Iodine-catalyzed guanylation of amines with N,N'-di-Boc-thiourea.

Herein, we report that iodine-catalyzed guanylation of primary amines can be accomplished with N,N'-di-Boc-thiourea and TBHP to afford the corresponding guanidines in 40-99% yields. Oxidation of the HI byproduct by TBHP eliminates the need for an extra base to prevent the protonation of substrates and makes the reaction especially useful for both electronically and sterically deactivated primary anilines.

Molecular Iodine-Mediated α-C-H Oxidation of Pyrrolidines to N,O-Acetals: Synthesis of (±)-Preussin by Late-Stage 2,5-Difunctionalizations of Pyrrolidine.

We previously reported an iterative synthesis of unsymmetrical 2,5-disubstituted pyrrolidines from pyrrolidine by two rounds of redox-triggered α-C-H functionalization. Although this approach can be used to introduce substituents at the 2- and 5-positions, it is lengthy because the redox auxiliary must be removed and then reinstalled. Therefore, we sought to develop a method to oxidize 2-functionalized pyrrolidine to cyclic N,O-acetal which could then react with a nucleophile for introduction of the 5-substituent. In this work, we found that molecular iodine can mediate the preferential oxidation of secondary over tertiary α-C-H bonds of α-substituted pyrrolidines to form cyclic N,O-acetals, improving the step economy of our previously reported method. With this strategy, (±)-preussin and its C(3) epimer were synthesized from (±)-pyrrolidin-3-ol.

Synthesis of γ-Lactams by Mild, o-Benzoquinone-Induced Oxidation of Pyrrolidines Containing Oxidation-Sensitive Functional Groups.

The late-stage oxidation of substituted pyrrolidines offers good flexibility for the construction of γ-lactam libraries, and especially in recent years the methods for functionalization of pyrrolidine have been available. We reported a new strategy for oxidation of pyrrolidines to γ-lactams: reaction of pyrrolidine with an o-benzoquinone gives an N,O-acetal by direct oxidation of the α-C-H bond of the pyrrolidine ring, and then the N,O-acetal is further oxidized by the o-benzoquinone to the γ-lactam. Because the first oxidation occurs selectively at the α-C-H of the pyrrolidine ring, oxidation-sensitive functional groups (allyl-, vinyl-, hydroxyl-, and amino groups) on pyrrolidine ring are unaffected. The synthetic utility of this novel method was demonstrated by the facile syntheses of (S)-vigabatrin and two analogues.

Redox-Triggered α-C-H Functionalization of Pyrrolidines: Synthesis of Unsymmetrically 2,5-Disubstituted Pyrrolidines.

By using o-benzoquinone as an internal oxidant, the regio- and diastereoselective functionalization of the secondary over the tertiary α-C-H bond of 2-substituted pyrrolidines is first realized. Subsequent intermolecular addition of a nucleophile to the generated N,O-acetal and cleavage of the aromatic substituent leads to 2,5-disubstituted pyrrolidines.