Tricyclic systems

Miscellaneous Tricyclic Systems.—The bicyclic ketone (740), available in four steps from the alcohol (739), is converted on irradiation at 310 nm in t-butyl alcohol into the tricyclic alcohol (741), a member of the hitherto unknown tricyclo[2,2,0,0 ]-hexane system.The base-promoted reaction of cyclic a-diketones yields tricyclic 

Reaction of 2,6-dimethyl-l,4-benzoquinone with the quinomethyl carbanion derived from 2,3-dimethyl-1,4-naphthoquinone is reported to give the tricyclo-[6,3,l,0 ]dodecane derivative (749). Pyrolysis of the sodium salt of the tosyl-hydrazone of 7-cycloheptatrienylmethyl methyl ketone in diglyme at 150 C afforded (750 7%) similar pyrolysis of the tosylhydrazone salt from l-(7-cycloheptatrienyl)-ethyl methyl ketone gave (751 9 %). Both compounds are examples of the previously 

Benzvalene (807) is now readily available and its reactions are being actively explored. Cycloadditions to the double bond can be effected without opening the bicyclobutane. Thus the dichloroketen adduct could be reduced with PhgSnH to (808) and the tosylhydrazone of this treated with a strong non-nucleophilic base to give (809) in 50 % yield. Attempts to open this to (810) by heat or Ag catalysis failed.  

Another route to the [4,1,0,0 ] system (824) is also reported. Reduction of the epoxide (834) with lithium in ammonia gives 90% of (835) by reductive cleavage of the diphenylcyclopropane and rear attack by a carbanion so formed on the epoxide ring. The homologue (836) behaves in the same way.  

Among other compounds from Kigelia pinnata, kigelinone (85) was isolated (81P2271). A related compound, 86, was proposed for one of the cytotoxic compounds isolated from the bark of Tabebuia cassinoides. Two other compounds isolated from K. pinnata are 87 and 88, and the structure of the latter was confirmed by synthesis (82MI4). 

Two naphthofurandiones, namely the 2-ethyl derivative of 84 and 89, were isolated from heartwood of P. peroba, in addition to lapachol, lapachone, and benzochromendiones (68N38). Related quinones 90 (mixtures of enantiomers) were isolated from wood of Rademachera sinica (81JCS(P1)2764). Helicquinone (91) was isolated from Helicteres angustifolia (87P578) and haemoventosin (92), a colored compound, was isolated from a lichen, Haematomma ventosum (71ACS483). 

Other quinones related structurally to dunnione were isolated from Trypethelium eluteriae (80LA779). The proposed structures for the anti- 

4-benzoquinones. The reaction proceeds regiospecifically in essentially one step. 

The formation of the furan ring by cyclization of a side chain has also been an efficient method in several cases. Simultaneous formation of the 

Tricyclic furanquinones were also obtained from cycloaddition reactions. 3-Methylbenzofuran-4,7-dione reacts with piperylene in a Diels-Alder reaction to give a mixture of maturinone and its isomer, a 3,8-dimethyl derivative of 84(69TL1929). 

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A interesting and useful reaetion is the intramolecular polycyclization reaction of polyalkenes by tandem or domino insertions of alkenes to give polycyclic compounds[l 38]. In the tandem cyclization. an intermediate in many cases is a neopentylpalladium formed by the insertion of 1,1-disubstituted alkenes, which has no possibility of /3-elimination. The key step in the total synthesis of scopadulcic acid is the Pd-catalyzed construction of the tricyclic system 202 containing the bicyclo[3.2. Ijoctane substructure. The single tricyclic product 202 was obtained in 82% yield from 201 [20,164). The benzyl chloride 203 undergoes oxidative addition and alkene insertion. Formation of the spiro compound 204 by the intramolecular double insertion of alkenes is an exam-ple[165]. 

The thiones are readily desulfurized with Raney nickel to give the corresponding unsubstituted compounds in bicyclic systems in the 2-, 4- and 7-positions, and in tricyclic systems such as (95). The 2-methylthio derivatives may be similarly desulfurized. Thione groups in the 4-position, but not the 2-position, in pyrido-[2,3- f ]- and -[3,2- f]-pyrimidines may be replaced directly with ammonia or amines. 

Complexation with metals has been observed with a variety of pyridopyridazinones, whilst electrophilic attack at nitrogen is involved in cyclizations to a variety of azolo and azino fused tricyclic systems, e.g. (65CPB586, 7UOC3812). 

Some tricyclic systems have been prepared by intramolecular cyclization from A-aryl-pyrazoles carrying substituents both in the pyrazole ring at C-5 and in the phenyl ring at the o-position. Thus pyrazolo[l,5-n]quinazolines (563) (69JHC947) and pyrazolo[l,5-n]-[l,4]benzodiazepines (564) (77JHC1163, 77JHC1171) can be prepared from suitable precursors. 

The lithium- -propylamine reducing system has been found capable of reducing julolidine (113) to /d -tetrahydrojulolidine (114, 66% yield) and 1-methyl-1,2,3,4-tctrahydroquinoline to a mixture of enamines (87% yield), l-methyl-J -octahydroquinoline (115) and 1-methyl-al -octahydro-quinoline (116) 102). This route to enamines of bicyclic and tricyclic systems avoids hydroxylation, which occurs during mercuric acetate oxidation of certain bicyclic and tricyclic tertiary amines 62,85 see Section III.A). 

M. P. Groziak and F. G. Jacobs, Tricyclic Systems Central Carbo-cyclic Ring with Fused Five- and Six-membered Rings Chapter 7.22 pp. 875-919 in Katritzky A. R., Rees Ch. W., and Scriven E. F. V, Comprehensive Heterocyclic Chemistry II A review of the Literature 1982-1995, Vol. 7 Fused Five- and Six-membered Rings without Ring Junction Heteroatoms, vol. ed. Ramsden Ch. A., Elsevier Science, Oxford, 1996. 

There are eight possible combinations of heteroatoms in that tricyclic system of oxazoloquinoline. However, examples of four of them only are reported in literature (Fig. 7). 

Reduction of anilines containing acid, ester, or carbonyl functions provides a convenient entry to bi- and tricyclic systems, cyclization occurring once the rigidity of the aromatic ring has been lost through saturation (1,2,61,77). 

Cyclization of bromostilbenes 6 to dibenz[/ ,/]oxepins 7 can be achieved by irradiation in excellent yield.102 103 Under solvolytic conditions (60% NaOH, EtOH), the yield is greatly reduced. When a silver salt (AgOAc) is used, however, complete conversion to the tricyclic system is accomplished.102 Tribenz[/>,catalyzed cyclization of biphenyl-2-yl 2 -chlorosulfonylphenyl ether in 44% yield.260... 

Tautomerism of benz- and dibenzazepines is much less common than with monocyclic azepines since, as pointed out in the introduction, with most of these bi- and tricyclic systems the number of tautomers in which the carbocyclic ring retains its benzenoid character is severely restricted. Rare examples in the benzazepine series are the thermal isomcrizations of butyl l-aryl-5//-2-benzazepine-5-carboxylates 1 (X = H, Cl, F) to their 3//-tautomers 2,7S and of 3-ethoxy-1-phenyl-5//-2-benzazepines 3 (R = Me, Bn) to the 1//-tautomers 4.240... 

These tricyclic systems are outside the scope of this section. For reviews, see ref 190e,m,n. 

When the cnolate of an enone is brought into reaction with an enone, usually a carbocyclic system is prepared by two consecutive Michael additions (M1MIRC reactions). Due to the lower temperatures employed and the absence of diene polymerization these reactions are useful alternatives for Diels-Alder reactions and proceed in general with high diastereoselectivities. When neither enolate nor enone is cyclic a monocyclic system is formed 338 which can be converted into a bicyclic system when the Michael addition is followed by an aldol reaction339. When, however, the enolate is cyclic a bicyclic or a tricyclic system is formed340 341. 

This crisscross or von Halban-White-type cyclization product is formed from the (E)-configured intermediate 87, which cannot undergo the 67r-electrocy-clization like the (Z)-configured isomer 88, to yield the benzannelation product 86 [78,79]. While the diastereoselectivity of the alkyne insertion must have been controlled by the electronic and not the steric factors of the substituents on the alkyne, the anti-configuration of the tricyclic system 85 was confirmed by an X-ray structure analysis [77]. 

The Rh2(DOSP)4 catalysts (6b) of Davies have proven to be remarkably effective for highly enantioselective cydopropanation reactions of aryl- and vinyl-diazoacetates [2]. The discovery that enantiocontrol could be enhanced when reactions were performed in pentane [35] added advantages that could be attributed to the solvent-directed orientation of chiral attachments of the ligand carboxylates [59]. In addition to the synthesis of (+)-sertraline (1) [6], the uses of this methodology have been extended to the construction of cyclopropane amino acids (Eq. 3) [35], the synthesis of tricyclic systems such as 22 (Eq. 4) [60], and, as an example of tandem cyclopropanation-Cope rearrangement, an efficient asymmetric synthesis of epi-tremulane 23 (Eq. 5) [61]. 

Guanacastepene A (444) is a novel tricyclic diterpene with fused five-, seven-, and six-membered rings. The possibility of constructing polycyclic compounds via tandem RCM of dienynes was used in Hanna s synthesis of a highly functionalized tricyclic system 443 related to 444. Under the conditions outlined in Scheme 87, trienyne 440 provided the desired tricycle 442 in a single step, as a result of sequential enyne RCM followed by RCM of intermediate 441. Compound 442 was then further functionalized to 443 [182]. 

Note Derivatives of this tricyclic system may also be made from appropriately substituted 1-phenyl-1,2,3-triazoles by several procedures. 

Lewis acids can be used to initiate this cyclization. Cyclization to a tricyclic systems that included formation of a dihydropyran ring was reported using mercuric... 

The molyhdopterin cofactor, as found in different enzymes, may be present either as the nucleoside monophosphate or in the dinucleotide form. In some cases the molybdenum atom binds one single cofactor molecule, while in others, two pterin cofactors coordinate the metal. Molyhdopterin cytosine dinucleotide (MCD) is found in AORs from sulfate reducers, and molyhdopterin adenine dinucleotide and molyb-dopterin hypoxanthine dinucleotide were reported for other enzymes (205). The first structural evidence for binding of the dithiolene group of the pterin tricyclic system to molybdenum was shown for the AOR from Pyrococcus furiosus and D. gigas (199). In the latter, one molyb-dopterin cytosine dinucleotide (MCD) is used for molybdenum ligation. Two molecules of MGD are present in the formate dehydrogenase and nitrate reductase. 

The utility of lOOC reactions in the synthesis of fused rings containing a bridgehead N atom such as pyrrolizidines, indolizidines, and quinolizidines which occur widely in a number of alkaloids has been demonstrated [64]. Substrates 242 a-d, that possess properly positioned aldoxime and alkene functions, were prepared from proline or pipecolinic acid 240 (Eq. 27). Esterification of 240 and introduction of unsaturation on N by AT-alkylation produced 241 which was followed by conversion of the carbethoxy function to an aldoxime 242. lOOC reaction of 242 led to stereoselective formation of various tricyclic systems 243. This versatile method thus allows attachment of various unsaturated side chains that can serve for generation of functionalized five- or six-membered (possibly even larger) rings. 

More extended polyenes can cyclize to tricyclic systems. 

Scheme 10.17 illustrates allylation by reaction of radical intermediates with allyl stannanes. The first entry uses a carbohydrate-derived xanthate as the radical source. The addition in this case is highly stereoselective because the shape of the bicyclic ring system provides a steric bias. In Entry 2, a primary phenylthiocar-bonate ester is used as the radical source. In Entry 3, the allyl group is introduced at a rather congested carbon. The reaction is completely stereoselective, presumably because of steric features of the tricyclic system. In Entry 4, a primary selenide serves as the radical source. Entry 5 involves a tandem alkylation-allylation with triethylboron generating the ethyl radical that initiates the reaction. This reaction was done in the presence of a Lewis acid, but lanthanide salts also give good results. 

Very recently, the Alcaide group constructed fused tricyclic systems from mono-cyclic precursors by a novel and elegant domino mesylation/[3,3] sigmatropic rearrangement/Diels-Alder reaction [467]. This domino process will be described in Chapter 4. 

One-pot multi-bond-forming reactions are one of the ways to address the ever growing demand for efficiency in organic synthesis. Rosini and coworkers have developed (tandem) processes for the synthesis of a highly functionalized tricyclic system. The reaction is simply performed by bringing together, at room temperature, a-bromo aldehydes, ethyl nitroacetate, and chlorodimethylvinylsilane in the presence of imidazole as the base (Eq. 8.83).134... 

Of the possible 16 pyridazino-, pyrimido-, and pyrazino-oxazines, 10 are known with 19 benzo-fused derivatives. Literature over the past 10 years reports 10 bicyclic and 9 tricyclic systems and these are shown in Table 2. Of the possible 16 N-bridgehead pyridazino-, pyrimido-, and pyrazino-thiazines, 7 are known along with 13 benzo-fused derivatives. In this review five bicyclic and four tricyclic systems are discussed and these are shown in Table 3. One bicyclic system has been reported with a Se heteroatom and this is shown in Table 4. 

Many of the linear conjugated tricyclic systems have interesting fluorescence or other electrophysical properties. Bis-pyrazolepyridines such as compound 30 have been incorporated into polymers as fluorescent chromophores <1999JMC339>, and used in doped polymer matrices <1997JMC2323>. They are electroluminescent at 425 nm and photoluminescent at 427 and 430 nm in a poly(vinylcarbazole) matrix with a quantum efficiency of 0.8. 

In an approach toward a synthesis of tetraponerine 37, Gevorgyan first synthesized the fully aromatic tricyclic system 49 and then reduced it over two steps, first via hydrogenation under pressure (50 psi) to give 36 followed by a second reduction by lithium aluminium hydride of the amidinium salt (Scheme 1) <2002OL4697, 2004JOC5638>. 

Reaction of the dihydroimidazole ring of the tricyclic system 55 with w-chloroperbenzoic acid (MCPBA) results in oxidation of the iminium nitrogen with concomitant ring opening to generate the tertiary nitro compound 56 (Equation 7) <1997BML1381>. 

Zinc dust has been used to reduce a tetrazole of the tricyclic system 57 to generate the corresponding bicyclic 2-amino-3,5,6-trimethyl-3//-thieno[2,3- /]pyrimidin-4-one 58 (Equation 8) <2000MOL835>. 

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