Intramolecular hydride shift

Similarly, if rearrangements in which there is a hydride shift (cf. p. 109) are carried out in a deuteriated solvent (e.g. D20, MeOD, etc.), no deuterium is incorporated into the new C—H(D) bond in the final rearranged product. In both cases the rearrangement is thus strictly intramolecular, i.e. the migrating group does not become detached from the rest of the molecule, as opposed to intermodular where it does. 

One very fascinating domino reaction is the fivefold anionic/pericydic sequence developed by Heathcockand coworkers for the total synthesis of alkaloids of the Daphniphyllum family [351], of which one example was presented in the Introduction. Another example is the synthesis of secodaphniphylline (2-692) [352]. As depicted in Scheme 2.154, a twofold condensation of methylamine with the dialdehyde 2-686 led to the formation of the dihydropyridinium ion 2-687 which underwent an intramolecular hetero- Diels-Alder reaction to give the unsaturated iminium ion 2-688. This cydized, providing carbocation 2-689. Subsequent 1,5-hydride shift afforded the iminium ion 2-690 which, upon aqueous work-up, is hydrolyzed to give the final product 2-691 in a remarkable yield of about 75 %. In a similar way, dihydrosqualene dialdehyde was transformed into the corresponding polycyclic compound [353]. 

Hydride and 1,2-alkyl shifts represent the most common rearrangement reactions of carbenes and carbenoids. They may be of minor importance compared to inter-molecular or other intramolecular processes, but may also become the preferred reaction modes. Some recent examples for the latter situation are collected in Table 23 (Entries 1-10, 15 1,2-hydride shifts Entries 11-15 1,2-alkyl shifts). Particularly noteworthy is the synthesis of thiepins and oxepins (Entry 11) utilizing such rearrangements, as well as the transformations a-diazo-p-hydroxyester - P-ketoester (Entries 6, 7) and a-diazo-p-hydroxyketone -> P-diketone (Entry 8) which all occur under very mild conditions and generally in high yield. 

In the course of dolastane synthesis (the dolastanes are a group of marine diterpenes) interesting rearrangements catalyzed by Lewis acids were found. Treatment of the trienone 293 with excess (1.5 eq) ethylaluminum dichloride at low temperatures (—5°C, 48 h) gave the tetracyclic enone 295 in 53% yield while the tricyclic dienone 296 (50%) was formed at room temperature (equation 102)156. It was assumed that both products can be derived from the common zwitterion 294 which undergoes intramolecular alkylation at low temperatures (path a) whereas an alkyl shift takes place at elevated temperatures (path b), followed by a 1,2-hydride shift (equation 102). 

Studies in deuterated water have shown that the hydroxyl proton does not end up in the ethanal formed. The decomposition of the 2-hydroxyethyl is not a simple P-elimination to palladium hydride and vinyl alcohol, which then isomerises to ethanal. Instead, the four protons stemming from ethene are all present in the initial ethanal product [6] (measured at 5 °C in order to suppress deuterium/hydrogen exchange in the product) and most authors have therefore accepted an intramolecular hydride shift as the key-step of the mechanism (see Figure 15.2). There remains some doubt as to how the hydride shift takes place. 

A different method of generating a nitrenium ion has been demonstrated the sulfur-nitrogen bond in (55) cleaves and then a novel intramolecular hydride shift to the arylnitrenium ion centre takes place. The nitrenium species (56) undergoes two nucleophilic additions to the double bond to give the product (57). Two studies concerning the physiological effects of nitrenium ions in vivo are reported. Products are formed from both the ion-paired nitrenium ion (59) and the free ion (60)... 

D-xylose was converted into 2-furaldehyde in acidified, tritiated water, no carbon-bound isotope was detected. This suggested that the 1,2-enediol (2) reacted immediately, as otherwise, tritium would have been detected at the aldehydic carbon atom of 2-furaldehyde, as a result of aldose-ketose interconversion.An acidic dehydration performed with d-[2- H]xylose showed that an intramolecular C-2-C-1 hydrogen transfer had actually occurred. Thus, these data indicated that an intramolecular hydride shift is more probable than the previously accepted step involving a 1,2-enediol intermediate. 

A different behavior is exhibited by naphthalene-1,8-dicarbocal-dehyde (73). No m-naphthane derivatives are obtained on reaction with nitromethane, nitroethane or other methylene components. The basic medium, required for aldol type additions, causes the dialdehyde to undergo Cannizzaro reaction to the naphthopyranon (74) via an intramolecular 1,5-hydride shift, which is sterically favoured by the peri-position of the two aldehyde functions 28). 

LiAlH4 as this avoids protonation of the enolate and the production of any over-reduction products. Cholest-4-en-3-one may be reduced to cholestanone (5a 5/8,1 19) with alkali-metal carbonyl chromates. The studies on intramolecular hydride shifts on hydroxy-ketones and -aldehydes have been extended. " The hydride shifts were examined in a number of y- and 5-hydroxy-carbonyI compounds by heating the substrates with alkaline alumina containing D2O. Exchange of protons on the carbon a to both oxygen functions signals the intramolecular hydride shift typically, the hemiacetals (95) and (96) each incorporate up to six deuterium atoms. The general conclusion, in common with literature precedent, is that, whereas 1,5-shifts are common, 1,4-shifts are rare. 

Another convenient method for the preparation of functionalized cyclobutanol derivatives is by treatment of 1,2-diphenylethylene acetals containing a 1,3-dithiane moiety in the y-position, e.g. 14c. with butyllithium. The isolation of 2,2-(propane-l,3-diyldisulfanyl)cyclobutanol (15c) together with benzyl phenyl ketone in 90 and 92 % yield, respectively, indicates that the reaction mechanism should involve the intramolecular attack of the metalated dithiane on the acetal carbon atom with concomitant hydride shift at the acetal group.15... 

Attack by the carbene on a suitably placed aryl ring (Scheme 58152) gives an intermediate 164, which undergoes a thermally allowed suprafacial [l,5]-hydrogen shift to give the indene 165.151,152 The intramolecular nature of the hydride shift was established by lack of exchange with deuterium in the solvent.152... 

The detailed composition of poly(3-methyl-l-butene) and poly(4-methyl-l-pentene) produced by cationic polymerization has been investigated using high resolution 300 MHz H NMR and 20 MHz 13C NMR spectroscopy. It has been confirmed that both monomers polymerize by a cationic isomerization polymerization involving intramolecular hydride shifts. The composition of poly(3-methyl- 1-butene) obtained by cationic polymerization at — 130° C has been shown to be predominantly -(-CH2—CH2—C(CH3)2. ... 

Intramolecular cycloaddition of diazoalkynes has been little studied. Cyclization of tosylhydrazone salt (191) illustrates the potential of these reactions (Scheme 60).104 The actual product was isomeric with the expected 1,3-cycloadduct presumably a 1,3-hydride shift followed the initial cyclization. 

A tandem 1,4-addition-Meerwein-Ponndorf-Verley (MPV) reduction allows the reduction of a, /i-unsaturated ketones with excellent ee and in good yield using a camphor-based thiol as reductant.274 The 1,4-addition is reversible and the high ee stems from the subsequent 1,7-hydride shift the overall process is thus one of dynamic kinetic resolution. A crossover experiment demonstrated that the shift is intramolecular. Subsequent reductive desulfurization yielded fiilly saturated compounds in an impressive overall asymmetric reductive technique with apparently wide general applicability. 

Bicyclobutanes are also obtained from the catalytic decomposition of diazo compound 17492 (equation 51). Copper(I) iodide was the catalyst of choice, whereas rhodium(II) acetate did not show any activity in this case. When the related diazo compound 175 was decomposed, the product pattern depended in an unusually selective manner on the catalyst92. Intramolecular cyclopropanation leading to 176 is obviously less favorable than for carbene 172 and must yield to the 1,2-hydride shift not observed with the former carbene. The configuration of the resulting butadiene 177 can be completely reversed by the choice of the catalyst. 

As shown in the biosynthesis of granaticin, a hydride shift occurs intramolecularly. This process is mediated by an enzyme-bond pyridine nucleotide. A concerted abstraction of H-4 as a hydride in la and a C-5 deprotonation in 2a leads to the 4,5-enol ether 3a. The reduced form of the pyridine nucleotide transfers the hydride to C-6, simultaneously releasing a hydroxide to give 4a. Final tautomerization yields the dTDP-4-keto-6-deoxy-sugar in v-xylo configuration 4a. In other enzymes of the oxidoreductase type, the active site may show a different configuration. Thus, the intermediate 3a can be protonated from above at C-5 to yield the l-arabino isomer of 4a [2]. The stereochemistry of this mechanism was demonstrated by double labelling (cf. l-4b series), and as a net result proved a suprafacial 4—>6 hydride shift. 

Enthalpies of activation, transition-state geometries, and primary semi-classical (without tunneling) kinetic isotope effects (KIEs) have been calculated for 11 bimolecu-lar identity proton-transfer reactions, four intramolecular proton transfers, four nonidentity proton-transfer reactions, 11 identity hydride transfers, and two 1,2-intramole-cular hydride shifts at the HF/6-311+G, MP2/6-311+G, and B3LYP/6-311+-1-G levels.134 It has been found that the KIEs are systematically smaller for hydride transfers than for proton transfers. The differences between proton and hydride transfers have been rationalized by modeling the central C H- C- unit of a proton-transfer transition state as a four-electron, three-centre (4-e 3-c) system and the same unit of a hydride-transfer transition state as a 2-e 3-c system. 

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