benzo[ 7]carbazole quinone derivatives for their cytotoxic activity against colon and lung cancer cells, and found that the heteroannelated 5H-benzo[ 7]carbazole quinone derivative 470 was the most active among the various analogs (407) (Scheme 4.2). 

Annelated benzenesVollhardt s cocyclization of bis(trimethylsilyl)ethyne with... 

Chloromethylation occurred in high yield at C-3 and C-4 when thienothiophene (73) was treated with paraformaldehyde and HC1 at 50 °C, to give chloromethyl derivative (96 Scheme 28). Treatment of the chloromethyl compound (96) with sodium acetate or sodium ethoxide gave the corresponding acetoxymethyl or ethoxymethyl derivatives (97). Analogous reaction with primary amines led only to the formation of bis-aminoalkyl compounds (98) and no peri-annelated products (99) could be detected (Scheme 29) <76AHC(19)123>. 

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