Hydrolysis carbinolamine

Amides can also be deacylated by partial reduction. If the reduction proceeds only to the carbinolamine stage, hydrolysis can liberate the deprotected amine. Trichloroac-etamides are readily cleaved by sodium borohydride in alcohols by this mechanism.237 Benzamides, and probably other simple amides, can be removed by careful partial reduction with diisobutylaluminum hydride (see Section 5.3.1.1).238... 

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... 

The binding of pyridoxal 5 -phosphate (vitamin Be) to enzymes has been modelled using homo- and co-polypeptides containing L-lysine as a source of reactive amino groups. This has now been extended to reaction of pyridoxal with polyallylamine, with the polymer acting as a control that cannot provide amido -CO- or -NH- functions to stabilize the Schiff base products, as occurs in enzymes and polypeptides. Rate constants for the formation and hydrolysis of the imines have been measured and interpreted in terms of formation of the carbinolamine (in its neutral or zwitterionic form). 

At pH >11, aniline production occurs via the anionic carbinolamine only and the overall reaction is first-order in hydroxide ion. At pH 8-10, the path via the carbinolanine gives a constant rate of hydrolysis and at pH 5.5-7 aniline arises solely through the neutral carbinolanine, present in its largest amounts. Eventually, acid catalysis leads to an increase in the rates of hydroly-... 

Furthermore, in place of reduction of 10 it was possible to add organolithium reagents such that the resulting alkyl carbinolamine, after hydrolysis, gave either 12 or 13 depending upon hydrolysis conditions.6 In summary, these bicyclic lactams have provided a route to a variety of chiral, nonracemic cyclohexenones and cyclopentenones containing quaternary stereocenters. 

Thus, the tricyclic urethane 219 (Scheme 34), obtained in 63% yield, on acid hydrolysis led to the carbinolamine 220 which, without purification was oxidised to anhydrolycorinone (201). 

N-Bromosuccinimide (NBS) reacted with the free tertiary alcohol group of veracevine D-orthoacetate triacetate 34 to cause a (presumably) free radical insertion into ring F, giving the carbinolamine 35. Cevine D-orthoacetate triacetate similarly gave 36, which on alkaline hydrolysis gave 37 (see Table XVIII) (47,53). Treatment of triacetylcevine with NBS gave 38 (47). 

Without looking back, propose a mechanism for the hydrolysis of this iminium salt to the alkylated ketone. The first step is attack by water, followed by loss of a proton to give a carbinolamine. Protonation on nitrogen allows pyrrolidine to leave, giving the protonated ketone. 

Reactions of organomagnesium compounds with /V,/V-disubstituted amides differ from those of other acyl derivatives (Section 6.2) in that the initial adducts are much more stable. However, although examples are known where a carbinolamine may be isolated following careful hydrolysis, acid hydrolysis without special precautions usually gives the... 

The hydrolysis rate of all three enamines (1-3) undergoes a sharp decline as the pH drops below 1 (for 2 and 3) or 0 (for 1). This result signifies that equation 23 (or 23a) is no longer the rate law and that another change in rate-controlling step has occurred. The last stage of Scheme 1 is the breakdown of the carbinolamine, equations 17-19. At the acidities in question (pH < 1), equations 14-17 are in equilibrium, that is, the enamine is fully protonated ([EH+] = [NH+] + [CH+], see Table 2) as is the hydration product, the carbinolamine72. Equation 24 describes the situation. The observed inverse... 

In the early 1960s, seminal work by Jencks and coworkers demonstrated that formation and hydrolysis of C=N bonds were proceeding via a carbinolamine intermediate, thus leading to a more general mechanism of addition reactions on carbonyl groups [17-19]. The dynamic nature of the reaction of imine formation can be exploited to drive the equilibrium either forward or backwards. Since the reaction involves the loss of a molecule of water, adding or removing water from the reaction mixture proved an efficient way to shift the equilibrium in either direction. The responsive behavior of imines to external stimuli makes the reversible reaction of imine formation perfectly suited for DCC experiments [20], Thermodynamically controlled reactions based on imine chemistry include (1) imine condensation/hydrolysis, (2) transiminations, and (3) imine-metathesis reactions... 

It can be speculated that protonation of 50 will afford the carbinolamine 51 besides L-tryptophan. Carbinolamine 51 is a masked acetaldehyde, and it will transfer this moiety to the more basic amino group on L-tryptophan to afford the protonated Schiff base 52, already encountered as an intermediate in the Pictet-Spengler cyclization to TBCs (Fig. 4). Spiroannelation of 52 will ultimately lead to TBCs 21a and 21b which both were found to be present in the products obtained in the acid hydrolysis of 50 (127). It is questionable whether TBCs 21a and/or 21b could account for the eosinophilia syndrome, since both compounds prepared by total synthesis were well tolerated in mice at doses up to 100 mg/kg (23). 

Studies using isotopic labeling as well as mechanism based on inactivation such as 4-alkyldihydropyridines and cycloalkylamines have supported the view that the first step involves an electron-transfer process (path a. Scheme 23) [18, 184-186, 211]. Deprotonation of the resultant aminium radical would yield the a-aminoalkyl radical. The formation of the dealkylated amine and carbonyl derivative has been proposed to occur via a second electron transfer to the enzyme and a nonenzymatic hydrolysis of the imine formed. In the P-450 catalyzed reaction, however this process is proposed to occur via a radical recombination process to yield a carbinolamine (99) which then decomposes to the dealkylated amine and the corresponding carbonyl derivative. Evidence for this was obtained by the incorporation of label from 02, into the carbonyl derivative [212-214]. 

The stereochemistry of Schiff base formation between fructose 1,6-bisphosphate and the aldolase from liver has also been addressed (777). Suggestive evidence for the intermediate formation of a (27 )-carbinolamine is based on the observation that BH4 reduction of substrate on the enzyme followed by acid hydrolysis of the protein gives exclusively glucitollysine and not mannitollysine. This indicates that the re face of the ketimine is exposed to solvent, and it implies that OH left from the same direction in other to form the ketimine. On this basis, the e-amino of the lysine must add to the si face of the substrate carbonyl lEq. (33)1 ... 

The mechanism of hydrolysis of enamines has been studied kinetically over a range of pH. In alkaline solution, rate-determining C-protonation is followed by attack of hydroxide ion on the resulting iminium ion. The carbinolamine intermediate then breaks down as in imine hydrolysis. In the neutral and weakly acidic pH range, water attack on the C-protonated enamine becomes rate limiting. As in imine hydrolysis, decomposition of the tetrahedral intermediate becomes rate limiting in strongly acidic solutions. ... 

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