In the past 20 years, high-valent iodine reagents as oxidants have attracted more and more chemists' attention because of their mild reaction conditions, high yield, good selectivity and environmental friendliness. 1,1,1-triaethoxy-1,1-dihydroxy-1,2-phenyliodyl-3 (1H) - one (DMP) is a typical high-valent iodine reagent, which has been widely used in organic synthesis.
1. Reaction of IBX with alcohol
1) Reaction of IBX with alcohol in DMSO: Oxidation of hydroxyl to carbonyl is a very important conversion reaction in organic synthesis. There are many ways to achieve this conversion under different experimental conditions. In DMSO or DMSO/THF solution, IBX can quickly oxidize primary and secondary alcohols to aldehydes and ketones respectively at room temperature, while primary alcohols will not be further oxidized to form carboxylic acids, effectively eliminating the generation of by-product carboxylic acids. Under the same conditions, IBX oxidizes 1,2-diol to obtain α- Ketone alcohol or α- The C-C bond of 1,2-diol was not oxidized. In the reaction process, it is not necessary to protect the amino group and not destroy the heterocycles such as furan, pyridine and indole, and the functional groups such as silyl ether, thioether, allyl, alkene, alkyne, acetal, ketone mercaptal, ester group and amide group are not affected in the reaction:
Benzyl, allyl, propargyl alcohol and glycol can be obtained by oxidation of IBX in one reactor in the presence of stable Wittig reagent α，β- Unsaturated esters. This method is particularly useful if the intermediate aldehyde is unstable or difficult to separate:
The oxidation reaction of IBX to alcohol is usually carried out in DMSO or DMSO/THF solution. Simply heating (80 ℃) the mixture of alcohol, IBX and organic solvents, such as ethyl acetate, chloroform, benzene, acetonitrile, acetone, dichloromethane, can oxidize the primary alcohol and secondary alcohol to corresponding aldehydes and ketones; After the reaction, the insoluble by-products and solvents can be filtered to obtain corresponding carbonyl compounds with a yield of 90%~100%.
2) Reaction of IBX with alcohol in solvent-free condition: In solvent-free condition, IBX reacts with primary alcohol (1.25 ∶ 1, mass ratio of substance) at 60~70 ℃ to obtain corresponding aldehyde, with yield of 72%~95%. If the amount of IBX is too much, or the reaction temperature is higher than 90 ℃, some aldehydes will be oxidized to carboxylic acid. Under the same conditions, secondary alcohols are oxidized to corresponding ketones, and the yield is relatively high. However, under solvent-free conditions, IBX is limited to oxidation of allyl alcohol and benzyl alcohol, and aliphatic alcohol does not react. In addition, it is only suitable for small dose reactions
In large-scale synthesis reaction; If the reaction temperature is relatively high, there is a risk of explosion.
3) Reaction of direct oxidation of primary alcohol by IBX to carboxylic acid: oxidation of primary alcohol by IBX in DMSO to obtain phase
Aldehydes will not be further oxidized to carboxylic acid. However, in the presence of O-nucleophilic reagents such as 2-hydroxypyridine (HYP), N-hydroxysuccinimide (NHS) or 1-hydroxybenzotriazole (HOBt), IBX can directly oxidize the primary alcohol to carboxylic acid at room temperature, with a yield of 64%~95%. Using this reaction, N-protected β- Amino alcohols are directly oxidized to corresponding amino acids without racemization:
2. Reaction of IBX with nitrogen-containing organic compounds
1) Application of IBX in the ring closing reaction of unsaturated N-arylamide, carbamate and urea: The methods of constructing C-N bond include: substitution of O-functional group by N-nucleophilic reagent, rearrangement of carbonyl functional group, reduction and amination, etc. However, the method of directly connecting N to C without O connection without producing harmless by-products is not to use IBX to react with unsaturated N-arylamide, carbamate and urea to obtain various nitrogen-containing five-membered heterocyclic compounds. By this method, the N-functional group is selectively connected to the non-activated alkene bond
Form a new C-N key. This is in synthesis γ- There are ingenious applications in important structural units and intermediates such as lactam, cyclic carbamate and aminosugar:
2) Application of IBX in the oxidative dehydrogenation of amines: The oxidation of amines to imines is a very useful conversion. There are many related literature reports, but each method has some major defects. In organic synthesis, there is a lack of a mild and universal method of oxidizing amine, which is very strange, because the structural units such as imines and oximes can be easily prepared by the oxidation of amine, and these structural units have important applications in the synthesis of many heterocyclic compounds. Therefore, the reaction of IBX with benzylamine was studied. It was found that IBX can oxidize secondary amine to imine under very mild conditions. The reaction time was short, and the yield was high, with selectivity.
3) The application of IBX in the aromatization reaction of nitrogen-containing heterocyclic compounds: many natural products and drugs with biological activities are nitrogen-containing heterocyclic compounds, so the synthetic methods of nitrogen-containing aromatic heterocyclic compounds have attracted wide attention of chemists. Using IBX, substituted aromatic heterocyclic compounds such as imidazole, isoquinoline, pyridine and pyrrole can be synthesized from cyclic amines:
3. Reaction of IBX with sulfur-containing organic compounds
1) IBX sulfide oxide is sulfoxide: it is a very useful compound. Through a series of reactions
To convert sulfoxide into many organic sulfides, which are very useful in the synthesis of drugs and natural products of sulfur. To oxidize sulfide to sulfoxide, the reaction conditions should be strictly controlled, including the oxidant
To reduce the formation of by-product sulfone. In the presence of a catalytic amount of tetraethyl ammonium bromide (TEAB), the thioether is oxidized by IBX to obtain sulfoxide, and the yield is almost quantitative. The formation of sulfoxide is not observed. If TEAB is not added, the reaction is relatively slow, requiring 12-36 hours.
2) Application of IBX in deprotection reaction of thioacetals (ketones): conversion of carbonyl to thioacetals (aldehydes) is a common method to protect carbonyl. However, it is difficult to protect them
The method requires harsh oxidation conditions or mercury salts, so it is necessary to find a mild reagent with low toxicity. Acetone-water (2:15, V ∶ V) as solvent β- Cyclodextrin（ β- Under the catalysis of CD), IBX is used to hydrolyze thioketal (aldehyde) to corresponding carbonyl compounds. The reaction can be carried out at room temperature with a yield of 85%~94%. In addition, halogen atoms, nitroso, hydroxyl, alkoxy, conjugated double bonds, etc. are not affected in the reaction.
4. Preparation of IBX oxidation aldehyde and ketone α，β- unsaturated carbonyl compounds
In organic chemistry α，β- Unsaturated carbonyl compounds are a kind of common and useful compounds, but their synthesis is sometimes a complex and difficult work. In the past, there have been many reports about their synthesis methods. A common method is to prepare enol silyl ether from carbonyl compounds, and then use palladium to catalyze oxidation α，β- Unsaturated carbonyl compounds. Another method is to use selenium reagent to prepare through one or two steps of reaction. By adjusting the amount of IBX, reaction temperature and reaction time, products with different saturations can be obtained:
5. Application of IBX in the preparation of lactones
Lactone can be prepared by oxidation of internal hemiacetal. The inner hemiacetal is insoluble or slightly soluble in most organic solvents, but soluble in DMSO. Using DMSO as solvent and IBX at room temperature
Oxidation of 1,4-diol γ- The yield of internal hemiacetal is 60% - 88%, but there is no lactone. They think it may be due to the large steric hindrance. Using ethyl acetate/DMSO (9 ∶ 1, V ∶ V) as solvent, heated and refluxed, IBX oxidized the inner hemiacetal to obtain lactone in a yield of 66%~91%.
6. IBX oxidizes carbon atoms attached to aromatic rings
The C atom attached to the aromatic ring is an electron-rich site, which can be oxidized to carbonyl by IBX. This method can be used to construct a carbonyl group at the position where the aromatic ring is attached. Dissolve the reaction substrate and IBX in fluorobenzene/DMSO (2 ∶ 1, V ∶ V) or pure DMSO, heat to 80~90 ° C, and the reaction can proceed with high yield and few by-products.
7. Other examples of successful application of IBX in organic synthesis
α- Hydroxyl ketone and α- Aminoketones are important synthetic intermediates in organic and pharmaceutical chemistry. stay β- In the presence of cyclodextrin, using water as solvent, IBX oxidizes epoxy compounds and azacyclopropane to obtain α- Hydroxyl ketone and α- Amino ketone. This is a one-step synthesis of azacyclopropane α- The first example of aminoketone:
α- Functionalized ketones are very useful intermediates in the synthesis of many heterocyclic compounds, natural products and related compounds. The compound o-iodobenzoic acid-1-o-iodobenzyloxy-2-oxoarylethyl ester was synthesized by using IBX in the presence of potassium iodide: