"Target molecules containing a 1,4-cyclodhexadiene unit are probably best prepared via the Birch reaction. These primary reduction synthons can be further elaborated into a variety of synthetically useful compounds … Isomerizations of l,4-cyclohexadienes with KOt-Bu in DMSO furnish the thermodynamically more stable conjugated 1,3-cyclohexadienes. … Hydrolysis of the initial enol ether (vinyl ether) formed from Birch reduction of anisole or substituted anisoles under mild acidic con- ditions leads to β,γ-unsaturated cyclohexenones. Under more drastic acidic condi- tions, these isomerize to the conjugated α,β-cyclohexenones. Birch reduction of anisoles followed by hydrolytic workup is one of the best methods available for preparing substituted cyclohexenone. It should be noted that Birch reduction of 4-substituted anisoles followed by acidic workup (aq HCl, THF) produces mixtures of isomeric cyclohexenones. … Selective cleavage of the more nucleophilic double bond of anisole-derived 1,4-cyclohexadienes by ozone provides highly function- alized acyclic compounds containing a stereodefined double bond. … Birch reduction-alkylation of benzoic acids and esters establishes quaternary carbon centers. Neighboring stereocenters will influence the stereochemical outcome of the tandem reaction sequence."

"Birch reduction of substrates containing methoxy or N,N-dimethylamino groups may be contaminated with appreciable amounts of conjugated products. In these cases, it is conceivable that the isomerization occurs during workup."

"The reduction is initiated by addition of a solvated electron to the aromatic system to generate a radical anion, which is then protonated by an alcohol cosolvent to furnish a pentadienyl radical. … The function of the alcohol in the metal -NH3 reduction is to provide a proton source… Furthermore, the presence of alcohol represses the formation of the amide ion NH2-, … is capable of isomerizing the 1,4-cyclohexadiene product…"

"Alkali metals in liquid ammonia in the presence of an alcohol reduce aromatic systems to 1,4-cyclohexadienes. These can be further elaborated into a host of derivatives. The availability of a wide variety of substituted aromatic compounds, either commercial or via synthesis, makes the Birch reduction an important tool in organic synthesis."

"The availability of a stereodefined alcohol from reduction of a cyclic ketone raises the question of how one can obtain the corresponding stereoisomer. A solution to this problem is the Mitsunobu reaction, which provides a powerful tool for inverting the configuration of a given alcohol to its stereoisomer. The reaction involves conversion of the alcohol into a good leaving group capable of being displaced by a relatively weak nucleophile, generally a carboxylate ion (RCOO-). The product of stereochemical inversion is an ester, which on saponification leads to the alcohol of opposite configuration."

"A carbonyl transposition can be effected via the addition of a vinyl or an alkyl Grignard reagent to an α,β-unsaturated ketone. Acid-catalyzed rearrangement of the resultant allylic alcohol during oxidation with PCC affords the transposed α,β-unsaturated carbonyl substrate. This reaction represents a useful alternative when Wittig olefination of the ketone is problematic. Tertiary bis(allylic) alcohols are oxidized by PCC or PDC to the carbonyl transposed dienones. Addition of silica gel (SiO2) to the PCC reaction greatly facilitates the workup, and application of ultrasound enhances the rate of the reaction and the yield of the product."

"MnO2 is a highly chemoselective oxidant—allylic, benzylic, and propargylic alcohols are oxidized faster than saturated alcohols. The oxidation takes place under mild conditions in H2O, acetone, or CHCl3. … Ba[MnO4]2 possesses similar chemoselectivites as MnO2 in oxidations of alcohols, but it is more readily available and does not require special treatment for its activation. … Silver carbonate is especially useful for small-scale oxidations since the products usually are recovered in high purity by simply filtering the Ago and evaporating the solvent. … TEMPO is a commercially available nitroxyl radical-containing reagent that catalyzes the oxidation of primary and secondary alcohols in conjunction with co-oxidants.… Chemoselective oxidation of a secondary OH group in the presence of a primary OH group has been achieved with (NH4)2Ce(NO3)6, NaBrO3. Note, however, that the reagent does not tolerate the presence of double bonds. … Triphenylcarbenium salts (Ph3C+X-) selectively oxidize secondary t-butyl or triphenylmethyl (trityl) ethers derived from alcohols. The oxidation proceeds via initial hydride abstraction followed by loss of the group on oxygen. … Chemoselective oxidation of a secondary OH group in the presence of a primary OH group is possible with NaOCl in aqueous acetic acid."

"The Swern oxidation proceeds rapidly at low temperatures and thus can be employed for the preparation of a-keto aldehydes and acylsilanes, which are hyperactive carbonyl compounds and prone to hydration, polymerization, and air oxidation. … The Dess-Martin oxidation of alcohols has proven to be an efficient method for the conversion of primary and secondary alcohol to aldehydes and ketones, respectively. The rate of oxidation is markedly accelerated in the presence of water. … [TPAP(Pr4N+RuO4-)] is commercially available and environmentally friendly since it is used in catalytic amounts in the presence of a co-oxidant such as N-methylmorpholine-N-oxide (NMO)."

"The classical procedure for oxidizing primary alcohols to aldehydes and secondary alcohols to ketones involves treatment of the appropriate alcohol with a chromium(VI) reagent. Oxidation of primary alcohols to aldehydes requires anhydrous conditions. In the presence of water, the resultant aldehyde can form the hydrate, which may be further oxidized to the carboxylic acid."

"CrO2·C5H5N is a mild reagent for the oxidation of alcohols that contain acid-sensitive groups. … Primary and secondary alcohols are readily oxidized in CH2Cl2 utilizing 1 to 1.5 equivalents of PCC. … PDC is soluble in H2O, DMF, and DMSO but sparingly soluble in CH2Cl2 or CHCl3. The reagent is less acidic than PCC. Hence, oxidations in CH2Cl2 can be carried out under nearly neutral conditions. This permits the conversion of primary alcohols containing acid-sensitive groups into the corresponding aldehydes or ketones, as illustrated below."

"The Jones reagent is an excellent reagent for the oxidation of secondary alcohols that do not contain acid-sensitive groups such as acetals. Oxidation of primary alcohols with Jones reagent may result in the conversion of the aldehydes initially formed to the corresponding carboxylic acids. … Chromic acid oxidation may also be performed in the presence of water-immiscible solvents."

"The Baeyer-Villiger oxidation involves an initial attack of a peroxy acid at the carbonyl carbon, which is followed by migration of an adjacent group from the carbonyl carbon to the electron-deficient oxygen of the peroxy acid moiety. The rearrangement proceeds in a concerted manner and is stereospecific. Thus, a chiral migrating group maintains its chiral integrity in the product. The overall reaction represents an insertion of an oxygen between the carbonyl carbon and the migrating group. The Baeyer-Villiger reaction applied to acylic ketones provides esters, whereas cyclic ketones furnish lactones. The observed relative ease of migration, tert-alkyl > sec-alkyl > phenyl > n-alkyl > methyl, reflects the ability of the migrating group to accommodate a partial positive charge at the transition state. In addition to electronic factors, steric and conformational constraints as well as reaction conditions may influence the ease of migration. However, the regiochemistry can usually be controlled by proper choice of migrating group. … Thus, the Baeyer-Villiger oxidation is not only stereospecific but frequently regioselective. By controlling reaction conditions and by proper choice of the peroxy acid, it is often possible to favor the Baeyer-Villiger reaction over epoxidation."

"The facile reactions of olefins and dienes with various hydroborating agents makes a variety of organoboranes readily available. Organoboranes tolerate many functional groups and are formed in a stereospecific manner. The boron atom in these organoboranes can be readily substituted with a variety of functional groups."

"The four-center transition state for hydroboration of alkenes discussed above implies that addition of the B-H bond to a double bond proceeds in a syn-manner."

"The rates of hydroboration of alkenes with dialkylboranes vary over a wide range."

"An important feature of the hydroboration reaction is the regioselectivity observed with unsymmetrical alkenes. Generally, boron attacks positions of highest electron density and lowest steric congestion. This working hypothesis rationalizes the regioselectivity and stereo- selectivity of most hydroboration reactions."

"Domino-type reactions involve careful design of a multistep reaction in a one-pot sequence in which the first step creates the functionality to trigger the second reaction and so on, making this approach economical and environmentally friendly."

"The hydration of alkenes via hydroboration-oxidation … provides a valuable tool for the synthesis of a wide variety of alcohols of predictable regio- and stereochemistry. … The mono- and dialkylboranes are themselves useful hydroborating agents for sterically less hindered alkenes."

"Birch reduction of monosubstituted benzenes could furnish either of two possible 1,4-cyclohexadienes … Generally, electron-donating groups (D) retard electron transfer and remain on unsaturated carbons. [D=-OH, -OR, -NR2, -SR, -PR2, -alkyl, -CH2OH, -CH2OR, -CO2R, -C(O)R, -CHO] … The reason why groups such as -C(O)R, -CHO, and -CO2R behave as electron-donating groups in this reaction is that they are reduced to -CH2O- … Electron-withdrawing groups (EWG) facilitate electron transfer and reside on saturated carbons.[EWG= -CO2H, -C(O)NH2, -aryl] … The carboxy group generally dominates the regiochemistry of the reduction when other substituents are present. The strong activation effect by the carboxyl group allows reduction to occur when only one equivalent of alcohol is present or even without an alcohol. In these cases, the intermediate dianion persists in solution and can be trapped with electrophilic reagents to generate a quaternary carbon center. … While ester groups are reduced competitively with the aromatic ring under the usual Birch conditions, addition of one or two equivalents of H2O or t-BuOH to NH3 before metal addition preserves the ester moiety."

"The carbonyl group is electrophilic at the carbon atom and hence is susceptible to attack by nucleophilic reagents. Thus, the carbonyl group reacts as a formyl cation or as an acyl cation. A reversal of the positive polarity of the carbonyl group so it acts as a formyl or acyl anion would be synthetically very attractive. To achieve this, the carbonyl group is converted to a derivative whose carbon atom has the negative polarity. After its reaction with an electrophilic reagent, the carbonyl is regenerated. Reversal of polarity of a carbonyl group has been explored and systematized by Seebach."

"Umpolung in a synthesis usually requires extra steps. Thus, one should strive to take maximum advantage of the functionality already present in a molecule."

"The most utilized Umpolung strategy is based on formyl and acyl anion equivalents derived from 2-lithio- 1,3-dithiane species."

"Water adds to alkenes to yield alcohols, a process called hydration.The reaction takes place on treatment of the alkene with water and a strong acid catalyst, such as H2SO4, by a mechanism similar to that of HX addition. … Acid-catalyzed alkene hydration is particularly suited to large-scale industrial procedures, and approximately 300,000 tons of ethanol is manufactured each year in the United States by hydration of ethylene. The reaction is of little value in the typical laboratory, however, because it requires high temperatures— 250 °C in the case of ethylene—and strongly acidic conditions."

"In the laboratory, alkenes are often hydrated by the oxymercuration–demercuration procedure. … Alkene oxymercuration is closely analogous to halohydrin formation."

"Treatment of an alkene with mercuric acetate in aqueous THF results in the electrophilic addition of mercuric ion to the double bond to form an intermediate mercurium ion. Nucleophilic attack by H2O at the more substituted carbon yields a stable organomercury compound, which upon addition of NaBH, undergoes reduction. Replacement of the carbon-mercury bond by a carbon-hydrogen bond during the reduction step proceeds via a radical process. The overall reaction represents Markovnikov hydration of a double bond, which contrasts with the hydroboration-oxidation process."

"The results demonstrate that organocatalysis can represent a valuable tool for solutions on industrial scale also. Albeit the use of organocatalysis in industry is still limited, it can be expected that the broad variety of already developed efficient organocatalytic syntheses, in combination with further breakthroughs and new applications, will contribute to an increasing number of organocatalytic large-scale reactions in the future."

"When the halogenation reaction is carried out on a cycloalkene, such as cyclopentene, only the trans stereoisomer of the dihalide addition product is formed rather than the mixture of cis and trans isomers that might have been expected if a planar carbocation intermediate were involved. We say that the reaction occurs with anti stereochemistry ..."

"Hydrohalogenation is the addition of hydrogen halides HX (X = Cl, Br, and I) to alkenes to form alkyl halides. Two bonds are broken in this reaction—the weak π bond of the alkene and the HX bond—bond two new σ bonds are formed—one to H and one to X. Because X is more electronegative than H, the H – X bond is polarized, with a partial positive charge on H. Because the electrophilic (H) end of HX is attracted to the electron-rich double bond, these reactions are called electrophilic additions."

"An example of electrophilic aromatic substitution is halogenation. Benzene is normally unreactive in the presence of halogens, because halogens are not electrophilic enough to disrupt its aromaticity. However, the halogen may be activated by Lewis acidic catalysts, such as ferric halides (FeX3) or aluminum halides (AlX3), to become a much more powerful electrophile. (...) The halogenation of benzene becomes more exothermic as we proceed from I2(endothermic) to F2 (exothermic and explosive). Chlorinations and brominations are achieved with the help of Lewis acid catalysts that polarize the X – X bond and activate the halogen by increasing its electrophilic power."

"Platinum and palladium are the most common laboratory catalysts for alkene hydrogenations. … Catalytic hydrogenation, unlike most other organic reactions, is a heterogeneous process rather than a homogeneous one. … An interesting feature of catalytic hydrogenation is that the reaction is extremely sensitive to the steric environment around the double bond. As a result, the catalyst usually approaches only the more accessible face of an alkene, giving rise to a single product. … Alkenes are much more reactive than most other unsaturated functional groups toward catalytic hydrogenation, and the reaction is therefore quite selective. … In addition to its usefulness in the laboratory, catalytic hydrogenation is also important in the food industry, where unsaturated vegetable oils are reduced on a large scale to produce the saturated fats used in margarine and cooking products."

"The catalytic hydrogenation of alkenes, ketones, and imines is arguably one of the most important transformations in chemistry. Powerful asymmetric versions have been realizedthat require metal catalysts or the use of a stoichiometric amount of metal hydrides ..."

"The hydrogenation of unsaturated organic compounds, such as olefins, carbonyls and imines is one of the most important and utilized transformation in both academia and in the chemical industry. With the ever increasing number of biologically active substances with hydrogen as part of the stereocenter, it is not surprising that the development of efficient asymmetric reductions has become acentral researcharea in enantioselective catalysis."

"Hydrogenation of the double bond in alkenes requires a catalyst. This transformation occurs stereospecifically by synaddition and, when there is a choice, from the least hindered side of the molecule. This principle underlies the development of enantioselective hydrogenation using chiral catalysts."

"The mechanism of heterogenous hydrogenation involves (1) dissociative chemisorption of H2 on the catalyst, (2) coordination of the alkene to the surface of the catalyst, and (3) addition of the two hydrogen atoms to the activated π-bond in a syn- manner.… For low-pressure hydrogenations (1-30 atm), Pt, Pd, Rh, and Ru are used. The reactivity of a given catalyst decreases in the following order: Pt > Pd > Rh ~ Ru > Ni. For high-pressure hydrogenations (100-300 atm), Ni is usually the metal of choice. … The activity of a given catalyst generally is increased by changing from a neutral to a polar to an acid solvent. EtOAc, EtOH, and HOAc are the most frequently used solvents for low-pressure hydrogenations. … The reactivity of unsaturated substrates decreases in the following order: RCOCl > RNO, > RC-CR > RCH≡CHR > RCHO > RC≡N > RCOR > benzene. Both Pt and Pd catalysts fail to reduce RCOOR', RCOOH, and RCONH, groups. Pd is usually more selective than Pt. The ease of reduction of an olefin decreases with increasing substitution of the double bond. Conjugation of a double bond with a carbonyl group can markedly increase the rate of hydrogenation of the double bond. … With Pt and Pd catalysts, hydrogenation of allylic and benzylic alcohols, ethers, esters, amines, and halides is often accompanied by hydrogenolysis of the C-X bond where X = OH, OR, OAc, NR2, or halide, respectively."

"Intramolecular H-bonding or chelation by an adjacent functionality, such as a hydroxyl group, can direct the approach of a metal catalyst to favor hydrogenation of one diastereotopic π-face over another. The most effective catalysts for directed hydrogenation are the coordinatively unsaturated Crabtree's catalyst and the 2,5-norbornadiene-Rh(I) catalyst…"

"Reductions of α,β-unsaturated ketones with solutions of Li, Na, or K in liquid NH3 are chemoselective, resulting in the exclusive reduction of the carbon-carbon double bonds. … The regiospecific generation of enolate ions from α,β-unsaturated ketones is an important tool in carbon-carbon- bond-forming reactions. Catalytic hydrogenation of an enone would not be chemoselective if an isolated double bond were also present in the molecule. However, isolated double bonds are inert to dissolving metal reduction. On the other hand, a variety of functional groups are reduced with alkali metals in liquid ammonia. These include alkynes, conjugated dienes, allylic, or benzylic halides and ethers. Nonconjugated ketones can be reduced in the dissolving metal medium to the corresponding saturated alcohol in the presence of excess alcohol prior to workup."

"In biological systems, hydrogen bonding is used extensively for molecular recognition, substrate binding, orientation and activation. In organocatalysis, multiple hydrogen bonding by man-made catalysts can effect remarkable accelerations and selectivities as well."

"By using related Mannich reactions it was also possible to open up a flexible entry to amino sugars, carbasugars, polyoxamic acid and phytosphingosine derivatives. Furthermore, novel ulosonic acid precursors were obtained via an organocatalytic entry. The concept was extended to multicomponent cascade reactions leading to tetrasubstitued cyclohexene carbaldehydes. (...) Starting from diene containing aldehyde substrates the organocatalytic domino process could be combined with an intramolecular Diels-Alder reaction in one pot providing tricyclic carbon frameworks under control of five carboncarbon bonds and up to eight stereocenters."

"Four recent developments in reaction methodology—two of them being organocatalytic reactions—now allow for a very efficient access to UCS1025A. (...) We have developed a straightforward strategy for the synthesis of an important class of lepidopteran sex pheromones starting from simple dialdehydes. The combination of a Wittig reaction and an organocatalytic reduction represents a useful sequence for the nontrivial two-carbon homologation of aldehydes. (...) In the early stages of the UCS1025A campaign, we developed a novel two-step approach to small N-heterocycles using an organocatalytic Mannich reaction and a novel CDI-mediated dehydrative cyclization. (...) Our work and that of others have clearly demonstrated that organocatalytic strategies can cut down the total number of synthetic operations."

"Organocatalysis offers several advantages not only with respect to its synthetic range. Among “typical” advantages of organocatalysis, in particular with respect to large-scale applications, are favorable economic data of many organocatalysts, the stability of organocatalysts as well as the potential for an efficient recovery"

"The suitability of organocatalytic reactions for larger-scale production processes of chiral building blocks has also already been demonstrated in some cases. Notably, different types of bond formation have been reported, comprising several carbon-carbon bond formations as well as oxidation processes. … The Hajos–Parrish–Eder–Wiechert–Sauer reaction certainly represents a historical landmark in the field of (asymmetric) organocatalysis. … A further strength of organocatalysis is its use for efficient carbon–carbon bond formation by means of alkylation processes. … Further great advancements in the field of asymmetric alkylation reactions have been made by several groups for the chiral phase transfercatalyzed alkylation of glycinates. This type of reaction offers attractive access to enantiomerically pure, particularly nonproteinogenic α-amino acids. … The asymmetric catalytic Strecker reaction is another elegant approach for the synthesis of optically active α-amino acids. … Epoxidation reactions belong to the most important (asymmetric) transformations. Besides asymmetric metal-catalyzed methodologies, analogous organocatalytic epoxidation has been known for a long time. … In addition to the Julia–Colonna epoxidation, also the Shi-epoxidation received commercial interest."

"… in organocatalysis, a purely organic and metal-free small molecule is used to catalyze a chemical reaction. In addition to enriching chemistry with another useful strategy for catalysis, this approach has some important advantages. Small organic molecule catalysts are generally stable and fairly easy to design and synthesize. They are often based on nontoxic compounds, such as sugars, peptides, or even amino acids, and can easily be linked to a solid support, making them useful for industrial applications. However, the property of organocatalysts most attractive to organic chemistsmay be the simple fact that they are organic molecules."

"Enamine catalysis often delivers valuable chiral compounds such as alcohols, amines, aldehydes, and ketones. Many of these are normally not accessible using established reactions based on transition metal catalysts or on preformed enolates or enamines, illustrating the complimentary nature of organocatalysis and metallocatalysis."

"In the proline-based enamine catalysis, proline actually plays a dual role. The amino-group of proline acts as Lewis base, whereas the carboxylic group acts as a Brønsted acid … The potential of using relatively strong chiral organic Brønsted acids as catalysts (Specific Brønsted acid catalysis) has been essentially ignored over the last decades. Achiral acids such as p-TsOH have been used as catalysts for a variety of reactions since a long time, but applications in asymmetric catalysis havebeen extremely rare."

"Enamine catalysis, Brønsted acid catalysis, and iminium catalysis turn out to be powerful new strategies for organic synthesis. (...) Despite its long roots, asymmetric organocatalysis is a relatively new and explosively growing field that, without doubt, will continue to yield amazing results for some time to come."

"Due to the increasing number of chiral drugs in the pipeline, asymmetric synthesis and efficient chiral separation technologies are steadily gaining in importance. Recently a third class of catalysts, besides the established enzymes and metal complexes, has been added to the tool kit of catalytic asymmetric synthesis: organocatalysts, small organic molecules in which a metal is not part of the active principle."

"The renaissance of organocatalysis since 2000 is truly impressive (Berkessel and Gröger 2004; Seayad and List 2005) (see also the other chapters in this monograph). Much of the design of organocatalysts for a variety of different reaction types is inspired by the knowledge that has accumulated regarding the mechanisms of enzyme catalysis. It has been estimated that about 40% of all enzymes are metalloenzymes, while the majority (60%) unfold their catalytic power in the absence of transition metals. Thus, the latter can be considered to be organocatalytic enzymes."

"In summary, in the first 3 years of our research we have made important contributions to the field of organocatalysis. In this highly competitive and fast moving topical area of organic chemistry we have set important milestones by, for example, developing the first metal-free, highly enantioselective Brønsted catalyzed biomimetic transferhydrogenations, cascade reductions, Strecker reactions, azaenamine additions, direct Mannich reactions, pyridine reductions, as well as domino Mannich-Michael additions. The enantioselectivities observed for such transformations are impressive with most exceeding 90% enantiomeric excess. In addition to these novel chiral ion pair catalyzed transformations, we were the first to realize that chiral Brønsted acids can activate carbonyl groups which resulted in the development of the first organocatalytic electrocyclic reactions. This is not only the first example of such a method but more significantly, it opens the door for many further enantioselective carbonyl transformations."

"Just as the chemistry of alkenes is dominated by addition reactions, the preparation of alkenes is dominated by elimination reactions. Additions and eliminations are, in many respects, two sides of the same coin."

"Another mode of reactivity of carbocations, in addition to regular SN1 and E1 processes, is rearrangement by hydride or alkyl shifts. In such rearrangements, the migrating group delivers its bonding electron pair to a positively charged carbon neighbor, exchanging places with the charge. Rearrangement may lead to a more stable cation — as in the conversion of a secondary cation into a tertiary one. Primary alcohols also can undergo rearrangement, but they do so by concerted pathways and not through the intermediacy of primary cations."