Amination reductive

An alternative synthetic approach to amine alkylation, reductive amination, has also been used in solution-phase combinatorial chemistry (Table 3.4). Parallel syntheses implying alkylation of amines via acylation and subsequent reduction with diborane has also been reported [29,86]. 

Carbonyl component Amino component Presence of other functional groups Reference 

We saw the importance of imines in The Chemistry of. . . Pyridoxal Phosphate (vitamin Bj) in WileyPLUS for Chapter 16 (Section 16.8). 

When ammonia or a primary amine is used, there are two possible pathways to the product via an amino alcohol that is similar to a hemiacetal and is called a hemiaminal or via an imine (Section 16.8A). When secondary amines are used, an imine cannot form, and, therefore, the pathway is through the hemiaminal or through an iminium ion  

The reducing agents employed include hydrogen and a catalyst (such as nickel) or NaBHsCN or LiBHsCN (sodium or lithium cyanoborohydride). The latter two reducing agents are similar to NaBH4 and are especially effective in reductive aminations. Three specific examples of reductive amination follow  

Outlined below is a synthesis of the stimulant amphetamine. Provide the intermediates A and B. 

Show how you might prepare each of the following amines through reductive amination NHg (c) 

Because amides are so easy to prepare, this is a versatile method for the preparation of amines. 

The preparation of amines by the methods described in this section involves the prior synthesis and isolation of some reducible material that has a carbon-nitrogen bond an azide, a nitrile, a nitro-substituted arene, or an amide. The following section describes a method that combines the two steps of carbon-nitrogen bond formation and reduction into a single operation. Like the reduction of amides, it offers the possibility of preparing primary, secondary, or tertiary amines by proper choice of starting materials. 

A class of nitrogen-containing compounds that was omitted from the section just discussed includes imines and their derivatives. Imines are formed by the reaction of aldehydes and ketones with ammonia (Section 17.10). Imines can be reduced to primary amines by catalytic hydrogenation. 

When primary amines are desired, the reaction is carried out as just described  

Secondary amines are prepared by hydrogenation of a carbonyl compound in the presence of a primary amine. An A-substituted imine, or Schijfs base, is an intermediate  

Aldehyde Ammonia or ketone Imine Primary amine 

Reductive amination has been successfully applied to the preparation of tertiary amines from carbonyl compounds and secondary amines even though a neutral imine is not possible in this case. 

Imines can be saturated in preference to the hydrogenation of aldehydes, ketones or nitriles and the hydrogenolysis of benzyl ethers and amines. Alkenes, alkynes and nitro groups are, however, usually hydrogenated in preference to an imine. 

Reductive alkylation of amines proceeds by the hydrogenation of the imine or enamine formed, in situ, by the condensation of the amine with a carbonyl compound. This reaction can give a mixture of products if the amine produced initially competes with the reactant amine in the carbonyl condensation step. The proper selection of reagent concentrations avoids this difficulty and leads to the formation of good yields of the desired product. 50 jhe use of a large excess of ammonia gives the primary amine as the predominant product (Eqn. 19.50). 51 An excess of a primary amine as the reactant leads to the preferential formation of the secondary amine product. An excess of the carbonyl compound gives the symmetrical secondary or tertiary amines (Eqn. 19.51). 50 

The extent to which secondary and tertiary amines are formed by reductive alkylation is controlled to some degree by the steric bulk of the amine and the carbonyl compound. The more hindered the system, the higher the temperature and hydrogen pressure needed to affect the reaction. While the reductive alkylation of secondary aliphatic amines with formaldehyde takes place under mild conditions (Eqn.l9.52X N,N-dimethylaniline was prepared by reductive alkylation over palladium at 120°C and 15 atmospheres pressure (Eqn. 19.53). 153 54 Reductive alkylation of aniline with acetone over palladium gave a 67% yield of the monoalkylaniline at 100°C and 40 atmospheres pressure but secondary amine formation using the more sterically accessible ketones, 2-tetralone or 2-indanone, took place at room temperature and 4 atmospheres pressure (Eqn. 19.54). 55 Palladium was the preferred catalyst in these reactions since with platinum or rhodium ring hydrogenation was also observed. 54,155 

Reductive alkylations with phenylglyoxal (57) took place exclusively on the aldehyde carbonyl group when the reaction was run over either palladium 5 or Raney nickel 59 at room temperature and atmospheric pressure (Eqn. 19.56). 

It is not essential for the reaction that the amine be present, as such, before hydrogenation. Any functional group that gives an amine on hydrogenation can be used (Eqn. 19.57). Interestingly, the reductive alkylation of acid hydrazides took place in preference to the hydrogenolysis of the N-N bond when the reaction was run over either platinum or palladium at 75°-100°C and 40 atmospheres pressure (Eqn. 19.58).  

Freifelder, Practical Catalytic Hydrogenation, Wiley Interscience, New York (1971), Chpt 16 M. Freifelder, Catalytic Hydrogenation in Organic Synthesis Procedures and Commentary, J. 

Wiley Sons, New York (1978), Chpt 10 Russ Chem Rev 49 14 (1980) 

Houben-Weyl, Methods of Organic Chemistry, 4th ed, Vol E21d, G. Thieme, Stuttgart-New York (1995), p 4199 (enantioselective) 

chiral Cp2Ti(BINAP)-n-BuLi-PhSiH3 H2, cat Ir-chiral bisphosphine (enantioselective) H2, cat [Ir(diphosphine)HI2]2 (enantioselective) H2, Raney nickel 

BH3Me2NH BH3 Me2NH, HOAc BH3 f-BuNH2 BH3 f-BuNH2, HOAc 

A process using a fixed-bed nickel catalyst for the preparation of 1-amino- 

1-deoxy-D-glucitol (glucitylamine) from o-glucose has recently been developed 

A/-methylglucamine is the most important reductive amination product of carbohydrates. It is further reacted with a fatty aeid to provide A/-methylglucamide, a new elass of biodegradable surfactant produced by Hoechst and used by Procter and Gamble as surfactants in detergent fonnulations. Annual production of A/-alkylglucamides is 5000 t. 

Hydrogenation of aldose oximes (aldoses D-arabinose, D-mannose and D-galactose) at 50 °C over 5 % Pt/C catalyst, under 100 bar hydrogen, resulted in quantitative conversion of the oximes to a mixture of mono- and dialditylamines from which the latter were isolated in fairly good yield (26-80%) [44]. 

The preparation of A -(4,5-dimethyl-2-nitrophenyl)-D-ribosylamine followed by hydrogenation to yield l-(2-amino-4,5-dimethylanilino)-l-deoxy-D-ribitol was also achieved. This compound is condensed with alloxan to form vitamin B2 (lactoflavin) [45] (Fig. 1). 

The reaction of dicarbonyl compounds, such as glyoxal or phenylglyoxal, with a guanidinyl group, such as that of an arginine residue, proceeds to yield a more stable linkage due to the formation of a cyclic derivative (Reaction 40). 

HS-Groups or sulphydryl groups are biologically important. The amino acid cysteine bears an HS-group and it is in this form that HS-groups are incorporated into proteins, including enzyme proteins. HS-Groups can be functionally important for enzymes and one then speaks of HS-enzymes, of which the fatty acid synthetase is an example. 

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Anyway, with catalyst in hand it is time to proceed with the reductive amination [56]. As far as Strike can see, this method will not work well in making MDA. It will not use ammonium acetate in the same way as NaBHaCN. So one is stuck with making MDMA or meth using this method. And without further ado, here s your recipe ... 

Method I. This procedure is used for most ketone reactions. A representative example is the reductive amination of cyclopenta-none [P2P] with hexamethyleneimine [MeNHa] Hexamethyl-eneamine (I.Og, lOmmol) and cylclopentanone (0.84g, lOmmol) were mixed in 1,2-dichloroethane (35mL) and then treated with... 

A variation of the classical reductive amination procedure uses sodium cyanoboro hydride (NaBH3CN) instead of hydrogen as the reducing agent and is better suited to amine syntheses m which only a few grams of material are needed All that is required IS to add sodium cyanoborohydride to an alcohol solution of the carbonyl compound and an amine... 

Methamphetannne is a notorious street drug One synthesis involves reductive amination of benzyl methyl ketone with methylamine What is the structure of methamphetamine ... 

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). 

The zwitterion (6) can react with protic solvents to produce a variety of products. Reaction with water yields a transient hydroperoxy alcohol (10) that can dehydrate to a carboxyUc acid or spHt out H2O2 to form a carbonyl compound (aldehyde or ketone, R2CO). In alcohoHc media, the product is an isolable hydroperoxy ether (11) that can be hydrolyzed or reduced (with (CH O) or (CH2)2S) to a carbonyl compound. Reductive amination of (11) over Raney nickel produces amides and amines (64). Reaction of the zwitterion with a carboxyUc acid to form a hydroperoxy ester (12) is commercially important because it can be oxidized to other acids, RCOOH and R COOH. Reaction of zwitterion with HCN produces a-hydroxy nitriles that can be hydrolyzed to a-hydroxy carboxyUc acids. Carboxylates are obtained with H2O2/OH (65). The zwitterion can be reduced during the course of the reaction by tetracyanoethylene to produce its epoxide (66). 

Cycloahphatic amine synthesis routes may be described as distinct synthetic methods, though practice often combines, or hybridi2es, the steps that occur amination of cycloalkanols, reductive amination of cycHc ketones, ring reduction of cycloalkenylarnines, nitrile addition to ahcycHc carbocations, reduction of cyanocycloalkanes to aminomethylcycloalkanes, and reduction of nitrocycloalkanes or cycHc ketoximes. 

Reductive amination of cyclohexanone using primary and secondary aHphatic amines provides A/-alkylated cyclohexylamines. Dehydration to imine for the primary amines, to endocycHc enamine for the secondary amines is usually performed in situ prior to hydrogenation in batch processing. Alternatively, reduction of the /V-a1ky1ani1ines may be performed, as for /V,/V-dimethy1 cyclohexyl amine from /V, /V- di m e th y1 a n i1 i n e [121 -69-7] (12,13). One-step routes from phenol and the alkylamine (14) have also been practiced. 

DCHA is normally obtained in low yields as a coproduct of aniline hydrogenation. The proposed mechanism of secondary amine formation in either reductive amination of cyclohexanone or arene hydrogenation iHurninates specific steps (Fig. 1) on which catalyst, solvents, and additives moderating catalyst supports all have effects. 

Amin omethyl-3,5,5-trimethyl cyclohexyl amine (21), commonly called isophoronediamine (IPD) (51), is made by hydrocyanation of (17) (52), (53) followed by transformation of the ketone (19) to an imine (20) by dehydrative condensation of ammonia (54), then concomitant hydrogenation of the imine and nitrile functions at 15—16 MPa (- 2200 psi) system pressure and 120 °C using methanol diluent in addition to YL NH. Integrated imine formation and nitrile reduction by reductive amination of the ketone leads to alcohol by-product. There are two geometric isomers of IPD the major product is ds-(22) [71954-30-5] and the minor, tram-(25) [71954-29-5] (55). 

Morpholiaoglucopyranosides have beea syathesized from sucrose by selective lead tetraacetate oxidatioa of the fmctofuranosyl ring to a dialdehyde (6). This product was subjected to reductive amination with sodium borohydride and a primary amine such as benzylamine to produce the /V-henzy1morpho1ino derivative (7) (99). 

Aliphatic Alcohols and Alkylene Glycols. Simple aliphatic alcohols, such as methanol [67-56-1], can be used to alkylate alkyleneamines. For example, piperazine reacts with methanol over a reductive amination catalyst to yield a mixture of 1-methyl- [109-01 -3J and 1,4-dimethylpiperazine [106-58-1] (12). 

Diaminopropane Processes. 1,2-Propylenediamine can be produced by the reductive amination of propylene oxide (142), 1,2-propylene glycol [57-55-6] (143), or monoisopropanolamine [78-96-6] (144). 1,3-Propanediol [504-63-2] can be used to make 1,3-diaminopropane (143). Various propaneamines are produced by reducing the appropriate acrylonitrile—amine adducts (145—147). Polypropaneamines can be obtained by the oligomerization of 1,3-diaminopropane (148,149). 

Ethylamines. Mono-, di-, and triethylamines, produced by catalytic reaction of ethanol with ammonia (330), are a significant outlet for ethanol. The vapor-phase continuous process takes place at 1.38 MPa (13.6 atm) and 150—220°C over a nickel catalyst supported on alumina, siUca, or sihca—alumina. In this reductive amination under a hydrogen atmosphere, the ratio of the mono-, di-, and triethylamine product can be controlled by recycling the unwanted products. Other catalysts used include phosphoric acid and derivatives, copper and iron chlorides, sulfates, and oxides in the presence of acids or alkaline salts (331). Piperidine can be ethylated with ethanol in the presence of Raney nickel catalyst at 200°C and 10.3 MPa (102 atm), to give W-ethylpiperidine [766-09-6] (332). 

These reductions are not important for preparative purposes. The same can be said for reductions with LiAlH4, and with hydrogen over a catalyst, converting diaziridines to a mixture of amines including products of reductive amination of the former carbon atom of the diaziridine ring. 

Reductive amination ol aldehydes or ketones by cyanoborohydride (or tnacetoxyborohydride) anion Selective reduction of carbonyls to alcohol, oximes to N alkylhydroxylarmnes, enamines to amines... 

LEUCKART - WALLACH ReductiveAmination Reductive amination of cartx)nyi groups with amines arxl formic add or Hj-NI (Miquonac) or NaBH4 (see Botch). 

Reductive amination (Section 22.10) Reaction of ammonia or an amine with an aldehyde or a ketone in the presence of a reducing agent is an effective method for the preparation of primary, secondary, or tertiary amines. The reducing agent may be either hydrogen in the presence of a metal catalyst or sodium cyanoborohy-dride. R, R, and R" may be either alkyl or aryl. 

The 20 fflnino 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 amination (Section 22.10). 

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