Carbinol amines

Primary amines undergo nucleo philic addition to the carbonyl group of aldehydes and ketones to form carbinol amines These carbinolamines dehydrate under the conditions of their formation to give N substituted imines Secondary amines yield enamines... 

In Robinson s now well-known suggestions, regarding the processes by which alkaloids may be produced in plants, two main reactions are used j the aldol condensation and the similar condensation of carbinol-amines, resulting from the combination of an aldehyde or ketone with ammonia or an amine, and containing the group. C(OH). N., with substances in which the group, CH. CO. is present. By these reactions it is possible to form the alkaloid skeleton, and the further necessary changes postulated include oxidations or reductions and elimination of water for the formation of an aromatic nucleus or of an ethylene derivative. 

The polarity of the C—-OH bond, i.e., the basicity of the carbinol-amine, depends on its structure, particularly on the stability of the ring system (degree of aromatic character), and the electron affinity of the substituents on nitrogen and carbon. Of course, external factors also play an important role in the equilibrium temperature, polarity of the solvent, and presence or absence of catalysts (the solvent can also act as a catalyst). 

Scheme 3 Cyclized Carbinol Amine Form of Z-Arg(N02)-Hlnl NH O...

Peptide aldehydes are fairly reactive and usually exist in solution partially as hydrates Xaa[CH(OH)2] (e.g., 3), which are identified using 13C NMR spectroscopy. 3 3" With amino acids containing nucleophilic side chains, cyclized forms predominate (Scheme 2). Argininal analogues such as Z-Leu-Phe-Arg-H have been shown to exist primarily as the carbinol amine 4 with no spectroscopic evidence for an iminium structure. Lysinal derivatives such as Z-Leu-Phe-Lys-H exist both as a cyclic carbinol amine 5 and as an iminium ion 6 as shown by 3H and 13C NMR spectra. The C-terminal ornithinal analogue Z-Leu-Phe-Orn-H exists primarily as the carbinol amine form 7 and the cyclic iminium form 8 as characterized by the 13C NMR spectra. 3,21 In general, the existence of carbinol and iminium cyclized forms does not preclude the existence of the free or hydrated aldehydes under aqueous conditions. 

The extent of racemization of peptide aldehydes exposed to silica gel has been determined as a function of time (Table 3).b0 The amount of racemization increases in the order Z-Cys(Bzl)-H > Z-Phe-H > Z-Leu-H > Z-Arg(N02)-HJ5 The unusually small amount of racemization observed with Z-Arg(N02)-H is probably due to its cyclic carbinol amine structure, which prevents racemization through a keto-enol mechanism. More racemization is seen in aldehydes possessing side chains such as Z-Cys(Bzl)-H that favor enolsJ15 ... 

In the approach of Snieckus [51] (Scheme 32), 201 was obtained in one step by palladium(0) promoted coupling of the known boronic acid 208 and 7-iodoindoline 209. The latter was prepared from N-acetylindoline via iodination of its 7-thallo derivative followed by hydrolysis of the resulting iodoamide. The initial product of coupling, the carbinol amine 210 readily suffered aerial oxidation to 201, which on dehydrogenation yielded 202. 

Oxidative Deamination. Oxidative deamination of amphetamine occurs in the rabbit liver but not to any extent in the liver of either the dog or the rat, which tend to hydroxylate the aromatic ring. A close examination of the reaction indicates that it is probably not an attack on the nitrogen but rather on the adjacent carbon atom, giving rise to a carbinol amine, which eliminates ammonia, producing a ketone ... 

A significant step in studying the chemistry of cyclopropanones has resulted from the discovery that many labile carbonyl derivatives such as hemiacetals and carbinol amines are useful precursors of the parent ketone. 4-6> Such derivatives may be isolated, purified and used as cyclopropanone substitutes or, alternatively, may be generated in solution and used as in situ precursors. As a result of these advances, exploration of cyclopropanone chemistry has recently been accelerated. The aim of this article is to review some of this chemistry, noting areas where there may be potential applications in synthesis. 

Cyclopropanones react with ammonia and aliphatic amines to form carbinol amines which usually undergo further amine substitution. For example, attempts to prepare the carbinol amines f> from dimethylamine and cyclopropanone resulted only in the isolation of the 1,1-diamino derivative 94. 86> When methyl amine is added to cyclopropanone, the... 

On the other hand, some carbinol amines are sufficiently stable to permit spectroscopic characterization, e.g., 1-cyclohexylamino- and... 

There is much evidence to suggest that a cyclopropanimine intermediate, e.g., 99, is involved in the transformation of the carbinol amines to diamines ... 

In some cases, 1,1-diaminocyclopropanes may be converted to the corresponding carbinol amines. Thus, as illustrated in Scheme 17, the 7-hydroxy 7-pyrrolidinobicycloheptane 56 52b> is obtained from the diamino compound 54 in aqueous acid, and reacts with methanol or ethanol affording the corresponding amino ethers 102a,b. 89> In the presence of methyl iodide, deamination occurs and the methylhemiketal 103 is obtained (95%). 

N-Methylaniline adds to cyclopropanone to give the expected carbinol amine in quantitative yield. 5-90> On the other hand, a mixture of addition products may be isolated from the reaction of cyclopropanone 5>90> or cyclopropanone ethyl hemiketal4) with aniline (Scheme 18). At — 78°C, the carbinol amine 104 (66%) and the dimeric species 105 (33%) were obtained when the reactants were present in stoichiometric amounts. With excess aniline, 104 was produced almost quantitatively. However, at 25 °C, both 104 and the dianilino product 106 were obtained. These products could be interconverted by the addition of aniline or cyclopropanone, respectively. At 125 °C, o-propionylaminopropiophenone (107) was formed, possibly by further reaction of the carbinol amine with cyclopropanone as shown. 4>... 

Other alkylation reactions are observed in the condensation of cyclo-propanium ions (generated in situ) with ketones 89.92)> enamines6, nitroalkanes 93>, dimethylmalonate 92>, and phenol. 92> Thus, 7-hydroxy-7-pyrrolidinobicyclo[4.1.0]heptane (56) as well as the 7,7-dipyrrolidino derivative (54) react with acetone to give the amino ketone 113. 89> This reaction may be pictured as an addition of the enol form of the ketone to the reactive iminium salt formed from the carbinol amine. In like manner, phenol undergoes ortho substitution with the carbinol amine 114 formed from cyclopropanone and dimethyl amine. 

An extension of this reaction leading to a general synthesis of N-substituted (3-lactams involves the addition of a primary amine to a freshly prepared solution of cyclopropanone, conversion of the resulting carbinol amine to the N-chloro derivative, and then decomposition of this intermediate with silver ion in acetonitrile. 87a> The method permits one to prepare N-substituted (3-lactams of great variety (Table 14), including those constructed from amino acid esters. 87b The use of valine ethyl ester (123) as a nitrogen source leading to 124 is illustrated. 

The presence of a tertiary methyl group and an exocyclic double bond in spiradine G was demonstrated by H-NMR analysis. Mild reduction of spiradine G with sodium borohydride afforded the triol 173, which indicated that the remaining two oxygen atoms exist as a part of two carbinol-amine ether (N—C—O—C) linkages in spiradine G. The presence of an exocyclic double bond in the six-membered ring was confirmed by catalytic hydrogenation of spiradine G to compound 174 and oxidation of 172 with potassium permanganate to compound 175. 

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. 

The intermediate is called a carbinol-amine. (Most of the other addition reactions presented so far stop at this stage where the nucleophile has added to the carbonyl carbon and a proton has added to the oxygen.)... 

New 7-substituted biopterin (L-primapterin) (361) and neopterin (anapterin) (360) analogues were discovered in 1988 as excretion products in the urine of patients suffering from a new form of atypical phenylketonuria <88BBR(153)715,88MI 718-03). This interconversion proceeds most probably on the quinonoid dihydrohydropterin level and is due to a 4a-carbinol-amine dehydratase defect allowing isomerization via an intermediary spiro-compound <90BBR(172)1060>. 

This and other evidence (16) indicated that eseretholemethine (VI R = C2H5) was a pseudo base or carbinol amine. Thus, on oxidation with silver nitrate an oxindole was obtained (dehydroeseretholemethine, VII R = C2H5), which on subsequent Hofmann degradation and reduction of the Hofmann elimination product gave 5-ethoxy-l,3-dimethyl-3-ethyloxindole (13). The methyl homolog (VII R = CHa),... 

The presence of the /3-hydroxypropionic ester unit in deacetylpicraline is established by oxidation with chromic acid in acetone, which yields an aldehyde base, picralinal, C21H22N2O4 the latter is readily deform yla ted by short treatment with methanolic potassium hydroxide, which affords picrinine in quantitative yield. Reduction of picralinal with sodium borohydride regenerates deacetylpicraline. Vigorous treatment of deacetylpicraline with sodium borohydride gives a noncrystalline indoline base, which exhibits the UV-absorption of an anilinium ion in concentrated perchloric acid hence, the Na-carbinol-amine ether function must have suffered reduction. Since acetylation of the noncrystalline base gives a product which exhibits acylaniline UV-absorption, picraline and its derivatives must contain an NaH group (53, 54). 

That the third oxygen atom of haplocine was present in a carbinol-amine ether ring was shown by methylation to O-methylhaplocine (CCI-G), followed by catalytic reduction which opened this ring stereo-specifically to give a single product, CCI-H, which contained a new... 

C-Calebassine contains two hydroxyl groups (123) present as carbinol-amine residues... 

It was from the study of the environment of the second nitrogen of aj maline that its unusual nature first became apparent. It was a carbinol-amine which had the nitrogen at a bridgehead hence it could not be converted into an iminium cation so that it showed many of the normal reactions of a tertiary amine and an unhindered alcoholic group. Other reactions were better interpreted as taking place via the ring-opened tautomeric amino aldehyde which we shall call cfomoajmaline. It should be mentioned here that ajmaline methiodide exists in the closed form at least in the solid state, since its Ilt-spectrum in a nujol dispersion con-... 

Reference spectra for these compounds involving anilines show differences between aniline anils and iV-vinyl anilines that are characterized by the difference in the spectra of 2,3,3-trimethylindolenine and l,3,3-trimethyl-2-methyleneindoline. No suitable carbinol-amine spectrum could be found, and the values given for this... 

Simple alicyclic enamines are readily hydrolysed by basic or weakly, acidic media, although strong acids merely protonate the nitrogen atom, leading to a stable ammonium ion (6a). Recent studies [222] on enamine hydrolysis show it to be a general-acid-catalysed process involving the unprotonated form (6). This can accept a proton from an acidic species HA at the a -carbon atom to give the iminium ion (7). Nucleophilic attack by solvent or a base then affords the carbinol-amine (8) which breaks down into ketone and amine. 

---