Side reactions between Boc2O/DMAP and Amines and Alcohols_Industrial Additives

DMAP is one of the few 4-dialkylaminopyridine derivatives that can efficiently catalyze acylations reactions. Boc is a widely used protective group for amines and alcohols. The use of DMAP to catalyze Boc2O to protect amines and alcohols has a high reaction yield and is easy to operate, so it has always been highly praised by everyone. However, recent research has found that in addition to the expected products of nitropyridine N-Boc and O-Boc, it has also been discovered There are some by-products. This article introduces the main by-products when DMAP catalyzes the synthesis of N-Boc and O-Boc. I hope it will be helpful to everyone’s synthesis work.

Side reactions of Boc2O/DMAP with Amines and Alcohols 1. Reaction of Amines with Boc2O/DMAP:

Amines can be generated by reacting with Boc2O without any catalyst N-Boc products. However, under the catalysis of DMAP, by-products 3 and 4 are produced (Scheme 1).

Take cyclohexylamine 1a as an example: cyclohexylamine 1a (in MeCN, at r.t.) and Boc2O (1.5 equiv)/DMAP (0.1 equiv) yield N-Boc derivatives, and the main by-products of the reaction follow varies with temperature and solvent. In experiments using the catalyst N-methylimidazole (MeIm) instead of DMAP, the reaction between cyclohexylamine 1a and Boc2O produced only a single product of N-Boc compound 2a (Table 1).

Side reactions between Boc2O/DMAP and Amines and AlcoholsExperimental Procedure:

Boc2O ( 1.2 equiv) was dissolved in 3 mL of MeCN and placed in an ice bath, and DMAP (0.2 equiv) was added. After 5 min., cyclohexyl amine (0.5 mmol) in 2 mL of MeCN was added dropwise in 1 min., and the reaction was allowed to proceed for 10 min.. At the end of the reaction chloroform (10 mL) was added, and the solution was washed with 5% HCl (20 mL), dried with MgSO4, and evaporated to give compound 4a in 80% yield.

Unlike primary amines, the reaction of secondary amines with Boc2O/DMAP only generates a single N-Boc product and does not generate urea. We infer that the mechanism of DMAP catalyzing primary amines to generate N-Boc 2, Urea 3 and Isocyanate 4 is as follows:

Boc2O/ Side reactions of DMAP with Amines and Alcohols 2. Reaction of Alcohols with Boc2O/DMAP

Usually alcohols do not react with Boc2O, and it is difficult to react even in the presence of Et3N, but the catalyst DMAP is added to the reaction Afterwards, O-Boc product will be generated immediately. Recent studies have found that the alcohol Boc2O/DMAP reaction produces carbonate 10 in addition to the O-Boc product. For example, the reaction of cinnamyl alcohol 8a (in MeCN, at r.t) with Boc2O/DMAP not only obtains product 9a, but also obtains a symmetric carbonate 10a, (9a: 10a=1:1).

We believe that the mechanism of DMAP catalyzing alcohol to generate O-Boc 9, Carbonate 10 is as follows:

Hydrated samarium carbonate

In view of the above conclusion, when doing Boc-protected reactions, we can easily infer the type of by-products in the reaction based on different substrates and reaction conditions.

References of side reactions between Boc2O/DMAP and Amines and Alcohols:

J. Org. Chem., 2000, 65, 6368-6380

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