Osmium Tetroxide

The OsO4 cis-hydroxylation of alkenes directly introduces vicinal hydroxy groups, and this may be the ultimate goal (as in the synthesis of Sativenediol below). However many other subsequent transformations of the diol lead to other functionalities. The most common is C-C bond cleavage of the diol with NaIO4 or Pb(OAc)4 to give aldehydes or ketones (Anatoxin), but many other transformations can be performed, such as Peterson olefination (Conduritol), reduction to mono alcohol (Adaline), oxidation to -hydroxy ketones or -diketones (Cephalotaxine). For most applications OsO4 is too expensive and toxic to use stoichiometrically, so it is usually used catalytically together with a stoichiometric oxidant, most commonly an amine oxide (N-methylmorpholine N-oxide (NMO) or trimethylamine oxide). If the goal is to cleave the double bond (and this is the most common use of OsO4), then sodium or potassium periodate is used, it functions as both reoxidant and diol cleavage agent.

In this example a bis-hydroxylation followed by reductive removal of one of the OH groups is equivalent to a regio- and stereo-selective hydration of the double bond

Ruthenium Oxidants A ruthenium based oxidant, tetrapropylammonium perruthenate (Pr4N+ RuO4-, with the acronym TPAP), introduced by Steve Ley in 1987, has turned out to be milder and more selective for alcohol oxidation than the chromium based reagents, and has been used more extensively than these recently. It has the additional advantage that it requires only a catalytic amount of ruthenium (typically 5% is used) if an amine oxide, usually Nmethylmorpholine oxide, is used as a stoichiometric oxidant. All chromium oxidations use stoichiometric amount of chromium.

Iejimalide B: Schweitzer, D.; Kane, J. J.; Strand, D.; McHenry, P.; Tenniswood, M.; Helquist, P. Org. Lett. 2007, 9, 4619 DOI

Rhyzoxin D: Jiang, Y.; Hong, J.; Burke, S. D. Org. Lett. 2004, 6, 1445. DOI

Oxidation with Peracids Peracids are general oxidants, usually with electrophilic properties (i.e. they react best with electron rich substrates). The reactivity of the peracid is determined by the electron wthdrawing character of the substituents. The stronger the parent acid, the more reactive the derived peracid. Thus trifluoroperacetic and 2,4-dinitroperbenzoic acids are stronger oxidants than peracetic and m-chloroperbenzoic (MCPBA) acids. Other peracid oxidants are based on persulfuric acid (oxone - KHSO5, and Caro's acid - H2SO5), percarbonic acid NaOOC(O)ONa) and perboric acid (sodium perborate). Peracids that are not commercially available are prepared by the reaction of the acid chloride or anhydride with high-strength hydrogen peroxide or urea-hydrogen peroxide.

The vast majority of uses of percarboxylic acids involves three types of oxidations: alkenes to epoxides, Baeyer-Villiger oxidation of ketones to ester and lactones, and oxidation of heteroatoms to oxides (sulfides to sulfoxides and sulfones, selenides to selenoxides, amines to amine oxides, phosphine to phosphine oxides). Peracids do not easily oxidize alcohols, ethers, esters, amides or carboxylic acids. The most commonly used peracid is m-chloroperbenzoic acid (MCPBA) because it stores well and is commercially available. However, for more difficult oxidations (e.g. of electronpoor double bonds) more strongly electron deficient peracids such as trifluoroperacetic acid and dinitroperbenzoic acid are required.
Formation of Epoxides

Electron poor alkenes like the one below require more aggressive peracids (the stronger the acid, the more reactive the peracid derived from it).

Oxidation of enol ethers leads to -hydroxyketones

Baeyer-Villiger Oxidation

The Baeyer-Villiger oxidation involves the peroxide-induced insertion of an oxygen between the carbonyl carbon and one the substituents to form an ester (or a lactone if the ketone was cyclic, as in the example below).

The choice of which of the two bonds on the carbonyl group is oxidized is dictated by the migratory aptitude of the substituents on the ketone, which generally follows that of carbonium ion rearrangements (Wagner-Meerwein): acyl > tertiary > secondary Ar H > primary > methyl. However, there are many exceptions to this sequence depending on the reagents used, as well as steric and electronic effects in the substrate. In addition to peracids, alkaline hydrogen peroxide or hydrogen peroxide together with a Lewis acid like BF3 can also be effective. The migratory tendency can be quite different with different reagents. For example, benzaldehyde gives mostly H migration with KSO5, mostly Ph migration with H2O2/NaOH, and about equal amounts of both with MCPBA. Electron rich aryl rings migrate preferentially over electron poor ones, and thus the sequence among secondary, aryl, and hydrogen migratory aptitudes can be changed by substituents on the aromatic ring. Vinyl groups migrate comparably to aryl, but the enol ester products are often epoxidized during the reaction.

Oxidation of Sulfides and Selenides:

Oxidation with Selenium Dioxide Selenium dioxide can perform several common types of oxidations, such as alcohols to ketones and aldehydes, as well as dehydrogenation of ketones to enones. Because of its toxicity, and the sometimes malodorous selenium-containing byproducts formed, SeO2 is used only where it competes well with other methods, or provides unique reactivity. One of these is the allylic oxidation of alkenes to allylic alcohols with regiocontrol (without migration of the double bond), and a second is the -oxidation of ketones to -diketones (only effective if there are no -hydrogens).

Oxidation with DMSO DMSO in combination with an activating agent (usually an acylating agent or an acid) and an amine base is a very mild and selective reagent for oxidation of alcohols to aldehydes and ketones. Over-oxidation of aldehydes is not a problem. The reagent does not cleave glycols and -hydroxy carbonyl compounds like the transition metal oxidants (Cr, Ru, Os, Mn) and even the otherwise very selective Dess-Martin periodinane will sometimes do.
Oxidation of Sensitive Substrates with DMSO-Lewis Acid (Moffat, Swern)

The oxidation was discovered by Moffat, who used acetic anhydride to activate the DMSO. However, a number of subsequent modifications which improved the procedure have become named reactions also. These differ in how the active intermediate Me2S-X A is generated. They include the Parikh-Doering (PySO3 + DMSO), Pfitzner-Moffat (carbodimides + DMSO), Corey-Kim (dimethyl sulfide and chlorine) and Swern (DMSO + oxalyl chloride or DMSO + trifluoroacetic anhydride) oxidations. Of these the procedure introduced by Swern using oxalyl chloride and triethylamine to activate the DMSO is by far the most popular one, so the reaction is often referred to as a Swern oxidation. Less commonly used is the Kornblum oxidation, in which the intermediate alkoxy sulfonium salt B is prepared by O-alkylation of DMSO by an allyl or benzyl halide.

Even aldehydes too unstable to be isolated can be prepared, since the reaction mixtures can be directly used for subsequent transformations, as in the two examples below. -Keto Aldehydes:

Formyl Silanes:

Lead Tetraacetate Lead tetracetate is a general purpose oxidant which can initiate a number of ionic and radical oxidative processes of alkenes, alcohols, amines and carboxylic acids. Two common uses are the bis-decarboxylation of 1,2-dicarboxylic acids and the cleavage of 1,2-diols and -hydroxy carbonyl compounds.

The decarboxylation makes a maleic anhydride cycloaddition the synthetic equivalent of an acetylene addition. Acetylene itself is not a useful dienophile in Diels-Alder reactions.

DIssolving Metal Reductions Transition Metal Reductants: There are a number of metals at the zero or low oxidation state that readily donate one or more electrons to molecules with an accessible LUMO orbital (Li, Na, K, Zn, Mg, Ca, Cr+2, Ti, Sm+2, etc). These function primarily as electon transfer reagents, although the transition metals and lanthanides also have a strong component of sigma bonding between cations and intermediate anions. Some typical reduction scenarios are outlined below. The initial process is usually an electron transfer to form a radical anion. This may be the end of the process, or a second electron transfer may occur to form a dianion. Alternatively, the radical anion can be protonated if there is a proton source available, or it may fragment if there is a leaving group (X) present. In each case a radical is formed, which can then be reduced a second time, and protonated if there is a sufficiently acidic proton source present. In favorable circumstances the final anion accumulates in the reaction, and can be trapped with electrophiles (E+) other than protons (e.g. alkylation).

Birch Reduction

The Birch reduction (Birch, A.J.; Smith, H. Quart. Rev. (London), 1958, 12, 17.) of aromatic compounds involves reaction with a solution of lithium or sodium in ammonia, basically solutions of M+ e-. Usually a proton donor such as t-butanol or ethanol is present to avoid the buildup of very basic LiNH2, which can be harmful to the integrity of the products. The major product is normally a 1,4-diene, resulting from protonation of the intermediate pentadienyl anion at the center carbon, which bears the highest electron density. Substituted benzenes lead to 1,4-cyclohexadienes with the more highly substituted double bonds

If Birch reductions are run without an alcohol proton source, the basic LiNH2 formed can cause double bond isomerization, and over-reduction (Rabideau JOC 1983, 48, 4266).

The Birch reduction of methoxybenzenes is a useful synthesis of cyclohexenones: Desogestrel: Corey, E. J.; Huang, A. X. J. Am. Chem. Soc. 1999, 121, 710. Note that the isolated double bond is not reduced.

Benzoic acids are reduced to form the cross-conjugated carboxylate dianion, which can be alkylated to form 1-substituted cylohexadienecarboxylic acids. Fichtelite: Taber, D.F, Saleh, S. A. J. Org. Chem. 1980, 102, 5085

Reduction of Enones to Enolates

Under typical Birch reduction conditions ,-unsaturated enones and carboxylic esters are reduced to enolates, which can be trapped regiospecifically by reactive alkylating agents or other electrophiles. Upial:Taschner, M. J.; Shahripour, A. J. Am. Chem. Soc. 1985, 107, 5570.

The reduction of double bonds in bicyclo[4.4.0] systems will usually give the trans-fused ring system (Stork J. Am. Chem. Soc., 1960, 82, 1512). Acanthoic Acid: Ling, T.; Chowdhury, C.; Kramer, B. A.; Vong, B. G.; Palladino, M. A.; Theodorakis, E. A. J. Org. Chem. 2001, 66, 8843

Hispidospermidine: Frontier, A. J.; Raghavan, S.; Danishevsky, S. J. J. Am. Chem. Soc. 2000, 122, 6151.

Reductive Dimerization of carbonyl compounds - Pinacol and McMurry reductions

The classical pinacol reduction involves the reductive dimerization of a ketone to form a 1,2 diol (pinacol). Like most dimerizations, the reaction is of limited use since it works well only to make symmetric compounds.

McMurry developed a reduction procedure that is more reliable than the Mg pinacol conditions using the much more oxophilic metal titanium. The reagent, thought to be a mixture of Ti(0) and Ti(II) species, is usually formed by reduction of TiCl3 with Zn/Cu, although other reductants such as LiAlH4, potassium-graphite (C8K), Zn, and Mg can be used. The reagent is most useful for intramolecular reductions to form cyclic glycols and alkenes, but can also perform high-yield cross-coupling of aldehydes and ketones if one reactant can be present in excess. The reaction can be stopped at the diol stage, as in the Sarcophytol and Taxol examples below, but under more vigorous conditions a second reduction to an alkene occurs. Sarcophytol B: McMurry, Tetrahedron Lett., 1989, 30, 1173.

Formation of 8-membered ring in Taxol synthesis: Nicolaou, Nature, 1994, 367, 630.

Use of Samarium iodide: Taxol Model: Swindell, Fan Tetrahedron Lett. 1996, 37, 2321.

Compactin: Clive, J. Am. Chem. Soc., 1990, 112, 3018.

Vetispirene: Paquette, L. A.; Yan, T. H. Tetrahedron Lett. 1982, 23, 3227

()--Araneosene: Hu, T.; Corey, E. J. Org. Lett. 2002, 4, 2441

Acyloin Reduction

Treatment of carboxylic esters with metallic sodium under aprotic conditions leads to a reductive dimerization to -hydroxyketones (acyloins). The reaction is best done in the presence of trimethylsilyl chloride, which traps the intermediate enolates. The reaction is especially useful for the formation of rings.

Reduction of C-X Bonds

Treatment of C-X compounds with dissolving metal reductants (where X is some reasonably good leaving group such as Cl, Br, I, OSO2R, OP(O) (OMe)2, OP(O)(NMe3)2, OAc, SPh, SePh, SO2Ph) can lead to reductive cleavage of the C-X bond and formation of a C-M bond, which can be protonated or used for further reactions. This is the most common way to make organolithium and organomagnesium reagents. If there is a sufficiently acidic proton source in the medium, the organometallic reagent C-M will be protonated to form C-H. Reactions of this type are especially facile for X substituents to carbonyl groups and those at allylic and benzylic positions (removal of benzyl protecting groups) because of the conjugative stabilization of the intermediate radical and anion, but reductions can be performed even of unactivated C-X bonds.

Common reagents are Zn/Cu (activated zinc), Mg/ether, Li/THF, Li/NH3, Na/NH3, Na(Hg), Al(Hg), Na/EtOH, SmI2. Lithium in ether solvents can be activated by the presence of a catalytic amount of an arene (naphthalene and 4,4'-di-t-butylbiphenyl are common ones). In this case the aromatic radical anion or dianion is the active reducing agent.
Reduction of Ketones to Alkenes

The conversion of ketones to alkenes can be achieved by conversion to enol phosphate or amidate, followed by dissolving metal reduction. In the first example below two reductions, the first of an enone and the second of an enol phosphate, are used to convert an ,-unsaturated ketone to an alkene. In the second the enolate intermediate in the enone reduction is trapped to form a phosphate, which is then reductively cleaved. -Elemenone: Majetich, G.; Grieco, P. A.; Nishizawa, N. J. Org. Chem. 1977, 42, 2327.

Cuauhtemone: Goldsmith, D. J.; Sakano, I. J. Org. Chem. 1976, 41, 2095.

Desulfonylation

Metalated sulfones have a number of important applications in synthetic chemistry, including alkylations, acylation, and condensation with ketones and aldehydes (Julia olefination). The sulfonyl group is often reductively removed during the process, or needs to be removed after the task is done. Buffered sodium or aluminum amalgam are commonly used reagents. Zizaene: Piers, E.; Banville, J. Chem. Commun. 1979, 1138

Reduction of Acetylenes

Alkynes are reduced to trans alkenes under dissolving-metal conditions:

There are several ways to perform the cis-reduction of alkynes: Hydroboration-protonation - Dehydroarachidonic Acid.: Corey, E. J.; Kang, J. Tetrahedron Lett., 1982, 23, 2651.

Lindlar reduction - Japonilure: Papillon, J. P. N.; Taylor, R. J. K. Org. Lett. 2002, 4, 119

Singlet Oxygen Singlet oxygen (1 O2, 22 kcal/mol higher in energy) can be generated by shining light on a solution of oxygen in the presence of a triplet sensitizer like Methylene Blue or Rose Bengal (photochemistry). There are also several chemical methods of generating singlet oxygen, most notably the reaction of hydrogen peroxide with hypochlorite.

The triplet ground state of dioxygen (3 O2) can be considered to have two half-double bonds, whereas the singlet excited state (1 O2) has a true bond (diatomic orbital diagrams)

Singlet oxygen has a lifetime of under a second, but it is very much more reactive towards organic compounds than is triplet oxygen, reacting readily with alkenes (ene reaction to form allylic hydroperoxides), dienes (cycloaddition to form 1,2-dioxanes), electron-rich aromatic compounds, phosphines, sulfides and selenides (to form oxides). Singlet oxygen is an electrophilic reagent (note the low-energy LUMO), and reacts more readily with electron rich double bonds, and slowly or not at all with electron poor ones.

Note that the singlet oxygen ene reaction corresponds to an allylic oxidation with migration of the double bond, analogous to the sequence epoxidation, elimination. The SeO2 oxidation of alkenes, on the other hand, leads to allylic oxidation with retention of double bond position. Radical chain oxidations will typically lead to mixtures of rearranged and unrearranged products from nonselective trapping of the intermediate allyl radical

Allylic hydroxylation, conversion of a diene to furan. Dendrolasin: Kondo, K.; Matsumoto, M. Tetrahedron Lett.. 1976, 391. DOI

Conversion of a furan to a hydroxy-butenolide. Dysidiolide: Madnuson, S. R.; Sepp-Lorenzino, L.; Rosen, N.; Danishefsky, S. J. J. Am. Chem. Soc. 1998, 120, 1615. DOI

Conversion of cyclopentadiene to a hydroxycyclopentenone. 15-Deoxyprostagladin E1: Sih, C. J.; Salomon, R. G.; Price, P.; Peruzzoti, G.; Sood, R. Chem. Commun. 1972, 240 DOI

Oxidation with Ozone Ozone reacts with alkenes to ultimately give products in which the double bond has been cleaved. The intermediate ozonide can be reduced with a variety of reagents, including Me2S, Zn, PPh3, or hydride reducing agents. Other functional groups that readily react with ozone are phosphines, sulfides and selenides, which give phosphine oxides, sulfoxides and selenoxides.

Androstene-3,17-dione, 4-: Schmidt, R.; Huesmann, P. L.; Johnson, W. S. J. Am. Chem. Soc. 1980, 102, 5122. DOI

As with most other oxidations, double bonds are more reactive than triple bonds. Japonilure (Japanese beetle sex pheromone

A commonly used alternative to ozonolysis to cleave double bonds is the OsO4/NaIO4 reagent combination (Lemieux-Johnson oxidation).
Oxidation of Selenides

Ozone is useful as a mild low-temperature oxidant for slenides to selenoxides: Akuammicine:

Oxidations with Dioxirane Dioxiranes perform a variety of oxygen transfer reactions, usually to nucleophilic reagents, including epoxidation of double bonds, -oxidation of enol silyl ethers, oxidation of amines to hydroxylamines and nitro compounds, oxidation of selenides to selenoxides, and sulfides to sulfoxides.

Preparation of Sensitive Epoxides:

Asymmetric Oxidations with Chiral Dioxiranes:

Amine oxidations:

Tertiary Hydrogen Abstraction

Chromium Oxidants A variety of chromium(VI) oxides derived from CrO3 were long among the most popular reagents for oxidation of alcohols to ketones and aldehydes. The properties of the reagent can be altered by Lewis base complexation. Pyridinium chlorochromate, pyridinium dichromate and chromic oxide-pyridine (Collins reagent) are the most commonly used ones. The oxidation of primary alcohols can usually be stopped at the aldehyde stage, although oxidation to carboxylic acids can also be achieved. 1,2-Glycols undergo C-C bond cleavage. The Oxidation of Alcohols by Modified Oxochromium(VI)-Amine Reagents, Luzzio, F. A. Org. React. 1998, 53, 1-221.

Solanapyrone: Hagiwara, H.; et al. J. Org. Chem. 2002, 67, 5969

Allylic Oxidation

The functionalization of allylic positions can be done by several distinct methods (allylic halogenation, singlet oxygen, selenium dioxide). Chromium oxide reagents are one of the options to do this difficult transformation. In favorable cases, Cr(VI) complexes will oxidize alkenes to enones. There are regioselectivity issues, and the reaction seems to work best when one of the double bond termini is fully substituted (i.e. cannot be oxidized to a ketone).

Manzamine:

Oxidations with Hypervalent Iodine Compounds Inorganic iodide (I-) and organoiodine compounds form a series of oxides by consecutive oxidations of the iodine lone pairs.

Several of these iodine oxides, suitably modified to improve solubility, reactivity, and/or accessibility have useful properties as oxidizing agents. Some chlorine and bromine analogs are also useful.
Oxidation with Periodate

NaIO4 (I+7) is a mild oxidant, whose most important uses are the oxidative cleavage of vicinal glycols, and as a reoxidant for OsO4. It is also useful for the mild and selective oxidation of sulfides and selenides to sulfoxides and selenoxides.
Oxidation with o-Iodoxybenzoic Acid (IBX)

ortho-Iodoxybenzoic acid can be prepared by the oxidation of ortho-iodobenzoic acid. It forms a cyclic "hemiacetal"-like structure. Although it is a powerful oxidant, its poor solubility properties limit its applicability, and result in relatively harsh reaction conditions being required.

Oxidation of Alcohols with Dess-Martin Periodinane-

The Dess-Martin periodinane closely related to IBX, is prepared similarly, except under dhydrating

conditions with acetic anhydride.

It has with much better solubility properties than IBX, and is currently the reagent of choice for the mild and convenient oxidation of alcohols to aldehydes and ketones, having displaced most transition metal oxidants in small scale operations where cost (and the hazard of working with a shocksensitive compound) is not an issue. It is competing well with Moffat-Swern DMSO-based oxidations, but does show some tendency to cleave glycols and -hydroxy ketones, so DMSO oxidations are usually the preferred method for oxidations of glycols to -hydroxyketones or 1,2diketones.

Reductions with Hydrazine Hydrazine itself and derivatives of hydrazine can behave as reducing agents, in most cases by formation of the very stable NN, which formally releases two molecules of H2.
Wolff-Kishner Reduction

The Wolff-Kisher reduction is used to convert ketones to methylene groups, and aldehydes to methyl groups. It does not function to reduce the carbonyl groups of amides and esters. The reaction involves conversion of the ketone or aldehyde to a hydrazone, which undergoes base-catalyzed isomerizion to the azo compound A followed by fragmentation. The conditions are very harsh - strongly basic and high temperatures - which limits the application of the method to hydrocarbons or molecules with very thermally and base-stable protecting groups. Genudin Model: Renoud-Grappin, M.; Vanucci, C.; Lhomet, G. J. Org. Chem. 1994, 59, 3902.

Reduction of Tosylhydrazones

A much milder method synthetically equivalent to the Wolff-Kishner is the reduction of tosylhydrazones with sodium borohydride or sodium cyanoborohydride. The mechanism is believed to go through the same intermediate azo compound A as the Wolff- Kishner reaction. Cytisine: Stead, D.; O'Brien, P.; Sanderson, A. J. Org. Lett. 2005, 7, 4459-4462

The unstable molecule diimide (HN=NH) can be generated in a variety of ways. It reacts with alkynes and unhindered alkenes to transfer two hydrogens in a cyclic process, resulting in a strictly cis reduction. This is the mildest way of performing such reductions.
Reduction with Diimide-

One generally useful application of diimide reduction is in the conversion of iodoalkynes to cis vinyl iodides. Most other reducting agents will cause competing or complete cleavage of the C-I bond. Brasilenyne: Denmark, S.; Yang, S. M. J. Am. Chem. Soc. 2004, 126, 12432. DOI

Oxidations with Quinones Quinones bearing multiple electron withdrawing groups can function as hydride abstracting agents in situations where removal of hydride leaves a stabilized cation. Dicyanodichloroquinone (DDQ) is the most frequently used and most effective quinone for such applications.

Deprotection of PMB Ethers

The most common use of DDQ in synthetic chemistry is the oxidative removal of p-methoxy benzyl groups, which allows the use of PMB as a protecting group orthogonal to almost all others. Tedanolide Macrolactone: Hassfeld, J.; Eggert, U.; Kalesse, M. Synthesis 2005, 1183. DOI

Dehydrogenation of Ketones

Although there are usually better reagents for this, DDQ and chloranil can be used to dehydrogenate ketones to enones. Warburganal: Kende, A. S.; Blacklock, T. J. Tetrahedron Lett. 1980, 21, 3119

Since these reactions proceed by hydride abstraction from the enol, prior conversion to enol silyl ether leads to more efficient reactions, with regiochemical control.. Carvone: Fleming, I.; Paterson, I. Synthesis 1979, 736

Boron Hydrides
Sodium Borohydride

NaBH4 is the most commonly used mild (selective) hydride reducing agent. It reacts well with aldehydes, ketones, acid chlorides, anhydrides and imides, but reacts sluggishly or not at all with esters, lactones, acids, nitriles, amides, nitro compounds, alkenes, epoxides and alkynes. It is not very effective in SN2 reductions of halides and tosylates. NaBH4 is also commonly used in the reduction of organomercury compounds (from oxymercurations) and in the complete reduction of ozonides.

Waol A: Gao, X.; Nakadai, M.; Snider, B. Org. Lett. 2003, 5, 451

Luche Reduction

NaBH4 shows significant tendency to do 1,4 reductions of ,-unsaturated ketones. This can be ameliorated by use of the Luche conditions: NaBH4/CeCl3 Acanthoic Acid: Ling, T.; Chowdhury, C.; Kramer, B. A.; Vong, B. G.; Palladino, M. A.; Theodorakis, E. A. J. Org. Chem. 2001, 66, 8843

Modified Borohydrides - Reductive Aminations

Sodium Cyanoborohydride A Highly Selective Reducing Agent for Organic Functional Groups, C. F. Lane, Synthesis 1975, 135. Sodium cyanoborohydride: The substitution of one H by CN leads to a great attenuation of the nucleophilicity of the remaining hydrides, to the extent that NaBH3CN reacts with ketones and aldehydes at a significant rate only at low pH (<4). Presumably only the protonated carbonyl compound is reduced. It does however, react with immonium salts formed in situ by reaction of ketones or aldehydes with amines under weakly acidic conditions, leading to reductive amination. Amine borane complexes (H3BNMe3) have similar reactivity ro cyanoborohydride, and can also be used for reductive aminations. R. F. Borch, M. Bernstein, H. D. Durst, J. Am. Chem. Soc. 1971, 93, 2897.

Dendrobine: A. S. Kende, T. J. Bentley, R. A. Mader, D. Ridge, J. Am. Chem. Soc. 1974, 96, 4332.

Modified Borohydrides - SN2 Reactions

Lithium Triethylborohydride is a much more nucleophilic hydride donor than is LiBH4 due to the effect of the electron releasing alkyl groups. This reagent is especially useful for SN2 reductions of alkyl halides and sulfonates, although it can also be used as a selective reductant for ketones

and aldehydes.

Modified Borohydrides - Triacetoxyborohydride

Adaline: Itoh, T.; Yamazaki, N.; Kibayashi, C. Org. Lett. 2002, 4, 2469. DOI

Modified Borohydrides - Steric Effects

Tri-sec-butylborohydrides (sold under the trade names L-Selectride and K-Selectride) show exceptional steric selectivity in the reduction of ketones and aldehydes. Brown J. Am. Chem. Soc. 1973, 95, 4101.

Conjugate Reduction: Tri-sec-butylborohydride reagents also show a strong tendency for conjugate reduction of enones (1,4- rather than 1,2reduction). The enolates formed can be trapped with various electrophiles, if desired. Ganem J. Org. Chem. 1976, 41, 2194.

Capnellene: Crisp, G. T.; Scott, W. J.; Stille, J. K. J. Am. Chem. Soc. 1984, 106, 7500

Avrainvillamide: Herzon, S. B.; Myers, A. G J. Am. Chem. Soc. 2005, 127, 5342 DOI

Dihydroxanthatin: Evans, M. A.; Morken, J. P. Org. Lett. 2005, 7, 3371

Boranes - Alkene Hydroboration

The Lewis acidic boron results in a substantially different reactivity profile for boranes vs anionic borohydrides. Most important is the high reactivity of most boranes towards alkenes and alkynes, which are essentially unreactive towards borohydrides. There are a large number of borane reagents that have a variety of special properties for selective reductions. For run-of-the-mill hydroborations the THF (H3BTHF) or dimethyl sulfide (H3BSMe2) complexes of borane are used. Hydroboration: The most important reaction of boranes is alkene hydroboration (usually followed by oxidation to an alcohol with alkaline hydrogen peroxide or an amine oxide). The hydroboration is strictly a cis addition of H and B across the multiple bond, and shows a strong tendency for placement of the boron at the less substituted end of the double bond.
Nobel-Prize-winning chemistry H. C. Brown, 1979

Hydroboration of unhindered alkenes is faster than reduction of ketones. In the example below, hydroboration of the terminal alkene proceeded without significant reduction of either the ester or ketone. Quadrone: Danishefsky, S.; Vaughan, K.; Gadwood, R. C.; Tsuzuki, K. J. Am. Chem. Soc. 1981, 103, 4136.

However, in the examples below the double bond is more hindered, and selective hydroboration was not possible. In the first example, both the ketone and double bond were reduced. In the second example protection of the ketone was needed: formation of an ethylene ketal was unsuccessful, but the hydrazone worked. Aromaticin: Majetich, G.; Song, J. S.; Leigh, A. J.; Condon, S. M. J. Org. Chem. 1993, 58, 1030.

Sativene, (): McMurry, J.E. J. Am. Chem. Soc., 1968, 90, 6821.

For unusual steric selectivity 9-BBN-H, disiamylborane and thexyl borane are useful.

Chiral Boranes for Asymmetric Reductions. Asymmetric Hydroboration Using Diisopinocampheyl Borane: H. C. Brown, et al. JACS, 1985, 107, 2564.

Boranes - Alkyne Hydroboration

Hydroboration of internal alkynes stops cleanly at the vinyl borane stage even with unhindered boranes. Terminal alkynes, on the other hand, usually give a poorly controlled mixture of mono and bis-hydroborated materials with H3BTHF (e.g. 1-hexyne gives mostly the 1,1-dihydroborated material). However, several substituted hindered boranes, such as HB(Cyclohexyl)2 (example below), catecholborane and 9-BBN-H will undergo selective mono-addition to form vinyl boranes, and these can be used in Suzuki coupling reactions, converted to vinyl halides, or protonated to give exclusively cis-alkenes. Ginkolide B: Corey, E. J.; Kang, M. C.; Desai, M. C.; Ghosh, A. K.; Houpis, I. N. J. Am. Chem. Soc. 1988, 110, 649-651.

Boranes - Selective Reduction of Carboxylic Acids

A very useful selectivity difference between boranes and borohydrides is that boranes will reduce carboxylic acids faster than they reduce carboxylic esters, whereas borohydrides and aluminohydrides show the opposite selectivity. This is because the acetoxy borane intermediate is an activated ester resulting from -donation of acetoxy oxygen to boron (essentially a mixed anhydride between the carboxylate and a borinic acid). In the example below a carboxylic acid is reduced in the presence of a lactone. Lactones are usually better electrophiles than acyclic esters, and this one is additionally activated by the -alkoxy substituent. Brasilenyne: Denmark, S.; Yang, S. M. J. Am. Chem. Soc. 2004, 126, 12432.

Aluminum Hydrides Reductions by Metal Alkoxyaluminum Hydrides, J. Malek, Org. React. 1985, 34, 1; 1988, 36, 249. Asymmetric Aluminum Hydride Reductions: Asymmetric Reductions with Chiral Complex Aluminum Hydrides and Tricoordinate Aluminum Reagents, Haubenstock, H. Top. in Stereochemistry, 1983, 14, 213. Reduction with Chiral Modifications of Lithium Aluminum Hydride, E. R. Grandbois, S. I. Howard, J. D. Morrison in "Asymmetric Synthesis" Vol. 2, J. D. Morrison, Ed., Academic Press, 1983.
Lithium Aluminum Hydride

LiAlH4 and its analogs (e.g. NaH2Al(OCH2CH2OMe)2) are the most powerful nucleophilic hydride reducing agents available. These reagents must be used in ether solvents, as they react violently with water and alcohols, and there is a substantial fire hazard while using them. LiAlH4 will reduce

all common unsaturated functional groups except for unactivated alkenes and alkynes, and is also a powerful SN2 reducing agent of halides and sulfonates.

LiAlH4 is usually the reagent of choice for the reduction of carboxylic acids and esters to primary alcohols, and the reduction of amides to amines. Farnesol: Yu, J. S.; Kleckley, T. S.; Wiemer, D. F. Org. Let. 2005, 7, 4803

Phenserine: Rigby, J. H.; Sidique,S. Org. Lett. 2007, 7, 1219 DOI

Enantioselective Reductions

Binaphthol aluminum hydrides: Noyori, JACS 1979, 101, 3129;

Prostaglandin E1: Noyori, R. et. al Tet. Lett., 1983, 24, 4103.

Gallium analog of BINAL-H: Catalytic reaductions. Ford, A.; Woodward, S. Angew. Chem. Int. Ed. 1999, 38, 335.

Alanes - Diisobutylaluminum Hydride

Applications of Diisobutylaluminum Hydride and Triisobutylaluminum Hydride as Reducing Agents in Organic Synthesis, Winterfeldt, E. Synthesis 1975, 617. By far the most important hydridoalane in synthetic chemistry is diisobutylaluminum hydride (DIBALH). Its most common use is the reduction of ,-unsaturated aldehydes, ketones, esters and carboxylic acids to alcohols with minimum competing 1,4-reduction. Also useful are the hydroalumination of alkynes as a route to vinyl halides, and the partial reduction of nitriles to give aldehydes on hydrolysis. Under carefully controlled low-temperature conditions DIBALH reduction of esters can be stopped at the aldehyde stage (presumably aluminum coordination stabilizes the tetrahedral intermediate), although usually conversion of esters to aldehydes is done by complete reduction followed by oxidation of primary alcohol to aldehyde. Mesembrine: Stevens, R. V.; Lesko, P. M.; Lapalme, R. J. Org. Chem. 1975, 40, 3495.

Reduction of Weinreb amide - Rhyzoxin D: Jiang, Y.; Hong, J.; Burke, S. D. Org. Lett. 2004, 6, 1445

Alkyne hydroalumination - Deplancheine: Overman, L. E.; Malone, T. C. J. Org. Chem. 1982, 47, 5297.

Tin Hydride Reductions Tin hydrides have the almost unique ability among metal hydrides to support radical chain reductions of a variety of C-X bonds (X = Cl, Br, I, SePh, SPh, NO2, OC(=S)R). They are thus commonly used for removal of unwanted functional groups. The radical chains are typically initiated with the radical initiator AIBN.

Free Radical Chain Reductions with Tin Hydrides.

Solanapyrone: Hagiwara, H.; et al. J. Org. Chem. 2002, 67, 5969

ilicon Hydride Reductions Hydrogen Donor Abilities of the Group 14 Hydrides, Chatgilialoglu, C.; Newcomb, M. Adv. Organometal. Chem. 1999, 44, 67-112. a) Organosilanes as Radical-Based Reducing Reagents in Synthesis, C. Chatgilialoglu Acc. Chem. Res. 1992, 25, 188. Applications of Ionic Hydrogenations to Organic Synthesis, D. N. Kursanov, Z. N. Parnes and N. M. Loim, Synthesis 1974, 663. Hydrosilanes as Reducing Agents, Y. Nagai, Org. Prep. Proc. Int. 1980, 12, 13. Controlling Benzylic and Anomeric Functionality and Stereochemistry: Methodology and Syntheses Utilizing Intramolecular Ionic Hydrogenation, McCombie, S. W.; Ortiz, C.; Cox, B.; Ganguly, A. K. Synlett 1993, 541. Chemo- and Enantioselective Hydrosilylation of Carbonyl and Imino Groups. An Emphasis on Non-Traditional Catalyst Systems, Carpentier, J.-F.; Bette, V. Curr. Org. Chem. 2002, 6, 913-36. Recent Advances in the Asymmetric Hydrosilylation of Ketones, Imines, and Electrophilic Double Bonds Riant, O.; Mostefai, N.; Courmarcel, J. Synthesis 2004, 2943-58. Silyl hydrides are very weak hydride donors (they are stable even to mild acids and oxidizing agents) and will not react with any neutral carbonyl compounds or imines. It is, however, possible to catalyze the reactions, either using Lewis or protic acids, or nucleophilic catalysts. Thus silyl hydrides will donate hydride to protonated carbonyl groups and most types of stabilized carbonium ions. Amine complexes of boranes (Me3NBH3) can also perform similar reductions.
Ionic Hydride Reductions

Reduction of Hemiacetals - Synthesis of Camptothecin: Curran, D. P.; Ko, S. B.; Josien, H. Angew. Chem., Int. Ed. Engl. 1995, 34, 2683.

Reduction of hemiaminals - Anatoxin A: Brenneman, G. B.; Martin, S. F. Org. Lett. 2004, 6, 1329. DOI

Radical Chain Reductions with Silyl Hydrides.

Tris(trimethylsilyl)silane: Chatgilialoglu, JOC., 1988, 53, 3641; TL, 1989, 30, 2733. Giese, OS, 1991, 70, 164.

Bilobalide: Deoxygenation of Epoxides: Corey, JACS, 1987, 109, 7534.

Stannyl-Based Radical Cyclizations

Tandem Radical Cyclization Approach to Hirsutene: D. P. Curran, D. M. Rakiewicz J. Am. Chem. Soc. 1985, 107, 1448.

Vinyl Radicals - Merrilactone: Birman, V. B.; Danishefsky, S. J. J. Am. Chem. Soc. 2002, 124, 2080-2081

Radical Cyclization to Achieve cis-Hydroxyalkylation

Stork, Kahn J. Am. Chem. Soc. 1985, 107, 500.

14-Deoxyisoamijiol: Majetich, G.; Song, J. S.; Ringold, C.; Nemeth, G. A. Tetrahedron Lett. 1990, 31, 2239

Acyl Radicals from Acyl Selenides

Spongian-16-one: Pattenden, Roberts Tetrahedron Lett. 1996, 37, 4191.

Generation of Iminoyl Radicals - Synthesis of Camptothecin: Curran, Ko, Josien Angew. Chem., Int. Ed. Engl. 1995, 34, 2683.