Lecture otes hemistry 42-2008 Mukund P. Sibi Synthesis of Amines Amines can be prepared from a variety of starting materials. All of these methods involve functional group transformations. The main methods are: Amines from amides Amines from nitriles Amines from nitro compounds Amines from Alkyl alides S 2 eactions Gabriel Amine Synthesis Amines from Aldehydes and Ketones eductive amination Amines from rearrangements eduction of Amides Amides readily prepared from carboxylic acid chlorides undergo reduction using a strong reducing agent to give amines. Typically lithium aluminum hydride (LA) is used as the reducing agent. In this method, the product amine has the same number of carbons as the starting carboxylic acid. Sl 2 l 2 1. LA, ether 2. 2 2 2 Primary Amine 2 1. LA, ether 2 1. LA, ether 2. 2 2. 2 Secondary Amine Tertiary Amine eduction of itriles itriles undergo reduction using strong reducing agents (LA) to provide primary amines. The nitriles can be synthesized from alkyl halides by an S 2 reaction. The method provides a primary amine with an additional carbon atom. An example starting from benzylbromide is shown. X a 1. LA, ether 2. 2 2 2 a 1. LA, ether 2. 2 2 2 Amines from itro ompounds Aromatic nitro compounds can be readily synthesized by nitration. The nitro group can be reduced using several different conditions to provide arylamines. The reagent choice
Lecture otes hemistry 42-2008 Mukund P. Sibi depends on what other functional groups are present in the molecule. For example, reduction of the nitro group using platinum/hydrogen is not compatible with an alkene. Metal/acidic conditions are quite effective. Iron, zinc, tin, and tin chloride in aqueous acidic conditions are useful in reducing nitro groups to amines. 2 + 2 Pt 2 2 1. Fe, + 2 2 1.Snl 2, + 2 2. - ote: The double bond will not reduce 2 2. - 2 The S 2 alkylation of alkyl halides Amines are good nucleophiles and can easily do S 2 substitutions on alkyl halides. This method allows for the preparation of a more highly substituted amine from a less substituted one. The alkyl halide (and the nucleophile) must conform to all the requirements for a successful S 2 reaction. ne of the drawbacks to this method is the formation of multiple alkylated products. In general, ammonia, primary amines, and secondary amines have similar reactivity and thus alkylations are not clean and multiple products are formed. 1 S 2 X 1 X 2 X 1 1 2 a a a Primary Amine 1 Secondary Amine 2 Tertiary Amine 1 1 2 X 1 2 Quaternary ammonium salt 2 Ammonium salt ~45% ~45% Trace Trace
Lecture otes hemistry 42-2008 Mukund P. Sibi An alternate method for primary amine synthesis, which also involves an S 2 reaction, is using azides. Alkyl halides undergo substitution with azide ion. The product azides are not nucleophilic and do not undergo over alkylation. Alkyl azides can be reduced to primary amines using LA. The only drawback to this method is that low molecular weight azides can be shock sensitive and thus have the potential for being explosive. a 1. LA, ether 2. 2 2 Alkyl halide Alkyl azide Primary amine Gabriel Amine Synthesis Another method for synthesizing primary amines involves the use of phthalimide anion as the nitrogen nucleophile in reaction with alkyl halides. The - bond in imides is acidic since the nitrogen is flanked by two carbonyl groups. Phthalimide can be deprotonated using bases such as a and K. The phthalimide anion reacts with alkyl halides in an S2 reaction to form the - bond. ydrolysis under basic conditions gives the primary amine and phthalic acid. K K + X DMF - 2 2 K K + DMF - 2 2 yclopentylmethylamine Amines from Aldehydes and Ketones: eductive Amination Aldehydes and ketones can be converted to an amine in a single step by treatment with ammonia (or an amine) and a reducing agent. This method is called eductive Amination. In this reaction an imine is formed as an intermediate, which is reduced to an amine. 2 /i 2 2 2 /i 2
Lecture otes hemistry 42-2008 Mukund P. Sibi ne can prepare primary, secondary, and tertiary amines using this method depending on the two components of the reaction. A variety of reducing agents can be used in this reaction. Sodium cyanoborohyride (ab ) is a common and effective reagent for the reduction. It has similar reactivity to ab 4 but more stable to weak acid. 2 /at 1 2 Primary Amine 2 ab 1 2 2 2 /at 4 2 /at 1 1 Secondary Amine 2 Tertiary Amine 4 ab + 2 Amine Synthesis through earrangements offmann and urtius rearrangements can convert carboxylic acids to primary amines. Both of these reactions proceed through similar mechanisms. In these reactions the amine product has one less carbon atom than the starting material. offmann earrangement urtius earrangement a, 2 2 2 2 2 2 eat 2 2 2 Amide Primary Amine Acyl Azide Primary Amine The mechanism for the offmann rearrangement involves several steps. It Step 1 a Step 2 Step Step 4 + - Step 5 Isocyanate arbamic acid Step 6 2 Step 1: Deprotonation of the acidic amide proton Step 2: The anion reacts with bromine to form an -bromoamide. This is similar to enolate alpha substitution
Lecture otes hemistry 42-2008 Mukund P. Sibi Step : Deprotonation of the remaining amide proton to yield bromoamide anion Step 4: The bromoamide anion rearranges with the migration of the group attached to the carbonyl carbon migrates to the nitrogen atom. A bromine atom leaves at the same time as the migration occurs. The product is an isocyanate. Step 5: Water nucleophile adds to the isocyanate to form a carbamic acid. Step 6: The carbamic acid is not stable and loses carbon dioxide spontaneously to give the primary amine. offmann reactions are very efficient and provide the product amines in high yields. Both alkyl and aryl amines can be prepared. Two examples are shown below. 2 a, 2 2 2 2 a, 2 2 2 urtius earrangement The urtius rearrangement also involves the migration of an group from the carbonyl group to an adjacent nitrogen atom. The process involves (1) the formation of an acyl azide from an acid chloride (2) thermal rearrangement and loss of nitrogen () hydrolysis of the resulting acyl isocyanate. l a - 2 2 2 2 2 Isocyanate Both offmann and urtius rearrangements are highly effective in providing primary amines in yields. They are used in the chemical industry to prepare important therapeutic agents.