Hydration enamines

When Dewar pyrimidinone 644 (R = /Bu) was left to stand in acetonitrile containing hydrogen sulfide at 0°C for 15-19 hours, hexahydro-4//-pyrido[2,l-fe][l,3]thiazin-4-one 223 and tetrahydro-4f/-pyrido[ 1,2-a] pyrimidin-4-one 643 (R = /Bu) were obtained in 52% and 32% yields, respectively [89JCS(P1)1231]. When pyrido[2,l-/ ][l,3]thiazine 223 was set aside for 64 hours at 35°C in CDC13, pyrido[ 1,2-a]pyrimidin-4-one 643 (R = /Bu) was obtained in 95% yield. The hydrated enamine 107 in methanol at 16-23°C reverted to the bicyclic pyrido[ 1,2-a]pyrimidin-4-one 643 (R = /Bu) after 2 days in almost quantitative yield [85JOC166, 85TL3247 89JCS(P1)1231]. 

This genera] scheme could be used to explain hydrogen exchange in the 5-position, providing a new alternative for the reaction (466). This leads us also to ask whether some reactions described as typically electrophilic cannot also be rationalized by a preliminary hydration of the C2=N bond. The nitration reaction of 2-dialkylaminothiazoles could occur, for example, on the enamine-like intermediate (229) (Scheme 141). This scheme would explain why alkyl groups on the exocyclic nitrogen may drastically change the reaction pathway (see Section rV.l.A). Kinetic studies and careful analysis of by-products would enable a check of this hypothesis. 

Another synthesis of Lyral (51) consists of the reaction of myrcene with acrolein to give the myrac aldehyde [37677-14-8] (52). The aldehyde group, which is sensitive to acid hydration conditions with strong acids, has to be protected by formation of the morpholine enamine. The enamine is then hydrolyzed on workup after the acid-catalyzed hydration to produce Lyral (93—95). 

The study of structure and reactivity of tertiary heterocyclic enamines is associated with the problem of equilibrium of the cyclic enamine form (70) and the tautomeric hydration products 173,174) quaternary hydroxide (71), pseudo base (so-called carbinolamine) (72) and an opened form of amino aldehyde or amino ketone (73). 

The salts of some enamines crystallize as hydrates. In such cases it is possible that they are derived from either the tautomeric carbinolamine or the amino ketone forms. Amino ketone salts (93) ( = 5, 11) can serve as examples. The proton resonance spectra of 93 show that these salts exist in the open-chain forms in trifluoroacetic acid solution, rather than in the ring-closed forms (94, n = 5, 11). The spectrum of the 6-methylamino-l-phenylhexanone cation shows a multiplet at about 2.15 ppm for phenyl, a triplet for the N-methyl centered at 7.0 ppm and overlapped by signals for the methylene protons at about 8.2 ppm. The spectrum of 93 ( = 11) was similar. These assignments were confirmed by determination of the spectrum in deuterium oxide. Here the N-methyl group of 93 showed a sharp singlet at about 7.4 ppm since the splitting in —NDjMe was much reduced from that of the undeuterated compound. 

While the usual eonsequence of hydration of enamines is eleavage to a secondary amine and an aldehyde or ketone, numerous cases of stable carbinolamines are known (102), particularly in examples derived from cyclic enamines. The selective terminal hydration (505) of a cross-conjugated dienamine-vinylogous amide is an interesting example which gives an indication of the increased stabilization of the vinylogous amide as compared to simple enamines, which is also seen in the decreased nucleophilicity of the conjugated amino olefin-carbonyl system. 

Extension of the hydration reaction to hydrogen peroxide has shown that stable peroxides are formed from enamines and the imonium salts derived from secondary amines and ketones (506,507). 

Different rate-determining steps are observed for the acid-catalyzed hydration of vinyl ethers (alkene protonation, ks kp) and hydration of enamines (addition of solvent to an iminium ion intermediate, ks increasing stabilization of a-CH substituted carbocations by 71-electron donation from an adjacent electronegative atom results in a larger decrease in ks for nucleophile addition of solvent than in kp for deprotonation of the carbocation by solvent. 

The detailed mechanism of inhibition of TEM-2 (class A) enzyme with clavulanate has been established (Scheme 1) [23,24], The inhibition is a consequence of the instability of the acyl enzyme formed between the /1-lactam of clavulanate and the active site Ser-70 of the enzyme. In competition with deacylation, the clavulanate acyl-enzyme complex A undergoes an intramolecular fragmentation. This fragmentation initially provides the new acyl enzyme species B, which is at once capable of further reaction, including tautomeriza-tion to an entity C that is much less chemically reactive to deacylation. This species C then undergoes decarboxylation to give another key intermediate enamine D, which is in equilibrium with imine E. The imine E either forms stable cross-linked vinyl ether F, by interacting with Ser-130 or is converted to the hydrated aldehyde G to complete the inactivation. 

Hong and co-workers have described a formal [3-t-3] cycloaddition of a,P-unsaturated aldehydes using L-proline as the catalyst (Scheme 72) [225], Although the precise mechanism of this reaction is unclear a plausible explanation involves both iminium ion and enamine activation of the substrates and was exploited in the asymmetric synthesis of (-)-isopulegol hydrate 180 and (-)-cubebaol 181. This strategy has also been extended to the trimerisation of acrolein in the synthesis of montiporyne F [226],... 

An interesting variation on the above theme for the biosynthesis of the pavines and isopavines has been proposed by Dyke (169). This proceeds via a quinone methine intermediate. The precursor, a l-benzyltetrahydroisoquinoline-3-car-boxylic acid 165 oxidizes to a quinone methide 166, which then decarboxylates to afford a reactive enamine 167. Cyclization then readily furnishes a pavine. Alternatively, hydration of the enamine 167 at C-4 would ultimately result in formation of an isopavine (Scheme 36). 

Aqueous acid has been utilized to cleave the enamine-like C—N bond of the 9-alkenylcarbazoles 94 and 95 ° and the products 82 of alkylation of the anions of 9-allyIcarbazoles hydrated ferric nitrate was used to remove the vinyl group from 3-halo-9-vinylcarbazoles, Strong base... 

Synthesis from Citronellal. One of the oldest routes to hydroxydihydrocitronellal is the hydration of the citronellal bisulfite adduct (obtained at low temperature) with sulfuric acid, followed by decomposition with sodium carbonate. A more recent development is hydration of citronellal enamines or imines, followed by hydrolysis [67]. 

Synthesisfrom 7-Hydroxygeranylj-neryl Dialkylamine. The starting material can be obtained by treatment of myreene with a dialkylamine in the presence of an alkali dialkylamide, followed by hydration with sulfuric acid. The 7-hydroxygeranyl/-neryl dialkylamine isomerizes to the corresponding 7-hydro-xyaldehyde enamine in the presence of a palladium(II) phosphine complex as catalyst. Hydrolysis of the enamine gives 7-hydroxydihydrocitronellal [70]. 

In fact the workers who wanted 7 for photochemical addition to alkenes (chapter 32) chose1 to use propargyl bromide 14 and an enamine 13 of the aldehyde 12. Mercury-catalysed hydration of 15 gave 8 which cyclised to 7 in base. 

Yet another method has been described (162) (Scheme 50) for the preparation of the tricyclic enamine (225). /V-Alkylation of ethyl pyrrole-2-carbox-ylate with 242 in the presence of sodium hydride gave, after hydrolysis, the amino acid (243). This was cyclized to 244, reduced to 238, then oxidized to 225. Alkylation of 225 with propargyl bromide, followed by hydration with a mercuric salt gave the ketone (227), but this could not be cyclized, thus confirming the observation made by Weinreb and Auerbach (156) but contrasting with the report of Dolby et al. (160). 

The salts of some enamines crystallize as hydrates. It is possible that these salts are actually derived from either the tautomeric carbinol-amine or the amino-ketone forms. Steric factors should again be decisive. The salts obtained by an intramolecular cyclization of a bicyclic amino-ketone (13)55 belong to the carbinolamine type their infrared spectra reveal the presence of a hydroxyl group. 

Fig. 9.27. Condensation of diamines with dicarbonyl compounds (and/or their hydrates) to give N heterocycles. Double imine formation yields quinoxalines (B), double enamine formation leads to dimethylpyrrole (D).

Iminium ions formed from an electrophile and an enamine are stable in the absence of a base. Upon aqueous workup they react via the unstable intermediate of an imine hydrate to furnish the corresponding a-functionalized aldehyde or ketone. Iminium ions formed in the presence of a base are deprotonated by this base to give an enamine. The latter is hardly ever isolated, but hydrolyzed upon a somewhat more aggressive workup with diluted... 

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