Vivian Marlowe
Amines are among the most valuable classes of compounds in chemistry, widely used in pharmaceuticals, agrochemicals, lubricants, and surfactants. The conversion of alcohols to amines is an important chemical transformation for the production of bulk and fine chemicals and pharmaceutical intermediates. There are several methods to convert an alcohol to an amine, including the use of nucleophilic substitution, the Ritter reaction, and the Buchwald-Hartwig amination. The choice of method depends on various factors, such as the availability of reactants, control over the reaction, and the desired yield.
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What You'll Learn
Using iron as a catalyst
Turning an alcohol into an amine is one of the most important chemical transformations for the production of bulk and fine chemicals and pharma intermediates. The direct N-alkylation of simple amines with alcohols by the "borrowing hydrogen" strategy is an atom-economic way of carrying out such C–N bond formations. Transition metal complexes based on precious metals have emerged as suitable catalysts for this transformation. However, the use of abundant, inexpensive, and environmentally friendly metals such as iron has not been accomplished until recently.
Iron-based catalysts have been shown to efficiently catalyze the direct alkylation of amines with alcohols, an atom-efficient and environmentally benign process. This process involves the selective conversion of carbon–oxygen bonds into carbon–nitrogen bonds to form amines. An example of an iron-based catalyst is the iron tetraphenylcyclopentadienone tricarbonyl complex, which acts as a precursor for the formation of C–N bonds through a "hydrogen-borrowing" reaction between amines and alcohols.
In one study, the readily available iron cyclone complex was used as a catalyst for the formation of C–N bonds in the reaction between benzyl alcohol and aniline to form an amine. The conversion was observed to be at least 99% when using 10 mol % of the catalyst in toluene, with a 2-fold excess of benzyl alcohol, and trimethylamine-N-oxide to activate the catalyst.
Another example of an iron-based catalyst is iron phthalocyanine, which has been shown to be an efficient and versatile catalyst for the N-alkylation of heterocyclic amines with alcohols. This catalyst was used for the direct N-alkylation of various amines, including aminobenzothiazoles, aminopyridines, and aminopyrimidines, with readily available alcohols as alkylating agents.
It is important to note that there are alternative methods for converting alcohols to amines that do not involve the use of iron-based catalysts. For example, the Ritter reaction is a combination of principles and reactions such as carbocation formation, nucleophilic addition, and hydrolysis. This reaction can be used to convert an alcohol to a nitrile, which can then be reduced to an amino group. Another approach involves first converting the OH group of the alcohol into a good leaving group, such as a mesylate or tosylate, and then reacting it with an amine.
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Converting OH into a good leaving group
When converting an alcohol to an amine, the first step is to convert the OH group into a good leaving group. This is because OH is a poor leaving group, and if it were to leave, it would be OH-, a very strong base that is ready to attack.
There are several methods to convert OH into a good leaving group. One approach is to treat the alcohol with an acid, such as HCl, HBr, or HI. This converts the OH group to H2O+, which is an excellent leaving group and can undergo an SN1 or SN2 substitution by the halide ion (Cl-, Br-, or I-). However, the reaction with HCl may not be as efficient and sometimes requires an additional catalyst like ZnCl2.
Another method is to activate the OH group with sulfonyl chlorides, such as Tosyl chloride (TsCl), p-Toluenesulfonyl chloride, Methanesulfonyl chloride, or Trifluoromethanesulfonyl chloride. This converts the OH group to a Tosylate (-OTs), Mesylate (-OMs), or Triflate (-OTf), respectively, which are all good leaving groups. For example, the reaction of alcohol with TsCl produces alkyl tosylate (ROTs), where OTs is an excellent leaving group.
Additionally, the OH group can be converted into a halide using reagents such as Thionyl chloride (SOCl2), Phosphorus tribromide (PBr3), or ZnCl2. SOCl2, in particular, can be used with pyridine to convert OH into Cl, and it works on primary and secondary alcohols. PBr3 is also effective in converting OH into Br for most primary and secondary alkyl halides, but it results in an inversion of stereochemistry due to the SN2 reaction in the second step.
By converting the OH group into a good leaving group, the subsequent reactions can be controlled, and the desired products can be obtained more effectively.
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Using cyanide substitution-reduction
The process of converting an alcohol to an amine involves the substitution of a hydroxyl group (-OH) with an amine group (-NH2). One method to achieve this conversion is through a cyanide substitution-reduction reaction. Here is a step-by-step guide on how to perform this transformation:
Step 1: Cyanide Substitution
In the first step, the hydroxyl group of the alcohol undergoes a nucleophilic substitution reaction with a cyanide anion (CN-). This reaction converts the alcohol into a nitrile, introducing a carbon-nitrogen triple bond. The cyanide anion acts as a nucleophile and replaces the hydroxyl group. This step can be facilitated by various reaction conditions, such as using appropriate catalysts and solvents.
Step 2: Nitrile Reduction
The resulting nitrile from the previous step can then be reduced to an amine using several methods. One common approach is to use catalytic hydrogenation, where the nitrile is reacted with hydrogen gas (H2) in the presence of a metal catalyst, such as nickel boride or ruthenium. This reaction breaks the carbon-nitrogen triple bond and adds hydrogen atoms to form the amine group.
Alternatively, other reducing agents can be employed, such as TMDS (tetramethyldisiloxane) or sodium dispersions, depending on the specific reaction conditions and desired yield. It is important to note that the choice of reducing agent may vary based on the structure of the starting material and the desired type of amine (primary, secondary, or tertiary).
Step 3: Workup and Purification
After the nitrile reduction step, the reaction mixture will typically require a workup to isolate the desired amine product. This may involve quenching the reaction, extracting the product, and purifying it through techniques such as chromatography or crystallization.
Precautions and Considerations:
When utilizing the cyanide substitution-reduction method, it is crucial to keep in mind that an extra carbon is introduced into the molecule. Therefore, careful consideration of the carbon chain length is necessary when planning the reaction. Additionally, the choice of reaction conditions, catalysts, and solvents may vary depending on the specific alcohol starting material and the desired amine product.
In summary, the cyanide substitution-reduction method provides a viable approach to converting an alcohol to an amine. By following the steps outlined above and selecting appropriate reaction conditions, one can successfully transform an alcohol functional group into an amine through the intermediate formation of a nitrile.
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The Ritter reaction
In the Ritter reaction, primary, secondary, tertiary, and benzylic alcohols react with nitriles in the presence of strong acids to form amides. A wide range of nitriles can be used, including cyanide, which can prepare formamides. These formamides are useful precursors to isocyanides or can be hydrolyzed to give amines. The Ritter reaction is particularly useful in the formation of amines and amides for pharmaceutical applications.
For example, the Ritter reaction is used in the industrial-scale synthesis of the anti-HIV drug Crixivan (indinavir) by Merck. It is also employed in the production of the falcipain-2 inhibitor PK-11195, the synthesis of the alkaloid aristotelone, and the synthesis of N-Benzhydrylamides from nitriles.
One key consideration in the Ritter reaction is the stability of carbocations. Tertiary and resonance-stabilized alcohols are the best candidates for forming carbocations, but the reaction can also be adapted to work with secondary and primary alcohols using strong Lewis acids. Additionally, the Ritter reaction can be modified to amidoselenate terminal and 1,2-disubstituted alkenes, yielding allylic amides.
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Converting the amine to a quaternary ammonium salt
To convert an alcohol to an amine, the hydroxyl group of the alcohol must be replaced with an amine group. This can be done by first converting the OH group into a good leaving group, such as a mesylate, tosylate, or halide. The latter can then be reacted with an amine. Another method is the Ritter reaction, which involves the nucleophilic addition of a nitrile to a carbocation, followed by the hydrolysis of the C-N triple bond. The cyanide ion can also be used as a nucleophile to convert the alkyl halide to a nitrile, which is then reduced to an amino group.
Once an amine has been obtained, it can be converted into a quaternary ammonium salt. One way to do this is through the Menshutkin reaction, which involves reacting a tertiary amine with an alkyl halide to form the quaternary ammonium salt. This reaction is typically conducted in polar solvents such as alcohols, and alkyl iodides are the superior alkylating agents. Another method to obtain quaternary ammonium salts is through the alkylation of chiral ammonium salts with dimethyl malonate and phenylzinc chloride, as demonstrated by Yamamoto.
Quaternary ammonium salts (QAS) have gained attention as alternative reagents in alkylation reactions due to their safety profile and ease of handling. They are non-carcinogenic, non-mutagenic, non-flammable, and non-corrosive, making them a promising alternative to traditional reagents that pose health and exposure risks. However, the synthesis of QAS currently relies on alkyl halides, which limits their attractiveness for industrial applications.
It is important to note that the conversion of amines to quaternary ammonium salts is a complex process that requires careful consideration of various factors, including the choice of reactants, solvents, and reaction conditions.
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Frequently asked questions
The strategy for preparing an amine from an alcohol involves first converting the OH group into a good leaving group, such as a mesylate, tosylate, or halide. Subsequently, the resulting compound is reacted with an amine. This process is crucial in the production of bulk and fine chemicals, pharmaceuticals, and intermediates.
There are several methods available for converting alcohols to amines, including the Gabriel synthesis, Mitsunobu reaction, and the combination of Appel and Staudinger reactions. The choice of method depends on the specific reactants and desired products.
Catalysts play a crucial role in facilitating the conversion of alcohols to amines. Transition metal complexes based on precious metals have been traditionally used as catalysts for this transformation. However, recent research has focused on employing more abundant, inexpensive, and environmentally friendly metals, such as iron, for this purpose.
Selectivity in the conversion of alcohols to amines can be achieved through careful control of reaction conditions and the choice of reactants. The use of specific leaving groups, such as mesylates or tosylates, can help avoid rearrangements and unwanted side reactions. Additionally, the choice of catalyst and reaction temperature can also influence the selectivity of the transformation.
