Bamford–Stevens Reaction

In the Bamford–Stevens reaction, the carbene centre is indiscriminately 1, 2-rearranged, resulting in a mixture of alkene products, making it ineffective for stereoselective production of alkenes by thermal breakdown of metallated Tosylhydrazones. Hydrogen migration can be improved by substituting an alkyl group for a trimethylsilyl (TMS) group on N-Aziridinyl Imines. Stereoelectronic effects on the C-H bond weaken the C-Si bond, resulting in the exclusive migration of the C-H bond, leading to nearly exclusive formation of allylsilanes instead of equal amounts of allylsilanes isomeric Homoallylsilanes, as in the dialkyl case, or other insertion products (i.e. cyclopropanes).

Reaction mechanism

It was established that the N-Tosylhydrazone could be generated in situ during the three-component coupling of aldehyde or ketones, Tosylhydrazones, and aryl halides. The yields of stereoselective olefins produced by this method are comparable to those produced using premade N-Tosylhydrazones.

N-Tosylhydrazones and boronic acids are reductively coupled. There is a wide range of functional groups on both substrates that can be tolerated by the reaction. This includes the aliphatic groups as well as the aromatic, heteroaromatic, and aliphatic groups. A hydrazone salt is assumed to be the catalyst for the reaction, which leads to the creation of a diazo molecule. To make Benzylboronic acid, the diazo molecule would first react with a boronic acid intermediate. When the Benzylboronic acid is reductively deboronated, the zwitterionic intermediate is converted into the final reductive product by protodeboronation under basic circumstances.

A diazo intermediate is used to initiate the reaction, and from there, one of two possible mechanisms can be followed. This approach can also be used to synthesise ethers and thioethers from heteroatom nucleophiles.

Stoltz invented a new method for synthesising a wide spectrum of olefins by combining the Bamford–Stevens reaction with the Claisen rearrangement. First, the N-Aziridinylhydrazones are thermally decomposed to create the diazo compound, which is then de-diazotized by rhodium and undergoes the syn 1, 2-hydride shift. The product is formed through a Claisen rearrangement of this substrate. The Claisen Rearrangement and the Bamford-Stevens reaction work together to synthesise a wide range of olefins. The hydrolysis reaction is the reversal of the formation reaction, and the carbonyl molecule is regenerated in the process.

Cross-coupling processes with N-Tosylhydrazone reagents

N-Tosylhydrazones were initially used as nucleophiles in cross-coupling processes by Barluenga and coworkers. Organometallic reagents, including organomagnesium, organozinc, organotin, organosilicon, and organoboron, are the most common nucleophilic reagents used in coupling processes. It is possible to synthesise polysubstituted olefins using N-Tosylhydrazones and electrophilic aryl halides under Pd-catalysed conditions without using expensive and time-consuming organometallic reagents.

Since both aldehydes and ketones can be used as N-Tosylhydrazone sources, the process can produce di- and trisubstituted olefins. A wide range of aromatic heterocyclic compounds, including those with electron-withdrawing and electron-donating groups and aryl halides, are permitted as coupling partners, including those containing both. When making polysubstituted olefins, stereochemistry must be taken into account. For trans olefins only, hydrazones produced from linear aldehydes were used, while trisubstituted olefins’ stereochemical outcomes were determined by their substituent sizes.

According to the theory, the breakdown of N-Tosylhydrazones in the presence of base generates diazo-compounds, which subsequently liberate nitrogen gas and provide a carbene, which can then be quenched with an electrophile behind this transition. In this scenario, the coupling reaction starts with the oxidative addition of the aryl halide to the Pd0 catalyst to give the aryl PdII complex. Carbene complexes are formed when the PdII complex reacts with Diazo Compounds produced from the hydrazone. Syn beta-hydride elimination of an alkyl Pd complex generates the trans aryl olefin and the Pd0 catalyst, which is then recycled. N-Tosylhydrazone. Terminal alkynes can also be used to synthesise conjugated enynes using the same Pd-catalysed conditions and follow the same reaction process.

Cyclopropanation

Certain cross-coupling reactions can also use Tosylhydrazones as starting ingredients. In the original publication on this reaction type, the coupling partners were a Tosylhydrazone, an aryl halide with catalyst system Dibenzylideneacetone. As part of the catalytic cycle, the diazo intermediate formed by the breakdown of the Tosylhydrazone produces a palladium-carbene complex with the oxidative addition complex of palladium with the aryl halide. The use of this potent technique can obtain bioactive molecules.

Tosylhydrazones

Tosylhydrazones are employed as a leaving group in elimination reactions in the Shapiro reaction. A solid substrate is required for this reaction. The Bamford–Stevens reaction occurs when sodium methoxide is used as the base. Reagents such as sodium borohydride and borane can be used to convert Tosylhydrazones to alkanes. Tosylhydrazone salts can react with metals to generate metal carbenes and are employed in cyclopropanations and epoxidations. The synthesis of tranylcypromine is an example of a transition metal-catalysed cyclopropanation. The sodium salt of benzaldehyde tosylhydrazone is transformed into a rhodium metal carbene through the diazo intermediate.

Conclusion

It is possible to use N-Tosylhydrazones in a wide range of synthetic processes. To create 3-substituted indazoles through one of two proposed routes, they were combined with arynes. The hydrazone of diazo compounds is first deprotonated with CsF. Alternatively, the conjugate base might undertake a [3+2] dipolar cycloaddition with the aryne and yield the diazo compound, or undergo an [3+2] annulation with the aryne and yield the end product. CsF was employed to promote the in-situ synthesis of arynes, where strong bases such as LiOtBu and Cs2CO3 are commonly used in this chemistry. Deprotonation of the N-Tosylhydrazone is also possible with CsF.