The Kulinkovich reaction describes the

organic synthesis Organic synthesis is a special branch of chemical synthesis and is concerned with the intentional construction of organic compounds. Organic molecules are often more complex than inorganic compounds, and their synthesis has developed into one o ...

cyclopropanol Cyclopropanol is an organic compound with the chemical formula C3H6O. It contains a cyclopropyl group with a hydroxyl group attached to it. The compound is highly unstable due to the three-membered ring, and is susceptible to reactions that open t ...

s via reaction of

ester In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides ar ...

s with dialkyldialkoxytitanium reagents, generated in situ from

Grignard reagent A Grignard reagent or Grignard compound is a chemical compound with the general formula , where X is a halogen and R is an organic group, normally an alkyl or aryl. Two typical examples are methylmagnesium chloride and phenylmagnesium bromide ...

s bearing

hydrogen Hydrogen is the chemical element with the symbol H and atomic number 1. Hydrogen is the lightest element. At standard conditions hydrogen is a gas of diatomic molecules having the formula . It is colorless, odorless, tasteless, non-toxic, an ...

in beta-position and titanium(IV) alkoxides such as

titanium isopropoxide Titanium isopropoxide, also commonly referred to as titanium tetraisopropoxide or TTIP, is a chemical compound with the formula . This alkoxide of titanium(IV) is used in organic synthesis and materials science. It is a diamagnetic tetrahedral mo ...

. This reaction was first reported by Oleg Kulinkovich and coworkers in 1989. Titanium catalysts are ClTi(OiPr)₃ or Ti(OiPr)₄, ClTi(OtBu)₃ or Ti(OtBu)₄, Grignard reagents are EtMgX, PrMgX or BuMgX. Solvents can be Et₂O, THF, toluene. Tolerated

Functional Group In organic chemistry, a functional group is a substituent or moiety in a molecule that causes the molecule's characteristic chemical reactions. The same functional group will undergo the same or similar chemical reactions regardless of the rest ...

Ether In organic chemistry, ethers are a class of compounds that contain an ether group—an oxygen atom connected to two alkyl or aryl groups. They have the general formula , where R and R′ represent the alkyl or aryl groups. Ethers can again be c ...

s R–O–R, R–S–R,

Imine In organic chemistry, an imine ( or ) is a functional group or organic compound containing a carbon–nitrogen double bond (). The nitrogen atom can be attached to a hydrogen or an organic group (R). The carbon atom has two additional single bo ...

s RN=CHR.

Amide In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a compound with the general formula , where R, R', and R″ represent organic groups or hydrogen atoms. The amide group is called a peptide bond when it is ...

s, primary and secondary

amine In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituen ...

Carbamate In organic chemistry, a carbamate is a category of organic compounds with the general formula and structure , which are formally derived from carbamic acid (). The term includes organic compounds (e.g., the ester ethyl carbamate), formally o ...

s typically do not tolerate the reaction conditions, but tert-butyl carbamates (N-Boc derivatives) survive the transformation. An asymmetric version of this reaction is also known with a TADDOL-based catalyst.

Reaction mechanism

The generally accepted

reaction mechanism In chemistry, a reaction mechanism is the step by step sequence of elementary reactions by which overall chemical change occurs. A chemical mechanism is a theoretical conjecture that tries to describe in detail what takes place at each stage of ...

initially utilizes two successive stages of

transmetallation Transmetalation (alt. spelling: transmetallation) is a type of organometallic reaction that involves the transfer of ligands from one metal to another. It has the general form: :M1–R + M2–R′ → M1–R′ + M2–R where R and R′ can be, but ...

of the committed

, leading to an intermediate dialkyldiisopropyloxytitanium complex. This complex undergoes a

dismutation In chemistry, disproportionation, sometimes called dismutation, is a redox reaction in which one compound of intermediate oxidation state converts to two compounds, one of higher and one of lower oxidation states. More generally, the term can b ...

to give an alkane molecule and a titanacyclopropane 1. The insertion of the

carbonyl In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups. A compound containing a ...

group of the

in the weakest carbon-titanium bond leads to an oxatitanacyclopentane 2 being rearranged to

ketone In organic chemistry, a ketone is a functional group with the structure R–C(=O)–R', where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group –C(=O)– (which contains a carbon-oxygen double bo ...

3. Lastly, the insertion of the carbonyl group of 3 in the residual carbon-titanium connection forms a cyclopropane ring. In the

transition state In chemistry, the transition state of a chemical reaction is a particular configuration along the reaction coordinate. It is defined as the state corresponding to the highest potential energy along this reaction coordinate. It is often marked wi ...

of this elementary stage, which is the limiting stage of the reaction, an

agostic interaction In organometallic chemistry, agostic interaction refers to the interaction of a coordinatively-unsaturated transition metal with a C−H bond, when the two electrons involved in the C−H bond enter the empty d-orbital of the transition metal, r ...

stabilizing between the beta hydrogen and the R2 group and the titanium atom was called upon to explain the

diastereoselectivity In stereochemistry, diastereomers (sometimes called diastereoisomers) are a type of stereoisomer. Diastereomers are defined as non-mirror image, non-identical stereoisomers. Hence, they occur when two or more stereoisomers of a compound have dif ...

observed. Complex 4 obtained is a tetraalkyloxytitanium compound able to play a part similar to that of the starting tetraisopropyloxytitanate, which closes the

catalytic cycle In chemistry, a catalytic cycle is a multistep reaction mechanism that involves a catalyst. The catalytic cycle is the main method for describing the role of catalysts in biochemistry, organometallic chemistry, bioinorganic chemistry, materials s ...

. At the end of the reaction, the product is mainly in the shape of the magnesium alcoholate 5, giving the cyclopropanol after hydrolysis by the reaction medium. In broad strokes, and in a formal retrosynthetic sense, titanacyclopropane 1 behaves like a 1,2-dianion which adds into the ester twice: after the first addition into the ester, the resultant tetrahedral intermediate 2 collapses to give β-titanio ketone 3, which undergoes a second intramolecular addition to give the titanium salt of the cyclopropanol (4). (This species then undergoes transmetalation with Grignard reagent to regenerate 1 and close the catalytic cycle and give the product in the form of the magnesium salt (5).) The reaction mechanism has been the subject of theoretical analysis. Certain points remain nevertheless obscure. Intermediate titanium complexes of the

ate Ate or ATE may refer to: Organizations * Active Training and Education Trust, a not-for-profit organization providing "Superweeks", holidays for children in the United Kingdom * Association of Technical Employees, a trade union, now called the Nat ...

type have been proposed by Kulinkovich.

Ligand exchange with olefins

In 1993, the team of Kulinkovich highlighted the aptitude of the titanacyclopropanes to undergo

ligand exchange In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electr ...

with olefins. This discovery was important, because it gave access to cyclopropanols more functionalized by making economic use of the Grignard of which normally at least two equivalents should have been engaged to obtain good yields. Cha and its team introduced the use of cyclic Grignard reagents, particularly adapted for these reactions. : The methodology has been extended to

intramolecular reaction Intramolecular in chemistry describes a process or characteristic limited within the structure of a single molecule, a property or phenomenon limited to the extent of a single molecule. Examples * intramolecular hydride transfer (transfer of a hy ...

De Meijere variation

With

amide In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a compound with the general formula , where R, R', and R″ represent organic groups or hydrogen atoms. The amide group is called a peptide bond when it is ...

s instead of

esters In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides are ...

the reaction product is an aminocyclopropane in the De Meijere variation : The intramolecular reaction is also known: :

Szymoniak variation

In the Szymoniak variation the substrate is a

nitrile In organic chemistry, a nitrile is any organic compound that has a functional group. The prefix ''cyano-'' is used interchangeably with the term ''nitrile'' in industrial literature. Nitriles are found in many useful compounds, including met ...

and the reaction product a cyclopropane with a primary

group. : The reaction mechanism is akin the Kulinkovich reaction: :

Additional reading

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References

{{Reflist, 35em Carbon-carbon bond forming reactions Coupling reactions Titanium Name reactions