1. Alkyne zipper reaction

The alkyne zipper reaction is an organic reaction which isomerizes an organic compound containing an internal alkyne into a terminal alkyne. This was first reported by Charles Allen Brown and Ayako Yamashita in 1975.[1] The isomerization reaction proceeds for straight-chain alkynes and acetylinic alcohols and provides a useful approach for remote functionalization in long-chain hydrocarbons.[2]

The reaction requires a strong base. The base used by Brown and Yamashita was potassium 1, 3-diaminopropanide, generated in situ by adding potassium hydride to the solvent 1, 3-diaminopropane. Alternative approaches have been investigated due to the expensive and hazardous nature of potassium hydride; ethylene diamine has been found to be an unsuitable replacement for 1,3-diaminopropane. As an example, for the synthesis of 9-decyn-1-ol from 2-decyn-1-ol, the lithium salt of 1,3-diaminopropane in the presence of potassium tert-butoxide affords yields of approximately 85%.[2]

HO–CH2C≡C–(CH2)6CH3 → HO(CH2)8–C≡CH

2. Allylic rearrangement

An allylic rearrangement or allylic shift is an organic reaction in which the double bond in an allyl chemical compound shifts to the next carbon atom. It is encountered in nucleophilic substitution.

In reaction conditions that favor a SN1 reaction mechanism the intermediate is a carbocation for which several resonance structures are possible. This explains the product distribution (or product spread) after recombination with nucleophile Y. This type of process is called an SN1' substitution.

Alternatively, it is possible for nucleophile to attack directly at the allylic position, displacing the leaving group in a single step, in a process referred to as SN2' substitution. This is likely in cases when the allyl compound is unhindered, and a strong nucleophile is used. The products will be similar to those seen with SN1' substitution. Thus reaction of 1-chloro-2-butene with sodium hydroxide gives a mixture of 2-buten-1-ol and 1-buten-3-ol:

Nevertheless, the product in which the OH group is on the primary atom is minor. In the substitution of 1-chloro-3-methyl-2-butene, the tertiary 2-methyl-3-buten-2-ol is produced in a yield of 85%, while that for the primary 3-methyl-2-buten-1-ol is 15%.

In one reaction mechanism the nucleophile attacks not directly at the electrophilic site but in a conjugate addition over the double bond:

The synthetic utility can be extended to substitutions over butadiene bonds:[1]

Reaction in methanol and catalyst diisopropylethylamine

In the first step of this macrocyclization the thiol group in one end of 1,5-pentanedithiol reacts with the butadiene tail in 1 to the enone 2 in an allylic shift with a sulfone leaving group which reacts further with the other end in a conjugate addition reaction.

In one study[2] the allylic shift was applied twice in a ring system:

In this reaction sequence a Jacobson epoxidation adds an epoxy group to a diene which serves as the leaving group in reaction with the pyrazole nucleophile. The second nucleophile is methylmagnesium bromide expulsing the pyrazole group.

An SN2' reaction should explain the outcome of the reaction of an aziridine carrying a methylene bromide group with methyllithium [3]:

In this reaction one equivalent of acetylene is lost.

Examples of allylic shifts:

Ferrier rearrangement Meyer–Schuster rearrangement

SN2' reduction

In one adaptation called a SN2' reduction a formal organic reduction on an allyl group containing a good leaving group is

accompanied by a rearrangement. One example of such reaction is found as part of a Taxol total synthesis (ring C):[4]

The hydride is lithium aluminium hydride and the leaving group a phosphonium salt. The product contains a new exocyclic double bond. Only when the cyclohexane ring is properly substituted will the proton add in a trans position with respect to the adjacent methyl group. A conceptually related reaction is the Whiting reaction forming dienes.

Electrophilic allyl shifts

Allyl shifts can also take place with electrophiles. In the example below the carbonyl group in benzaldehyde is activated by diboronic acid prior to reaction with the allyl alcohol (see: Prins reaction):[5][6]

3. Alpha-ketol rearrangement

The α-ketol rearrangement is the acid-, base-, or heat-induced 1,2-migration of an alkyl or aryl group in an α-hydroxy ketone or aldehyde to give an isomeric product.[1]

Introduction

Like other ketogenic rearrangements, the α-ketol rearrangement involves the transformation of an alkoxide into a carbonyl group with concomitant movement of the bonding electrons of the migrating group towards an adjacent trigonal center. A distinctive feature of this particular rearrangement, however, is its reversibility—as a result, the more stable α-hydroxy carbonyl compound is favored. A general scheme for the rearrangement is shown below.

(1)

This rearrangement differs from similar isomerizations of carbohydrates, which involve the migration of hydrogen and proceed through discrete enediol intermediates. These include the Lobry–de Bruyn–van Ekenstein transformation,[2] the Heyns[3] and Amadori rearrangements,[4] and the Voight[5] and Bilik[6] reactions. α-hydroxy imines may also undergo the

rearrangement, although the thermodynamic driving force to amino ketones is often weak (in the absence of protic acids; see below).

Advantages: Large thermodynamic energy differences between reactants and products can be harnessed to drive these reactions to completion. Reaction progress can also be influenced through conformational control and often exhibit asymmetric induction.

Disadvantages: Because the reaction is reversible and thermodynamically controlled, it cannot be used to synthesize unstable α-hydroxy carbonyl products. Ideal conditions are often difficult to pinpoint and can require extensive catalyst screening.

Mechanism and stereochemistry

Prevailing mechanism

Under basic conditions, the reation is initiated by deprotonation of the hydroxyl group.[7] Substrates must lack α-hydrogens to prevent competitive reactions involving enolates. Under Brønsted- or Lewis-acidic conditions, coordination to the carbonyl oxygen occurs first, and under thermal conditions, intramolecular proton transfer takes place at the same time as migration. The reversibility of the reaction implies that reaction products are more thermodynamically stable than the corresponding starting materials. Starting materials incorporating ring strain, for instance, will rearrange to products lacking strain.

(2)

When metal salts are used to promote rearrangement, stereoelectronic effects derived from chelation to the metal salt can enhance the speed and selectivity of the reaction. In the conversion of 1 to 2, for instance, coordination of both the hydroxyl and carbonyl groups to aluminum facilitates rapid, selective migration of the bond to the one-carbon bridge.[8]

Similar stereoelectronic effects were observed in studies of the rearrangement of 17-hydroxy-20-ketosteroids. In this case, Lewis-acidic conditions switched the sense of stereoselectivity observed for the base-catalyzed process.

(3)

α-Hydroxy imines may also undergo rearrangement to amino ketones. Hammett analysis and a very negative entropy of activation suggest that the reaction proceeds in a single step through a concerted transition state.[9] As a result, subtle conformational and steric factors can play a role in the speed and extent of these reactions. Allylic transposition has been observed in migrations of allyl groups, but propargyl groups undergo simple alkyl migration.[10]

Enantioselective variants

Although examples of enantioselective α-ketol rearrangements starting from achiral α-hydroxy ketones are fairly limited, a number of examples of 1,2-asymmetric induction (due to stereoelectronic factors) have been observed. In one example of an enantioselective process, use of nickel(II) diacetoacetonate and pybox provided 4 in 34% ee.[11]

(4)

If the relative orientation of the carbonyl and hydroxy group can be controlled (through intramolecular hydrogen bonding, for instance), stereoselectivity can be achieved. This conformational control forces the migrating group to form its new bond to a single face of the carbonyl group.

Scope and limitations

The scope of rearrangements of α-hydroxy ketones and aldehydes is limited only by the fact that the product must be more thermodynamically stable than the starting material. In some cases, very subtle structural differences dictate the favored direction of isomerization. For instance, according to the "Favorskii rule," an empirical guideline with numerous exceptions, products with the carbonyl group adjacent to a methyl group or distal to a phenyl group are favored over the corresponding isomers.[12] In many subtle cases, such as the one below, decreased nonbonding interactions in dominant conformations of the favored isomers are often invoked[13]

(5)

Alkoxyallenes with an α-hydroxy substituent may provide allylic alcohols after rearrangement. Ring expansion provides the thermodynamic driving force in this case.[14]

(6)

Steroidal ketols have been subjected to rearrangement conditions to give steroids of different ring sizes. These rearrangements often proceed with a high degree of stereocontrol.[15]

(7)

Bridged ketols also undergo rearrangement, oftentimes stereospecifically.[16]

(8)

α-Hydroxy aldehydes have a strong thermodynamic preference for rearrangement to the corresponding ketols in the absence of steric or other factors.

Rearrangements of α-hydroxy imines are more difficult to predict because of the small energy differences between isomers. One synthetically useful application of this rearrangement is to the synthesis of spirocycles: fused hydroxyimines can rearrange to give the corresponding spiro isomers.[17]

(9)

Comparison with other methods

Ketol isomerizations of secondary α-hydroxy carbonyl compounds, which proceed via tautomerization, are probably the closest relative of the α-ketol rearrangement discussed here. Also closely related are carbohydrate rearrangements such as the Lobry–de Bruyn–van Ekenstein transformation,[18] which involve conversion to the open form followed by rearrangement and re-closing.

Synthesis of α-hydroxy carbonyl compounds is most commonly accomplished by either chain extension or oxidation of carbonyl compounds. In conjunction with aldehydes and ketones, tosyl isocyanides can be used to form α-hydroxy ketones after hydroylsis of the resulting oxazolines. The sp-hybridized isocyanide carbon becomes the carbonyl carbon of the product.[19] A variety of reagents exist to oxidize enolates to α-hydroxy carbonyl compounds—in the example here, oxy-Cope

rearrangement generates an enolate, which is then oxidized in the presence of molecular oxygen.[20]

(10)

Experimental conditions and procedure

Typical conditions

The most common experimental procedures for the rearrangement of α-ketols involve simple heating or exposure to a base or an acid. However, discovering the ideal conditions for the reaction often requires extensive optimization—simple Bronsted acids and bases do not always work well. Group 13 Lewis acids have been shown to work well as catalysts; however coordination of the catalyst has important stereoelectronic consequences. Additionally, under thermal conditions, intramolecular hydrogen bonding may influence the product

distribution. Conditions for the rearrangement of α-hydroxy imines are similar, although the resulting amino ketone products are usually isolated as the corresponding acid salts.

4. Amadori rearrangement

The Amadori rearrangement is an organic reaction describing the acid or base catalyzed isomerization or rearrangement reaction of the N-glycoside of an aldose or the glycosylamine to the corresponding 1-amino-1-deoxy-ketose.[1][2] The reaction is important in carbohydrate chemistry.

The reaction mechanism is demonstrated starting from the reaction of D-mannose in its closed (1) and open-form (2) with ammonia the 1,1-amino-alcohol 3, which is unstable and loses water to the glycosylamine (again the open imine (5) and the closed form hemiaminal (4)), which is the starting point for the actual Amadori rearrangement.[3]

By treatment of the glycosylamine with pyridine and acetic anhydride, the imine group rearranges and the intermediate enol, in turn, rearranges to the ketone. In this particular reaction, the all alcohol and amino groups are acylated as well.

The reaction is associated with the Maillard reaction with reagents naturally occurring sugars and amino acids.

Amadori product

An Amadori product is an intermediate in the production of an advanced glycation end-product (AGE) as a result of glycation.

The formation of an advanced glycation end-product involves the following steps:

1. Formation of a Schiff base: For example the aldehyde group of a glucose molecule will combine with the amino

group of a lysine molecule (in a protein) to form an imine or Schiff base, which is a double bond between the carbon atom of the glucose and the nitrogen atom of the lysine.

2. Formation of an Amadori product: The Amadori product is a re-arrangement from the Schiff base, wherein the hydrogen atom from the hydroxyl group adjacent to the carbon-nitrogen double bond moves to bond to the nitrogen, leaving a ketone.

3. Formation of an advanced glycation end-product (AGE): The Amadori product is oxidized, most often by transition metal catalysis.

The first two steps in this reaction are both reversible, but the last step is irreversible.

5. Arndt–Eistert reaction

The Arndt-Eistert synthesis is a series of chemical reactions designed to convert a carboxylic acid to a higher carboxylic acid homologue (i.e. contains one additional carbon atom) and is considered a homologation process.[1][2][3] Named for the German chemists Fritz Arndt (1885–1969) and Bernd Eistert (1902–1978), Arndt-Eistert synthesis is a popular method of producing β-amino acids from α-amino acids. Acid chlorides react with diazomethane to give diazoketones. In the presence of a nucleophile (water) and a metal catalyst (Ag2O), diazoketones will form the desired acid homologue.[4][5]

While the classic Arndt-Eistert synthesis uses thionyl chloride to convert the starting acid to an acid chloride, any procedure can be used that will generate an acid chloride.

Diazoketones are typically generated as described here, but other methods such as diazo-group transfer can also apply.[6]

Since diazomethane is toxic and violently explosive, many safer alternatives have been developed,[7] such as the usage of ynolates (Kowalski ester homologation)[8] or trimethylsilyldiazomethane.[9][10]

Reaction mechanism

The key step in the Arndt-Eistert synthesis is the metal-catalyzed Wolff rearrangement of the diazoketone to form a ketene.[11] In the insertion homologation of t-BOC protected (S)-phenylalanine (2-amino-3-phenylpropanoic acid), t-BOC protected (S)-3-amino-4-phenylbutanoic acid is formed.[5]

Wolff rearrangement[12][13] of the α-diazoketone intermediate forms a ketene via a 1,2-rearrangement, which is subsequently hydrolysed to form the carboxylic acid. The consequence of the 1,2-rearrangement is that the methylene group α- to the carboxyl group in the product is the methylene group from the diazomethane reagant. It has been demonstrated that the rearrangement preserves the stereochemistry of the chiral centre as the product formed from t-BOC protected (S)-phenylalanine

retains the (S) stereochemistry with a reported enantiomeric excess of at least 99%.[5]

Heat, light, platinum, silver, and copper salts will also catalyze the Wolff rearrangement to produce the desired acid homologue.

Variations

In the Newman-Beal modification, addition of triethylamine to the diazomethane solution will avoid the formation of α-chloromethylketone side-products.[14]

6. Aldol condensation

An aldol condensation is an organic reaction in which an enol or an enolate ion reacts with a carbonyl compound to form a β-hydroxyaldehyde or β-hydroxyketone, followed by a dehydration to give a conjugated enone.

Aldol condensations are important in organic synthesis, providing a good way to form carbon–carbon bonds. The Robinson annulation reaction sequence features an aldol condensation; the Wieland-Miescher ketone product is an important starting material for many organic syntheses. Aldol

condensations are also commonly discussed in university level organic chemistry classes as a good bond-forming reaction that demonstrates important reaction mechanisms.[1][2][3] In its usual form, it involves the nucleophilic addition of a ketone enolate to an aldehyde to form a β-hydroxy ketone, or "aldol" (aldehyde + alcohol), a structural unit found in many naturally occurring molecules and pharmaceuticals.[4][5][6]

The name aldol condensation is also commonly used, especially in biochemistry, to refer to the aldol reaction itself, as catalyzed by aldolases. However, the aldol reaction is not formally a condensation reaction because it does not involve the loss of a small molecule.

The reactions between a ketone and an aldehyde (crossed aldol condensation) or between two aldehydes also go by the name Claisen-Schmidt condensation. These reactions are named after two of its pioneering investigators Rainer Ludwig Claisen and J. G. Schmidt, who independently published on this topic in 1880 and 1881.[7][8][9] An example is the synthesis of dibenzylideneacetone.

Mechanism

The first part of this reaction is an aldol reaction, the second part a dehydration—an elimination reaction. Dehydration may be accompanied by decarboxylation when an activated carboxyl group is present. The aldol addition product can be dehydrated via two mechanisms; a strong base like potassium t-butoxide, potassium hydroxide or sodium hydride in an enolate mechanism,[10] or in an acid-catalyzed enol mechanism.

 :

Condensation types

It is important to distinguish the aldol condensation from other addition reactions to carbonyl compounds.

When the base is an amine and the active hydrogen compound is sufficiently activated the reaction is called a Knoevenagel condensation.

In a Perkin reaction the aldehyde is aromatic and the enolate generated from an anhydride.

A Claisen condensation involves two ester compounds. A Dieckmann condensation involves two ester groups in

the same molecule and yields a cyclic molecule A Henry reaction involves an aldehyde and an aliphatic

nitro compound. A Robinson annulation involves a α,β-unsaturated ketone

and a carbonyl group, which first engage in a Michael reaction prior to the aldol condensation.

In the Guerbet reaction, an aldehyde, formed in situ from an alcohol, self-condenses to the dimerized alcohol.

In the Japp-Maitland condensation water is removed not by an elimination reaction but by a nucleophilic displacement

Aldox process

In industry the Aldox process developed by Royal Dutch Shell and Exxon, converts propylene and syngas directly to 2-Ethylhexanol via hydroformylation to butyraldehyde, aldol condensation to 2-ethylhexenal and finally hydrogenation.[11]

In one study crotonaldehyde is directly converted to 2-ethylhexanal in a palladium / Amberlyst / supercritical carbon dioxide system [12]:

Scope

Ethyl 2-methylacetoacetate and campholenic aldehyde react in an Aldol condensation.[13] The synthetic procedure [14] is typical for this type of reactions. In the process, in addition to water, an equivalent of ethanol and carbon dioxide are lost in decarboxylation.

Ethyl glyoxylate 2 and diethyl 2-methylglutaconate 1 react to isoprenetricarboxylic acid 3 (isoprene skeleton) with sodium ethoxide. This reaction product is very unstable with initial loss of carbon dioxide and followed by many secondary reactions. This is believed to be due to steric strain resulting from the methyl group and the carboxylic group in the cis-dienoid structure.[15]

Occasionally an aldol condensation is buried in a multistep reaction or in catalytic cycle such as the one sketched below:[16]

In this reaction an alkynal 1 is converted into a cycloalkene 7 with a ruthenium catalyst and the actual condensation takes place with intermediate 3 through 5. Support for the reaction mechanism is based on isotope labeling.[17]

The reaction between menthone and anisaldehyde is complicated due to steric shielding of the ketone group. The solution is use of a strong base such as potassium hydroxide and a very polar solvent such as DMSO in the reaction below [18]:

Due to epimerization through a common enolate ion (intermediate A) the reaction product has (R,R) cis configuration and not (R,S) trans as in the starting material. Because it is only the cis isomer that precipitates from solution this product is formed exclusively.

7. Acyloin condensation

Acyloin condensation is a reductive coupling of two carboxylic esters using metallic sodium to yield an α-hydroxyketone, also known as an acyloin.[1][2][3]

The reaction is most successful when R is aliphatic and inert. To achieve the condensation, the reaction is performed in an aprotic solvents with a high boiling point, such as benzene and toluene. Usage of protic solvents results in the Bouveault-Blanc reduction of the separate esters rather than condensation. Depending on ring size and steric properties, but independent from high dilution, the acyloin condensation of diesters favours intramolecular cyclisation over intermolecular polymerisation.

[Mechanism

The mechanism consists on four steps:

(1) Oxidative ionization of two sodium atoms on the double bond of two ester molecules.

(2) Free radical coupling between two molecules of the homolytic ester derivative (A Würtz type coupling). Alkoxy-eliminations in both sides occur, producing a 1,2-diketone.

(3) Oxidative ionization of two sodium atoms on both diketone double bonds. The sodium enodiolate is formed.

(4) Neutralization with water to form the enodiol, which tautomerizes to acyloin.[4]

Variations

Rühlmann-method

The method according to Rühlmann[5] employs trimethylchlorosilane as a trapping reagent; by this, competing reactions are efficiently subdued. Generally, yields increase considerably. The hydrolytic cleavage of the silylether gives the acyloin. To achieve a mild cleavage methanol can be used in several cases.

Usually toluene, dioxane, tetrahydrofuran or acyclic dialkylethers are employed as solvents. Advantageously also N-methyl-morpholine has been used. It allowed in some cases a successful reaction, in which otherwise the reaction failed in less polar media.