Secondary amines preparation

Di-n-propylamine can be produced in industrial scale by the alkylation of ammonia with n-propanol on Ba(OH)2 modified Ni/Al203 catalyst [2], by the reductive amination of propionaldehyde over a cobalt-containing catalyst [3] or by the hydrogenation acrylonitrile in n-exane on Ni/Al203 catalyst [4,5]. However, only scare data is available about the alkylation of ammonia or i-butylamine with i-butanol [6-10]. Di-i-butylamine was prepared from i-butanol over alumina at 370-380 C with 28 % yield [7]. 20 wt% Co - 5 wt% Ni catalyst supported on alumina was used to prepare di-i-butylamine fi"om i-butanol and i-butylamine at 200 °C with a yield of 60. 6 [10]. Aliphatic mixed secondary amines prepared from a pimary amine and an alcohol were usually obtained on copper-containing catalysts at 190-200 C with 30-50 % yields [11-13]. 

One interesting variation of this kind of linker is the formylindole linker of Estep (20) [61]. It is used in exactly the same manner as other formylalkoxybenzyl-type linkers and has properties similar to the BAL linker. The low steric hindrance of the indole group compared to the o-alkoxybenzyl moiety means acylation of secondary amines prepared on the former linker is easier. 

Research was carried out by our group on the use and regeneration of the Wang aldehyde scavenger 9 to eliminate excess primary amines in libraries of secondary amines prepared by reductive amination. The reaction in this process can be easily followed by gel-phase HR-MAS NMR. The signal of the aldehyde proton disappears at 9.8 ppm a new peak for the imine proton appears at 8.3 ppm in the spectrum as shown in Figure 4.4 and Scheme 4.4. 

In another vein, secondary amines prepared by the reductive amination of appropriate carbonyl compounds with methyl 12,14-dinitrodehydroabietate (Fig. 4.22) gave promising results when used as stabilizers against thermal, photochemical and oxidative degradation of low-density polyethylene and ethylene-propylene elastomers [114—116]. This active role is not surprising given the well-known fact that aromatic amines are excellent free radical traps. 

Heil997 Heinonen, P. and Lonnberg, H., A Novel Support for Derivatisation and Subsequent N-Alkylation of Secondary Amines Preparation of N-Alkylated 5- and 6-Alkoxy-l,2,3,4-tetrahydroisoquinolines via Mitsunobu Reaction, Tetrahedron Lett., 38 (1997) 8569-8572. 

Mono-substituted and unsymmetrical di-substituted ureas may be prepared by a modification of Wohler s urea synthesis, salts of primary or secondary amines being used instead of the ammonium salt for interaction with potassium cyanate. Thus when an aqueous solution containing both aniline hydrochloride and potassium cyanate is heated, aniline cyanate is first formed, and then C,HjNH,HCl -h KCNO = C,H6NHj,HCNO -h KCl C,HsNH HCNO = C.H NHCONH, by the usual molecular rearrangement is converted into monophenyburea. 

The preparation of pure primary amines by the interaction of alkyl halides and ammonia is very difficult, because the primary amine which is formed reacts with unchanged alkyl halide to give the secondary amine the latter... 

Note. Secondary amines, etc. in Class (ii) can be identified by their derivatives (C) and (D) above, and by their picrates when these can be readily isolated. The preparation of derivatives (D) requires the dry amine, whereas water does not aifect that of derivatives (C). 

The chloroplatinates prepared as above are sufficiently pure for direct analysis without recrystallisation. The chloroplatinates of the amines are usually freely soluble in hot water, but recrystallisation (when required) should not be attempted until the process has been found to be successful with a small test-portion of the chloroplatinate. The chloroplatinates of many primary and secondary amines decompose in hot water, the amine being oxidised, and the chloroplatinate reduced to the metal some amines furthermore co-ordinate readily with the metal when the chloroplatinate is boiled with water and a mixed product is obtained on cooling. 

By the hydrolysis of dialkyl cyanamides with dilute sulphuric acid this method gives pure secondary amines. The appropriate dialkyl cyanamide is prepared by treating sodium cyanamide (itself obtained in solution from... 

The experimental details describe the use of a free secondary amine for the preparation of a nitrosainine. Identical results are, of course, obtained by employing solid diethylamine hydrochloride. 

P-Phenylethylamine is conveniently prepared by the hydrogenation under pressure of benzyl cyanide with Raney nickel catalyst (see Section VI,5) in the presence of either a saturated solution of dry ammonia in anhydrous methyl alcohol or of liquid ammonia the latter are added to suppress the formation of the secondary amine, di- P phenylethylamine ... 

The nitroso compound (diphenyinitrosamine) of the purely aromatic secondary amine diphenylamine is a crystalline solid, and therefore provides an interesting preparation eminently suitable for students ... 

Hinsberg procedure for the separation of primary, secondary and tertiary amines is given under (viii) above, and this method may be used. The following experimental details may, however, be found useful for the preparation of derivatives of primary and secondary amines. 

For this reason, acetic anhydride is generally preferred for the preparation of acetyl derivatives, but acetyl chloride, in view of its greater reactivity, is a better diagnostic reagent for primary and secondary amines. 

Amines are powerful nucleophiles which react under neutral or slightly basic conditions with several electron-accepting carbon reagents. The reaction of alkyl halides with amines is useful for the preparation of tertiary amines or quaternary ammonium salts. The conversion of primary amines into secondary amines is usually not feasible since the secondary amine tends towards further alkylation. 

A special problem arises in the preparation of secondary amines. These compounds are highly nucleophilic, and alkylation of an amine with alkyl halides cannot be expected to stop at any specifle stage. Secondary amides, however, can be monoalkylated and lydrolyzed or be reduced to secondary amines (p. 11 If.). In the elegant synthesis of phenyl- phrine an intermediate -hydroxy isocyanate (from a hydrazide and nitrous acid) cyclizes to pve an oxazolidinone which is monomethylated. Treatment with strong acid cleaves the cyclic irethan. 

Carbonylation of halides in the presence of primary and secondary amines at I atm affords amides[351j. The intramolecular carbonylation of an aryl bromide which has amino group affords a lactam and has been used for the synthesis of the isoquinoline alkaloid 498(352], The naturally occurring seven-membered lactam 499 (tomaymycin, neothramycin) is prepared by this method(353]. The a-methylene-d-lactam 500 is formed by the intramolecular carbonylation of 2-bromo-3-alkylamino-l-propene(354]. 

Hydroxylysine (328) was synthesized by chemoselective reaction of (Z)-4-acet-oxy-2-butenyl methyl carbonate (325) with two different nucleophiles first with At,(9-Boc-protected hydroxylamine (326) under neutral conditions and then with methyl (diphenylmethyleneamino)acetate (327) in the presence of BSA[202]. The primary allylic amine 331 is prepared by the highly selective monoallylation of 4,4 -dimethoxybenzhydrylamine (329). Deprotection of the allylated secondary amine 330 with 80% formic acid affords the primary ally-lamine 331. The reaction was applied to the total synthesis of gabaculine 332(203]. 

N-(2-thiazolyl)dithiocarbamates are prepared by the action of carbon disulfide on 2-aminothiazoles (see Section III.3.C and Ref. 505). When refluxed with secondary amines these heterocyclic dithiocarbamates yield l,T-dialkyl-3-(2-thiazoIyI)thioureas (261) (491). 

Secondary amines are prepared by hydrogenation of a carbonyl compound m the presence of a primary amine An N substituted mine or Schijfs base is an intermediate... 

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

Amides. Reaction of acryhc acid with ammonia or primary or secondary amines forms amides. However, acrylamide (qv) is better prepared by... 

Secondary amines having one oi two chiral groups attached to the nitrogen atom are prepared from boronic esters by their conversion into alkyldichlotobotanes, followed by treatment with organic azides (518). The second chiral group can be derived from an optically active azide. 

Refluxing linoleic acid and a primary or secondary alkyl amine with -toluenesulfonic acid in toluene for 8—18 h also yields the substituted amides (32—34). The reaction of methyl esters with primary or secondary amines to make substituted amides is catalyzed with sodium methoxide. Reactions are rapid at 30°C under anhydrous conditions (35). Acid chlorides can also be used. Ai,A/-dibutyloleamide [5831-80-17 has been prepared from oleoyl chloride and dibutyl amine (36). 

Eatty alcohols, prepared from fatty acids or via petrochemical processes, aldol or hydroformylation reactions, or the Ziegler process, react with ammonia or a primary or secondary amine in the presence of a catalyst to form amines (10—12). 

In addition to the nitrile and alcohol routes for fatty amine preparation, processes have been described by Unocal and Pennwalt Corporation, using an olefin and secondary amine (14—16) by Texaco Inc., hydrogenation of nitroparaffins (17—20) by Onyx Corporation, reaction of an alkyl haUde with secondary amines (21,22) by Henkel Cie, GmbH, reduction of an ester in the presence of a secondary amine (23) by catalytic hydroammonolysis of carboxyhc acids (24) and by the Hofmann rearrangement (25). 

A mixture of primary and secondary amines is formed when ammonia is not used during the nitrile reduction. It is possible to prepare high purity secondary amines by carrying the reduction out at low pressure and passing hydrogen through the reaction in a batch process (47,48),... 

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