Bicyclic intermediates

F. 1-26. (a) ir-Bond order of the C-S bonds in the ground state, (fc) ir-Bond order of the C-S bonds in the first excited state, (c) Free-valence number of the intermediate diradicaf. (Most probable bicyclic intermediate resulting from the ring closure of the diradicai. 

This synthetic appproach has been used in a few cases for the preparation of pyridazines from diazo compounds and cyclopropenes. In general, cycloadducts (176) are formed first and these rearrange in the presence of acid or alkali to pyridazines (Scheme 98) (69TL2659, 76H(5)40l). Tetrachlorocyclopropene reacts similarly and it was found that the stability of the bicyclic intermediates is mainly dependent on substitution (78JCR(S)40, 78JCR(M)0582>. 

Cyanopyrrole undergoes photochemical rearrangement to 3-cyanopyrrole. If the analogous rearrangement of IV-methyl-2-cyanopyrrole (22) is carried out in methanol, in addition to the 3-cyanopyrrole (24) the bicyclic intermediate (23) is trapped as the methanol adduct (25) (78CC131). 

The light-induced rearrangement of 2-phenyl- to 3-phenyl-thiophene may occur by a similar mechanism an equilibrium between the bicyclic intermediate (26) and the cyclopro-penylthioaldehyde (27) has been suggested (Scheme 2). The formation of IV-substituted pyrroles on irradiation of either furans or thiophenes in the presence of a primary amine supports this suggestion (Scheme 3). Irradiation of 2-phenylselenophene yields, in addition to 3-phenylselenophene, the enyne PhC=C—CH=CH2 and selenium. Photolysis of 2-phenyltellurophene furnishes solely the enyne and tellurium (76JOM(108)183). 

In contrast to pyrazolenines, there are only a few publications on the photochemistry of isopyrazoles and they concern exclusively their iV-oxides (390). Irradiation of (390) affords the iV-oxides of pyrazolenine (391) (70CC289). Bicyclic intermediates (392) and (393 Scheme 36) are believed to be implicated in this reaction (75MI40400). The final step is similar to that reported from studies of the valence bond isomerization of pyrazolenines (68JA173). 

Solvolysis of tosylate (303) yields, in addition to aziridinyl alcohol (304), ring expanded products (305) and (306) (68TL6179). These products and the observed rates of solvolysis were explained in terms of bicyclic intermediate (301). 

The classic method for controlling stereochemistry is to perform reactions on cyclic substrates. A rather lengthy but nonetheless efficient example in the prostaglandin field uses bicyclic structures for this purpose. Bisacetic acid derivative S is available in five steps from Diels-Alder reaction of trans-piperylene and maleic anhydride followed by side-chain homologation. Bromolactonization locks the molecule as bicyclic intermediate Esterification, reductive dehalogen-... 

Antidepressant activity is retained when the two carbon bridge in imipramine is replaced by a larger, more complex, function. Nucleophilic aromatic substitution on chloropyridine 31 by means of p-aminobenzophenone (32) gives the bicyclic intermediate 33. Reduction of the nitro group (34), followed by intramolecular Schiff base formation gives the required heterocyclic ring system 35. Alkylation of the anion from 35 with l-dimethylamino-3-chloropropane leads to tampramine 36 [8]. 

The first fully unsaturated 1,4-oxazepines 3 were prepared by the photoisomerization of 3-oxa-6-azatricyclo[3.2.0.02,4]hept-6-enes l.29,30 The reaction proceeds via the bicyclic intermediates 2 which undergo valence isomerization. 

A key step in the synthesis in Scheme 13.11 was a cycloaddition between an electron-rich ynamine and the electron-poor enone. The cyclobutane ring was then opened in a process that corresponds to retrosynthetic step 10-IIa 10-IIIa in Scheme 13.10. The crucial step for stereochemical control occurs in Step B. The stereoselectivity of this step results from preferential protonation of the enamine from the less hindered side of the bicyclic intermediate. 

The synthesis in Scheme 13.13 leads diastereospecifically to the erythro stereoisomer. An intramolecular enolate alkylation in Step B gave a bicyclic intermediate. The relative configuration of C(4) and C(7) was established by the hydrogenation in Step C. The hydrogen is added from the less hindered exo face of the bicyclic enone. This reaction is an example of the use of geometric constraints of a ring system to control relative stereochemistry. 

Scheme 13.33 shows broad retrosynthetic formulations of the longifolene syntheses that are discussed in this subsection. Four different patterns of bond formation are represented. In A, the C(7)-C(10) bond is formed from a bicyclic intermediate. This pattern corresponds to the syntheses in Schemes 13.24, 13.25, 12.26, and 13.29. In retrosynthesis B, there is concurrent formation of the C(l)-C(2) and C(10)-C(ll) bonds, as in the synthesis in scheme 13.28. This is also the pattern found in the synthesis in Scheme 13.32. The synthesis in Scheme 13.29 corresponds to retrosynthesis C, in which the C(l)-C(2) and C(6)-C(7) bonds are formed and an extraneous bond between C(2) and C(5) is broken. Finally, retrosynthesis D, corresponding to formation of the C(2)-C(3) bond, is represented by the synthesis in Scheme 13.31.

Another epoxidation, followed by fragmentation gave the bicyclic intermediate that contains the eight-membered ring and bridgehead double bond properly positioned for conversion to Taxol (Steps B-2 and B-3). 

The favorable stereochemistry and the displacement of the very good leaving group promoted the formation of a [3.2.0] bicyclic intermediate (see Scheme 2). Owing to the absence of a C2 symmetry axis two different [3.2.0] bicyclic sulfonium salt intermediates, 8a and 8b, can be generated by nucleophilic transannular attack of sulfur on the... 

A different approach to 1 is available32,33 for somewhat larger quantities in good yields. The procedure (Scheme 2) is based upon the condensation of ethyl /f-bromomethacrylate (9) or its precursor, diethyl /i,/7 -dibromoisobutyr-ate, with the pyrrolidine enamine (10) of Af-toluene-p-sulfonylpiperid-4-one to afford the bicyclic intermediate (11). If the carbonyl group is modified... 

The reverse process has also been examined. 2-Phenyloxazole is converted in a similar fashion to 3-phenyl-2//-azirine-2-carbaldehyde on irradiation in benzene or cyclohexane.128 Further rearrangement to the corresponding isoxazole can be effected thermally but not photochemically. A competing pathway leading to the formation of 4-phenyloxazole has also been observed and is thought to involve a bicyclic intermediate arising by 2,5-bonding. 

The possible involvement of bicyclic intermediates in the photorearrangement of hindered pyrid-4-ones to the corresponding pyrid-2-ones has been considered,163 but the mechanism for the photochemical conversion of 4,6-dimethyl-l-(l -piperidinyl)pyrid-2-one into the 3-piperidinyl isomer is less... 

The observation of bicyclic intermediates in the chemistry of the naph-thylcarbenes suggests that 2a may also lie along the reaction coordinate for ring expansion of phenylcarbene. Nevertheless, if 2a is an energy minimum, the... 

The assumed mechanism proceeds via ruthenacyclopentadiene intermediates of type 160 or structure 161 as possible intermediates. Subsequently, the common bicyclic intermediate 162 is formed through insertion of the C=N double bond into the C-Ru bond, and reductive elimination of the ruthenium fragment gives rise to the desired bicyclic pyridones 163. 

Skeletal ring contraction steps of primary C7 and Cg rings are more probable than bicyclic intermediates (132b). Aromatization of methylcyclo-pentane indicated no carbonium mechanism with a nonacidic catalyst. Instead, Pines and Chen (132b) proposed a mechanism similar to that defined later as bond shift. This is a methyl shift. Two additional isomerization pathways characteristic of chromia have also been demonstrated vinyl shift (94) and isomerization via C3 and C4 cyclic intermediates (90a). These were discussed in Section III. 1,1-Dimethylcyclohexane and 4,4-dimethyl-cyclohexene gave mainly toluene over various chromia catalysts. Thus, both skeletal isomerization and demethylation activities of chromia have been verified. The presence of an acidic almnina support enhances isomerization dual function effects are thus also possible. 

The bicyclic intermediate 106 used in the synthesis of octosyl acid A became the starting point for the synthesis of octosyl acid C (Figure 24). Disilylation of 106 followed by hydrogenolysis liberated the C-5 hydroxyl group which was oxidized to afford the... 

A rather more complex scheme is required for preparation of the analogue gestrinone (27) which contains unsaturation in rings A, B, and C. The key intermediate 24 can be obtained by Robinson annulation on dione with enone 15 to give the bicyclic intermediate J. Successive... 

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