org.chem b
Barton-McCombie Reaction
Barton Deoxygenation
A method for the deoxygenation of alcohols. The alcohol is first converted to the thiocarbonyl derivative, and is then treated with Bu3SnH. Once the radical chain has been initiated, attack on the Bu3Sn carrier by sulphur initiates a decomposition yielding the alkyl radical, for which Bu3SnH serves as hydrogen radical (H·) donor. The driving force for the reaction is the formation of the very stable S-Sn bonds.
MECHANISM OF THE BARTON-MCCOMBIE REACTION
Initiation:
The catalytic cycle, in which low concentration of .SnBu3 effects the reaction:
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Baylis-Hillman Reaction
This coupling of an activated alkene derivative with an aldehyde is catalyzed by a tertiary amine (for example: DABCO = 1,4-Diazabicyclo[2.2.2]octane). Phosphines can also be used in this reaction, and enantioselective reactions may be carried out if the amine or phosphine catalyst is asymmetric.
MECHANISM OF THE BAYLIS-HILLMAN REACTION
A key step is the addition of the amine catalyst to the activated alkene to form a stabilized nucleophilic anion. This in situ-generated nucleophile then adds to the aldehyde. Subsequent elimination of the catalyst leads to the observed products.
Other activating nitrogen nucleophiles may be suitable too and DMAP and DBU are superior to DABCO in some cases:
product of the addition of DBU and methylacrylateFor aryl aldehydes under polar, nonpolar, and protic conditions, it has been determined that the rate-determining step is second-order in aldehyde and first-order in DABCO and acrylate. On the basis of this reaction rate data, Tyler McQuade recently proposed (J. Org. Chem. 2005, 70, 3980. DOI) the following mechanism involving the formation of a hemiacetal intermediate:
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Beckmann Rearrangement
An acid-induced rearrangement of oximes to give amides.
This reaction is related to the Hofmann and Schmidt Reactions and the Curtius Rearrangement, in that an electropositive nitrogen is formed that initiates an alkyl migration.
MECHANISM OF THE BECKMANN REARRANGEMENT
Oximes generally have a high barrier to inversion, and accordingly this reaction is envisioned to proceed by protonation of the oxime hydroxyl, followed by migration of the alkyl substituent "trans" to nitrogen. The N-O bond is simultaneously cleaved with the expulsion of water, so that formation of a free nitrene is avoided.
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Benzilic Acid Rearrangement
1,2-Diketones undergo a rearrangement in the presence of strong base to yield α-hydroxycarboxylic acids. The best yields are obtained when the subject diketones do not have enolizable protons.
The reaction of a cyclic diketone leads to an interesting ring contraction:
Ketoaldehydes do not react in the same manner, where a hydride shift is preferred (see Cannizzaro Reaction)
MECHANISM OF BENZILIC ACID REARRANGEMENT
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Benzoin Condensation
The Benzoin Condensation is a coupling reaction between two aldehydes that allows the preparation of α-hydroxyketones. The first methods were only suitable for the conversion of aromatic aldehydes.
MECHANISM OF BENZOIN CONDENSATION
Addition of the cyanide ion to create a cyanohydrin effects an umpolung of the normal carbonyl charge affinity, and the electrophilic aldehyde carbon becomes nucleophilic after deprotonation: A thiazolium salt may also be used as the catalyst in this reaction (see Stetter Reaction).
A strong base is now able to deprotonate at the former carbonyl C-atom:
A second equivalent of aldehyde reacts with this carbanion; elimination of the catalyst regenerates the carbonyl compound at the end of the reaction:
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Bergman Cyclization
Bergman Cycloaromatization
The Bergman Cyclization allows the construction of substituted arenes through the thermal or photochemical cycloaromatization of enediynes in the presence of a H• donor such as 1,4-cyclohexadiene.
MECHANISM OF THE BERGMAN CYCLIZATION
The cyclization is induced thermally or photochemically. Most cyclizations have a high activation energy barrier and therefore temperatures around 200 °C are needed for the cycloaromatization. The Bergman Cyclization forms a 1,4-benzenediyl diradical - a highly reactive species, that reacts with a H• donor to give the corresponding arenes.
The interest in the Bergman Cyclization was somewhat low, due to its limited substrate scope and the availability of alternative methods for the construction of substituted arenes. However, natural products that contain the enediyne moiety have been discovered recently, and these compounds have cytotoxic activity.
An example is calicheamicin, which is able to form the reactive diradical species even under physiological conditions. Here, the Bergman Cyclization is activated by a triggering reaction. A distinguishing property of this diradical species is that it can effect a dual-strand cleavage of DNA:
With the discovery of calicheamicin and similar natural products, interest in the Bergman Cyclization has increased. Many enediynes can now be viewed as potential anticancer drugs. Thus, the development of Bergman Cyclization precursors that can undergo cyclization at room temperature has attracted much attention. Now, most publications on this topic deal with the parameters that control the kinetics of the Bergman Cyclization.
For example, as shown by calicheamicin, cyclic enediynes have a lower activation barrier than acyclic enediynes. As suggested by Nicolaou in 1988, the distance between the acetylenic carbons that form the covalent bond influences the rate of cyclization. Another theory developed by Magnus and Snyder is based on the molecular strain between ground state and transition state; this seems to be more general, especially for strained cyclic systems. Often, as both the distance and the strain are not known, the development of suitable precursors remains difficult, as exemplified by the following enediyne, in which a slight change leads to a cycloaromatization:
In contrast to the Bergman Cyclization, the Myers-Saito Cyclization of allenyl enynes exhibits a much lower activation temperature while following a similar pathway:
Cyclic enyne allenes are also reactive. Neocarzinostatin is a bacterial antibiotic that also shows antitumor activity. Here, the occurrence of a Myers-Saito Cyclization sets the stage for the cleavage of DNA:
For synthetic purposes, organometallic reagents can be used to generate a precursor to the Bergman Cyclization in which the metal center forms a part of the cumulated unsaturated system; these cyclizations occur at relatively low temperatures, as shown in the example reported by Finn (J. Am. Chem. Soc. 1995, 117, 8045). Here the cyclization can be viewed as a Myers-Saito Cyclization that gives rise to a metal-centered radical:
For a review of natural products, chelation control of the cyclization and recent developments in catalyzed Bergman Cyclizations, please refer to the review by Basak and references cited therein (Chem. Rev. 2003, 103, 4077. DOI).
Bergman Cyclization
Bergman Cycloaromatization
The Bergman Cyclization allows the construction of substituted arenes through the thermal or photochemical cycloaromatization of enediynes in the presence of a H• donor such as 1,4-cyclohexadiene.
MECHANISM OF THE BERGMAN CYCLIZATION
The cyclization is induced thermally or photochemically. Most cyclizations have a high activation energy barrier and therefore temperatures around 200 °C are needed for the cycloaromatization. The Bergman Cyclization forms a 1,4-benzenediyl diradical - a highly reactive species, that reacts with a H• donor to give the corresponding arenes.The interest in the Bergman Cyclization was somewhat low, due to its limited substrate scope and the availability of alternative methods for the construction of substituted arenes. However, natural products that contain the enediyne moiety have been discovered recently, and these compounds have cytotoxic activity.
An example is calicheamicin, which is able to form the reactive diradical species even under physiological conditions. Here, the Bergman Cyclization is activated by a triggering reaction. A distinguishing property of this diradical species is that it can effect a dual-strand cleavage of DNA:
With the discovery of calicheamicin and similar natural products, interest in the Bergman Cyclization has increased. Many enediynes can now be viewed as potential anticancer drugs. Thus, the development of Bergman Cyclization precursors that can undergo cyclization at room temperature has attracted much attention. Now, most publications on this topic deal with the parameters that control the kinetics of the Bergman Cyclization.
For example, as shown by calicheamicin, cyclic enediynes have a lower activation barrier than acyclic enediynes. As suggested by Nicolaou in 1988, the distance between the acetylenic carbons that form the covalent bond influences the rate of cyclization. Another theory developed by Magnus and Snyder is based on the molecular strain between ground state and transition state; this seems to be more general, especially for strained cyclic systems. Often, as both the distance and the strain are not known, the development of suitable precursors remains difficult, as exemplified by the following enediyne, in which a slight change leads to a cycloaromatization:
In contrast to the Bergman Cyclization, the Myers-Saito Cyclization of allenyl enynes exhibits a much lower activation temperature while following a similar pathway:
Cyclic enyne allenes are also reactive. Neocarzinostatin is a bacterial antibiotic that also shows antitumor activity. Here, the occurrence of a Myers-Saito Cyclization sets the stage for the cleavage of DNA:
For synthetic purposes, organometallic reagents can be used to generate a precursor to the Bergman Cyclization in which the metal center forms a part of the cumulated unsaturated system; these cyclizations occur at relatively low temperatures, as shown in the example reported by Finn (J. Am. Chem. Soc. 1995, 117, 8045). Here the cyclization can be viewed as a Myers-Saito Cyclization that gives rise to a metal-centered radical:
For a review of natural products, chelation control of the cyclization and recent developments in catalyzed Bergman Cyclizations, please refer to the review by Basak and references cited therein (Chem. Rev. 2003, 103, 4077. DOI).
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Seyferth-Gilbert Homologation
Bestmann-Ohira Reagent
The Seyferth-Gilbert Homologation is the base-promoted reaction of dimethyl (diazomethyl)phosphonate with aldehydes and aryl ketones at low temperatures, and provides a synthesis of alkynes. The Ohira-Bestmann modification using dimethyl 1-diazo-2-oxopropylphosphonate allows the conversion of base-labile substrates such as enolizable aldehydes, which would tend to undergo aldol condensation under the Seyferth-Gilbert conditions:
MECHANISM OF THE SEYFERTH-GILBERT HOMOLOGATION
The mechanism is described in detail in a report by Gilbert (J. Org. Chem., 1982, 47, 1837-1845. Abstract).The deprotonated Seyferth-Gilbert reagent adds to the carbonyl compound forming an alkoxide that closes to give an oxaphosphetane:
Comparable to the Wittig Reaction, a cycloelimination yields a stable dimethyl phosphate anion and a diazoalkene:
Upon warming of the reaction mixture to room temperature, loss of nitrogen gives a vinylidene carbene that yields the desired alkyne after 1,2-migration of one of the substituents:
For substrates with substituents that have low migratory aptitudes, such as 4-nitrobenzaldehyde, the existence of the nitrene can be demonstrated by adding an excess of amine or alcohol to the reaction mixture, which yields the products of insertion reactions:
An alternative mechanism would involve nitrogen loss at an earlier stage of the mechanism, prior to the cycloelimination; i.e. N2 loss and rearrangement would occur from the oxaphosphetane to yield an oxaphosphete, to be followed by the cycloelimination:
The failure of several attempts to use Wittig-like reactions for the direct synthesis of alkynes tends to rule out this alternative mechanism. One could argue that the generation of alkynes is very fast, but this possibility can be excluded through comparison with similar structures. The Seyferth-Gilbert reagent should be more stable than a comparable alkyl azide. Ring strain is expected not to be important, since diazocyclobutane is still stable at -40°C and its decomposition to the azine is slow even at 0°C. The diazooxaphosphetane should have a similar molecular geometry in addition to a stabilizing neighbor group effect, so that a fast reaction cannot be anticipated.
The dimethyl (diazomethyl)phosphonate anion can also be generated by mild acyl cleavage of dimethyl diazo-2-oxopropylphosphonate.
Here the gentle reaction conditions allow the conversion of even enolizable aldehydes in good yields:
S. Müller, B. Liepold, G. J. Roth, H. J. Bestmann, Synlett, 1996, 521-522.
Originally, a single example of the conversion of an n-alkylaldehyde under basic methanolysis of the reagent was reported in 1986 by Ohira (Synth. Commun., 1986, 19, 561. DOI). The scope and limitations of the reaction were later examined by Bestmann, who obtained several alkynes in good to excellent yields and in pure form after simple work-up. Dimethyl diazo-2-oxopropylphosphonate is also referred as Bestmann-Ohiro Reagent.
Note: the reaction of ketones yield methyl enol ethers in the presence of methanol due to trapping of the intermediate carbene.
Both the Seyferth-Gilbert reagent and the Bestmann-Ohira reagent can conveniently be prepared by using diazo transfer reagents. An in situ generation of the Bestmann-Ohira reagent can be found in the recent literature section.
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Birch Reduction
The Birch Reduction offers access to substituted 1,4-cyclohexadienes.
MECHANISM OF THE BIRCH REDUCTION
The question of why the 1,3-diene is not formed, even though it would be more stable through conjugation, can be rationalized with a simple mnemonic. When viewed in valence bond terms, electron-electron repulsions in the radical anion will preferentially have the nonbonding electrons separated as much as possible, in a 1,4-relationship.
This question can also be answered by considering the mesomeric structures of the dienyl carbanion:
The numbers, which stand for the number of bonds, can be averaged and compared with the 1,3- and the 1,4-diene. The structure on the left is the average of all mesomers depicted above followed by 1,3 and 1,4-diene:
The difference between the dienyl carbanion and 1,3-diene in absolute numbers is 2, and between the dienyl carbanion and 1,4-diene is 4/3. The comparison with the least change in electron distribution will be preferred.
Reactions of arenes with +I- and +M-substituents lead to the products with the most highly substituted double bonds:
The effect of electron-withdrawing substituents on the Birch Reduction varies. For example, the reaction of benzoic acid leads to 2,5-cyclohexadienecarboxylic acid, which can be rationalized on the basis of the carboxylic acid stabilizing an adjacent anion:
Alkene double bonds are only reduced if they are conjugated with the arene, and occasionally isolated terminal alkenes will be reduced.
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Bischler-Napieralski Reaction
Bischler-Napieralski Cyclization
The Bischler-Napieralski Reaction allows the synthesis of 3,4-dihydroisoquinolines from the β-ethylamides of electron-rich arenes using condensation reagents such as P2O5, POCl3 or ZnCl2.
MECHANISM OF THE BISCHLER-NAPIERALSKI REACTION
According to detailed studies by Fodor and Nagubandi (Tetrahedron 1980, 36, 1279. DOI), the Bischler-Napieralski Reaction involves an initial dehydration step of the amide followed by a cyclization. Fodor was able to prepare stable imidoyl salts at room temperature that formed nitrilium salts upon mild heating, whereas the Bischler-Napieralski Reaction required elevated temperatures to form dihydroisoquinolines. A mechanism that includes nitrilium salts also accounts the occurrence of styrenes as side products as will be explained later.In the dehydration, reagents such as PCl5, POCl3, SOCl2, ZnCl2 can be used to promote loss of the carbonyl oxygen. Use of POCl3 leads first to formation of imidoyl phosphates in which phosphate is a good leaving group. Use of P2O5 or addition of P2O5 to a reaction with POCl3 leads to pyrophosphates, which are even better leaving groups.
For the cyclization, an activated arene is needed to effect ring closure at reflux temperature if the solvent is toluene. Alternatively, xylene can be used, and microwave-assisted chemistry in superheated solvents is also a viable solution.
One of the most important side reactions is the retro-Ritter reaction forming styrenes, which is also evidence for nitrilium salts as intermediates:
In this example, the formation of a conjugated system favors the retro-Ritter reaction. A possible solution is the use of the corresponding nitrile as solvent, which shifts the equilibrium to the left side, but some nitriles (R' ≠ Me) can be expensive. Another solution was recently presented by Larsen using oxalyl chloride to form an N-acyliminium intermediate, so that elimination of the amide group as the nitrile is avoided.
R. D. Larsen, R. A. Reamer, E. G. Corley, P. Davis, E. J. J. Grabowski, P. J. Reider, I. Shinkai, J. Org. Chem., 1991, 56, 6034-6038.In the following recently published procedure by Movassaghi, Tf2O is used in the presence of 2-chloropyridine to provide a mild cyclodehydration reaction. Here the authors suggest that electrophilic activation of N-alkylamides may lead to a transient highly electrophilic nitrilium ion (or pyridinium adduct) that is trapped by the arene ring.
M. Movassaghi, M. D. Hill, Org. Lett., 2008, 10, 3485-3488.
The two-step procedure reported by Larsen and the method described by Movassaghi allow the transformation of a broad range of substrates into 3,4-dihydroisoquinolines and the use of milder conditions. Some more procedures can be found in the Recent Literature section.
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Blaise Reaction
The Blaise Reaction allows the synthesis of β-enamino esters or β-keto esters (depending on the work-up conditions) via the zinc-mediated reaction of nitriles with α-haloesters.
MECHANISM OF THE BLAISE REACTION
Formation of an organozinc compound from the α-haloester is followed by addition to the nitrile, yielding the Blaise intermediate.
The Blaise intermediates can either be hydrolyzed to β-enamino esters or β-keto esters. Work-up with 50% aq. K2CO3 delivers β-enamino esters in the organic phase. An additional acidification of the product phase with 1 M aq. HCl hydrolyzes the β-enamino esters to give β-keto esters.
Further derivatization of the Blaise intermediate is possible, although rarely described. Some examples can be found in the recent literature section.
Drawbacks of the originally reported Blaise Reaction, such as low yield, narrow scope and competing side reactions such as self-condensation of the α-haloesters, are overcome by some recent modifications:
Use of activated zinc, tetrahydrofuran as solvent and an excess of α-haloester, added over 30 - 60 min, substantially improve the yield:
S. M. Hannick, Y. Kishi, J. Org. Chem., 1983, 48, 3833-3835.
For the work-up, it is important that the reaction mixture is diluted with THF until a total volume of 3 mL for each mmol of α-haloester is reached and then 1/3 mL of 50% aqueous K2CO3 should be added with vigorous stirring. Rapid stirring for 30 minutes gives two cleanly separated layers. It's important to follow this protocol exactly; otherwise, emulsions will form, making the work-up tedious and decreasing the yield. The organic layer can be worked up using column chromatography on solvent-wetted silica gel to isolate the pure enamino ester. For the isolation of β-keto esters, the organic phase is first treated with 1 M aq. HCl at room temperature for 30 min.
The use of ultrasound allows a more convenient, one-step synthesis using zinc powders without specific activation. The amount of self-condensation side product is also lowered, as exemplified by the use of only a slight excess of bromoacetate:
A. S.-Y. Lee, R.-Y. Cheng, Tetrahedron Lett., 1997, 38, 443-446.
Some more reactions can also be found in the recent literature section, making the Blaise Reaction a potentially useful method for the synthesis of β-enamino esters, β-keto esters and related compounds.
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Blanc Reaction
This reaction, which is comparable to a Friedel-Crafts Alkylation, is useful for the preparation of chloromethylated arenes (for example, the Merrifield resin based on polystyrene) from the parent arene with formaldehyde, HCl, and ZnCl2.
MECHANISM OF THE BLANC REACTION
The Lewis acid ZnCl2 effects formation of an oxonium ion which is reactive in electrophilic aromatic substitution. The intermediate zinc alkoxide reacts with the arene to form the chloromethylated product and zinc oxides:
When the concentration (or, effective concentration in the case of polymer residues) is high, the formation of side products due to a second addition are observed:
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Bohlmann-Rahtz Pyridine Synthesis
The Bohlmann-Rahtz Pyridine Synthesis allows the generation of substituted pyridines in two steps. Condensation of enamines with ethynylketones leads to an aminodiene intermediate that, after heat-induced E/Z isomerization, undergoes a cyclodehydration to yield 2,3,6-trisubstituted pyridines.
MECHANISM OF THE BOHLMANN-RAHTZ PYRIDINE SYNTHESIS
The reaction is related to the well-known Hantzsch Dihydropyridine Synthesis, in which in situ-generated enone and enamine species give dihydropyridines. The direct use of ynones instead of enones obviates the need for an aromatizing oxidation step to get the target pyridines. Although the Bohlmann-Rahtz Synthesis is more versatile, purification of the intermediate and the high temperatures required for the cyclodehydration are significant drawbacks that have limited its synthetic utility. Some of the drawbacks have been overcome recently, making the Bohlmann-Rahtz Synthesis more valuable for the generation of pyridines.Although no mechanistic studies have been conducted, intermediates can be characterized by 1H-NMR, which clearly shows that the main product of the initial Michael Addition and subsequent proton transfer is a 2Z-4E-heptadien-6-one, which is isolated and purified by column chromatography.
High cyclodehydration temperatures are therefore required to facilitate Z/E isomerizations that are a prerequisite for heteroannelation.
Some methods that allow the synthesis of tri- and tetrasubstituted pyridines in a one-step procedure have recently been developed. Instead of using butynone as the substrate, Bagley screened different solvents for the conversion of the less volatile and cheaper 4-(trimethylsilyl)but-3-yn-2-one. It was shown that only EtOH and DMSO are suitable solvents, with EtOH clearly favored as being protic and polar solvent vs. DMSO as a polar aprotic solvent. In both solvents, spontaneous protodesilylation took place. Bagley has also shown that acid catalysis allowed the cyclodehydration to proceed at a significantly lower temperature.
As Brønstedt acid catalysis also promotes the conjugate addition, a range of enamines were then reacted with ethynyl ketones in a (5:1) mixture of toluene and acetic acid to afford functionalized pyridines in a single step in good to excellent yields.
M. C. Bagley, J. W. Dale, J. Bower, Synlett, 2001, 1149-1151.
Following the success of Brønstedt acid catalysis, Bagley investigated the potential of Lewis acid catalysts. The best conditions utilized either 20 mol% ytterbium triflate or 15 mol% zinc bromide in refluxing toluene. Although mechanistic studies were not undertaken, it is assumed that coordination by the catalyst accelerates the Michael Addition, isomerization and cyclodehydration steps. A drawback is the limited compatibility with acid-sensitive substrates. For example, acid-catalyzed decomposition of the starting enamines occurs with tert-butylester and cyano as electron withdrawing groups. A mild alternative is the use of Amberlyst-15 ion exchange reagent that allows a simple work up and tolerates tert-butylesters.
As the enamines are not readily available, and to improve the facility of the process, a three-component reaction was developed using ammonium acetate as the amino group source. In this efficient procedure, the enamine is generated in situ and then reacts with the alkynone present.
In a first attempt, AcOH and ZnBr2 were used as additional catalysts with toluene as solvent, but it has been shown more recently that acid-sensitive substrates react under milder (acid-free) conditions with EtOH as solvent.
X. Xiong, M. C. Bagley, K. Chapaneri, Tetrahedron Lett., 2004, 45, 6121-6124.
A review of the Bohlmann-Rahtz Pyridine Synthesis can be found in a recent report by Bagley (Synthesis, 2007, 2459. DOI). Here, some additional synthetic alternatives are described, such as the use of microwaves, and recent applications such as the synthesis of fused heterocycles and natural products are covered.
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Petasis Reaction
The Petasis Reaction is a multicomponent reaction (MCR) that enables the preparation of amines and their derivatives such as α-amino acids.
The reaction is also referred to as the Boronic Acid Mannich Reaction, since it proceeds via an imine with the organic ligand of the boronic acid acting as the nucleophile, similar to the role of the enolizable ketone component in the original Mannich Reaction.
MECHANISM OF THE PETASIS REACTION
As in the classical reaction that it resembles, the Petasis Reaction also involves a large number of interdependent equilibrium steps, some of them identical to those in the Mannich Reaction.
Little is known with certainty in connection with the key step that involves the nucleophilic addition of the organic ligand from the boronate to the imine. One proposal is that the transfer is actually intramolecular, and takes place via the adduct pictured above:
Regardless of how it does take place, the fact that this addition is irreversible certainly imparts a clear advantage. In the classical Mannich, the reversibility of the final step limits the number of cases where the yields are synthetically useful. By comparison, the Boronic Acid Mannich Reaction permits a much broader scope of conversions to be carried out.
The direct reaction with glyoxylic acid merits particular mention, since it leads to interesting, unnatural α-amino acids in a single step, while avoiding the appearance of toxic byproducts such as seen with the Strecker Synthesis.
This reaction can be carried out with secondary amines, sterically hindered primary amines, hydrazines or anilines in dichloromethane at room temperature. The range of potential nucleophilic partners includes alkenylboronic acids, and electroneutral as well as electron-rich (hetero-)arylboronic acids. The conversion of electron-poor boronic acids can be effected at elevated temperatures (MW) in suitable solvents (M. Follmann et al. Synlett 2005, 1009. DOI)
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Bouveault-Blanc Reduction
This method is an inexpensive substitute for LAH reductions of esters in industrial production, and was the only alternative prior to the development of the metal hydride reducing agents. This dissolving metal reduction is also related to the Birch Reduction.
MECHANISM OF THE BOUVEAULT-BLANC REDUCTION
Sodium serves as single electron reducing agent and EtOH is the proton donor. If no proton donor is available, dimerization will take place, as theAcyloin Condensation.
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Brook Rearrangement
The [1,2]-Brook Rearrangement of α-silyl carbinols is an intramolecular 1,2-anionic migration of a silyl group from carbon to oxygen in the presence of a catalytic amount of a base such as Et2NH, NaH or NaOH. The migratory aptitude is general over a range of homologues, and [1,n]-carbon to oxygen migrations are commonly referred to as Brook Rearrangements.
MECHANISM OF THE BROOK REARRANGEMENT
The mechanism as described by Brook (Acc. Chem. Res. 1974, 7, 77. DOI) includes the formation of a cyclic pentavalent silicon species immediately following the deprotonation. Subsequent ring opening and irreversible, fast protonation of the carbanion by the starting alcohol or the conjugate base leads to the corresponding silyl ether:
The greater strength of the oxygen-silicon bond compared to the carbon-silicon bond provides the driving force for the conversion of silyl carbinols to the corresponding silyl ethers. An electron-withdrawing R group facilitates the kinetics of the carbanion formation.
In the presence of a strong base in stoichiometric amounts, the equilibrium between alkoxide and carbanion is relative to the stabilities of the corresponding anionic species:
Here, the presence of an electron withdrawing group R shifts the equilibrium to the right, whereas counterions that form strong ion pairs with oxygen such as lithium favor an oxygen to carbon silyl migration (retro-Brook Rearrangement). Destabilization of the alkoxides using polar solvents such as THF also shifts the equilibrium towards the silyl ethers.
The use of a stoichiometric amount of base and the control of the equilibrium enables tandem strategies to introduce electrophiles:
The use of acylsilanes makes even more sophisticated tactics possible:
For concrete reactions, please check the recent literature section at the end of this site and the review written by Moser (Tetrahedron 2001, 57, 2065. DOI), which explains the basics for tandem bond formation strategies and gives several additional, interesting examples.
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Brown Hydroboration
The syn-addition of hydroboranes to alkenes occurs with predictable selectivity, wherein the boron adds preferentially to the least hindered carbon. This selectivity is enhanced if sterically demanding boranes are used.
Coupling the hydroboration with a subsequent oxidation of the new formed borane yields anti-Markovnikov alcohols. The hydroboration/oxidation sequence constitutes a powerful method for the regio- and stereoselective synthesis of alcohols.
The product boranes may also be used as starting materials for other reactions, such as Suzuki Couplings (see Recent Literature).
MECHANISM OF THE BROWN HYDROBORATION
The selectivity of the first addition of borane can be relatively low:
The subsequent additions are more selective as the steric bulk increases, and anti-Markovnikov selectivity predominates in the end:
Oxidation with hydrogen peroxide leads to alcohols:
Sterically demanding boranes offer enhanced selectivity. One example of a sterically demanding borane (9-BBN) is generated by the double addition of borane to 1,5-cyclooctadiene:
9-Borabicyclo[3.3.1]nonane
The reactivity and selectivity of the borane reagent may be modified through the use of borane-Lewis base complexes.
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Bucherer-Bergs Reaction
A multi-component reaction between a ketone, potassium cyanide and ammonium carbonate, which leads to the formation of hydantoins.
A pre-formed cyanohydrin can react with ammonium carbonate to give the same product:
MECHANISM OF THE BUCHERER-BERGS REACTION
The Bucherer-Bergs Reaction is equivalent to the Strecker Synthesis with "additional CO2". Hydantoins may be opened to yield N-carbamoylamino acids which form amino acids by treatment with acid or with a suitable enzyme:
Buchwald-Hartwig Cross Coupling Reaction
Palladium-catalyzed synthesis of aryl amines. Starting materials are aryl halides or pseudohalides (for example triflates) and primary or secondary amines.
The synthesis of aryl ethers and especially diaryl ethers has recently received much attention as an alternative to the Ullmann Ether Synthesis.
Newer catalysts and methods offer a broad spectrum of interesting conversions.
MECHANISM OF THE BUCHWALD-HARTWIG COUPLING
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prof premraj pushpakaran writes -- 2018 marks the 100th birth year of Derek Harold Richard Barton!!!
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