Acetophenone reductive amination

An efficient method has been reported478,479 for the asymmetric synthesis of chiral 1-arylethylamines. The method is the reductive amination with optically active 1-phenylethylamine of substituted acetophenones via the corresponding imines (equation 52). 

Even if the imine may not be isolated, the transient species may sometimes be trapped by reaction with a suitable nucleophile. This is the basis of the reductive amination reaction in which an amine is formed from the reaction of ammonia with a carbonyl compound in the presence of a reducing agent such as sodium borohydride or formate. Use of a primary or secondary amine results in the specific formation of secondary or tertiary amines respectively (Fig. 5-45). This synthetic method allows the preparation of high yields of amines, in contrast to the unselective and uncontrollable reaction of alkylating agents with amines. A specific example involving the preparation of a-phenylethylamine from acetophenone is presented in Fig. 5-46. 

The yields of primary amines over platinum oxide were improved in the presence of an excess molar equivalent of ammonium chloride in low pressure reductive alkylation of ammonia with ketones in methanol saturated with ammonia.10 With acetophenone and 4-methyl-2-pentanone, the yields of primary amine increased from 37 and 49% in the absence of ammonium chloride to 69 and 57-65%, respectively, in the presence of ammonium chloride. Moller obtained a much higher yield (>90%) of 1-phenethylamine from acetophenone by adding a small amount of acetic acid to methanol-ammonia with Raney Ni (eq. 6.6).15 The reductive amination of benzophenone in the presence of Raney Co and some ammonium acetate gave 70% yield ofbenzohy-drylamine, compared to only 19% under usual conditions with Raney Ni.3... 

The procedure has been shown applicable to the reductive amination of cyclohepta-none, cyclooctanone, acetophenone, norhomanonc, and benzaldehyde. Amines used include ammonia, methylamine, dimethylamine, morpholine, aniline, and hydroxyl-... 

In 2009, Xiao employed a half sandwich Cp lr(l 11) complex with different chiral monosulfonated OPEN ligands (Figure 7.2), earlier developed for imine reduction by the same group, in combination with a BINOL based chiral phosphate counteranion (TRIP anion), to reductively aminate 24 acetophenone derivatives (1.2 equiv) with p anisidine (limiting reagent) under the conditions of 1.0 mol% of the indicated Ir catalyst (Table 7.1), 5 bar (73 psi) H2, toluene, 35 °C, and 15 24h [14]. 

Table 7.1 Ee values for Ir based reductive amination of acetophenone derivatives with p anisidine.

The resulting achiral iminium cations, with chiral phosphate counteranion, were then enantioselectively reduced using an achiral Hantzsch ester (dihydropyridine) providing enantioenriched amines. During this imine reduction study, one example was shown in which acetophenone and p anisidine [16] were prestirred in the presence of toluene and 4 A molecular sieves [17] for 9h (imine formation), after which the temperature was raised to 35 °C, and the Hantzsch ester (1.4 equiv) and phosphoric acid (TRIP, 5 mol%) were added to give the amine product in 88% ee over an additional 45 h. This is an exciting observation and while not a reductive amination, it is an operational improvement over simple imine reduction which requires imine isolation. 

Once acetophenone has been obtained, it may be converted to the required product by reductive amination. 

The related ACTC 18 with a phosphinite unit yielded a product with only 18% ee in acetophenone reduction. This result was explained assuming unfavourable steric interactions which result in partly reversed coordination preferences. However, electronic reasons also have to be taken into account because an increase in electron density on the complexed arene ring will undoubtedly affect the electronic nature of the amine and thereby sHghtly decrease the Lewis acidity of the complex as a whole. 

For a preparation of alkaloids 35 configurated beyond all doubt, synthetic pathways from the ehiral pool were also elaborated (71). The C3N unit destined to represent the crucial chiral center at C-3 turned out to be the amino acid alanine, in its natural L-form 118, which should easily be incorporated into the isoquinoline framework by reductive amination with the acetophenone 119 and subsequent intramolecular acylation, as outlined in Scheme 29. The practical realization of such a non-biomimetic synthesis (see Scheme 30), however, differs from this very simple concept in three ways ... 

Aqueous ammonia was found to increase the yield of the alcohol but not of the amine in the highly enantioselective hydrogen-transfer reductive amination of acetophenone, as recently described by Kadyrov et al. [18]. AU these reactions were performed in methanol/NHj with [((Kj-tol-binapjRuClJ as catalyst with a best asymmetric induction of 98% ee. 

Soon afterward, MacMillan s group properly explored this organocatalytic reductive amination, observing that the ortho-triphenylsilyl phosphoric acid 17n in the presence of 5-A MS facilitates the desired coupling of acetophenone and 4-OMe-aniline in high conversion and with excellent levels of enantiocontrol at 40 C (87% yield, 94% ee) [55]. Authors report also the reduction of the pyruvic acid-derived cyclic imino ester with excellent enantioselectivity. However, implementation of the corresponding ethyl-substituted imine resulted in a dramatic decrease in... 

A carbene derived from triazole was used in IPA with K2CO3 as base, for direct reductive amination of aldehydes with primary amines to form secondary amine products [179]. Other recent examples include (1) a base-free catalyzed reduction of a series of C=0 bonds and of the C=N bond of benzylideneaniline (>99 % conversion was achieved in 48 h, with 0.1 mol% catalyst) [180] (2) heteroditopic dicarbene Rh(I) and Ir(I) complexes containing 1,2,3-triazolylidene-imidazolyli-dene ligands, mostly tested on acetophenone but with one imine example [181] (3) Ir complexes of A-benzyl-substituted A-heterocyclic carbenes where 0.5 mol% catalyst is used with 5 % KOH in IPA in reductions to give products in >99 %... 

Complex 54 displayed a high activity in the reduction of cyclohexanone with a TOF value of 6000 h (Figure 13.7)." Tetrahydropyridoimidazolin-2-yli-dene-containing 55 was also evaluated for TH of acetophenone and cyclohexanone in z-PrOH/KOH. ° Cationic triazol-5-ylidene complexes 56 were found highly active for the TH of C=0 and C=C functions as well as for reductive amination of aldehydes. 

As mentioned. List et al. used TRIP derivative 31 in combination with a Hantzsch ester to perform the first asymmetric, oiganocatalytic reductive amination. Acetophenone was stirred for 9 hours at room temperature with anisi-dine in the presence of 4 A molecular sieves to first form the imine. Subsequently, 5 mol% 31 and 1.4 equivalents... 

Aldehydes and ketones may be converted into the corresponding primary amines by reduction of their oximes or hydrazones (p. 93). A method of more limited application, known as the Leuckart Reaction, consists of heating the carbonyl compound with ammonium formate, whereby the formyLamino derivative is formed, and can be readily hydrolysed by acids to the amine. Thus acetophenone gives the i-phenylethylformamide, which without isolation can be hydrolysed to i-phenylethylamine. 

Acetophenone similarly gives an oxime, CHjCCgHjlCtNOH, of m.p. 59° owing to its lower m.p. and its greater solubility in most liquids, it is not as suitable as the phenylhydrazone for characterising the ketone. Its chief use is for the preparation of 1-phenyl-ethylamine, CHjCCgHslCHNHj, which can be readily obtained by the reduction of the oxime or by the Leuckart reaction (p. 223), and which can then be resolved by d-tartaric acid and /-malic acid into optically active forms. The optically active amine is frequently used in turn for the resolution of racemic acids. 

The present procedure was developed from those of Wallach and Freylon, based upon the general method discovered by Leuckart. a-Phenylethylamine also can be prepared satisfactorily by the reduction of acetophenone oxime with sodium and absolute alcohol or sodium amalgam, but the reagents are more expensive and the processes less convenient. The amine has been obtained by reducing acetophenone oxime electro-lytically, by reducing acetophenone phenylhydrazone with sodium amalgam and acetic acid, from a-phenylethyl bromide and hexamethylenetetramine, and by the action of methyl-magnesium iodide upon hydrobenzamide, as well as by other methods of no preparative value. 

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