24.7: Synthesis of Amines

Reduction of Nitriles, Amides, and Nitro Compounds

We’ve already seen in Section 20.7 and Section 21.7 how amines can be prepared by reduction of nitriles and amides with LiAlH₄. The two-step sequence of S_N2 displacement with CN^– followed by reduction thus converts an alkyl halide into a primary alkylamine having an additional carbon atom. Amide reduction converts carboxylic acids and their derivatives into amines with the same number of carbon atoms.

Arylamines are usually prepared by nitration of an aromatic starting material, followed by reduction of the nitro group (Section 16.2). The reduction step can be carried out in many different ways, depending on the circumstances. Catalytic hydrogenation over platinum works well but is often incompatible with the presence elsewhere in the molecule of other reducible groups, such as $\text{C=C}$ bonds or carbonyl groups. Iron, zinc, tin, and tin(II) chloride (SnCl₂) are also effective when used in acidic aqueous solution. Tin(II) chloride is particularly mild and is often used when other reducible functional groups are present.

CH₃CH₂CH₂NH₂

(b) (CH₃CH₂CH₂)₂NH (c) Benzylamine, C₆H₅CH₂NH₂ (d) N-Ethylaniline

S_N2 Reactions of Alkyl Halides

Ammonia and other amines are good nucleophiles in S_N2 reactions. As a result, the simplest method of alkylamine synthesis is by S_N2 alkylation of ammonia or an alkylamine with an alkyl halide. If ammonia is used, a primary amine results; if a primary amine is used, a secondary amine results; and so on. Even tertiary amines react rapidly with alkyl halides to yield quaternary ammonium salts, R₄N⁺ X^–.

Unfortunately, these reactions don’t stop cleanly after a single alkylation has occurred. Because ammonia and primary amines have similar reactivity, the initially formed monoalkylated substance often undergoes further reaction to yield a mixture of products. Even secondary and tertiary amines undergo further alkylation, although to a lesser extent. For example, treatment of 1-bromooctane with a twofold excess of ammonia leads to a mixture containing only 45% octylamine. A nearly equal amount of dioctylamine is produced by double alkylation, along with smaller amounts of trioctylamine and tetraoctylammonium bromide.

A better method for preparing primary amines is to use azide ion, N₃^–, rather than ammonia, as the nucleophile for S_N2 reaction with a primary or secondary alkyl halide. The product is an alkyl azide, which is not nucleophilic, so overalkylation can’t occur. Subsequent reduction of the alkyl azide with LiAlH₄ then leads to the desired primary amine. Although this method works well, low-molecular-weight alkyl azides are explosive and must be handled carefully.

Another alternative for preparing a primary amine from an alkyl halide is the Gabriel amine synthesis, which uses a phthalimide alkylation. An imide ($\mathbf{\text{O=C–N–C=O}}$N-alkylated imide then yields a primary amine product. The imide hydrolysis step is analogous to the hydrolysis of an amide (Section 21.7).

Write the mechanism of the last step in Gabriel amine synthesis, the base-promoted hydrolysis of a phthalimide to yield an amine plus phthalate ion.

Show two methods for the synthesis of dopamine, a neurotransmitter involved in regulation of the central nervous system. Use any alkyl halide needed.

Reductive Amination of Aldehydes and Ketones

Amines can be synthesized in a single step by treatment of an aldehyde or ketone with ammonia or an amine in the presence of a reducing agent, a process called reductive amination. For example, amphetamine, a central nervous system stimulant, is prepared commercially by reductive amination of phenyl-2-propanone with ammonia using hydrogen gas over a nickel catalyst as the reducing agent. In the laboratory, either NaBH₄ or the related NaBH(OAc)₃ is commonly used (OAc = acetate).

Reductive amination takes place by the pathway shown in Figure 24.6. An imine intermediate is first formed by a nucleophilic addition reaction (Section 19.8), and the $\text{C═N}$ bond of the imine is then reduced to the amine, much as the $\text{C═O}$ bond of a ketone can be reduced to an alcohol.

Figure 24.6 MECHANISM Mechanism for reductive amination of a ketone to yield an amine. Details of the imine-forming step are shown in Figure 19.7.

Ammonia, primary amines, and secondary amines can all be used in the reductive amination reaction, yielding primary, secondary, and tertiary amines, respectively.

Reductive aminations also occur in various biological pathways. In the biosynthesis of the amino acid proline, for instance, glutamate 5-semialdehyde undergoes internal imine formation to give 1-pyrrolinium 5-carboxylate, which is then reduced by nucleophilic addition of hydride ion to the $\text{C═N}$ bond. Reduced nicotinamide adenine dinucleotide, NADH, acts as the biological reducing agent.

Worked Example 24.1

Using a Reductive Amination Reaction

How might you prepare N-methyl-2-phenylethylamine using a reductive amination reaction?

Strategy

Look at the target molecule, and identify the groups attached to nitrogen. One of the groups must be derived from the aldehyde or ketone component, and the other must be derived from the amine component. In the case of N-methyl-2-phenylethylamine, two combinations can lead to the product: phenylacetaldehyde plus methylamine or formaldehyde plus 2-phenylethylamine. It’s usually better to choose the combination with the simpler amine component—methylamine in this case—and to use an excess of that amine as reactant.

Solution

(b)

(c)

Problem 24-12

How could you prepare the following amine using a reductive amination reaction?

Hofmann and Curtius Rearrangements

Carboxylic acid derivatives can be converted into primary amines with loss of one carbon atom by both the Hofmann rearrangement and the Curtius rearrangement. Although the Hofmann rearrangement involves a primary amide and the Curtius rearrangement involves an acyl azide, both proceed through similar mechanisms.

Hofmann rearrangement occurs when a primary amide, RCONH₂, is treated with Br₂ and base (Figure 24.7). The overall mechanism is lengthy, but most of the individual steps have been encountered before. Thus, the bromination of an amide in steps 1 and 2 is analogous to the base-promoted bromination of a ketone enolate ion (Section 22.6), and the rearrangement of the bromoamide anion in step 4 is analogous to a carbocation rearrangement (Section 7.11). Nucleophilic addition of water to the isocyanate carbonyl group in step 5 is a typical carbonyl-group process (Section 19.4), as is the final decarboxylation step 6 (Section 22.7).

Figure 24.7 MECHANISM Mechanism of the Hofmann rearrangement of an amide to an amine. Each step is analogous to a reaction studied previously.

Despite its mechanistic complexity, the Hofmann rearrangement often gives high yields of both arylamines and alkylamines. For example, the appetite-suppressant drug phentermine is prepared commercially by Hofmann rearrangement of a primary amide. Commonly known by the name Fen-Phen, the combination of phentermine with another appetite-suppressant, fenfluramine, is suspected of causing heart damage.

The Curtius rearrangement, like the Hofmann rearrangement, involves migration of an –R group from the $\text{C═O}$ carbon atom to the neighboring nitrogen with simultaneous loss of a leaving group. The reaction takes place on heating an acyl azide that is itself prepared by nucleophilic acyl substitution of an acid chloride.

Also like the Hofmann rearrangement, the Curtius rearrangement is often used commercially. The antidepressant drug tranylcypromine, for instance, is made by Curtius rearrangement of 2-phenylcyclopropanecarbonyl chloride.

Worked Example 24.2

Using the Hofmann and Curtius Rearrangements

How would you prepare o-methylbenzylamine from a carboxylic acid, using both Hofmann and Curtius rearrangements?

Strategy

Both Hofmann and Curtius rearrangements convert a carboxylic acid derivative—either an amide (Hofmann) or an acid chloride (Curtius)—into a primary amine with loss of one carbon, RCOY → RNH₂. Both reactions begin with the same carboxylic acid, which can be identified by replacing the –NH₂ group of the amine product by a –CO₂H group. In the present instance, o-methylphenylacetic acid is needed.

Solution

Problem 24-13 How would you prepare the following amines, using both Hofmann and Curtius rearrangements on a carboxylic acid derivative?

(a)

(b)