Amination of aldehydes

Amination-lactamization cascade for the preparation of valuable lactams, (a) 6-Methyl-piperidin-2-one, (b) 4-phenylpyr-rolidin-2-one, and (c) synthesis of niraparib precursor. 

Combining regio- and enantioselecbve amination of 1,5-diketones provided the shortest route to date for tiie preparation of 2,6-disubstituted piperidines, a group of bioactive molecules present in a vast number of natural products [74, 75], Most of the 00-TAs showed exquisite levels of regioselectivity as the amination occurred exclusively at the sterically less demanding ketone (oo-l), which spontaneously cyclized to the corresponding enantiopure cyclic imine denoted as ACpiperideine ( heme 2.12) [76]. 

A representative panel of diketones (50 mM) containing cyclic, aromatic, and aliphatic moieties was effectively converted with a perfect stereoselectivity and reactivity (Table 2.5). Simply by tiie choice of enantiocomplementary co-TAs, both (R)- and (S)-ACpiperideines were accessible in enantiopure form. 

TABLE 2.5 Regioselective Monoamination leading to Enantiomerically Pure A -Piperidines after Spontaneous Cyclization  

Chemoenzymatic route for the preparation of the natural alkaloids dihydropinidine (c/s) and ep/-dihydropinidine trans). 

---

Sodium cyanoborohydride is remarkably chemoselective. Reduction of aldehydes and ketones are, unlike those with NaBH pH-dependent, and practical reduction rates are achieved at pH 3 to 4. At pH 5—7, imines (>C=N—) are reduced more rapidly than carbonyls. This reactivity permits reductive amination of aldehydes and ketones under very mild conditions (42). 

Both von Hirsch 1U) and Weingarten and White 39) have reported the amination of aldehydes and ketones by tris(dimethylamino)arsine (142) to yield the corresponding gem diamine (143) or enamine (144). Von Hirsch s... 

Synthesis of heterocyclic amines by hydrogenative amination of aldehydes and ketones 99MI29. 

Besides direct reduction, a one-pot reductive amination of aldehydes and ketones with a-picoline-borane in methanol, in water, and in neat conditions gives the corresponding amine products (Scheme 8.2).40 The synthesis of primary amines can be performed via the reductive amination of the corresponding carbonyl compounds with aqueous ammonia with soluble Rh-catalyst (Eq. 8.17).41 Up to an 86% yield and a 97% selectivity for benzylamines were obtained for the reaction of various benzaldehydes. The use of a bimetallic catalyst based on Rh/Ir is preferable for aliphatic aldehydes. 

To investigate the feasibility of employing 3-oxidopyridinium betaines as stabilized 1,3-dipoles in an intramolecular dipolar cycloaddition to construct the hetisine alkaloid core (Scheme 1.8, 77 78), a series of model cycloaddition substrates were prepared. In the first (Scheme 1.9a), an ene-nitrile substrate (i.e., 83) was selected as an activated dipolarophile functionality. Nitrile 66 was subjected to reduction with DIBAL-H, affording aldehyde 79 in 79 % yield. This was followed by reductive amination of aldehyde x with furfurylamine (80) to afford the furan amine 81 in 80 % yield. The ene-nitrile was then readily accessed via palladium-catalyzed cyanation of the enol triflate with KCN, 18-crown-6, and Pd(PPh3)4 in refluxing benzene to provide ene-nitrile 82 in 75 % yield. Finally, bromine-mediated aza-Achmatowicz reaction [44] of 82 then delivered oxidopyridinium betaine 83 in 65 % yield. 

Table 14. organosilane reductive amination of aldehydes and ketones... 

Table 14. Organosilane Reductive amination of aldehydes and Ketones (Continued)...

Supplemental References for Table 14. Organosilane Reductive Amination of Aldehydes and Ketones... 

Although imine hydrogenation is discussed in greater detail in Chapter 34, it seems appropriate at this point to describe one-pot reductive amination of aldehydes and ketones. The reductive amination of aldehydes and ketones using so-... 

Given the previous discussion on reductive amination, it is surprising that the potentially more complicated domino hydroformylation-reductive amination reactions have been more thoroughly developed. The first example of hydroaminomethylation was reported as early as 1943 [83]. The most synthetically useful procedures utilize rhodium [84-87], ruthenium [88], or dual-metal (Rh/Ir) catalysts [87, 89, 90]. This area was reviewed extensively by one of the leading research groups in 1999 [91], and so is only briefly outlined here as the second step in the domino process is reductive amination of aldehydes. Eilbrachfs group have shown that linear selective hydroaminomethylation of 1,2-disubstituted alkenes... 

Quaternary ammonium cyanoborohydrides have been used for the reduction of iminium salts [14] and in the reductive amination of aldehydes and ketones [15]. 

Treatment of aldehydes or ketones with ammonia, primary or secondary amines in reducing media is called reductive alkylation (of ammonia or amines) or reductive amination (of aldehydes or ketones). Reducing agents are most frequently hydrogen in the presence of catalysts such as platinum, nickel or Raney nickel [955], complex borohydrides [705, 954, 955], formaldehyde or formic acid [522]. 

It is true that highly enantioselective reactions are possible with proline in the asymmetric a-amination of aldehydes by azodicarboxylates and in a-oxidation with nitrosobenzene. However, good rather than excellent yields and enantioselectivities are more common in intermolecular Michael and aldol reactions. Moreover, the high catalyst loadings required for proline-catalyzed aldol reactions (up to 30%), and low TOFs (from hours to days to achieve a good conversion, even at a high catalyst... 

Abdel-Magid, A. F. Carson, K. G. Harris, B. D. Maryanoff, C. A. Shah, R. D. Reductive Amination of Aldehydes and Ketones with Sodium Triace-toxyborohydride. Studies on Direct and Indirect Reductive Amination Procedures, J. Org. Chem. 1996, 67, 3849. 

The results described in the following, part of which have been presented as a preliminary communication, are collected in a full paper. A. Dondoni, S. Franco, F. Junquera, F. L. Merch n, P. Merino, T. Tejero, and V. Bertolasi, Stereoselective homologation-amination of aldehydes by addition of their nitrones to C-2 metalated thiazoles. A general entry to a-amino aldehydes and amino sugars, Chem. Eur. J. 1 505 (1995). 

Seductive animation. The limited solubility of NaBH3CN restricts its use to aprotic, ethereal solvents. Tetrabulylammonium cyanoborohydride or NaBHjCN in combination with Aliquat 336 can be used in most common organic solvents. Either reagent is useful for reductive amination of aldehydes or ketones. 

A dynamic kinetic resolution has been employed to achieve a catalytic asymmetric reductive amination of aldehydes.332 Reductive amination of ketones and aldehydes by sodium triacetoxyborohydride has been reviewed, highlighting its advantage over other reagents.333... 

A review describing the major advances in the field of asymmetric reduction of achiral ketones using borohydrides, exemplified by oxazaborolidines and /9-chlorodiisopino- camphenylborane, has appeared. Use of sodium borohydride in combination with chiral Lewis acids has been discussed.298 The usefulness of sodium triacetoxyboro-hydride in the reductive amination of aldehydes and ketones has been reviewed. The wide scope of the reagent, its diverse and numerous applications, and high tolerance for many functional groups have been discussed.299 The preparation, properties, and synthetic application of lithium aminoborohydrides (LABs) have been reviewed. 

The alkylation of ammonia, Gabriel synthesis, reduction of nitriles, reduction of amides, reduction of nitrocompounds, and reductive amination of aldehydes and ketones are methods commonly used for preparing amines. 

The proline-catalyzed direct asymmetric a-amination of aldehydes was reported in 2002 by both List [46] and j0rgensen [47]. As shown in Scheme 4.27 a variety of azodicarboxylates 58 can be added to aldehydes, affording the a-aminated products 59 in very good yields and with excellent ee. The experimental procedures are, furthermore, very convenient. The primary addition products 59 are configuration-ally unstable and are usually either reduced to the corresponding alcohols 60 (e.g. 

The List group synthesized a broad variety of N-protected amino alcohols 6 by proline-catalyzed a-amination of aldehydes (Scheme 7.5) [6], Under optimized conditions, the desired products of type 6 were obtained in high yields (93-99%) and with excellent enantioselectivity (up to >95% ee). Acetonitrile was found to be the preferred solvent and a catalytic amount (10 mol%) of proline was used. 

The a-amination of aldehydes and subsequent reduction to form oxazolidinones (Scheme 7.6) was developed by the Jorgensen group [7]. In the presence of 10 mol% L-proline as catalyst a variety of aldehydes reacted with azodicarboxylates, 3a and 3a, affording the oxazolidinones 7 after subsequent reduction with borohydride and cyclization. Selected examples of the synthesis of products 7, which were obtained in yields up to 92% and with enantioselectivity up to 95% ee, are shown in Scheme 7.6. 

In conclusion, the organocatalytic asymmetric a-amination of aldehydes and ketones using proline as catalyst is a new and attractive access to optically active N-protected a-amino aldehydes and ketones and related derivatives, e.g. a-amino acid esters. 

The reagent combination TiCl(0 Pr)3-NaBH(OAc)3 performs reductive amination of aldehydes by electron-deficient and heteroaromatic primary amines, to give secondary amine.317... 

The direct a-amination of aldehydes by azodicarboxylates as the electrophilic nitrogen source can be catalyzed by, for example i-proline 3a, to give the a-hydrazino aldehydes 4 having (R -configuration in moderate to good yields and with excellent enantioselectivities (89-97% ee) (Scheme 2.27) [4]. The optically active a-hydrazino aldehydes 4 are prone to racemization, and it was found beneficial to reduce them directly with NaBFU to stereochemical stable compounds which, by treatment with NaOH, can cyclize to form the N-amino oxazolidinones 5 in a one-pot process. The N-amino group in 5 could be cleaved with Zn/acetone to give the oxazolidinone 6 (Scheme 2.27). 

Scheme 2.27 Direct enantioselective a-amination of aldehydes catalyzed by L-proline, and further transformations to optically active oxazolidinones. (For experimental details see Chapter 14.8.1).

---