Preparation of amines

Amines are both valuable synthetic intermediates and interesting target molecules. A number of solid-phase syntheses have been developed, most of which are also suitable for the automated, parallel synthesis of this class of compound. 

Related Methods Amines from Ketones (Section 102) 

SECTION 95 Amines from Alkyl, Methylenes, and Aryls 

Related Methods Protection of Amines (Section 105A) SECTION 97 Amines from Amines 

Review Nucleophilic Additions to Tetrahydropyridinium Salts Applications to Alkaloid Syntheses  

SECTION 99 Amines from Ethers, Epoxides, and Thioethers 

Ammonia and unhindered amines are good nucleophiles. Therefore, it would appear that amines should be readily prepared by reacting these nucleophiles with the appropriate alkyl halide or sulfonate ester in an SN2 reaction, according to the following general equations  

As illustrated in the following reaction, this method provides acceptable yields of tertiary amines, using secondary amines as nucleophiles. Quaternary ammonium salts can also be prepared from tertiary amines as nucleophiles. 

O Ammonia acts as the nucleophile in an Sn2 reaction, replacing the bromine. 

0 Even when a large excess of ammonia is present, some of the primary amine reacts to produce a secondary amine. 

In this particular case, in which an eightfold excess of ammonia is used, the product mixture consists of 53% of the primary amine and 39% of the secondary amine. 

Cocaine, amphetamines, and several other addicting drugs increase the level of dopamine in the brain, which results in a pleasurable high. With time, the brain adapts to increased dopamine levels, so more drug is required for the same sensation. 

Understanding the neurochemistry of these compounds has led to the synthesis and availability of several useful drugs. Fentanyl is a common narcotic pain reliever used in surgical procedures, and sumatriptan (trade name Imitrex) is used to relieve pain and light sensitivity in patients who suffer from migraine headaches. 

In the preparations of a given functional group, many different starting materials form a common product (amines, in this case). 

LSD (a hallucinogen) and codeine (a narcotic) are structurally more complex derivatives of 2-phenylethylamine. Identify the atoms of 2-phenylethylamine in each of the following compounds. 

Three types of reactions are used to prepare an amine  

In this section we discuss a variety of ways to synthesize amines. Some of these methods wiU be new to yon, while others are methods yon have studied earlier in the context of related functional groups and reactions. Later, in Chapter 24, you wiU see how some of the methods presented here, as well as some others for asymmetric synthesis, can be used to synthesize a-amino acids, the building blocks of peptides and proteins. 

Alkylation of Ammonia Salts of primary amines can be prepared from ammonia and alkyl halides by nucleophilic substitution reactions. Subsequent treatment of the resulting aminium salts with a base gives primary amines  

When ethyl bromide reacts with ammonia, for example, the ethylaminium bromide that is produced initially can react with ammonia to liberate ethylamine. Ethylamine can then compete with ammonia and react with ethyl bromide to give diethylaminium bromide. Repetitions of alkylation and proton transfer reactions ultimately produce some tertiary amines and even some quaternary ammonium salts if the alkyl halide is present in excess. 

Multiple alkylations can be minimized by using a large excess of ammonia. (Why ) An example of this technique can be seen in the synthesis of alanine from 2-bromopropanoic acid  

Alkylation of Azide Ion and Reduction A much better method for preparing a primary amine from an alkyl halide is first to convert the alkyl halide to an alkyl azide (R—N3) by a nucleophilic substitution reaction, then reduce the azide to a primary amine with sodium and alcohol or with lithium aluminum hydride. 

Reactions of ammonia with alkyl halides yield ammonium salts. Treating these ammonium salts with bases produces primary amines. 

If primary amines react with alkyl halides, secondary amines are produced. If the reactions are allowed to proceed, tertiary amines can be obtained. 

Almost all organic compounds containing nitrogen in their structure can be reduced to amines. 

Unsaturated nitrogen compounds (nitriles) can be reduced by the addition of hydrogen to give primary amines. 

Nucleophilic substitution is the key step in two different methods for synthesizing amines direct nucleophilic substitution and the Gabriel synthesis of 1° amines. 

Conceptually, the simplest method to synthesize an amine is by Sn2 reaction of an alkyl halide with NH3 or an amine. The method requires two steps  

The identity of the nitrogen nucleophile determines the type of amine or ammonium salt formed as product. One new carbon-nitrogen bond is formed in each reaction. Because the reaction follows an Sn2 mechanism, the alkyl halide must be unhindered—that is, CH3X or RCHgX. 

Mizushima, E. Havashi.T. Tanaka. M. Org. Lett. 2003,5,3349. l.r-BuNH2,C6D6,65°C 

Pohlki, F. Heutling, A. Bytschkov, I. Hotopp, T. Dove. S. Svnlett 2002.799. 

Kimura. M. Futamata, M. Shibata, K. Tamaru. Y. Chem. Commun. 2003, 234. 

Aspinall,H.C. Bissett, J.S. Greeves. N. Levin,D. Tetrahedron Lett.2002,43,323 

Choudarv.B.M, Jyothi, K. Madhi, S. Kantam, M.L. Synlett2004,231 PhNH2, bmim PF6 

Solladi6-Cavallo. A. Bencheqroun, M. Bonne, F. Synth. Commun., 1993, 23, 1683 

Related Methods Section 102 (Amines from Ketones) 

SECTION 95 AMINES FROM ALKYLS, METHYLENES AND ARYLS 

NO ADDITIONAL EXAMPLES SECTION 96 AMINES FROM AMIDES O 

Bozee-Ogor, S. Salou-Guiziou, V. Yaouanc, J.J. Handel. H. Tetrahedron Lett., 1995, 36, 6063 Ph 

Related Methods Section 105A (Protection of Amines) 

reflux Klepacz, A. /wiwezak. A. Svnth. Commun., 2001, 31, 1683. 

Likhotvorik, I.T. Tippmann, E, Platz. M.S. Tetrahedron Lett., 2001, 42, 3049. EtOjC 

Inagaki, T. Miyoshi, N. Ogawa, A. Sonoda. N. Chem. Lett., 1987,1275. 

Tanaka, H. Yamashita, S. Ikemoto, Y. Torii, S. Chem. Lett., 1987,673. 

(Ppyz)Zr(BH4)2Cl2 Heydari, A. Khaksar, S. Esfandyari, M. Tajbakhsh, M. Tetrahedron 2007, 63, 3363. 

2 2-piperidone, DCM Suginome, M. Tanaka, Y. Hasui, T. Synlett 2006, 1047. 

Shibata, I. Yasaka, Y. Tsunoi, S. Yasuda, M. Baba, A. Chem. Commun. 2006, 4189. 

Schroth. W. Tetrahedron Lett., 1993, 34, 5863 I.C5H11CHO, BER.EtOH 

Saoudi, A. Benguedadi, A. Benhaoua. H. Synth. Commun., 1995, 25, 2349 Related Methods Section 102 (Amines from Ketones) 

HOSA s hydioxylamine 0-sulfonic acid L Barker. J.M. Wood, M.L. Synthesis. 1990, 1143. 

YonemiUii. Q. Tabata, M. Sohma, J. Tetrahedron Lett., 1992, 33, 1459. 

Bianchini, C. Lee, H.M. Mantovani, G. Meli, A. Oberhauser, W. New J. Ghent. 2002,26,387. Related Method Section 102 (Amines from Ketones) 

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The reaction is applicable to the preparation of amines from amides of aliphatic aromatic, aryl-aliphatic and heterocyclic acids. A further example is given in Section IV,170 in connexion with the preparation of anthranilic acid from phthal-imide. It may be mentioned that for aliphatic monoamides containing more than eight carbon atoms aqueous alkaline hypohalite gives poor yields of the amines. Good results are obtained by treatment of the amide (C > 8) in methanol with sodium methoxide and bromine, followed by hydrolysis of the resulting N-alkyl methyl carbamate ... 

The preparation of amines by the methods described m 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 prepar mg primary secondary or tertiary amines by proper choice of starting materials... 

The reaction of amines with alkyl halides was seen earlier (Section 22 7) as a complicat ing factor in the preparation of amines by alkylation of ammonia... 

Preparation of Amines. Amines are prepared by heating aUphatic, aromatic, or cycHc ketones with ammonium formate, formamide, or an A/-substituted ammonium formate at 165—190°C (Leuckart reaction). For example, cx-methylbenzylamine is prepared by the reaction of acetophenone with ammonium formate. 

In catalytic hydrogenation, a compound is reduced with molecular hydrogen in the presence of a catalyst. This reaction has found appHcations in many areas of chemistry including the preparation of amines. Nitro, nitroso, hydroxylamino, azoxy, azo, and hydrazo compounds can all be reduced to amines by catalytic hydrogenation under the right conditions. Nitriles, amides, thioamides, and oximes can also be hydrogenated to give amines (1). Some examples of these reactions foUow ... 

Monochloramine is also used in organic synthesis for preparation of amines, substituted hydrazines, etc. For example, reaction of NH2CI with 3-azabicyclo [3.3.0]octane [5661-03-0] yields A/-amino-3-azabicyclo[3.3.0]octane [54528-00-6] a pharmaceutical intermediate (38). 

Reductive amination (Section 22.10) Method for the preparation of amines in which an aldehyde or a ketone is treated with ammonia or an amine under conditions of catalytic hydrogenation. 

Preparation of Amine or Hydrazide Derivatives by Reductive Amination... 

The condensation of activated thiols onto adjacent nitriles is a common method for the preparation of amine-substituted thiophenes. A three component condensation was utilized to prepare a-aminothiophene 11 <00TL1597>. An alternate method for preparing amino-substituted thiophenes involved the treatment of ketene S,JV-acetal 12 with an activated carbonyl compound 13 which gave thiophene 14 <00JOC3690>. This type of reaction has also been utilized to prepare building blocks for the synthesis of fused thiophenes <00JHC363>. 

This procedure illustrates a general method for the preparation of amines by reductive cleavage of sulfonamides by hydrobromic acid in the presence of phenol.9 The present synthesis makes 1,3-dihydroisoindole readily accessible and is superior in certain respects to the other two practical methods of preparation. Thus the method here described is shorter and gives a higher overall yield than the three-step synthesis of Neumeyer,7 and obviates the special apparatus and careful control required by the electrochemical process of Dunet, Rollet, and Willemart.4... 

PREPARATION OF AMINE TERMINATED PAMAM STAR-BRANCHED PRECURSOR [NH2-(CH2)2 6-NHJ ... 

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