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Application of Boc-anhydride
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Introduction to the application of Boc-anhydride


Boc-acid anhydride is also known as di-tert-butyl dicarbonate, with a molecular formula of C10H18O5, a molecular weight of 218.25, and a boiling point of 185.2°C. Its structural formula is shown in Figure 1.


Boc酸酐-图1.png

Figure 1


Boc-acid anhydride is often used as a tert-butoxycarbonyl protecting group in organic synthesis, especially for the protection of amino groups in amino acids [1]. Widely used in the synthesis of various products such as medicine, protein and peptide synthesis, biochemistry, food, cosmetics, etc. This article will briefly introduce the method and mechanism of Boc-anhydride introducing and removing Boc protecting group.

Introduction of Boc protecting group


There are many strategies for using Boc-anhydride to add Boc to the amino group. The commonly used inorganic bases are NaOH and NaHCO3; the organic bases are triethylamine, etc.; the solvents are often dioxane, water or alcohol. Some amines with low nucleophilicity need to add dmap as a catalyst.

For example, Joseph A. reported that the utilization of 2-amino-1-(4-bromophenyl) ethyl-1-ketone and Boc-acid anhydride under the organic base triethylamine, stirring overnight at room temperature can be achieved in almost quantitative yield The product with the Boc protecting group was obtained. The reaction conditions are mild and the yield is high [2].


Boc酸酐-图2.png

Figure II


The substrate of sulfonamides may be that the nucleophilicity of the amino group is not high due to the strong electron-withdrawing effect of the sulfonyl group, so it is necessary to add a catalytic amount of dmap (4-dimethylaminopyridine) to catalyze the reaction on Boc [3 ], such as Figure 3.


Boc酸酐-图3.png

Figure three


When the substrate contains two amino groups at the same time, the Boc reaction is often selective [4]. For example, in Fig. 4, Boc-anhydride is single Boc on aliphatic amine in 97% yield under sodium bicarbonate basic condition. This is because the basicity and nucleophilicity of aliphatic amines are stronger than those of aromatic amines; and the halogen chlorine in the ortho position of aromatic amines is a weak electron-withdrawing group, which further reduces the nucleophilicity of aromatic amines.


Boc酸酐-图4.png

Figure four

 

In addition, literature research has found that in protic solvents, such as methanol and ethanol, some aliphatic or aromatic amines can obtain Boc-upped products in high yields without adding a base [5]. For example, as shown in Figure 5.


Boc酸酐-图5.png

Figure five


The authors proposed a possible mechanism: in the presence of protic solvents, Boc anhydride can form hydrogen bonds with alcohols, thereby activating the carbonyl group. As shown in Figure 6.


Boc酸酐-图6.png

 

Figure six

When ethanol is used as a solvent, in addition to adding Boc without alkali, it can also react with Z-OSu or Fmoc-OSu to add corresponding protecting groups.


Deprotection of Boc protecting group


The Boc protecting group is an acid-sensitive group. In the liquid-phase peptide synthesis, TFA or 50% TFA (TFA:CH2Cl2 = 1:1, v/v) can be used to remove Boc. In solid-phase peptide synthesis, since TFA will bring some side reactions (such as a trifluoroacetyl group on the obtained amine, etc.), 1-2M HCl/organic solvent is often used. Generally speaking, HCl/dioxane is more common. The reaction formula of deprotection is shown in Figure 7.


Boc酸酐-图7.png

Figure seven


Under acidic conditions, the mechanism of deprotection is shown in Figure 8. Protic acid activates the tert-butoxycarbonyl group, releasing carbon dioxide to give the corresponding amine as well as the tert-butyl cation. Rearrangement of the tert-butyl cation gives isobutene. When the system contains alcohol or carboxylic acid, it can be captured by tert-butyl cations to obtain the corresponding by-products.


Boc酸酐-图8.png

Figure eight


This article briefly introduces the properties of Boc-anhydride, as well as some precautions when it is used as a Boc protecting group for introduction and removal.

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references:

[1] Chankeshwara, SV; Chakraborti, AK Org. Lett. 2006, 8, 3259-3262.

[2] Niu, X.; Joseph, A. Bioorg. Med. Chem. Lett, 2010, 20, 4812-4815.

[3] Li, J. ; Smith, D. ; Wong, HS ; Campbell, JA ; Meanwell , NA ;  

Synlett, 2006, 5, 725-728.

[4] WO2012/22792, 2012, A1.

[5] Tirayut, V. Terahedron Lett. 2006, 47, 6739-6742.

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