Bamford–Stevens reaction
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The Bamford–Stevens reaction is a
chemical reaction A chemical reaction is a process that leads to the IUPAC nomenclature for organic transformations, chemical transformation of one set of chemical substances to another. Classically, chemical reactions encompass changes that only involve the pos ...
whereby treatment of tosylhydrazones with strong base gives
alkene In organic chemistry, an alkene is a hydrocarbon containing a carbon–carbon double bond. Alkene is often used as synonym of olefin, that is, any hydrocarbon containing one or more double bonds.H. Stephen Stoker (2015): General, Organic, an ...
s. It is named for the British chemist William Randall Bamford and the Scottish chemist Thomas Stevens Stevens (1900–2000). The usage of aprotic solvents gives predominantly Z-
alkene In organic chemistry, an alkene is a hydrocarbon containing a carbon–carbon double bond. Alkene is often used as synonym of olefin, that is, any hydrocarbon containing one or more double bonds.H. Stephen Stoker (2015): General, Organic, an ...
s, while
protic solvent In chemistry, a protic solvent is a solvent that has a hydrogen atom bound to an oxygen (as in a hydroxyl group ), a nitrogen (as in an amine group or ), or fluoride (as in hydrogen fluoride). In general terms, any solvent that contains a labile ...
gives a mixture of E- and Z-alkenes. As an alkene-generating transformation, the Bamford–Stevens reaction has broad utility in synthetic methodology and complex molecule synthesis. The treatment of tosylhydrazones with alkyl lithium reagents is called the
Shapiro reaction The Shapiro reaction or tosylhydrazone decomposition is an organic reaction in which a ketone or aldehyde is converted to an alkene through an intermediate hydrazone in the presence of 2 equivalents of organolithium reagent. The reaction was disc ...
.


Reaction mechanism

The first step of the Bamford–Stevens reaction is the formation of the diazo compound 3. (''also in th
Collective Volume (1990) 7:438
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In protic solvents, the diazo compound 3 decomposes to the carbenium ion 5. In aprotic solvents, the diazo compound 3 decomposes to the carbene 7.


Directed Bamford-Stevens reaction

The Bamford–Stevens reaction has not proved useful for the stereoselective generation of alkenes via
thermal decomposition Thermal decomposition, or thermolysis, is a chemical decomposition caused by heat. The decomposition temperature of a substance is the temperature at which the substance chemically decomposes. The reaction is usually endothermic as heat is re ...
of metallated tosylhydrazones due to the indiscriminate 1,2-rearrangement of the carbene center, which gives a mixture of products. By replacing an alkyl group with a trimethylsilyl (TMS) group on N-aziridinylimines, migration of a specific hydrogen atom can be enhanced. With the
silicon Silicon is a chemical element with the symbol Si and atomic number 14. It is a hard, brittle crystalline solid with a blue-grey metallic luster, and is a tetravalent metalloid and semiconductor. It is a member of group 14 in the periodic ta ...
atom beta to H, a σC-Si → σ*C-H
stereoelectronic effect In chemistry, primarily organic and computational chemistry, a stereoelectronic effectAlabugin, I. V. Stereoelectronic Effects: the Bridge between Structure and Reactivity. John Wiley & Sons Ltd, Chichester, UK, 2016. http://eu.wiley.com/WileyCDA/W ...
weakens the C-H bond, resulting in its exclusive migration and leading to the nearly exclusive formation of allylsilanes instead of equal amounts of allylsilanes and isomeric homoallylsilanes, analogous to the mixture of products seen in the dialkyl case, or other insertion products (i.e. cyclopropanes). See
beta-silicon effect The beta-silicon effect also called silicon hyperconjugation in organosilicon chemistry is a special type of hyperconjugation that describes the stabilizing influence of a silicon atom on the development of positive charge at a carbon atom one pos ...
.


Synthesis of 3-substituted indazoles from arynes and N-tosylhydrazones

''N''-tosylhydrazones can be used in a variety of synthetic procedures. Their use with arynes has been used to prepare 3-substituted indazoles via two proposed pathways. The first step is the deprotonation of the hydrazone of diazo compounds using CsF. At this point, the conjugate base could either decompose to give the diazo compound and undergo a +2dipolar
cycloaddition In organic chemistry, a cycloaddition is a chemical reaction in which "two or more unsaturated molecules (or parts of the same molecule) combine with the formation of a cyclic adduct in which there is a net reduction of the bond multiplicity". T ...
with the
aryne Arynes and benzynes are highly reactive species derived from an aromatic ring by removal of two substituents. Arynes are examples of didehydroarenes (1,2-didehydroarenes in this case), although 1,3- and 1,4-didehydroarenes are also known. Arynes a ...
to give the product, or a +2
annulation In organic chemistry annulation (from the Latin ''anellus'' for "little ring"; occasionally annelation) is a chemical reaction in which a new ring is constructed on a molecule. : Examples are the Robinson annulation, Danheiser annulation and ce ...
with aryne which would also give the final product. While strong bases, such as LiOtBu and Cs2CO3 are often used in this chemistry, CsF was used to facilitate the in situ generation of arynes from o-(trimethylsilyl)aryl triflates. CsF was also thought to be sufficiently basic to deprotonate the N-tosylhydrazone.


''N''-tosylhydrazones as reagents for cross-coupling reactions

Barluenga and coworkers developed the first example of using N-tosylhydrazones as
nucleophilic In chemistry, a nucleophile is a chemical species that forms bonds by donating an electron pair. All molecules and ions with a free pair of electrons or at least one pi bond can act as nucleophiles. Because nucleophiles donate electrons, they are ...
partners in cross-coupling reactions. Typically, nucleophilic reagents in
coupling reactions A coupling reaction in organic chemistry is a general term for a variety of reactions where two fragments are joined together with the aid of a metal catalyst. In one important reaction type, a main group organometallic compound of the type R-M (R = ...
tend to be of the organometallic variety, namely organomagnesium, -zinc, -tin, -silicon, and –boron. Combined with electrophilic aryl halides, N-tosylhydrazones can be used to prepare polysubstituted olefins under Pd-catalyzed conditions without the use of often expensive, and synthetically demanding organometallic reagents.
The scope of the reaction is wide; N-tosylhydrazones derived from aldehydes and ketones are well tolerated, which leads to both di- and trisubstituted olefins. Moreover, and variety of aryl halides are well tolerated as coupling partners including those bearing both electron-withdrawing and electron-donating groups, as well as π-rich and π-deficient
aromatic In chemistry, aromaticity is a chemical property of cyclic ( ring-shaped), ''typically'' planar (flat) molecular structures with pi bonds in resonance (those containing delocalized electrons) that gives increased stability compared to satur ...
heterocyclic compounds. Stereochemistry is an important element to consider when preparing polysubstituted olefins. Using hydrazones derived from linear aldehydes resulted in exclusively trans olefins, while the stereochemical outcomes of trisubstituted olefins were dependent on the size of the substituents.
The mechanism of this transformation is thought to proceed in a manner similar to the synthesis of alkenes through the Bamford–Stevens reaction; the decomposition of N-tosylhydrazones in the presence of base to generate diazocompounds which then release nitrogen gas, yielding a carbene, which then can be quenched with an electrophile. In this case, the coupling reaction starts with the
oxidative addition Oxidative addition and reductive elimination are two important and related classes of reactions in organometallic chemistry. Oxidative addition is a process that increases both the oxidation state and coordination number of a metal centre. Oxid ...
of the aryl halide to Pd0 catalyst to give the aryl PdII complex. The reaction of the diazocompound, generated from the hydrazone, with the PdII complex produces a Pd-carbene complex. A
migratory insertion In organometallic chemistry, a migratory insertion is a type of reaction wherein two ligands on a metal complex combine. It is a subset of reactions that very closely resembles the insertion reactions, and both are differentiated by the mechanis ...
of the aryl group gives an alkyl Pd complex, which undergoes syn beta-hydride elimination to generate the trans aryl olefin and regenerate the Pd0 catalyst. This reaction has also seen utility in preparing conjugated enynes from N-tosylhydrazones and terminal alkynes under similar Pd-catalyzed reaction conditions and following the same mechanism.
Moreover, Barluenga and coworkers demonstrated a one-pot three-component coupling reaction of aldehydes or ketones, tosylhydrazides, and aryl halides in which the ''N''-tosylhydrazone is formed in situ. This process produces stereoselective olefins in similar yields compared to the process in which preformed ''N''-tosylhydrazones are used. Barluenga and coworkers also developed metal-free reductive coupling methodology of N-tosylhydrazones with boronic acids. The reaction tolerates a variety of functional groups on both substrates, including aromatic, heteroaromatic, aliphatic, electron-donating and electron-withdrawing substituents, and proceeds with high yields in the presence of potassium carbonate. The reaction is thought to proceed through the formation of a diazo compound that is generated from a hydrazone salt. The diazo compound could then react with the boronic acid to produce the benzylboronic acid through a boronate intermediate. An alternate pathway consists of the formation of the benzylboronic acid via a zwitterionic intermediate, followed by protodeboronation of the benzylboronic acid under basic conditions, which results in the final reductive product. This methodology has also been extended to heteroatom nucleophiles to produce ethers and thioethers.


A tandem rhodium-catalyzed Bamford-Stevens/thermal aliphatic Claisen rearrangement

A novel process was developed by Stoltz in which the Bamford–Stevens reaction was combined with the
Claisen rearrangement The Claisen rearrangement is a powerful carbon–carbon bond-forming chemical reaction discovered by Rainer Ludwig Claisen. The heating of an allyl vinyl ether will initiate a ,3sigmatropic rearrangement to give a γ,δ-unsaturated carbonyl, ...
to produce a variety of olefin products. This transformation proceeds first by the thermal decomposition of N-aziridinylhydrazones to form the diazo compound (1), followed by a rhodium-mediated de-diazotization (2) and the syn 1,2-
hydride shift A sigmatropic reaction in organic chemistry is a pericyclic reaction wherein the net result is one σ-bond is changed to another σ-bond in an uncatalyzed intramolecular reaction. The name ''sigmatropic'' is the result of a compounding of the lon ...
(3). This substrate undergoes a thermal aliphatic
Claisen rearrangement The Claisen rearrangement is a powerful carbon–carbon bond-forming chemical reaction discovered by Rainer Ludwig Claisen. The heating of an allyl vinyl ether will initiate a ,3sigmatropic rearrangement to give a γ,δ-unsaturated carbonyl, ...
(4) to yield the product.


Application to total synthesis

Trost et al. utilized the Bamford–Stevens reaction in their
total synthesis Total synthesis is the complete chemical synthesis of a complex molecule, often a natural product, from simple, commercially-available precursors. It usually refers to a process not involving the aid of biological processes, which distinguishes i ...
of (–)-isoclavukerin to introduce a
diene In organic chemistry a diene ( ) (diolefin ( ) or alkadiene) is a covalent compound that contains two double bonds, usually among carbon atoms. They thus contain two alk''ene'' units, with the standard prefix ''di'' of systematic nomenclature. ...
moiety found in the natural product. A bicyclic trisylhydrazone was initially subjected to
Shapiro reaction The Shapiro reaction or tosylhydrazone decomposition is an organic reaction in which a ketone or aldehyde is converted to an alkene through an intermediate hydrazone in the presence of 2 equivalents of organolithium reagent. The reaction was disc ...
conditions (alkyllithiums or LDA), which only led to uncharacterizable decomposition products. When this bicyclic trisylhydrazone was subjected to strong base (KH) and heat, however, the desired diene product was generated. Moreover, it was shown that olefin generation and the following decarboxylation could be performed in one pot. To that end, excess NaI was added, along with an elevation in temperature to facilitate the Krapcho decarboxylation.


References


See also

*
Shapiro reaction The Shapiro reaction or tosylhydrazone decomposition is an organic reaction in which a ketone or aldehyde is converted to an alkene through an intermediate hydrazone in the presence of 2 equivalents of organolithium reagent. The reaction was disc ...
{{DEFAULTSORT:Bamford-Stevens Reaction Olefination reactions Elimination reactions Name reactions