Intermediates formyl

To make MDMA from the formyl intermediate obtained by the Leuckart reaction the chemist is going to have to distill it to get the clean-yellow oil first. That black crap one gets from the formamide... 

METHOD 5 Contributed by Osmium [53], The paper reads (at least to Strike) that this reduction method can work to reduce the formyl intermediate made in the Leuckart reaction directly into MDMA instead of needing to hydrolyze to MDA with HCi (don t ask). For this reaction one substitutes an equimolar amount of p-Nitropropene for the 3,4-dimethoxybenzylcyanide in the representative experimental below ... 

The CO reductions generally could likely proceed through formyl intermediates, probably at a multinuclear site (420) hydride migration to a coordinated CO [e.g., as in the hypothetical scheme outlined in Eq. (72)] has not yet been observed, although metal formyl complexes have been synthesized via other methods (422-425). A ir-bonded formyl also seems plausible (426), since 7r-bonded acyl groups have been demonstrated (427). A stoichiometric hydrogen reduction of CO to methanol under mild conditions via a bis(pentamethylcyclopentadienyl)zirconium complex is considered to go through a formyl intermediate (428, 429) ... 

These prodrugs underwent spontaneous hydrolysis in aqueous solution. The mechanism of reaction (Fig. 11.10) was postulated to involve nucleophilic hydration of the C=N bond to yield an intermediate carbinolamine. The latter breaks down with loss of the dialkylamine to form an Af4-formyl intermediate, which, in turn, hydrolyzes to the active agent (11.68, Fig. 11.10). The hydrolysis of these prodrugs followed pseudo-first-order kinetics with tm values at pH 7.4 and 37° that were mostly influenced by the steric properties of the dialkylamino group. Thus, tm values were ca. 4, 9 - 10, 14 -15, and 48 - 52 h for R = Me, Et, Pr, and i-Pr, respectively. Interestingly, the rates of hydrolysis were decreased in human serum, indicating protective... 

Pichler and Schulz were the first to suggest that the initial step in metal-catalyzed CO/H2 reactions might be the migration of catalyst-bound hydride to CO to yield a formyl intermediate [Eq. (1)] (3). The alkyl ligand in many isolable metal carbonyl alkyls can similarly be induced to migrate to coordinated CO (4. ). Thus, Eq. (1) has some precedent in homogeneous chemistry. Other suggestions for the involvement of formyl intermediates have come from Wender (6) and Henrici-Olive and Olive (7). 

Good evidence has been obtained that heterogeneous iron, ruthenium, cobalt, and nickel catalysts which convert synthesis gas to methane or higher alkanes (Fischer-Tropsch process) effect the initial dissociation of CO to a catalyst-bound carbide (8-13). The carbide is subsequently reduced by H2to a catalyst-bound methylidene, which under reaction conditions is either polymerized or further hydrogenated 13). This is essentially identical to the hydrocarbon synthesis mechanism advanced by Fischer and Tropsch in 1926 14). For these reactions, formyl intermediates seem all but excluded. 

Reagents such as LiAlH4 and KH are not effective for the synthesis of formyl complexes. LiAlH4 does react with many metal carbonyl compounds, but it can transfer more than one and usually effects the formation of metal hydride products (50). Similar results are usually found with NaBH4(50), although some neutral formyl complexes (vide infra) can be obtained under special conditions. KH will also react with some metal carbonyls. However, rates are not very rapid, and any formyl intermediates are likely to decompose faster than they form (51). 

C. Other Stoichiometric Reactions That Are Likely to Involve Formyl Intermediates and/or Bridging CHO Species... 

Protonation of lH-pyrrolizin-l-ones appears to take place on oxygen (see Sections III,A,2 and III,A,4). The other derivative of type 258 is the Vilsmeier formylation intermediate from l-chloro-3H-pyrrolizine, the perchlorate... 

In ergosterol biosynthesis, side chain alkylation of lanosterol normally takes place to build 24-methylenedihydrolanosterol, which itself is then the substrate for demethylation reactions at and C. The C -demethylation has been studied in detail. It is an oxidative demethylation catalyzed by a cytochrome P -system. The first step involved in this reaction is the hydroxylation of the Cj -methy1-group to form the C -hydroxymethyl derivative. A second hydroxylation and loss of water lead to the C -formyl intermediate, which is hydroxylized a third time to form the corresponding carboxylic acid. Decarboxylation does not directly take place, but proceeds instead by abstraction of a proton from C, followed by elimination and formation of a A 4-double bond. The NADPH-dependent reduction of the A14 -double bond finishes the demethylation reaction. Subsequently, demethylation at has to take place twice, followed by a dehydrogenation reaction in A" -position and isomerization from A8 to A7 and A24(28) to A22. respectively. 

Formation of a formyl intermediate by migration of CO into a Zr-H bond and reduction of this by Cpf ZrH2. 

Formyl intermediates are easily hydrogenated to give methanol. Copper based catalysts are very active methanol catalysts. Because Cu has a completely filled d... 

Turning to recent syntheses which have involved the addition of extra carbon atoms to androstanes, an efficient sequence of reactions has been proposed for the conversion of a 17-keto-steroid into a 20-keto-steroid.78 The route is illustrated by the conversion of 3/3-hydroxyandrost-5-en-17-one into the 20/3-formyl intermediate (184 R = H) by means of methoxymethylenetriphenylphosphorane, followed by oxidation to the etianic acid (184 R = OH) using silver oxide it is... 

Figure 2.29 Metal hydride synthesis (a) employing borohydride reagents, (b) via tetrahydroborate ligands and (c) via formyl intermediates...

However, kinetic studies of XM(CO) compounds indicate that when X = H, the rate of CO substitution reactions is much faster than when X = Cl or CH3, so that it is possible to have kinetically significant amounts of a formyl intermediate. Rapid substitution reactions involving formyls occur only for first row transition elements and ruthenium ... 

Formyl intermediates have been postulated as steps in the Fischer-Tropsch reduction of CO to hydrocarbons (Section 22-5). Coordinated CO can insert into the M—H bonds of metal hydrides, particularly when the reaction is driven by the oxophilic character of early transition metals. Such reactions may lead to C—C bond formation. Some examples are ... 

Inderwildi et al. (62) reported an overall barrier of 130 kj/mol for hydrogen-assisted CO bond cleavage on Co(OOOl). In an earlier investigation of the reaction on ruthenium, Ciobica and van Santen (5) had also found that, on terrace sites, dissociation of CO fhrough an adsorbed formyl intermediafe is characterized by a tower barrier than direct dissociation of adsorbed CO. However, fhey also concluded fhaf on a sfepped surface, direct dissociation of CO is more favorable fhan dissociation through the formyl intermediate on the same site. 

As mentioned above, there are several computational investigations that indicate that the addition of adsorbed hydrogen atoms to CO lowers the overall activation energy for CO dissociation. Ciobica and van Santen (5) demonstrated that on the (0001) terrace of ruthenium, activation of CO through a formyl intermediate would proceed with a barrier of 140 kj/mol. This value is substantially lower than the barrier of 210 kJ/ mol that was found for direct CO dissociation on the same surface. However, on stepped surfaces, the pathway via association with H atoms was found not to be competitive with direct CO dissociation. 

The formation of a metal formyl complex by the transfer of hydrogen to a coordinated CO molecule is an attractive route for a catalytic CO iydrogena-tion. Formyl intermediates can account for C species such as methanol or formaldehyde. They can also be considered as intermediates leading to nrethane. 

A stepwise reduction of carbon monoxide to methane via a formyl intermediate has also been demonstrated on an Osj cluster face yielding Os3(CO)i CHj... 

Scheme 2 favours the insertion of CO into a metal-hydride bond yielding formyl intermediates [M]. Further reduction leads to a hydroxymcthylene intermediate analogous to that shown in Scheme 1. 

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