tert-Butanesulfinamide is an organosulfur compound and a member of the class of sulfinamide

Sulfinamide

Sulfinamide is a functional group in organic chemistry containing a sulfur-oxygen double bond and a sulfur-nitrogen single bond. Sulfinamides are amides of sulfinic acid....

s . Both enantiomeric forms are commercially available and are relevant to the asymmetric synthesis of amines as a chiral ammonia

Ammonia

Ammonia is a compound of nitrogen and hydrogen with the formula . It is a colourless gas with a characteristic pungent odour. Ammonia contributes significantly to the nutritional needs of terrestrial organisms by serving as a precursor to food and fertilizers. Ammonia, either directly or...

 equivalent. This methodology was introduced in 1997 by Jonathan A. Ellman.

Synthesis

Chiral tert-butanesulfinamide can be prepared by enantioselective oxidation of inexpensive di-tert-butyl disulfide to the thiosulfinate

Thiosulfinate

In organosulfur chemistry, thiosulfinate is a functional group consisting of the linkage R-S-S-R . The thiosulfinate functional group is rare, but these compounds are invoked as intermediates in the oxidation of thiols to sulfonic acids, which is a common transformation. They feature a S center...

 followed by disulfide bond cleavage by lithium amide

Lithium amide

Lithium amide is an inorganic compound with the chemical formula Li+NH2-, i.e. it is composed of a lithium cation, and the conjugate base of ammonia. It is a white solid with a tetragonal crystal structure.-Lithium amides:...

. In the original scope the chiral ligand

Chiral ligand

In chemistry a chiral ligand is a specially adapted ligand used for asymmetric synthesis. This ligand is an enantiopure organic compound which combines with a metal center by chelation to form an asymmetric catalyst. This catalyst engages in a chemical reaction and transfers its chirality to the...

 used together with vanadyl acetylacetonate

Vanadyl acetylacetonate

Vanadyl acetylacetonate is the chemical compound with the formula VO2. This blue-green coordination complex consists of the vanadyl group, VO2+, bound to two acetylacetonate anions, acac−. Like other charge-neutral acetylacetonates, this complex is soluble in organic solvents.-Synthesis:The...

 was prepared by condensing a chiral aminoindanol with 3,5-di-tert-butyl salicylaldehyde

3,5-Di-tert-butylsalicylaldehyde

3,5'-Di-tert-butylsalicylaldehyde is an organic compound. It is a pale yellow solid. This aldehyde is a building block for preparing salen ligands.-Preparation:This compound is commercially available...

.

tert-Butanesulfinamide synthesis

Amine synthesis

Condensation with ketone

Ketone

In organic chemistry, a ketone is an organic compound with the structure RCR', where R and R' can be a variety of atoms and groups of atoms. It features a carbonyl group bonded to two other carbon atoms. Many ketones are known and many are of great importance in industry and in biology...

s and aldehyde

Aldehyde

An aldehyde is an organic compound containing a formyl group. This functional group, with the structure R-CHO, consists of a carbonyl center bonded to hydrogen and an R group....

s yield the corresponding N-tert-butanesulfinyl aldimines and ketimines. These intermediates are more resistant to hydrolysis

Hydrolysis

Hydrolysis is a chemical reaction during which molecules of water are split into hydrogen cations and hydroxide anions in the process of a chemical mechanism. It is the type of reaction that is used to break down certain polymers, especially those made by condensation polymerization...

 than other imine

Imine

An imine is a functional group or chemical compound containing a carbon–nitrogen double bond, with the nitrogen attached to a hydrogen atom or an organic group. If this group is not a hydrogen atom, then the compound is known as a Schiff base...

s but more reactive towards nucleophile

Nucleophile

A nucleophile is a species that donates an electron-pair to an electrophile to form a chemical bond in a reaction. All molecules or ions with a free pair of electrons can act as nucleophiles. Because nucleophiles donate electrons, they are by definition Lewis bases.Nucleophilic describes the...

s. A nucleophile adds diastereoselectively

Diastereomer

Diastereomers are stereoisomers that are not enantiomers.Diastereomerism occurs when two or more stereoisomers of a compound have different configurations at one or more of the equivalent stereocenters and are not mirror images of each other.When two diastereoisomers differ from each other at...

 over the imine group in an electrophilic addition

Electrophilic addition

In organic chemistry, an electrophilic addition reaction is an addition reaction where, in a chemical compound, a π bond is broken and two new σ bonds are formed...

 with the tert-butanesulfinyl group acting as a chiral auxiliary

Chiral auxiliary

A chiral auxiliary is a chemical compound or unit that is temporarily incorporated into an organic synthesis so that it can be carried out asymmetrically with the selective formation of one of two enantiomers...

. This tert-butanesulfinyl group is also a protecting group

Protecting group

A protecting group or protective group is introduced into a molecule by chemical modification of a functional group in order to obtain chemoselectivity in a subsequent chemical reaction...

. On addition of hydrochloric acid

Hydrochloric acid

Hydrochloric acid is a solution of hydrogen chloride in water, that is a highly corrosive, strong mineral acid with many industrial uses. It is found naturally in gastric acid....

 the tert-butanesulfinyl group is removed forming the chiral primary ammonium salt or amine (from aldehyde precursor) or the chiral secondary amine (ketone precursor).

tert-Butanesulfinamide chiral amine synthesis

Typical nucleophiles are Grignard reagents, organozinc compound

Organozinc compound

Organozinc compounds in organic chemistry contain carbon to zinc chemical bonds. Organozinc chemistry is the science of organozinc compounds describing their physical properties, synthesis and reactions....

s, organolithium compounds, and enolates.

Chiral sulfinimines as intermediates for the asymmetric synthesis of amines have also been developed by Davis.

Applications

tert-Butanesulfinamide has been used as an auxiliary in an asymmetric synthesis of cetirizine

Cetirizine

Cetirizine , a second-generation antihistamine, is a major metabolite of hydroxyzine, and a racemic selective H1 receptor inverse agonist used in the treatment of allergies, hay fever, angioedema, and urticaria.-Availability:...

 (more potent than the achiral drug) starting from p-chlorobenzaldehyde and phenylmagnesium bromide

Phenylmagnesium bromide

Phenylmagnesium bromide, with the simplified formula , is a magnesium-containing organometallic compound. It is so commonly used that it is commercially available as a solution in diethyl ether or tetrahydrofuran . Phenylmagnesium bromide is a Grignard reagent...

:

Asymmetric cetirizine synthesis