Tricyclic Compounds

The tricyclic tellurium-containing compounds 92 are the most thoroughly studied group of the tellurium heterocycles. Moreover, phenoxatel-lurine (92, M = O) synthesized by Drew (26JCS223) some 70 years ago 

Two important methods of synthesis of heterocycles 92 (M = NR, O, S) are described in Sections a and b. As explained below these methods cannot be applied to the synthesis of tellurantrene 92 (M = Te). Therefore, the relevant approaches to 92 (M = Te) will be considered separately. 

12 h provides the targeted heterocycle, although in a low yield of 6%. In a higher yield (42%), 10,10-dichlorophenothiatellurine was prepared when 2-(phenylthio)phenyltellurium trichloride 93 (M = S) (synthesized from 2-(phenylthio)phenylmercury chloride and TeCl4 was heated at 240°-250°C (60T15). 

However, a number of other diaryl oxides, 4-chloro-4 -bromo-, 4-chloro-4 nitro- (76RRC733), 4,4 dibromo-(73MIl),4-bromo-,4-iodo- (76RRC739), and 4-nitro- (27JCS116), on reacting with TeCl4 do not afford phenoxatel- 

A more general method of preparation of various 10,10-dichlorophen-oxatellurines comprises intramolecular electrophilic cyclization of 2-phenoxyphenyl tellurium trichlorides, which are readily accessible from the corresponding arylmercury chlorides or aryltrimethylsilanes (83MI2). 

An excellent review by Bradsher52 has dealt with benzoquinolizinium salts hence, work prior to 1968 is only summarized in the present account. 

Up to 1967 benzo[ ]quinolizinium salts could be made by the general methods shown in Eqs. (28-32). Two syntheses of benzo[a]quinolizinium 

Akabashi, T. Kato, and A. Saiga. Chem. Pharm. Bull. 11, 1446 (1963). 

There are only two general syntheses of benzo[6]quinolizinium salts, shown in Eqs. (33 and 34). The former, due to Bradsher and co-workers64-69 

By cyclization of 2-(o-cyanobenzyl) pyridine in acid Bradsher and Sherer76 obtained 6-aminobenzo[h]quinolizinium salts 64. A variation gave 11- 

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Unlike the intermolecular reaction, the intramolecular aminopalladation proceeds more easily[13,14,166], Methylindole (164) is obtained by the intramolecular exo amination of 2-allylaniline (163). If there is another olefinic bond in the same molecule, the aminopalladation product 165 undergoes intramolecular alkene insertion to give the tricyclic compound 166[178]. 2,2-Dimethyl-l,2-dihydroquinoline (168) is obtained by endo cyclization of 2-(3,3-dimethyiallyl)aniline (167). The oxidative amination proceeds smoothly... 

Another interesting transformation is the intramolecular metathesis reaction of 1,6-enynes. Depending on the substrates and catalytic species, very different products are formed by the intramolecular enyne metathesis reaction of l,6-enynes[41]. The cyclic 1,3-diene 71 is formed from a linear 1,6-enyne. The bridged tricyclic compound 73 with a bridgehead alkene can be prepared by the enyne metathesis of the cyclic enyne 72. The first step of... 

Atypical Antidepressants. StmcturaHy diverse dmgs such as the tetracyclic mianserin (46) and various bicyclic and tricyclic compounds such as trazodone (47), venlafaxine (48), nefazodone (49), and amfebutamone (50) are atypical antidepressants. The exact mechanism of action is unclear but probably... 

Research for an antidepressant among non-tricyclic compounds with pharmacological effects qualitatively different from those of the conventional tricyclic compounds led to the preparation and testing of a series of indazole derivatives for reserpine-like activity in mice. l-[3-(Dimethylamino)propyl]-5-methyl-3-phenyl-l//-indazole (FS-32 692) antagonizes reserpine-induced effects and potentiates amphetamine-induced self-stimulation and l-Dopa-induced increase in motor activity. FS-32 produces an anticholinergic action mainly on the central nervous System, while the action of imipramine occurs centrally as well as peripherally (79AF511). 

Some C(3) modifications are described in other sections the preparation of penems in Section 5.11.4.6, and the synthesis of the tricyclic compound (26) in Scheme 10. 

A careful and NMR study of 1,5-benzoxazine and 1,5-benzo-diazepine shows that these compounds exist in the amino-thione forms 55 and 56, respectively. Compound 55 displays a solvent-dependent amino/imino tautomerism (92MRC673).Tricyclic compounds 57, analogous to the bicyclics discussed above have been described they exist in the tautomeric form shown below (87BSB399,92BSB995,96BSB345). 

The tricyclic compounds 35 are among the most studied six-member Te-containing heterocycles with two heteroatoms in the ring. The first representive... 

A similar reaction is probably involved in the reaction of 4-nitrophthalodi-nitrile (27) with dimedone (28), which provided under milder condition compound 29 and at a higher temperature tricyclic compound 30 (87ZOR2629). Similarly as in the vicarious nucleophilic reactions, intermediate 29 is formed by nucleophilic displacement of the ort/io-hydrogen atom in 27 (Scheme 3). 

Disodium salt of 2-(dimercaptomethylene)malonodinitrile (82) afforded with 81 tricyclic compound 83 (Eq. 11) (91ZOR185). 

Reaction of nitro-2f/-chromene derivatives 134 with 135 in methanol at room temperature afforded a mixture of the Z-isomer 136 and tricyclic compound 137, which could be formed by denitrocyclization reaction of the corresponding primarily formed E-isomer and the following dehydrogenation (Eq. 15). The structural identification was based on the MS and H-NMR, however, it is not sufficiently documented and similar examples are not known (91IJC(B)297). 

The 8-nitro group in intermediate quinolone 225 can be easily displaced even with aliphatic oxygen nucleophiles. Starting compound 224 under various conditions provided directly tricyclic compound 226 and all attempts to isolate the expected intermediate 225 failed (Scheme 34) (91CCC1937). 

Denitrocyclization strategy is potentially useful for the synthesis of a wide range of tricyclic compounds. The approach was found useful for the synthesis of thienobenzothiazole 339 and 343 starting from the corresponding bromonitro-thiophenes 336 and 340, respectively (Scheme 52) (68MI2, 72IJS(B)109). 

The smooth intramolecular nucleophilic displacement of biphenyl carboxylic acids leading to benzocoumarins (See Section II.A.) inspired also investigation of the behavior of similar diphenyl ether, diphenyl sulfide and A-methyldiphenyl amine derivatives 458 under similar conditions. However, all these attempts to achieve cyclization to tricyclic compounds 459 were unsuccessful, probably due to the unfavorable stereochemistry for the formation of the required seven-mem-bered transition states and also to the presence of the deactivating bridge groups X (Eq. 42) [68JCS(C)1030]. 

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). 

Heating of diphenylcyclopropenone 67 with the cyclic amidine 68 in dimethoxyethane afforded the tricyclic compound 69 that upon heating... 

Reaction of aniline derivatives with 4-chlorobutyroyl chloride followed by cyclization with sodium ethoxide and subsequent thionation promoted by sonication gave the corresponding A -arylpyrrolidine-2-thiones 126. Zinc-mediated condensation of diethyl bromomalonate with 126 using iodine as activator gave the vinylogous urethanes 127 whose cyclization with PPA gave the tricyclic compound 128 which upon hydrolysis afforded the acid 129 (96TL9403). 

Reaction of 4-cyano-3-imino-2,3,5,6,7,8-hexahydro-l//-pyrido[l,2-c]pyr-imidin-l-one 169 with 2-chloroethyl isocyanate at ambient temperature and under reflux gave N-acylated 170 and tetracyclic derivative 171, respectively (95MI1). Similar reaction of 3-amino-4-cyano-2,4a5,6,7,8-hexahydro-l// pyrido[l,2-c]pyrimidin-1-ones 172 afforded tricyclic compounds 173. 

R = Ar) and cyclized tricyclic compound 240 (R = Ar) was obtained when 2-bromoacetophenones were reacted with 8-hydroxyquinolin-2(l//)-one under the above conditions. Presence of a 4-methoxy substituent shifted the equilibrium to the ring-opened product 241 (R = 4-MeOPh), while that of 4-nitro group gave only cyclized product 240 (R = N02). Similarly, mixtures of ring-opened and 2,3,6,7-tetrahydro-5//-pyrido[l,2,3- /e]-l,4-benzoxazin-5-one derivatives were formed in the reaction of 8-hydroxy-l,2,3,4-tetrahydroquinolin-2-one and halomethyl ketones (00HCA349). 

The importance of the 1,3-dipolar cycloaddition reaction for the synthesis of five-membered heterocycles arises from the many possible dipole/dipolarophile combinations. Five-membered heterocycles are often found as structural subunits of natural products. Furthermore an intramolecular variant makes possible the formation of more complex structures from relatively simple starting materials. For example the tricyclic compound 10 is formed from 9 by an intramolecular cycloaddition in 80% yield ... 

For the performance of an enantioselective synthesis, it is of advantage when an asymmetric catalyst can be employed instead of a chiral reagent or auxiliary in stoichiometric amounts. The valuable enantiomerically pure substance is then required in small amounts only. For the Fleck reaction, catalytically active asymmetric substances have been developed. An illustrative example is the synthesis of the tricyclic compound 17, which represents a versatile synthetic intermediate for the synthesis of diterpenes. Instead of an aryl halide, a trifluoromethanesul-fonic acid arylester (ArOTf) 16 is used as the starting material. With the use of the / -enantiomer of 2,2 -Z7w-(diphenylphosphino)-l,F-binaphthyl ((R)-BINAP) as catalyst, the Heck reaction becomes regio- and face-selective. The reaction occurs preferentially at the trisubstituted double bond b, leading to the tricyclic product 17 with 95% ee. °... 

The fully unsaturated tricyclic compounds are also used clinically as antidepressants. Carbamazepine (62), for example, is prepared from 10,ll-dihydro-5H-dibenz[b,f]azepine (49) by N-acetylation followed by bromination with W-bromosuccinimide to give 60. Dehydrohalogenation by heating in collidine introduces the double bond. Saponification with potassium hydroxide in ethanol leads to dibenz[b,f]azepine (61), the parent substance for the fully unsaturated analogs. Treatment of the secondary... 

DinitrQ-ll-Qxatricyclo[6 2 1 0 undec-9-ene has been prepared by an intramolecular Diels-Alder reacdon of the furan with a idtroalkene group as shown in Eq 8 26 This tricyclic compound is a versatile synthedc tool for the preparadon of ergot alkaloids... 

Its molecular refraction is 42 37, appearing to indicate a tricyclic compound, whilst the value calculated for a tricyclic body is... 

Semmier and Stenzel have isolated a sesquiterpene which they term opaene, from African copaiha oil. It is prohahly a tricyclic compound. Its physical characters are as follows —... 

Cedrene is the naturally occurring sesquiterpene of cedar wood oil of which it forms the principal constituent. It is a tricyclic compound having the following characters —... 

For the construction of the I ring, the vinylic group introduced to activate the y-hydroxy epoxide moiety of 28 towards cyclization is an acrylic ester residue, which concomitantly allows cyclization on the allylic position, with formation of the tricyclic compound 29 containing the IJK fragment of the natural product, and fur-... 

The diastereosclectivity in this particular cyclization was exploited in a number of direct syntheses of terpenes from the eudesmane type (see Table 2). By this technique tricyclic compounds can be synthesized generating three new asymmetric centers55. 

Tricyclic compounds can be obtained directly by annulation on to cyclic allylsilanes, using either ethylaluminum dichloride or titanium(IV) chloride as Lewis acids57. The stereochemical outcome of this particular cyclization is controlled by the relative configuration of the cyclic allylsilane. The reaction follows the usual anti" SE2 process for reactions of allylsilanes with electrophiles. Thus, the reaction was stereospecific, which makes it very useful for stereocon-trolled syntheses of complex ring systems57. 

This strategy resulted in a direct and stereoselective synthesis of the dolestane skeleton, in which the relative configuration at the quaternary C-5 and C-12 carbons was established. It was shown that the key reaction produced the tricyclic compound slereospecifically in a remarkably high chemical yield57. 

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