Reductive dehalogenation of halo ketones
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In
organic chemistry Organic chemistry is a subdiscipline within chemistry involving the scientific study of the structure, properties, and reactions of organic compounds and organic materials, i.e., matter in its various forms that contain carbon atoms.Clayden, J.; ...
, α-halo ketones can be reduced with loss of the
halogen The halogens () are a group in the periodic table consisting of five or six chemically related elements: fluorine (F), chlorine (Cl), bromine (Br), iodine (I), astatine (At), and tennessine (Ts). In the modern IUPAC nomenclature, this group is ...
atom to form
enolate In organic chemistry, enolates are organic anions derived from the deprotonation of carbonyl () compounds. Rarely isolated, they are widely used as reagents in the synthesis of organic compounds. Bonding and structure Enolate anions are electr ...
s. The α-halo ketones are readily prepared from
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 ...
s by various
ketone halogenation In organic chemistry, α-keto halogenation is a special type of halogenation. The reaction may be carried out under either acidic or basic conditions in an aqueous medium with the corresponding elemental halogen. In this way, chloride, bromide, a ...
reactions, and the products are
reactive intermediate In chemistry, a reactive intermediate or an intermediate is a short-lived, high-energy, highly reactive molecule. When generated in a chemical reaction, it will quickly convert into a more stable molecule. Only in exceptional cases can these comp ...
s that can be used for a variety of other
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 ...
s.


Introduction

The reduction of α-halo ketones generates a variety of product structures that may exhibit unique substitution patterns and reactivity. For instance, reduction of α,α'-dihalo ketones leads to 2-oxyallyl metal complexes, which participate in +3and +2
cycloaddition In organic chemistry, a cycloaddition is a chemical reaction in which "two or more Unsaturated hydrocarbon, unsaturated molecules (or parts of the same molecule) combine with the formation of a cyclic adduct in which there is a net reduction of th ...
reactions as the 2Ï€ component.Rigby, J.; Pigge, C. ''Org. React.'' 1997, ''51'', 351. 2-Oxyallyl metal intermediates may also intercept nucleophiles in a process that involves
umpolung In organic chemistry, umpolung () or polarity inversion is the chemical modification of a functional group with the aim of the reversal of polarity of that group. This modification allows secondary reactions of this functional group that would oth ...
at the α carbon. In addition, because reduction of monohalo ketones produces enolates in a site-specific fashion, reactions associated with enolates (
alkylation Alkylation is the transfer of an alkyl group from one molecule to another. The alkyl group may be transferred as an alkyl carbocation, a free radical, a carbanion, or a carbene (or their equivalents). Alkylating agents are reagents for effecting ...
,
aldol In organic chemistry, an aldol describes a structural motif consisting of a 3-hydroxy ketone or 3-hydroxyaldehyde. Aldols are usually the product of aldol addition. When used alone, the term "aldol" may refer to 3-hydroxybutanal. Stereochemistr ...
,
Michael Michael may refer to: People * Michael (given name), a given name * Michael (surname), including a list of people with the surname Michael Given name "Michael" * Michael (archangel), ''first'' of God's archangels in the Jewish, Christian an ...
) may be carried out using halo ketone substrates under reductive conditions. ''(1)''


Mechanism

Many reducing agents used in this type of reaction are commercially available. A few require preparation and immediate use, including zinc–copper couple and zinc/silver couples. and organocuprates


Monohalo ketones

Monohalo ketones are reduced by both one-electron and two-electron reducing agents to afford the parent ketones, derivatives functionalized with electrophiles, or products of
dimerization A dimer () (''wikt:di-, di-'', "two" + ''-mer'', "parts") is an oligomer consisting of two monomers joined by bonds that can be either strong or weak, Covalent bond, covalent or Intermolecular force, intermolecular. Dimers also have significant im ...
. The mechanism of reduction itself depends on the nature of the reducing agent. One-electron reducing agents, such as ''d''6 or ''d''1
transition metal complex A coordination complex consists of a central atom or ion, which is usually metallic and is called the ''coordination centre'', and a surrounding array of bound molecules or ions, that are in turn known as ''ligands'' or complexing agents. Many m ...
es, initially donate a single electron to the halo ketone. Fragmentation of the resulting
radical anion In organic chemistry, a radical anion is a free radical species that carries a negative charge. Radical anions are encountered in organic chemistry as reduced derivatives of polycyclic aromatic compounds, e.g. sodium naphthenide. An example of a ...
yields an organic radical and halide anion. Donation of a second electron from a ''second equivalent'' of reducing agent leads to the formation of a metal enolate in which the
oxidation state In chemistry, the oxidation state, or oxidation number, is the hypothetical charge of an atom if all of its bonds to different atoms were fully ionic. It describes the degree of oxidation (loss of electrons) of an atom in a chemical compound. C ...
of the reducing agent has increased by one.Alper, H.; Keung, E. C. H ''J. Org. Chem.'' 1972, ''37'', 2566. ''(2)'' Two-electron reducing agents, the most prominent of which is
zinc Zinc is a chemical element with the symbol Zn and atomic number 30. Zinc is a slightly brittle metal at room temperature and has a shiny-greyish appearance when oxidation is removed. It is the first element in group 12 (IIB) of the periodi ...
metal, undergo direct
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. Oxidat ...
to monohalo ketones to afford metal enolates in which the oxidation state of the metal has increased by two. Subsequent
disproportionation 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 ...
with unreacted halo ketone sometimes leads to the formation of two equivalents of enol radical, which may subsequently dimerize. ''(3)'' Treatment of enolates derived from either one- or two-electron reducing agents with an electrophile affords α-functionalized ketones as the final product.


α,α-Dihalo ketones

Similar to monohalo ketones,
geminal In chemistry, the descriptor geminal () refers to the relationship between two atoms or functional groups that are attached to the same atom. A geminal diol, for example, is a diol (a molecule that has two alcohol functional groups) attached to ...
dihalo ketones initially form metal enolates upon exposure to one- or two-electron reducing agents. In the presence of a
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# ...
, reduction stops at this stage to afford the monohalo ketone (which may be further reduced to the parent ketone). However, in the absence of a trapping electrophile or protic solvent, loss of the remaining halide from the enolate intermediate affords α-keto carbenes or carbenoids, which undergo C-H insertion reactions. ''(4)''


α,α'-Dihalo ketones

Initial reduction of α,α'-dihalo ketones leads to metal enolate intermediates. Loss of the remaining halide generates 2-oxyallyl metal complexes, which undergo +3and +2cycloaddition reactions in the presence of
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. ...
s or olefins. Isomerization of 2-oxyallyl metal complexes to
cyclopropanone Cyclopropanone is an organic compound with molecular formula (CH2)2CO consisting of a cyclopropane carbon framework with a ketone functional group. The parent compound is labile, being highly sensitive toward even weak nucleophiles. Surrogates o ...
and
allene oxide In organic chemistry, an allene oxide is an epoxide of an allene. The parent allene oxide is CH2=C(O)CH2 (CAS RN 40079-14-9), a rare and reactive species of only theoretical interest. Typical allene oxides require steric protection for their isol ...
forms is rapid and reversible; increasing the covalent character of the oxygen–metal bond favors the 2-oxyallyl isomer. ''(5)''


Scope and Limitations

Reductions of α-halo ketones may afford the parent ketones, partially reduced halo ketones, or products arising from interception of intermediates along the reduction pathway with nucleophiles or electrophiles. The products obtained depend on both the reducing agent and the substitution pattern of the halo ketone.


Monohalo ketones

Monohalo ketones may be reduced to the corresponding parent ketone with
lithium Lithium (from el, λίθος, lithos, lit=stone) is a chemical element with the symbol Li and atomic number 3. It is a soft, silvery-white alkali metal. Under standard conditions, it is the least dense metal and the least dense solid el ...
metal, followed by
protonation In chemistry, protonation (or hydronation) is the adding of a proton (or hydron, or hydrogen cation), (H+) to an atom, molecule, or ion, forming a conjugate acid. (The complementary process, when a proton is removed from a Brønsted–Lowry acid, ...
of the enolate. Other useful reducing agents for this transformation include lithium dialkylcuprates and molybdenum hexacarbonyl-alumina. ''(6)'' Alkylation of enolates generated through the reduction of monohalo ketones is limited to the most reactive
alkyl halide The haloalkanes (also known as halogenoalkanes or alkyl halides) are alkanes containing one or more halogen substituents. They are a subset of the general class of halocarbons, although the distinction is not often made. Haloalkanes are widely ...
s. However, reduction in the presence of an aldehyde leads to reductive aldol products, analogous to the
Reformatsky reaction The Reformatsky reaction (sometimes misspelled Reformatskii reaction) is an organic reaction which condenses aldehydes or ketones with α-halo esters using metallic zinc to form β-hydroxy-esters: The organozinc reagent, also called a 'Reformat ...
of haloesters. Zinc dust may be used alone; or as an
amalgam Amalgam most commonly refers to: * Amalgam (chemistry), mercury alloy * Amalgam (dentistry), material of silver tooth fillings ** Bonded amalgam, used in dentistry Amalgam may also refer to: * Amalgam Comics, a publisher * Amalgam Digital ...
, in combination with diethylaluminum chloride, or with
catalytic Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...
amounts of
copper(I) bromide Copper(I) bromide is the chemical compound with the formula CuBr. This diamagnetic solid adopts a polymeric structure akin to that for zinc sulfide. The compound is widely used in the synthesis of organic compounds and as a lasing medium in c ...
. ''(7)'' Reductive dimerization may result from the combination of two intermediate α-acyl radicals or nucleophilic attack of a metal enolate on unreacted halo ketone. Although complex reaction mixtures often result, selective dimerization is possible in some cases. In the example below, the product distribution is solvent dependent ''(8)''


α,α-Dihalo ketones

Depending on the conditions employed, geminal dihalo ketones may be reduced to the parent ketone, monohalo ketone, or functionalized monohalo ketone with
organocuprate A Gilman reagent is a lithium and copper (organocopper compound, diorganocopper) reagent compound, R2CuLi, where R is an alkyl or aryl. These reagents are useful because, unlike related Grignard reagents and organolithium reagents, they react wit ...
s. Warming functionalized α-halo ketones produced under these conditions from −40 °C to room temperature leads to the corresponding α,β-unsaturated ketone. ''(9)''


α,α'-Dihalo ketones

Organocuprates may also be employed for the reduction of α,α'-dihalo ketones to alkylated ketones. In the absence of an electrophile the monoalkyl ketone is isolated in good yield; when an alkyl iodide is added, the dialkyl ketone is isolated (geminal alkylation is a problematic side reaction). ''(10)'' The 2-oxyallyl metal intermediates generated during reductions of α,α'-dihalo ketones with iron(0) complexes participate in +3and +2cycloaddition reactions to form cycloheptenones and cyclopentanones, respectively. During +2cycloaddition reactions, the substituent on the
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 ...
may eliminate to provide cyclopentenones from alkenes in one pot. ''(11)'' The scope of +3cycloadditions is broad—the reaction may be used to form cycloheptenones, as well as bridged or fused polycyclic products. Reduction may be carried out in the presence of the 4π component ''(12)''


Synthetic applications

+3cycloadditions of
pyrrole Pyrrole is a heterocyclic aromatic organic compound, a five-membered ring with the formula C4 H4 NH. It is a colorless volatile liquid that darkens readily upon exposure to air. Substituted derivatives are also called pyrroles, e.g., ''N''-meth ...
s may be used to establish the bicyclic skeleton of
tropane alkaloid Tropane alkaloids are a class of bicyclic .2.1alkaloids and secondary metabolites that contain a tropane ring in their chemical structure. Tropane alkaloids occur naturally in many members of the plant family Solanaceae. Certain tropane alkal ...
s. For instance, a synthesis of
scopine Scopine is a tropane alkaloid found in a variety of plants including '' Mandragora'' root, '' Senecio mikanioides'' (''Delairea odorata''), ''Scopolia carniolica'', and '' Scopolia lurida''. Scopine can be prepared by the hydrolysis of scopolami ...
uses the +3cycloaddition of ''N''-methoxycarbonylpyrrole and α,α,α',α'-tetrabromoacetone as a key step.
Diastereoselective 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 ...
reduction with
diisobutylaluminum hydride Diisobutylaluminium hydride (DIBALH, DIBAL, DIBAL-H or DIBAH) is a reducing agent with the formula (''i''-Bu2AlH)2, where ''i''-Bu represents isobutyl (-CH2CH(CH3)2). This organoaluminium compound is a reagent in organic synthesis. Properties Lik ...
(DIBAL-H) followed by
epoxidation In organic chemistry, an epoxide is a cyclic ether () with a three-atom ring. This ring approximates an equilateral triangle, which makes it strained, and hence highly reactive, more so than other ethers. They are produced on a large scale for ...
with
trifluoroperacetic acid Trifluoroperacetic acid (trifluoroperoxyacetic acid, TFPAA) is an organofluorine compound, the peroxy acid analog of trifluoroacetic acid, with the condensed structural formula . It is a strong oxidizing agent for organic oxidation reactions, suc ...
Hayakawa, Y.; Baba, Y.; Makino, S.; Noyori, R. ''J. Am. Chem. Soc.'' 1978, ''100'', 1786. affords the target. ''(13)''


References

{{reflist, 30em Organic reduction reactions