Reductive animation amine synthesis

Reductive Animation for Synthesis of PAL-Resin-Bound Amines (59) (Fig. 10)15. To a suspension of 4-formyl-3,5-dimethoxyphennoxymethyl functionalized polystyrene resin (PAL)25 (10.0 g, 11.3 mmol) in DMF (350 ml) a primary amine (56.5 mmol) is added followed by addition of sodium triacetoxyborohydride (7.18 g, 33.9 mmol) and acetic acid (6.52 ml, 113 mmol). The suspension is shaken gently at RT overnight. Resin 59 is washed with methanol (4 x 300 ml) and CH2C12 (4 x 300 ml) and dried under vacuum. Subsequent derivatization products can be cleaved from the resin by a 2 h treatment with CH2Cl2/TFA/Me2S/H20 45 45 5 5. 

We did not explore the first of these two approaches too deeply. The synthesis of the epoxide 76, an ideal partner for the alkylation of any trisaccharide amine, was daunting and seemingly difficult but there was available in the literature an excellent route to the enone 77 from tetra-O-benzyl-D-gluconolactone 38 [53]. However, earlier work by Kuzuhara suggested that any reductive animation of the enone 77 would probably proceed in low yield and certainly give a mixture of diastereoisomeric amines [54], We did prepare the amine 78, via the azide 79, but the amine 78 would not condense with the enone 77 to give the... 

The 20 amino acids listed in Table 27.1 are biosynthesized by a number of different pathways, and we will touch on only a few of them in an introductory way. We will examine the biosynthesis of glutamic acid first because it illustrates a biochemical process analogous to a reaction we discussed earlier in the context of amine synthesis, reductive animation (Section 22.10). 

Massing described a synthesis of systematically modified cationic lipids by solid-phase chemistry starting with the immobihsation of (/f)-2,3-epoxy-1 -propanol on 4-methoxytrityl chloride resin [157], Reaction of the epoxide with distinct long-chained amines was followed by reductive animation and tertiary amine quatemisation (see Fig. lib). This interesting method allowed the solid-phase coupling of three different lipophUic moieties on an amino group and the synthesis... 

The norbelladine derivative 408, which served as the starting material for the synthesis of ( )-oxocrinine (415) (Scheme 35), may be readily prepared from the reductive animation of piperonal with tyramine followed by acylation with trifluoroacetic anhydride (191,192). When the N-acylated monophenol 408 was treated with excess thallium tris(trifluoroacetate) in methylene chloride, the di-enone 412 was obtained in 19% yield (191), whereas use of the oxidant vanadium oxyfluoride in trifluoroacetic acid/trifluoroacetic anhydride afforded 412 in 88% yield (192). Base-induced N-deacylation of 412 was accompanied by spontaneous cyclization to furnish racemic oxocrinine (415). Attempts to oxidize the free amine derived from 408 led to the formation of a number of products, some of which resulted from oxidation at nitrogen. 

One published synthesis of this amine 17 is by reductive animation.2 Note that it is not necessary, nor usually desirable, to isolate the rather unstable imine as reduction with NaB(CN)H3 or NaB(OAc)3H occurs under the conditions of imine formation.3 Since the imine is in equilibrium with the starting materials, slightly acidic conditions must be used so that the protonated imine is reduced more rapidly than the aldehyde or ketone. These two reducing agents are stable down to about pH 5. 

Graebin CS, Eifler-Lima VL, da Rosa RG (2008) One-pot synthesis of secondary and tertiary amines from R(+)-limonene by tandem hydroformylation/reductive animation (hydroamino-methylation). Catal Commun 9 1066—1070. doi 10.1016/j.catcom.2007.10.008... 

One problem with reductive amination. as a method of amine synthesis is that hy< pToduvta are sometimes obtained, for example, reductive animation of ben alde-hyde with methvlamine leads to n mixture of iV-methylbcnrylamine and N-mcthyldibenzylamine. How do you aiippone the tertiary amitie by-product is formed Propose a mechanism. 

Separation of the syn and anti diastereoisomers by crystallisation of the HC1 salt revealed that it was the syn diastereoisomer that was active and the reductive animation of 44 could be controlled to give 70%. vvn-45. The diastereoisomers of 45 were separated before the resolution. There is no point in resolving any earlier compound in the synthesis as even more material would be wasted in the reductive amination step. Natural ()-(/ )-mandelic acid 46 was a good resolving agent for 45 and 50% of the material derived from 44 could be isolated as the active (I )-vyn-(TS, 4S )-45. 

The conversion of prochiral centres in cyclic intermediates into fully blown chiral centres is a profitable way to transmit stereochemical information. The ant trail pheromone monomorine 42 when re-drawn so that we can see all three hydrogen atoms on the same surface of the molecule 42a, is an ideal candidate for synthesis by reductive animation. One of the three centres must be made asymetrically and then the other two set up by reduction of imines formed from that amine and two ketones as in 43. 

Aqueous organometallic catalysis allows the use of NH3-solutions in water for the direct synthesis of amines from olefins in a combined hydroformylation/reductive animation procedure (Scheme 4.19). The hydroformylation step was catalyzed by the proven Rh/TPPTS or Rh/BINAS (44) catalysts, while the iridium complexes formed from the same phosphine ligands and [ IrCl(COD) 2] were found suitable for the hydrogenation of the intermediate imines. With sufficiently high NHs/olefin ratios (8/1) high selectivity towards the formation of primary amines (up to 90 %) could be achieved, while in an excess of olefin the corresponding... 

Reductive animation of a-keto acid derivatives gives rise to optically active amino acids if chiral amines are used1 7. In the synthesis of natural (S)-alanine (R = CH3) an ee of 67 % is obtained by using (S)-a-methylbenzylamine as the chiral amine118-120. 

The Staudinger reduction has found its way into the synthesis of many biologically relevant molecules in both academia and industry. The following example, published in 2004 from scientists at Abbott Laboratories, comes from their work toward synthesizing new famesyltransferase inhibitors. Quinolone 62 is one example from this publication.29 In the synthesis of this particular inhibitor, bromide 59 was reacted with sodium azide to afford the corresponding azide in 70% yield. Addition of an excess of triphenylphosphine to compound 60 in refluxing THF/H2O delivered the desired amine 61 in 83% yield. Reductive animation then afforded the final target compound 62. 

Employing enolate chemistry. Ley et developed a solid-phase synthesis of bicyclo[2.2.2] octanes of type 316 based on a double Michael addition strategy. As depicted in Scheme 4.6.2, polymer-bound acrylate 313 was treated with cyclohexenone enolates derived from 314 to give 315. After reductive animation, resin-bound bicyclo[2.2.2]octanes 316 were cleaved under a set of different conditions. Aminolysis with different amines and acidolysis using TEA led to the formation of 317 and 318, whereas reduction with DIBAH gave alcohols of type 319. 

Answer Our product is a secondary amine, so we will explore if we can achieve this synthesis using a reductive animation. Let s work backwards. 

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