Exocyclic methylene

Thompson points out that there is no evidence that adducts give other than acetates on thermolysis. The exocyclic methylene intermediate (iv) postulated by Robinson could arise by proton abstraction from a Wheland intermediate analogous to (vll) above, rather than from the adduct (in). Similarly its decomposition does not necessarily require the intermediacy of the adduct (v). The fact that i -methyl-4-nitromethylnaphthalene is the product even when the nitrating medium is nitric acid and nitromethane would then require no separate explanation. 

The course of the ring opening in epoxides derived from various exocyclic methylene compounds by treatment with lithium aluminum deuteride has been studied in the norbornane series. ... 

Although steroidal spiro oxiranes are difficult to obtain stereochemically pure by peracid epoxidations of exocyclic methylenes,the recently developed methylene transfer reagents, dimethylsulfonium methylide and di-methylsulfoxonium methylide in tetrahydrofuran, proved useful in the stereoselective transformation of steroid ketones to a- and -oxiranes, (87) and (88), respectively. ... 

A common consequence of migration in complex molecules is that tetrasubstituted olefins result, which can be hydrogenated only with difficulty, if at all. It is easier to try to prevent hindered olefin formation than it is to correct it. Attempted hydrogenation of the exocyclic methylene group in 15 proved difficult when using an aged 10% Pd-on-C catalyst there was a... 

In the third sequence, the diastereomer with a /i-epoxide at the C2-C3 site was targeted (compound 1, Scheme 6). As we have seen, intermediate 11 is not a viable starting substrate to achieve this objective because it rests comfortably in a conformation that enforces a peripheral attack by an oxidant to give the undesired C2-C3 epoxide (Scheme 4). If, on the other hand, the exocyclic methylene at C-5 was to be introduced before the oxidation reaction, then given the known preference for an s-trans diene conformation, conformer 18a (Scheme 6) would be more populated at equilibrium. The A2 3 olefin diastereoface that is interior and hindered in the context of 18b is exterior and accessible in 18a. Subjection of intermediate 11 to the established three-step olefination sequence gives intermediate 18 in 54% overall yield. On the basis of the rationale put forth above, 18 should exist mainly in conformation 18a. Selective epoxidation of the C2-C3 enone double bond with potassium tm-butylperoxide furnishes a 4 1 mixture of diastereomeric epoxides favoring the desired isomer 19 19 arises from a peripheral attack on the enone double bond by er/-butylper-oxide, and it is easily purified by crystallization. A second peripheral attack on the ketone function of 19 by dimethylsulfonium methylide gives intermediate 20 exclusively, in a yield of 69%. 

The exocyclic methylene C —C double bond can be reduced to give the corresponding methyl-substituted chlorin.25... 

Although the o-xylylene complex is thermally unstable, it was characterized at — 50 °C by its 1H- and 13C-NMR spectra showing the exocyclic methylene at 5 = 5.04,4.42 ppm (JH) and 5 = 144.8 ppm (13C) using C6D5CD3 as the solvent. Its reaction with benzoyl chloride on the exocyclic carbon leaves a very acidic methylene group which transfers a proton onto the adjacent methylene unit. The double bond is benzoylated again in in situ and a di-cation of the [bis(arene)Fe]2+ type is obtained [47] Scheme VIII. 

Scheme 5.1 illustrates some hydrogenations in which the syn addition from the less hindered side is observed. Some exceptions are also included. Entry 1 shows the hydrogenation of an exocyclic methylene group. This reaction was studied at various H2 pressures and over both Pt and Pd catalysts. 4-Methyl- and 4-r-butylmethylene cyclohexane also give mainly the cis product.3 These results are consistent with a favored (2.3 1) equatorial delivery of hydrogen. 

The Crabtree catalyst also exhibited superior stereoselectivity in comparison with other catalysts in reduction of an exocyclic methylene group.20... 

The prototype o-quinone methide (o-QM) and / -quinone methide (p-QM) are reactive intermediates. In fact, they have only been detected spectroscopically at low temperatures (10 K) in an argon matrix,1 or as a transient species by laser flash photolysis.2 Such a reactivity is mainly due to their electrophilic nature, which is remarkable in comparison to that of other neutral electrophiles. In fact, QMs are excellent Michael acceptors, and nucleophiles add very fast under mild conditions at the QM exocyclic methylene group to form benzylic adducts, according to Scheme 2.1.2a 3... 

Nucleophiles, at the exocyclic methylene when bonded to Ir, Rh, and Co cyclopentadienyl complexes.17... 

Quinone methides (QMs), especially the simple ones (those not having substituents at the exocyclic methylene group), are very unstable compounds. Their isolation is very difficult and normally requires very dilute solutions and low temperatures.2 Due to the aromatic z witterionic form (Scheme 3.1), quinone methides react very rapidly with both electrophiles and nucleophiles, with the medium, or in self-condensation reactions. 

As mentioned earlier, metal complexation not only allows isolation of the QM derivatives but can also dramatically modify their reactivity patterns.29o-QMs are important intermediates in numerous synthetic and biological processes, in which the exocyclic carbon exhibits an electrophilic character.30-33 In contrast, a metal-stabilized o-QM can react as a base or nucleophile (Scheme 3.16).29 For instance, protonation of the Ir-T 4-QM complex 24 by one equivalent of HBF4 gave the initial oxo-dienyl complex 25, while in the presence of an excess of acid the dicationic complex 26 was obtained. Reaction of 24 with I2 led to the formation of new oxo-dienyl complex 27, instead of the expected oxidation of the complex and elimination of the free o-QM. Such reactivity of the exocyclic methylene group can be compared with the reactivity of electron-rich enol acetates or enol silyl ethers, which undergo electrophilic iodination.34... 

Amouri and coworkers also demonstrated that the nucleophilic reactivity of the exocyclic carbon of Cp Ir(T 4-QM) complex 24 could be utilized to form carbon -carbon bonds with electron-poor alkenes and alkynes serving as electrophiles or cycloaddition partners (Scheme 3.17).29 For example, when complex 24 was treated with the electron-poor methyl propynoate, a new o-quinone methide complex 28 was formed. The authors suggest that the reaction could be initiated by nucleophilic attack of the terminal carbon of the exocyclic methylene group on the terminal carbon of the alkyne, generating a zwitterionic oxo-dienyl intermediate, followed by proton transfer... 

FIGURE 6.16 ortho-Quinone methide 3 stabilization of the zwitterionic rotamer in a complex with /V-methyImorpholine /V-oxide (17). The zwitterionic, aromatic precursor 3a affords the common quinoid form of the o-QM 3 by in-plane rotation of the exocyclic methylene group. 

The stabilization of the zwitterionic o-QM precursors is due to electrostatic interactions. It was reasonable to assume that also the other methods of stabilizing the zwitterions might be viable, and indeed it was confirmed that both steric and electronic effects are able to stabilize such intermediates. In 5-(4-octyl)-y-tocopherol (5a-butyl-5a-propyl-a-tocopherol, 21), the octyl group acts as a flywheel, which impedes the rotation of the C-5a moiety into the ring plane as compared to the parent zwitterions with the unsubstituted exocyclic methylene group. The situation is... 

Stabilization of the zwitterionic intermediate in o-QM formation can also occur intramolecularly. In this case, the stabilizing moieties must be able to dissipate the positive charge at the benzylic group by a resonance effect and prevent rotation of the exocyclic methylene group by a steric blocking. One example for such a temporary stabilization is the nitration of a-tocopheryl acetate (25) by concentrated HNO3, which produced 6-0-acetyl-5-nitro-a-tocopherol (27) in quite good yields,48 the... 

If the formation of an exocyclic methylene group at C-4, and thus the formation of a styrene intermediate such as 64, is impossible due to structural prerequisites, oxidation of the corresponding 3-oxa-chromanols will involve the o-QM formed... 

The final stages of the synthesis of (—)-A-58365B, a Streptomyces metabolite that inhibits the angiotensin-converting enzyme, involve several reactions at substituents attached to ring carbon atoms of a quinolizidine system. Thus, ozonolysis of the exocyclic methylene side chain of compound 107, followed by base-induced elimination and carboxyl deprotection, gave 108 (Scheme 12) <1999JOC1447>. 

Axisonitrile-1 (1) and axisothiocyanate-1 (2) were the first pair of NC/NCS compounds isolated from Axinella cannabina, see Introduction [1]. That both compounds possessed a new skeleton was evident, when 1 was reduced (Li/EtNH2) to axane (6). Other transformations involving the exocyclic methylene which survived selective reduction (Na/NH3) of 1, coupled with evaluation of the lHNMR data, supported its gross structure. Confirmation of 2 was secured when 1 was heated with sulfur and the resultant purified product found to be identical to the natural product. 

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