A Scalable Metal-, Azide-, and Halogen-Free Method for the Preparation of Triazoles.

A scalable metal-, azide-, and halogen-free method for the synthesis of substituted 1,2,3-triazoles has been developed. The reaction proceeds through a 3-component coupling of α-ketoacetals, tosyl hydrazide, and a primary amine. The reaction shows outstanding functional-group tolerance with respect to both the α-ketoacetal and amine coupling partners, providing access to 4-, 1,4-, 1,5-, and 1,4,5-substituted triazoles in excellent yield. This robust method results in densely functionalised 1,2,3-triazoles that remain challenging to prepare by azide-alkyne cycloaddition (AAC, CuAAC, RuAAC) methods and can be scaled in either batch or flow reactors. Methods for the chemoselective reaction of either aliphatic amines or anilines are also described, revealing some of the potential of this novel and highly versatile transformation.

Synthesis of small molecules with high scaffold diversity: exploitation of metathesis cascades in combination with inter- and intramolecular Diels-Alder reactions.

Our knowledge of the biological relevance of regions of chemical space is shaped, in large part, by the synthetic accessibility of small molecules. Historically, however, chemists have explored chemical space in an exceptionally uneven and unsystematic way. We have previously demonstrated that metathesis cascade chemistry may be harnessed to yield small molecule collections with high scaffold diversity. Here, we describe the extent to which inter- and intramolecular Diels-Alder reactions, when used in conjunction with metathesis cascades, can extend the range of molecular scaffolds that are accessible. A range of metathesis substrates was prepared from combinations of two or three building blocks. Metathesis cascades were exploited to "reprogram" the molecular scaffolds. In many cases, the metathesis products were 1,3-dienes, which were potential substrates for either inter- or intramolecular Diels-Alder reactions. The synthesis and functionalisation of the products was often facilitated by fluorous tagging, for example by using a "safety-catch" linker that we have developed. It was demonstrated that, in certain cases, Diels-Alder reactions could extend the range of molecular scaffolds that may be prepared by using metathesis cascade reactions.

A fluorous-tagged "safety catch" linker for preparing heterocycles by ring-closing metathesis.

A fluorous-tagged "safety catch" linker is described for the synthesis of heterocycles with use of ring-closing metathesis. The linker facilitates the purification of metathesis substrates, the removal of the catalyst, the functionalization of the products, and the release of only metathesis products. The synthesis of a range of heterocycles is described.

Rapid generation of molecular complexity using "hybrid" multi-component reactions (MCRs): application to the synthesis of alpha-amino nitriles and 1,2-diamines.

Methyleneaziridines can be converted into a wide range of 1,2-diamines and 2-cyanopiperidines in a single operation with the formation of three intermolecular carbon-carbon bonds using a "hybrid" MCR.

Rare example of nucleophilic substitution at vinylic carbon with inversion: mechanism of methyleneaziridine formation by sodium amide induced ring closure revisited.

Intramolecular nucleophilic substitution of the C-Br bond of (E)- and (Z)-2-bromobut-2-enylamines by the pendant nitrogen atom leads to 2-ethyleneaziridines by way of stereochemical inversion at the vinylic carbon atom. The stereochemistry of the products is unambiguously established by X-ray crystallography performed on two derivatives. These cyclizations represent some of the first examples of substitution with inversion in unactivated vinylic substrates. In conjunction with additional deuterium-labeling experiments, the accepted mechanism for this reaction is shown to be flawed.

Multicomponent reactions involving 2-methyleneaziridines: rapid synthesis of 1,3-disubstituted propanones.

Ring opening of 1-alkyl-2-methyleneaziridines 1 or 2 is accomplished with organocopper reagents (R(2)CuLi or RMgX/CuI) in the presence of boron trifluoride diethyl etherate giving 1-substituted propan-2-ones 3-9 in 42-88% yield. Ring opening with RMgCl/CuI in the absence of the Lewis acid allows further alkylation of the metalloenamine (metalated imine) intermediate in a regiocontrolled manner. The sequential formation of two new intermolecular carbon-carbon bonds in this reaction provides a rapid entry into a variety of 1,3-disubstituted propan-2-ones, including 11 and 14-23. The scope and mechanism of this multicomponent reaction (MCR) has been assessed. It is established that this MCR tolerates alkyl, aryl, and benzylic Grignard reagents and a wide range of electrophiles, including alkyl iodides, bromides, and tosylates, as well as epoxides and aldehydes. In addition, gem-dimethyl substitution on the exocyclic double bond of the 2-methyleneaziridine is tolerated. This MCR has been applied to the one-pot synthesis of (Z)-6-heneicosen-11-one, 25, an important sex attractant of the Tussock moth. Using 3-deuterio-1-(1-phenylethyl)-2-methyleneaziridine, 26, we determined that this MCR occurs predominantly by direct ring opening at the sp(3)-hybridized aziridine carbon atom (C-3).