Reductive dehalogenation of halo ketones
Encyclopedia
Reductive dehalogenations of halo ketones are organic reaction
s that result in the formation of ketone
s and functionalized derivatives of ketones from α-halo ketones in the presence of metallic reducing agents
.
s 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 [4+3] and [3+2] cycloaddition
reactions as the 2π component. 2-Oxyallyl metal intermediates may also intercept nucleophiles in a process that involves umpolung
at the α carbon. In addition, because reduction of monohalo ketones produces enolates in a site-specific fashion, reactions associated with enolates (alkylation
, aldol
, Michael
) may be carried out using halo ketone substrates under reductive conditions.
(1)
One-electron reducing agents, such as d6 or d1 transition metal complexes, initially donate a single electron to the halo ketone. Fragmentation of the resulting radical anion 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
of the reducing agent has increased by one.
(2)
Two-electron reducing agents, the most prominent of which is zinc
metal, undergo direct oxidative addition
to monohalo ketones to afford metal enolates in which the oxidation state of the metal has increased by two. Subsequent disproportionation
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.
dihalo ketones initially form metal enolates upon exposure to one- or two-electron reducing agents. In the presence of a protic solvent
, 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)
s or olefins. Isomerization of 2-oxyallyl metal complexes to cyclopropanone
and allene oxide forms is rapid and reversible; increasing the covalent character
of the oxygen-metal bond favors the 2-oxyallyl isomer.
(5)
metal. 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 halides. However, reduction in the presence of an aldehyde leads to reductive aldol products. Zinc dust may be used either alone or in combination with diethylaluminum chloride and catalytic amounts of copper(I) bromide
.
(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)
(9)
(10)
The 2-oxyallyl metal intermediates generated during reductions of α,α'-dihalo ketones with iron(0) complexes participate in [4+3] and [3+2] cycloaddition reactions to form cycloheptenones and cyclopentanones, respectively. During [3+2] cycloaddition reactions, the substituent on the alkene
may eliminate to provide cyclopentenones from alkenes in one pot.
(11)
The scope of [4+3] cycloadditions
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)
s may be used to establish the bicyclic skeleton of tropane alkaloid
s. For instance, a synthesis of scopine uses the [4+3] cycloaddition of N-methoxycarbonylpyrrole and α,α,α',α'-tetrabromoacetone as a key step. Diastereoselective reduction with diisobutylaluminum hydride (DIBAL-H) followed by epoxidation with trifluoroperacetic acid affords the target.
(13)
Most commercially available reducing agents can be used as received or after simple purification. A few require preparation and immediate use; these include zinc/copper and zinc/silver couples and organocuprates
A mixture of 5.0 g (14 mmol) of 1,3-dibromo-1,3-diphenylpropan-2-one, 25 g (167 mmol) of sodium iodide, 50 mL (40 g, 606 mmol) of cyclopentadiene, and 150 mL of acetonitrile
was boiled for 15 minutes. Chloroform was added, and the mixture was washed, first with sodium thiosulfate solution, then water, and dried over sodium sulfate. Concentration gave the crude material, which was chromatographed on a long column of silica gel to afford 7.4 g (99%) of a mixture of 2α,4α- and 2α,4β-diphenylbicyclo[3.2.1]oct-6-en-3-ones in a 40:60 ratio as judged by the IR spectrum. Crystallization from ethanol yielded mainly the cis isomer as the first crop of crystals, and crystallization of the material in the mother liquor from acetone gave mainly the trans isomer. The cis adduct melted at 149.5–151.5° (from ethanol): IR (Nujol) cm–1: 1700, 755, 740, 705. The trans adduct melted at 134–136° (from acetone); IR (Nujol) cm–1: 1700, 1665, 750, 740, 700.
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 reactions and redox reactions. In organic synthesis,...
s that result in the formation of 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 functionalized derivatives of ketones from α-halo ketones in the presence of metallic reducing agents
Reducing agent
A reducing agent is the element or compound in a reduction-oxidation reaction that donates an electron to another species; however, since the reducer loses an electron we say it is "oxidized"...
.
Introduction
α-Halo ketones are readily prepared from enolates by treatment with electrophilic halogen sources. The reduction of α-halo ketones generates reactive intermediateReactive intermediate
In chemistry a reactive 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 compounds be isolated and stored, e.g. low temperatures, matrix isolation...
s 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 [4+3] and [3+2] cycloaddition
Cycloaddition
A cycloaddition is a pericyclic chemical reaction, in which "two or more unsaturated molecules combine with the formation of a cyclic adduct in which there is a net reduction of the bond multiplicity." The resulting reaction is a cyclization reaction.Cycloadditions are usually described by the...
reactions as the 2π component. 2-Oxyallyl metal intermediates may also intercept nucleophiles in a process that involves umpolung
Umpolung
Umpolung or polarity inversion in organic chemistry 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 otherwise not be possible. The concept was introduced by...
at the α carbon. In addition, because reduction of monohalo ketones produces enolates in a site-specific fashion, reactions associated with enolates (alkylation
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 . Alkylating agents are widely used in chemistry because the alkyl group is probably the most common group encountered in...
, aldol
Aldol reaction
The aldol reaction is a powerful means of forming carbon–carbon bonds in organic chemistry.Discovered independently by Charles-Adolphe Wurtz and Alexander Porfyrevich Borodin in 1872, the reaction combines two carbonyl compounds to form a new β-hydroxy carbonyl compound...
, Michael
Michael reaction
The Michael reaction or Michael addition is the nucleophilic addition of a carbanion or another nucleophile to an alpha, beta unsaturated carbonyl compound. It belongs to the larger class of conjugate additions. This is one of the most useful methods for the mild formation of C-C bonds...
) may be carried out using halo ketone substrates under reductive conditions.
(1)
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. The mechanism of reduction itself depends on the nature of the reducing agent.One-electron reducing agents, such as d6 or d1 transition metal complexes, initially donate a single electron to the halo ketone. Fragmentation of the resulting radical anion 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
Oxidation state
In chemistry, the oxidation state is an indicator of the degree of oxidation of an atom in a chemical compound. The formal oxidation state is the hypothetical charge that an atom would have if all bonds to atoms of different elements were 100% ionic. Oxidation states are typically represented by...
of the reducing agent has increased by one.
(2)
Two-electron reducing agents, the most prominent of which is zinc
Zinc
Zinc , or spelter , is a metallic chemical element; it has the symbol Zn and atomic number 30. It is the first element in group 12 of the periodic table. Zinc is, in some respects, chemically similar to magnesium, because its ion is of similar size and its only common oxidation state is +2...
metal, undergo direct oxidative addition
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...
to monohalo ketones to afford metal enolates in which the oxidation state of the metal has increased by two. Subsequent disproportionation
Disproportionation
Disproportionation, also known as dismutation is used to describe a specific type of redox reaction in which a species is simultaneously reduced and oxidized so as to form two different products....
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, geminalGeminal
In chemistry, the term geminal refers to the relationship between two functional groups that are attached to the same atom...
dihalo ketones initially form metal enolates upon exposure to one- or two-electron reducing agents. In the presence of a protic solvent
Protic solvent
In chemistry a protic solvent is a solvent that has a hydrogen atom bound to an oxygen or a nitrogen . In general terms, any molecular solvent that contains dissociable H+ is called a protic solvent. The molecules of such solvents can donate an H+...
, 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 [4+3] and [3+2] cycloaddition reactions in the presence of dieneDiene
In organic chemistry a diene or diolefin is a hydrocarbon that contains two carbon double bonds.Conjugated dienes are functional groups, with a general formula of CnH2n-2. Dienes and alkynes are functional isomers...
s or olefins. Isomerization of 2-oxyallyl metal complexes to cyclopropanone
Cyclopropanone
Cyclopropanone is an organic compound with molecular formula C3H4O consisting of a cyclopropane carbon framework with a ketone functional group. The parent compound is labile with melting point −90 °C and has been prepared by reaction of ketene with diazomethane at −145 °C...
and allene oxide forms is rapid and reversible; increasing the covalent character
Covalent bond
A covalent bond is a form of chemical bonding that is characterized by the sharing of pairs of electrons between atoms. The stable balance of attractive and repulsive forces between atoms when they share electrons is known as covalent bonding....
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. This section describes conditions for the reduction or reductive functionalization of monohalo, α,α-dihalo, and α,α'-dihalo ketones.Monohalo Ketones
Monohalo ketones may be reduced to the corresponding parent ketone with lithiumLithium
Lithium is a soft, silver-white metal that belongs to the alkali metal group of chemical elements. It is represented by the symbol Li, and it has the atomic number 3. Under standard conditions it is the lightest metal and the least dense solid element. Like all alkali metals, lithium is highly...
metal. 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 halides. However, reduction in the presence of an aldehyde leads to reductive aldol products. Zinc dust may be used either alone or in combination with diethylaluminum chloride and catalytic amounts of copper(I) bromide
Copper(I) bromide
Copper 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....
.
(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 organocuprates. 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 [4+3] and [3+2] cycloaddition reactions to form cycloheptenones and cyclopentanones, respectively. During [3+2] cycloaddition reactions, the substituent on the alkene
Alkene
In organic chemistry, an alkene, olefin, or olefine is an unsaturated chemical compound containing at least one carbon-to-carbon double bond...
may eliminate to provide cyclopentenones from alkenes in one pot.
(11)
The scope of [4+3] cycloadditions
4+3 cycloaddition
[4+3] Cycloaddition is the annulation of an allyl or oxyallyl cation with a four-atom pi system to form a seven-membered ring. It represents one of the relatively few synthetic methods available to form seven-membered rings stereoselectively in high yield....
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
[4+3] cycloadditions of pyrrolePyrrole
Pyrrole is a heterocyclic aromatic organic compound, a five-membered ring with the formula C4H4NH. It is a colourless volatile liquid that darkens readily upon exposure to air. Substituted derivatives are also called pyrroles, e.g., N-methylpyrrole, C4H4NCH3...
s may be used to establish the bicyclic skeleton of tropane alkaloid
Tropane alkaloid
Tropane alkaloids are a class of alkaloids and secondary metabolites that contain a tropane ring in their chemical structure...
s. For instance, a synthesis of scopine uses the [4+3] cycloaddition of N-methoxycarbonylpyrrole and α,α,α',α'-tetrabromoacetone as a key step. Diastereoselective reduction with diisobutylaluminum hydride (DIBAL-H) followed by epoxidation with trifluoroperacetic acid affords the target.
(13)
Typical Conditions
α-Halo ketones may be prepared by a number of methods, but should be stored cold under an inert atmosphere to avoid decomposition. Care should be exercised while handling, as α-halo ketones are lachrymators and skin irritants.Most commercially available reducing agents can be used as received or after simple purification. A few require preparation and immediate use; these include zinc/copper and zinc/silver couples and organocuprates
Example Procedure
(14)A mixture of 5.0 g (14 mmol) of 1,3-dibromo-1,3-diphenylpropan-2-one, 25 g (167 mmol) of sodium iodide, 50 mL (40 g, 606 mmol) of cyclopentadiene, and 150 mL of acetonitrile
Acetonitrile
Acetonitrile is the chemical compound with formula . This colourless liquid is the simplest organic nitrile. It is produced mainly as a byproduct of acrylonitrile manufacture...
was boiled for 15 minutes. Chloroform was added, and the mixture was washed, first with sodium thiosulfate solution, then water, and dried over sodium sulfate. Concentration gave the crude material, which was chromatographed on a long column of silica gel to afford 7.4 g (99%) of a mixture of 2α,4α- and 2α,4β-diphenylbicyclo[3.2.1]oct-6-en-3-ones in a 40:60 ratio as judged by the IR spectrum. Crystallization from ethanol yielded mainly the cis isomer as the first crop of crystals, and crystallization of the material in the mother liquor from acetone gave mainly the trans isomer. The cis adduct melted at 149.5–151.5° (from ethanol): IR (Nujol) cm–1: 1700, 755, 740, 705. The trans adduct melted at 134–136° (from acetone); IR (Nujol) cm–1: 1700, 1665, 750, 740, 700.