The Ferrier carbocyclization (or Ferrier II reaction) is an

organic reaction Organic reactions are chemical reactions involving organic compounds. The basic organic chemistry reaction types are addition reactions, elimination reactions, substitution reactions, pericyclic reactions, rearrangement reactions, photochemical rea ...

that was first reported by the

carbohydrate In organic chemistry, a carbohydrate () is a biomolecule consisting of carbon (C), hydrogen (H) and oxygen (O) atoms, usually with a hydrogen–oxygen atom ratio of 2:1 (as in water) and thus with the empirical formula (where ''m'' may or ...

chemist

Robert J. Ferrier Robert John Ferrier FRSNZ, FNZIC, (7 August 1932 – 11 July 2013) was an organic chemist who discovered two chemical reactions, the Ferrier rearrangement and the Ferrier carbocyclization. Originally from Edinburgh, he moved to Wellington, New Ze ...

in 1979. It is a

metal A metal (from Greek μέταλλον ''métallon'', "mine, quarry, metal") is a material that, when freshly prepared, polished, or fractured, shows a lustrous appearance, and conducts electricity and heat relatively well. Metals are typi ...

-mediated rearrangement of

enol ether In organic chemistry an enol ether is an alkene with an alkoxy substituent. The general structure is R2C=CR-OR where R = H, alkyl or aryl. A common subfamily of enol ethers are vinyl ethers, with the formula ROCH=CH2. Important enol ethers includ ...

pyran In chemistry, pyran, or oxine, is a six-membered heterocyclic, non-aromatic ring, consisting of five carbon atoms and one oxygen atom and containing two double bonds. The molecular formula is C5H6O. There are two isomers of pyran that differ by th ...

s to

cyclohexanone Cyclohexanone is the organic compound with the formula (CH2)5CO. The molecule consists of six-carbon cyclic molecule with a ketone functional group. This colorless oily liquid has an odor reminiscent of acetone. Over time, samples of cyclohex ...

s. Typically, this reaction is catalyzed by mercury salts, specifically mercury(II) chloride. Ferrier carbocyclization

Several reviews have been published.

Reaction mechanism

Ferrier proposed the following reaction mechanism: Ferrier carbocyclization mech

In this mechanism, the terminal

olefin 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 ...

undergoes hydroxymercuration to produce the first intermediate, compound 2, a

hemiacetal A hemiacetal or a hemiketal has the general formula R1R2C(OH)OR, where R1 or R2 is hydrogen or an organic substituent. They generally result from the addition of an alcohol to an aldehyde or a ketone, although the latter are sometimes called hemike ...

. Next, methanol is lost and the dicarbonyl compound cyclizes through an attack on the

electrophilic In chemistry, an electrophile is a chemical species that forms bonds with nucleophiles by accepting an electron pair. Because electrophiles accept electrons, they are Lewis acids. Most electrophiles are positively charged, have an atom that car ...

aldehyde to form the carbocycle as the product. A downside to this reaction is that the loss of CH₃OH at the

anomer In carbohydrate chemistry, a pair of anomers () is a pair of near-identical stereoisomers that differ at only the anomeric carbon, the carbon that bears the aldehyde or ketone functional group in the sugar's open-chain form. However, in order f ...

ic position (carbon-1) results in a mixture of α- and β-anomers. The reaction also works for substituted alkenes (e. g. having an -O Ac group on the terminal alkene). Ferrier also reported that the final product, compound 5, could be converted into a conjugated ketone (compound 6) by reaction with

acetic anhydride Acetic anhydride, or ethanoic anhydride, is the chemical compound with the formula (CH3CO)2O. Commonly abbreviated Ac2O, it is the simplest isolable anhydride of a carboxylic acid and is widely used as a reagent in organic synthesis. It is a c ...

(Ac₂O) and

pyridine Pyridine is a basic (chemistry), basic heterocyclic compound, heterocyclic organic compound with the chemical formula . It is structurally related to benzene, with one methine group replaced by a nitrogen atom. It is a highly flammable, weakl ...

, as shown below. Ferrier carbocyclization 2

Modifications

In 1997, Sinaÿ and co-workers reported an alternative route to the synthesis (shown below) that did not involve cleavage of the bond at the anomeric position (the

glycosidic bond A glycosidic bond or glycosidic linkage is a type of covalent bond that joins a carbohydrate (sugar) molecule to another group, which may or may not be another carbohydrate. A glycosidic bond is formed between the hemiacetal or hemiketal gr ...

). In this case, the major product formed had maintained its original configuration at the anomeric position. Sinay modification

(Bn =

benzyl In organic chemistry, benzyl is the substituent or molecular fragment possessing the structure . Benzyl features a benzene ring () attached to a methylene group () group. Nomenclature In IUPAC nomenclature, the prefix benzyl refers to a subst ...

, ''i''-Bu =

isobutyl In organic chemistry, butyl is a four-carbon alkyl radical or substituent group with general chemical formula , derived from either of the two isomers (''n''-butane and isobutane) of butane. The isomer ''n''-butane can connect in two ways, givi ...

)

Sinaÿ proposed this reaction went through the following transition state: Sinay transition state

Sinaÿ also discovered that titanium (IV) derivatives such as ''i''Pr)">isopropyl.html" ;"title="iCl₃(Oisopropyl">''i''Pr)worked in the same reaction as a milder version of the Lewis acid, ''i''-Bu₃Al, which goes through a similar transition state involving the retention of configuration at the anomeric center. In 1988, Adam reported a modification of the reaction that used catalytic amounts of

palladium Palladium is a chemical element with the symbol Pd and atomic number 46. It is a rare and lustrous silvery-white metal discovered in 1803 by the English chemist William Hyde Wollaston. He named it after the asteroid Pallas, which was itself nam ...

(II) salts, which brought about the same conversion of enol ethers into carbosugars in a more environmentally friendly manner.

Applications

The development of the Ferrier carbocyclization has been useful for the synthesis of numerous natural products that contain the carbocycle group. In 1991, Bender and co-workers reported a synthetic route to pure

enantiomers In chemistry, an enantiomer ( /ɪˈnænti.əmər, ɛ-, -oʊ-/ ''ih-NAN-tee-ə-mər''; from Ancient Greek ἐνάντιος ''(enántios)'' 'opposite', and μέρος ''(méros)'' 'part') – also called optical isomer, antipode, or optical ant ...

of ''myo''-

inositol Inositol, or more precisely ''myo''-inositol, is a carbocyclic sugar that is abundant in the brain and other mammalian tissues; it mediates cell signal transduction in response to a variety of hormones, neurotransmitters, and growth factors an ...

derivatives using this reaction. It has also been applied to the synthesis of aminocyclitols in work done by Barton and co-workers. Finally, Amano ''et al.'' used the Ferrier conditions to synthesise complex conjugated cyclohexanones in 1998.

References

{{reflist, 2 Carbohydrate chemistry Carbon-carbon bond forming reactions Name reactions Rearrangement reactions