reactions of aldehydes and ketones and their …...1 reactions of aldehydes and ketones and their...

CHAPTER 1

Reactions of Aldehydes and Ketones and their Derivatives

B. A. MURRAY

Department of Applied Sciences, Institute of Technology Tallaght, Dublin, Ireland

Formation and Reactions of Acetals and Related Species . . . . . . . . . . . . . . 1Reactions of Glucosides and Nucleosides . . . . . . . . . . . . . . . . . . . . . . . . . 3Reactions of Ketenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4Formation and Reactions of Nitrogen Derivatives . . . . . . . . . . . . . . . . . . . 5

Imines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5Oximes, Hydrazones, and Related Species . . . . . . . . . . . . . . . . . . . . . 10

C–C Bond Formation and Fission: Aldol and Related Reactions . . . . . . . . 12Regio-, Enantio-, and Diastereo-selective Aldol Reactions . . . . . . . . . . . 12The Baylis–Hillman Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15Miscellaneous Aldol-type Reactions . . . . . . . . . . . . . . . . . . . . . . . . . 17Allylations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

Other Addition Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19General and Theoretical . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19Hydrates and Hydrate Anions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21Addition of Organozincs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21Addition of Other Organometallics . . . . . . . . . . . . . . . . . . . . . . . . . . 22The Wittig Reaction and Variants . . . . . . . . . . . . . . . . . . . . . . . . . . . 23Addition of Other Carbon Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . 24Miscellaneous Additions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

Enolization and Related Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26Enolates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

Oxidation and Reduction of Carbonyl Compounds . . . . . . . . . . . . . . . . . . 28Regio-, Stereo-, Enantio-, and Diastereo-selective Reductions . . . . . . . . 28Other Reductions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30Atmospheric Oxidations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30Other Oxidations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

Other Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

Formation and Reactions of Acetals and Related Species

The α,α′-dihaloketone 2,4-dichlorobicyclo[3.2.1]oct-6-en-3-one (1, a mixture ofax–ax, ax–eq, and eq–eq isomers) undergoes a 1,3-transposition in alkoxide–alcoholmedia to give α-ketoacetals (2, R = CH3, CH2CF3, −CH2CH2−), all of which arereadily hydrolysable to the corresponding α-diones.1 The acetal is favoured by anO,O-geminal stabilization relative to the α,α′-dialkoxy ketone: none of the latter

Organic Reaction Mechanisms 2001. Edited by A. C. Knipe 2005 John Wiley & Sons, Ltd

1

2 Organic Reaction Mechanisms 2001

was observed. An enolization–ionization mechanism is proposed. In an attempt toproduce the α-dione directly, (1) was treated with aqueous NaOH–THF at 0 ◦C, butthis reaction yielded the ring-contracted product (3), via a 1,2-anionotropic shift.

Trimethylsilyl triflate catalyses diastereoselective ring-opening reactions of semi-cyclic N ,O-acetals (4) with nucleophiles such as silyl enol ethers.2 �de

(1) (3)

O

Cl

Cl

OCl CO2H

OH

OR

OR

(2)

RO−/ROH

(5)(4) (6)

O

OR

NHCO2Bn

O

OOTMSTMSO

OO

Acetal (5), with a tethered acyloin, undergoes an intramolecular geminal acylation,catalysed by boron trifluoride etherate, to give 1,3-diketone (6).3 The mechanismnecessarily differs from the intermolecular version.

Cyclic ketones can be acetalysed under mild conditions using methanol, withtitanium tetrachloride catalyst, whereas cyclic β-diketones form β-keto enol ethersunder the same conditions.4 In the case of β-keto aldehydes, either type of protectioncan be achieved, depending on the conditions chosen.

Threo- and erythro-alcohols, (8t) and (8e), have been prepared by ring openingof a cyclic ketene ortho-ester (7) with a range of aldehydes.5 Enantioselectivitiesrange from 45 to 99%, with de values of up to 96%. �de

(8t) (8e)

(7) + R2CHO

O SR1EtO

EtO

EtO SR1

OO

HOH

R2

EtO SR1

OO

HOH

R2

H H

A new thioacetal, 1-chloro-2-mercapto-propan-2-ol (10), has been isolated fromthe treatment of 1-chloro-2-propanethione (9) with hydrochloric acid; in the presenceof water it cyclizes to 2,4,6-tris(chloromethyl)-2,4,6-trimethyl-1,3,5-trithiane (11).6

1 Reactions of Aldehydes and Ketones and their Derivatives 3

(10)(9) (11)

S

S

S

Cl

Cl

ClCl

S HS OH

Cl

A stereoelectronic correlation of the relative rates of hydrolysis of ketone-derivedacetals with their proton affinities considers both cyclic and acyclic cases.7

Terminal isopropylidene acetals have been chemoselectively hydrolysed to thecorresponding 1,2-diols using Yb(OTf)3·H2O.8 Similar functional groups, even iso-propylidene acetals elsewhere in the substrate, are left untouched.

Synthesis and reactions of sugar acetals have been reviewed (21 references).9

A stereoselective Prins-pinacol synthesis of acyltetrahydrofurans from cyclicacetals has been reported.10 Five- and six-membered cyclic acetals have been �de

oxidatively ring opened to give ω-hydroxy esters using hypervalent t-butylperoxy-λ3-iodanes.11

1,3-Dioxan-4-ones, a useful class of cyclic acetals, are described later under TheBaylis–Hillman Reaction .

Reactions of Glucosides and Nucleosides

Synthesis and conformational characterization of six new N -(pentopyranosyl)imida-zoles and their conjugate acids led to a claim that apparent reverse anomeric effectsin these systems and, by implication, in many related ones are more accuratelydescribed as normal anomeric effects subject to unusual dipolar interactions.12

Dynamic density functional theory has been used to identify the conformationalorigin of the barrier to producing neighbouring group assistance in glycosylations.13

The authors stress the role of conformation in the kinetic stability of oxocarbeniumions in determining the ultimate outcome of such reactions.

HCl-catalysed mutarotation of N -(p-chlorophenyl)-β-D-glucopyranosylamine(12) in methanol proceeds via a low-energy acyclic immonium ion formed byprotonation of the in-ring oxygen atom; activation parameters are reported.14

Rates and equilibria have been calculated for the mutarotation of glucose.15

When 2,3 : 4,5-di-O-isopropylidene-D-ribose diethyl dithioacetal [13, R = CH-(SEt)2] is treated under ‘standard’ hydrolytic deprotection conditions of mercuric

(12) (14)

O

OH

H

HN Cl

(13)

H2C

HC

HC

HC

R

O

O

O

O

NH

X

OHHO 4


chloride and oxide in aqueous acetone, a reductive dimeric coupling product isobtained in addition to the expected aldehyde (13, R = CHO).16

Isofagomines (e.g. 14; X = CH2) are aza-analogues of monosaccharides, and thepKas of their conjugate acids are lowered by 0.4 units if the 4-hydroxyl is switchedfrom axial to equatorial, a finding also seen in azafagomines (14; X = NH). Lookingat other aza-sugars and less highly substituted hydroxyazacyclohexanes, a patternof 0.4 pKa units difference emerges when the hydroxyl is in the γ - and 0.8 whenit is in the β-position. Although modest, the base-strengthening effect of 2.5 or6.3 for a γ - or β-hydroxyl conformational switch is significant, and is not readilyexplained except as a substituent effect. Such effects should also be evident inring carbocation stability, and a free energy relationship between rates of acidichydrolysis of glycosides and pKas of isofagomines has now been reported.17

Kinetic isotope effects have been measured for the hydrolyses of methyl α- andβ-xylopyranosides in aqueous perchloric acid18a and compared with data for thecorresponding glucopyranosides.18b The degree of coupling of resonance stabiliza-tion of the developing carbenium ion (by the ring oxygen) with exocyclic C−Ocleavage is compared for the four systems and extended to the corresponding 5-thio-xylo analogues, which undergo hydrolysis 13.6 (α-) and 18.5 (β-) times faster,respectively.

2,3-Anhydro-β-D-lyxofuranosylglycosides (16) have been prepared in a stereo-controlled synthesis from either the thioglycoside or glycosyl sulfoxide [15, R1 = S- �de

Tol or S(O)-Tol].19

(15) (16)

O

OR1

BzO O

O

BzO OR2

The ‘natural’ electrophilic reactivity of the anomeric centre in sugars dominatedmuch of their chemistry well into the 1980s. Driven by the increasing recognition ofoligosaccharide interactions with proteins or lipids in the cell, synthetic sugar chem-istry increasingly involves nucleophilic reactivity. Such umpolung methodologyusing anomeric carbanionoid intermediates has been reviewed (370 references).20

The coverage systematically works through a wide range of stabilizing groups, suchas NO2, +PPh3, C=O, CO2R, CONH2, CN, SO2R, SPh, and Cl, the elaborationof which allows more control and milder conditions. ‘Unstabilized’ strategies usingglycals are also examined, including their metallations.

Reactions of Ketenes

Camphorketene (17), an early example of an α-oxoketene first prepared in 1920,has been reinvestigated.21 The stereochemistry of its dimers has been determined.It fails to react with benzaldehyde, and camphoric acid derivatives in general show


(17) (18)

CO

O N

SR1

R2

no enol tautomers, both phenomena apparently arising from ring strain. Evidencefor pseudopericyclic mechanisms in some of the reactions of (17) is presented.

The products and mechanisms of a series of reactions of 2,4-disubstituted-2,3-dihydro-1,5-benzothiazepines (18) with in situ-generated chloro- and dichloro-ketenehave been investigated for a range of alkyl and aryl substituents R1 and R2.22

N+ parameters have been reported for a wide range of amines reacting with cyclicketenes,23 covering rate constants (in acetonitrile) of 104 –109 mol−1 dm3 s−1.

A new route to fluorine-containing aziridines and α-amino esters exploits thereaction of silyl ketene acetals with fluoroalkanesulfonyl azides.24

Formation and Reactions of Nitrogen Derivatives

Imines

The mechanisms of acid-catalysed Z–E isomerization of imine derivatives (19;X = Cl, O-alkyl; R = H, Ph, substituted phenyl, CH=CH2, CH=CH−Ph) havebeen investigated.25 Two mechanisms have been identified:

(i) iminium ion rotation, the dominant mechanism for the α,β-unsaturated hydrox-imate (19; X = OMe; R = CH=CH−Ph); and

(ii) nucleophilic catalysis, i.e. nucleophilic attack on the protonated imine to form atetrahedral intermediate, which undergoes stereomutation and subsequent lossof nucleophile.

Hydroximoyl chlorides (19; X = Cl; R = Ph, CH=CH−Ph) proceed via the lattermechanism. In general, the rate of iminium ion rotation is increased by increasedconjugation in the protonated imine.

(19)

N

OMeX

R

Z- to E-isomerization has also been studied for azobenzenes and N -benzyliden-eanilines, as a probe reaction for the scope and limitations of transition state theoryin viscous solvents.26 The effects on the rates of slow, diffusive thermal fluctuations


of solvent molecules is discussed, as are the implications for conformational fluc-tuations in proteins.

Ab initio computations suggest that conversion of methane imide azide, HN=CH−N3, to diimide, HN=C=NH, is more exothermic than converting it to tetrazole.27

Ab initio density functional theory calculations have been used to estimate thegeometries and energies of monosubstituted carbodiimides, RN=C=NH, and imines,RN=CH2.28 Electronegative substituents destabilize carbodiimides whereas elec-tropositive substituents stabilize them. Strongly electropositive groups give a lineargeometry, owing to charge repulsion and a preference for sp-hybridization at nitro-gen. Nitro groups are an exception, stabilizing via a π-acceptor effect. Comparingother cumulenes, carbodiimides are less sensitive to substituents than isocyanates,but more sensitive than ketenes or ketenimines.

Several papers deal with the formation of imines. New fluorogenic 1,2-indane-dione derivatives show potential for use in the identification of fingerprints. Themechanisms of their reactions with amino acids have been probed, and possi-ble intermediates in the form of C−N−C 1,3-dipoles have been trapped withdipolarophiles.29

Solvent effects on the rate of condensation of phenylhydrazine with benzaldehydeare reported for pH 11.5 at 25 ◦C, using aqueous alcoholic solvent mixtures.30

The kinetics of interconversion of secondary amines in the condensation of ani-line and formaldehyde, and the implications for the manufacture of polymethylenepolyphenyl polyamines, have been studied in acidic solution.31

Rate and equilibrium constants have been determined for the formation of Schiffbases from pyridoxal 5′-phosphate and a range of hydrazinic pharmaceuticals;hydrolysis of the imines was also measured.32

Stereoselective reactions include an N -protected α-imino ester, EtO−CO−CH=N−P, undergoing an enantioselective nitro-Mannich reaction with nitroalkanes (O2N−CH2−R), to give optically active β-nitro-α-amino esters, EtO−CO−CH(NH−P)−CH(R)−NO2, in up to 94% de and 97% ee, using a chiral bisoxazoline catalyst.33

�de

In a similar approach, an N -tosyl-α-imino ester (trans-Ts−N=CH−CO2Et) reactswith α-carbonyl esters to give highly functionalized 4-oxoglutamic acid esters withcomparable de and 97% ee.34

�eeA Mannich-type reaction, in which a lithium enolate of an acetate is added

diastereoselectively to aniline-derived aldimines with catalysis by a chiral phenol,depends on the aldimine having an o-alkoxy or o-fluoro substituent (on the nitro- �de

gen side).35 In addition, the aldimine, which is readily isomerizable, is held in anappropriate conformation by the Lewis acid employed.

A Mannich reaction with imines has been used to prepare virtually enantiopure β-substituted α-methyl-β-amino esters [trans-R1−CH*(NHR2)−*CHMe−CO2Me].36

Chiral α-amino phosphonates have been prepared by diastereoselective hydrophos-phonylation of heterocyclic imines, mediated by Lewis acid catalysts.37

�de

N -Sulfinylimines undergo stereoselective nucleophilic trifluoromethylation withtrimethylsilyltrifluoromethane (Me3SiCF3).38 This reagent also trifluoromethylatesalicyclic perfluoroimines.39


Catalytic asymmetric aziridination of imines has been achieved, mediated bysulfur ylids derived from sulfides, and either phenyldiazomethane, a diazo ester, or �de

a diazoacetamide.40 �eeCrossover experiments have been used to assess whether such aziridination of N -

tosylimines by sulfur ylids is under kinetic or thermodynamic control.41 Whereasbenzyl-stabilized (‘semi-stabilized’) ylids react irreversibly with imines so that their �de

stereoselectivity is based on the syn-/anti-betaine ratio, stabilized cases (e.g. ester-or amide-ylids) react reversibly. Accordingly, stereocontrol will require differentstrategies, depending on the degree of stabilization selected.

Base treatment of racemic oxiranyl carbaldimine (20) gives polyfunctionalizedaziridine (21), in a new type of highly diastereoselective aza-Darzens reaction.42

The diastereoselection arises from one enantiomer of (20) being deprotonated to �de

form an oxiranyl anion (i.e. a 1-aza allyl anion bearing a β-oxirane moiety), withthe resultant anion attacking the imine carbon of the other enantiomer, i.e. a mutualkinetic resolution by double diastereofacial selection. Enantiopure (20) does notgive (21).

(20) (21)

O

NPri N

OH

HO

NPriPri

2

A novel reductive dimerization–oxidative dehydrogenation sequence has beenreported for aromatic aldimines (22), yielding vicinal diimines (23), using 0.5 molof ytterbium metal and 1-naphthaldehyde (as oxidant).43

Ar1 H

NAr2

Ar1

Ar1

NAr2

NAr2

Yb

THF/HMPA

Oxidant

(23)(22)

A tetra-aza ligand containing two N -hydroxyimine functions (24) reacts withcopper(II) in alkaline permanganate to give the quasi-aromatic metal complex, ‘AH’(25),44 a structure equivalent to [Cu(24) − 6H]0. This complex is fairly acidic atthe C(12) position, and reacts with aromatic aldehydes to give benzyl alcohols,A−CH(Ar)−OH, and further reaction gives the bis-product, A−CH(Ar)−A.

N -Salicylidene-2-aminophenolate (26), and variants substituted in the aminophe-nol ring, react with phenylboronic acid to give a [4.3.0]boron heterocycle (27a).45


(24) (25; ‘AH’)

HN

HN

N

N

HO

HO

N

N

N

N

O

OCuH H12

The imine function is now activated by boron, and (27a) reacts with acetone to givethe all-cis-product (27b). �de

In other stereoselective reactions of imines, a Lewis acid–Lewis base chiralbifunctional catalyst promotes an enantioselective Strecker-type reaction of TMScyanide with fluorenylimines, including n-aldimines and α,β-unsaturated imines,the latter ultimately giving aminonitriles.46

(26)

(27b)

(27a)

OB

N

O

OB

N

O

O

N

OHOH

H

O

PhB(OH)2

THF/∆

Asymmetric protected 1,2-amino alcohols have been prepared from t-butanesul-finyl aldimines and ketimines bearing an α-benzyloxy or α-silyloxy substituent.47

�de

cis-Fused furano- and pyrano-benzopyrans (28, n = 1, 2) can be prepared inhigh diastereoselectivity from o-hydroxybenzaldimines and 2,3-dihydrofuran or 3,4-dihydropyran respectively, using LiBF4 catalysis.48


(28) (30)

O O

( )n

NHR2

H

H

R1

NH

OH

NH

(29)

O

R CHO

O

A study of the mechanism and diastereoselectivity of the reaction of naphtholswith imines has been undertaken.49

In other transformations, a simple iridium(I) complex catalyses direct addition oftrimethylsilylacetylene to aldimines, to give β,γ -alkynylamines,50 and a zirconiumcatalyst Cp2ZrCl2, facilitates the addition of Grignard reagents to both aldiminesand ketimines.51 Indeed, the latter substrates are unreactive in the absence of thezirconocene, so this method now opens up a route to amines with a quaternaryα-carbon. An azazirconapentacycle intermediate is proposed, and initial kinetic andisotope experiments suggest good prospects for an enantioselective version of thereaction. A library screening protocol has been used to synthesize arylamines inup to 98% ee and yield, via zirconium-catalysed addition of dialkylzincs to ben-zaldimines.52 �ee

Several reports describe the tautomerism of C=N systems. The mechanism oftautomerization of 3-hydroxy-2(1H )-pyridinimine (29), from exo- to endo-cyclicimine, has been probed computationally.53

Condensation of aromatic amino acids with 3-formylchromones (30) yields anenaminone product in dry aprotic solvent, whereas alcoholic reflux can give animine-enone tautomer.54 Structural, hydrogen-bonding, and substituent effects onthe tautomeric ratio and on the effective synthetic conditions for maximizing theyield of each structure are reported. Kinetic studies tend to confirm the first tautomeras kinetic product and the second as thermodynamic.

3-Methyl-4-phenyl-1,2,5-thiadiazole 1,1-dioxide (31a) undergoes tautomerizationto the ene structure (31b), via an imine α-anion (31−);55 (31a) can also react withthe anion to form a dimer.

Aliphatic amines react with β-alkoxyvinyl methyl ketones, R1O−CR2=CH−CO−CX3 (X = H, F, Cl) to form enaminones; kinetics of the reaction have been measured

(31a) (31b)

NNSO2

Ph CH3

NHNSO2

Ph CH2

NNSO2

Ph CH2

−

(31−)


in a range of solvents.56 Addition to give a zwitterion is followed by rate-limitingelimination.

Rates of chlorination of substituted benzaldehyde anils by chloramines have beeninvestigated: pH–rate profiles and a Hammett plot have been constructed for theaction of dichloramine-B in aqueous methanol,57 while the use of chloramine-T inaqueous acetic–perchloric acid mixtures exhibits complex acid-catalysed kinetics,with three phases of H+ catalysis.58

Studies of imine hydrolysis include a series (32, n = 0, 2, 4, 6) with cetyloxygroups in either the ortho- or para-positions of the benzene rings being subjectedto acidic conditions in microemulsion systems containing either an anionic (dode-cyl sulfate) or cationic (cetyltrimethylammonium) surfactant.59 The kinetic resultshave been interpreted as sensors that map the polarity pockets of the microemul-sion droplets.

(32; R = o-/p-O-C16)

N (CH2)n N

RR

Other papers include measurements of rates and pH profiles for hydrolysis ofdifunctional Schiff bases derived from p-phenylenediamine and aromatic alde-hydes,60,61 and also an examination of the hydrolysis of (benzalamino)quinazolin-4(3H )-ones.62

The synthetic utility of the addition of alkyl radicals to imines has been inves-tigated, using Lewis acids to control the reaction and to accelerate it.63 Cases ofboth activating and deactivating substituents on nitrogen are covered, and modestenantioselectivity can be achieved using a BINAP catalyst. The topic has also beenreviewed.64 �ee

Oximes, Hydrazones, and Related Species

Rate and equilibrium effects have been studied in an investigation of steric andelectronic contributions to the reaction of hydroxylamine with a variety of mono-,di-, and tri-cycloketones,65 and a polarographic method has been used to study thekinetics of the hydrolysis of the 1,3-dioxime of cyclohexane-1,2,3-trione.66

(E)-Phenyl hydrogen α-hydroxyiminobenzylphosphonate (33) undergoes twocompeting reactions in aqueous acid: (i) fragmentation to phenyl phosphate andbenzonitrile and (ii) hydrolytic cleavage of the oxime to give the ketone (34), whichfurther hydrolyses to phenol and benzoylphosphonic acid, PhCOP(=O)(OH)2.67 Therate of direct hydrolysis of the ester moiety of (33) is estimated as 100 times slowerthan that of the ketone (34), owing to initial protonation of the oxime nitrogen, i.e.the acid-catalysed hydrolysis of the ester in (33) is itself retarded by acid, in a typeof ‘siren effect’ in which the ‘wrong’ site is protonated.


(33) (34)

OP

O O

OH

OP

N O

OH

HO

Pentathiepin (36) has been prepared from a cyclopentanone oxime (35), usingdisulfur dichloride (S2Cl2), with catalysis by lithium sulfide.68 A novel cascadesequence, including a vinylogous Beckmann fragmentation assisted by sulfur, isproposed. Structures such as (36) are related to natural products such as benzopen-tathiepins; the latter class include potent antifungals characterized by remarkablestability and a high resistance to inversion of the chair-like pentathiepin ring.

CN

NOH

CN

SS

S

S SS S

N

(35) (36)

Lewis acid catalysts such as aluminium chloride help to optimize Beckmannrearrangements of 1-indanone oximes.69

Oximes with γ - and δ-alkenyl substituents have been cyclized to nitrones,using halogen reagents.70 In an examination of intramolecular cycloadditions of3-(N -substituted allylamino)propionaldehyde oximes (37), the extent and influenceof oxime–nitrone isomerizations, to both acyclic and cyclic nitrones, have beenconsidered.71

Carbon–nitrogen double-bonded compounds (38: oximes, oxime ethers and esters,and hydrazones; R4 = H) bearing an allenic ‘tether’ undergo a variety of cycliza-tion and isomerization reactions in the presence of tributyltin radical, the productmainly depending on the nature of the Z and R3 substituents;72 the correspondingdithiosemicarbazides [38, Z = N(Me)CS2Me, R4 = Me] typically cyclize under sim-ilar conditions to give a range of pyrrole, pyrroline, and pyrrolidine ring systems.73

The use of imine derivatives, especially oxime ethers, as radical acceptors in C−Cbond construction has been reviewed (25 references).74

The reactivities of a series of α-acylenamino ketones (39) with hydrazine nucle-ophiles, to form pyrazoles, have been rationalized by a combination of principalcomponent analysis and frontier orbital considerations.75,76

Kinetics of pyrazole formation from the reaction of E-4-(para-substituted-phenyl)-3-phenylbut-3-en-2-ones with hydrazines have been reported.77


(37) (39)

N

R

NOH

C

NZ

R2

R1

R3

R4

R4

(38)

NHMe

Me

Me

O

O

R

The lithio derivative of methoxyallene (H2C=C=CH−OMe) reacts with alde-hyde hydrazones to give α-allenyl hydrazines, useful precursors to a range of ringsystems, especially enantiopure 3-pyrrolines, when SAMP-hydrazones are used;78

�de

the mechanistic factors determining the balance between the various outcomes havebeen investigated.79

Formaldehyde N ,N -dialkylhydrazones, H2C=N−NR1R2, undergo 1,2-addition tocarbohydrate-derived α-alkoxyaldehydes under neutral conditions, with high anti- �de

diastereoselectivity.80 The hydrazono group can then be manipulated to give an alde-hyde (i.e. achieving homologation of the carbohydrate), or converted to a cyanohy-drin, and ultimately a nitrile.

Homoallylic amines have been prepared rapidly in high yield in DMF at 0 ◦C with-out a catalyst, by addition of allyl- and crotyl-trichlorosilanes to benzoylhydrazones.81

The reactions tolerate considerable steric hindrance in both reactants, and the croty-lations display excellent diastereoselectivity.

Benzophenone N -(diphenylacetyl)hydrazone reacts with diphenylketene to givea 1,3,4-diazol-2-ene.82

Synthetic and mechanistic aspects of heterocyclization of carbohydrate thiosemi-carbazones have been examined.83,84

For several examples of oxidative deoximation, see Other Oxidations , below.

C–C Bond Formation and Fission: Aldol and Related Reactions

Regio-, Enantio-, and Diastereo-selective Aldol Reactions

L-Proline has moved centre stage not merely as a readily available source of chirality,but also as a catalyst whose sophistication belies its modest structure. Its catalysisof the aldol reaction shows many of the characteristics of an enzymatic systemsuch as aldolase, including high de and ee.85 Recent progress in the exploitation of �ee

�desuch small molecule ‘enzyme mimics’ has been reviewed. Other reviews deal moregenerally with the discovery and development of the asymmetric aldol86 and withrecent advances87 (47 and 23 references, respectively).

Following screening of commercially available chiral secondary amines, L-prolineand 5,5-dimethyl thiazolidinium-4-carboxylate (40), have emerged as powerful cat-alysts for the direct asymmetric aldol additions of acyclic and cyclic ketones to aro- �eematic and aliphatic aldehydes with high regio-, diastereo-, and enantio-selectivity.88

Apparently proceeding via enamine intermediates, these reactions do not requireinert conditions, they tolerate water, and they work at room temperature in vari-ous solvents. The catalyst can be recovered or immobilized. Extension to imines


(40)

S

NH

CO2H

(i.e. Mannich-type reactions) and to Michael versions (nitroalkenes, α,β-unsaturateddiesters) are also reported. α-Unsubstituted aldehydes have also been employed (inthe case of proline).89

The origin of the enantioselectivity observed in the proline-catalysed intramolec-ular aldol reaction has also been elucidated:90 both selective hydrogen-bonding andthe geometry of the proton transfer in the transition state play important roles. �ee

A highly diastereoselective aldol reaction between a β,γ -dialkoxyaldehyde and asilyl enol ether depends on catalysis by magnesium bromide diethyl etherate, whichapparently activates both species: the silyl enol ether transmetallates to a magnesiumenolate and the magnesium also chelates the alkoxy substituents of the aldehyde.91

�de

In other bifunctional catalyses, a lanthanide Lewis acid–Brønsted base speciesaccelerates a direct asymmetric aldol reaction,92 and two binaphthoxide-derivedcatalysts, one an La–Li bimetallic combination and the other with dinuclear zinc,catalyse direct asymmetric aldol reactions to give anti- or syn-α,β-dihydroxy ketonesrespectively, with modest de and good ee.93

�de

�eeZinc is also used in a phenolate complex with flanking chiral o,o-bis(amino alco-

hol) substituents to produce an efficient catalyst: using as little as a 10% excess ofan α-hydroxyacetophenone and an alkylaldehyde as second reactant, α,β-dihydroxyketones [Ar−CO−*CH(OH)−*CH(OH)−R] have been prepared in high ee andgood to excellent de, using a low catalyst loading.94

�ee

�de

Titanium enolates continue to produce diastereoselective aldols: chlorotitaniumenolates of N -acyloxazolidinone, oxazolidinethione, and thiazolidinethionepropionate substrates, using (−)-sparteine as base, can have their facial selectivity �de

switched by altering the Lewis acid/amine base ratio, apparently bringingabout a change from a chelated to a non-chelated transition state.95 Similarly,titanium enolates of α-seleno esters give predominantly syn-α-seleno-β-hydroxyesters, with elimination then yielding (Z)-α,β-unsaturated esters96 (and α-selenocyclopentanones react in like manner). Iodide-induced ring opening ofcyclopropyl ketones yields enolates that undergo stereoselective aldols, and �de

the α-iodoethyl-β-hydroxy ketone products can be produced in complementarystereochemistries: TiCl4 –n-Bu4NI catalyst gives the syn-product, whereas Et2AlIgives the anti-product.97

Temperature studies of diastereoselectivities in the aldol condensation of thelithium enolate of t-butyl acetate and 2-phenylpropanal in THF and n-hexane sol-vents have allowed separation of enthalpic and entropic contributions.98

�de

Long-range structural effects on the stereochemistry of the aldol condensationplay an important role in a new, efficient synthesis of epothilones (microtubulemodulators with anti-cancer potential).99


The first catalytic, diastereo- and enantio-selective crossed-aldol reaction of alde-hydes has been claimed; using chiral dimeric phosphoramides based on binaphthyl-2,2′-diamine as catalysts, des of up to 98% and a wide range of ee performances �eeare reported for the reaction of geometrically defined trichlorosilyl enolates of alkyl �de

aldehydes with a variety of aldehyde acceptors, both aryl and alkyl.100

In other diastereoselective aldol reactions, a butane-2,3-diacetal (41), acting as adesymmetrized glycolic acid building block, undergoes reaction with aromatic andaliphatic aldehydes to yield enantiopure 2,3-dihydroxy esters (42)101 (following anacidic methanolysis deprotection step). A tandem chain extension–aldol reaction �de

converts β-keto esters to α-substituted-γ -keto esters,102 and an aldol reaction of a �eechiral α-silyloxy ethyl ketone is also described.103

(41) (42)

OO

O

OO

MeO2CR

OH

OH

Several nitro-aldol-type transformations are also reported, including a proline-catalysed Michael addition of an unmodified ketone to nitroalkenes, to giveγ -nitro ketones in high yield, excellent diastereoselectivity, and moderate �de

enantioselectivity.104 A similar Michael addition of unmodified aldehydes tonitroalkenes, to produce diastereomeric γ -formylnitroalkanes, has been achieved in �eehigh yield, good ee, and excellent de, via a morpholinomethylpyrrolidine catalyst.105

A catalytic enantioselective Henry reaction of nitromethane with α-keto esters usesa chiral bisoxazoline–copper(II) catalyst: the product α-hydroxy-β-nitro esters areuseful in themselves, but particularly so as a step towards the corresponding β-aminocompounds.106

3,7,7-Trimethyl-4,7,8,9-tetrahydro-2H -pyrazolo[3,4-b]quinolin-5(6H )-ones (43),linear tricyclic enaminones, can be prepared in one pot from 5-amino-3-methylpyrazole, dimedone, and an aldehyde (RCHO). When R = H, the productdehydrogenates to the corresponding pyrazolpyridine. No non-linear tricyclic wasisolated, and tests using varying order of addition indicate that (i) Knoevenagelcondensation of dimedone with aldehyde is the most likely route and (ii) the

(43)

NH

HNN

R O


alternative of the pyrazolamine condensing with dimedone does give an enaminone,but this does not then react with aldehyde. NOESY experiments confirm the 2H -structure for (43) shown, and not its 1H -tautomer.107

Knoevenagel condensation of 2-hydroxybenzaldehydes with active methylenederivatives, to produce 2-oxo-2H -1-benzopyrans (coumarins), is catalysed by samar-ium(III) iodide.108

Examples of stereoselective Mukaiyama aldols include the use of chiral BINAP- �eezirconate enantioselective catalysts109 (also employed for Mannich reactions ofimines), in addition to two vinologous variants of the reaction.110,111

�de

The Baylis–Hillman Reaction

This reaction has really come into its own in the last few years, its utilizationbeing driven by marked advances in catalysis, leading to much more convenientreaction times and conditions. An example of the earlier problems is seen in aseries of acrylates reacted with aldehydes, using DABCO as a catalyst. Using alkyl,fluoroalkyl, and benzyl acrylates in an attempt to stabilize the enolate intermediate,reasonable yields took days, or even weeks.112 Phenyl and β-naphthyl acrylates weresomewhat faster, but α-naphthyl (44) gave (45, R = Ph) in 88% yield in 20 min.Further exploration of (44) with other aldehydes showed a significant by-product(46) for R = Me, Et, and C6H4-4-NO2. Such 1,3-dioxan-4-ones are a very usefulclass of cyclic acetals, and excess aldehyde plus ‘long’ reaction times (i.e. 1–4 h,rather than 20 min) gave (46) as major product in 75–91% yield. It is presumedthat (46) forms from (45), followed by elimination of α-naphthoxide.

(44) (45)

O

O

O

O

DABCOMeCN

R

OH

RCHO

O

O RO

R

+

(46)

Using a Lewis acid such as boron trifluoride etherate, (methylsulfanyl)phenylpro-penone (47) undergoes a tandem Michael–aldol reaction to give Baylis–Hillman


(48b)

(47) (48a)

NO2

O OH

S

Me

NO2

O OH

S

Me

O

S

Me

+

+

adduct (48a) and onium salt (48b). Analogous products are obtained from the cor-responding seleno reactants, plus some selenochromanone.113

Tetramethylguanidine [Me2N−C(=NH)−NMe2] effectively catalyses the reac-tion, including examples with simple aliphatic aldehydes. An unsuccessful attemptto use derivatized or supported analogues suggest that the NH is critical to thecatalysis.114

Titanium(IV) chloride-catalysed Baylis–Hillman reactions are promoted to someextent by oxy compounds, including common oxy solvents such as acetone or alco-hols. Aryl aldehydes with electron-withdrawing groups tend to give chlorinatedproducts.115

In a modified Baylis–Hillman protocol, a chlorinated aldol adduct has beenobtained using quaternary ammonium salts, R4NX, in the presence of titanium(IV)chloride at −78 ◦C. The bromide and iodide salts are more active than the chloride,whereas the fluoride fails.116

syn-α-Halomethyl-β-hydroxy ketones (49) have been formed by coupling vinylketones and aldehydes using TiCl4 –n-Bu4NX, with >99 : 1 syn-selectivity.117

�de

(49)

R1 R2

X

O OH

Baylis–Hillman reaction of p-nitrobenzaldehyde with methyl vinyl ketone (50)gives the expected product (51a), but also the diadduct (51b). Using DABCO as


Lewis base in DMF, high yields are obtained at room temperature in a few days,with the proportion of the dione reaching over 60% when excess MVK (50) isemployed. A conjugate (Michael) addition is proposed for the second reaction, andsubstituent and steric effects have been explored.118

(51b)(50) (51a)

Ar

OH O

Ar

OH OO

O

+ArCHO

The reactions of N -benzylidene-4-methylbenzenesulfonamide (Ph−CH=N−Ts)with cyclohex- or cyclopent-2-en-1-one give a range of ‘normal’ and ‘abnormal’products, depending on the Lewis base employed.119

A catalytic asymmetric aldol reaction of allenoates with aldehydes using N -fluoroacyloxazaborolidine as catalyst has been reported.120

�ee

Miscellaneous Aldol-type Reactions

Coupling the enolate of a ketone with the enolate of a carboxylic acid derivative hasbeen reviewed (35 references), focusing in particular on achieving stereoselectivity,especially in the preparation of 1,4-dicarbonyl compounds.121

�de

�eeThe mechanism, reactivity, and stereoselectivity of amine-catalysed aldol reac-

tions involving enamine intermediates have been studied using density functionaltheory.122 When primary amines are employed, the reactions involve half-chair tran-sition states with proton transfer set up via hydrogen bonding. This substantiallystabilizes charges and lowers the activation energy: without such H-transfer in thetransition state (i.e. with secondary amines), oxetane intermediates become impor-tant. Stereoselectivities have also been modelled, and intramolecular aldol reactionsas well.

Intramolecular aldol condensations and crotonizations of a wide range of 1,5-diketones and their oxo derivatives have been reviewed (137 references).123

The role of tetrachlorosilane in mediating self-condensation of 3,5-dibromoacetophenone in absolute alcohol has been investigated.124 As well asproducing 1,3-bis(3,5-dibromophenyl)but-2-en-1-one, an even larger fraction of theyield turned out to be 1,3,5-tris(3,5-dibromophenyl)benzene.

In a supramolecular exploitation of Curtin–Hammett kinetics, a formylbenzo-15-crown-5 undergoes a potassium-accelerated aldol reaction with an acetylbenzo-15-crown-5, through the fast reversible formation of a 1 : 1 : 1 sandwich complexbetween the crown ethers and the potassium cation.125

Aldol-type C−C bond formation has been reported in the rhodium(II)-catalysedreaction of aromatic aldehydes with diazooxopropyldioxolanes (52; R = H, Me) to


give ring expansion products (54).126 This is the first report of such bond formationfrom ethereal oxonium ylids such as (53) via enol silyl ether intermediates. It is sug-gested that previously such reactions had been unsuccessful since the short lifetimeof such zwitterions precluded (kinetic) electrophilic attack of carbon nucleophiles.TMS chloride traps the intermediate, preventing [1,2]-rearrangement, and promotesthe β-elimination (i.e. ring expansion).

(52) (54)(53)

OON2

O

R R

OO O O

ORR

Ar

OHORR

+

−

In a series of papers, the two-step, one-pot synthesis of porphyrins from pyrroleand aromatic aldehydes has been probed by a wide range of spectroscopic and chro-matographic methods. The growth, interconversion, and closure of linear oligomershave been studied with a view to optimizing porphyrin yield and purity, including anexamination of the synthesis of trans-A2B2-tetraarylporphyrins, from two differentbenzaldehydes.127 – 130

The kinetics of the isomerization and monomerization reactions of glycolalde-hyde dimer have been studied in D2O (pD = 4.3) at 25 ◦C.131 Using 1H NMRspectroscopy, seven dimeric and two monomeric forms have been identified andtheir interconversions characterized.

A kinetic study of the benzoin condensation catalysed by a range of thiazoliumions shows that, with benzaldehyde concentrations typical of synthetic conditions,the three steps of the mechanism are each partially rate determining. This is similarto cyanide catalysis, and may also be relevant to nature’s selection of thiaminediphosphate as a coenzyme: many enzymatic processes evolved through the loweringof (high) energy barriers in such a way as to make all barriers in a sequenceapproximately equal in size under prevailing conditions.132

Catalysis of glyoxalate–ene reactions by chiral phosphine–Pt(II) complexes issubject to anion-dependent additive effects, even when the ee is little affected. �eeAddition of acidic phenols apparently speeds up the reaction by disrupting contaction pairs and/or sequestering trace water.133

A ligand-controlled addition of acetylene to aldehydes (with in situ generation ofa zinc acetylide) features a 98% ee.134

�eeA titanocene(III) complex, Cp2TiPh, promotes inter- and intra-molecular

pinacol couplings of aliphatic and aromatic aldehydes to give 1,2-diols �ee

diastereoselectively.135 Air-stable titanium(IV) complexes derived from chiral �de

Schiff bases catalyse enantioselective pinacol coupling of benzaldehydes.136

Stereoselection in pinacol coupling reactions of C=O and C=N double bonds hasbeen reviewed (99 references).137


Boron enolates of norephedrine-based glycolate esters react with various aldehy-des to produce syn-aldol products in high yield.138 Remote 1,5-stereoinduction has �de

been reported in boron aldol reactions of methyl ketones.139

α-Stannyl esters have been reacted with α-alkoxy and α-hydroxy ketones in highyield and >98% de.140 Achieved at room temperature in a few hours, the efficiency �de

of the stereoselection depends on chelation control via a stannous chloride catalyst.

Allylations

Indium-mediated allylations of α-ketoimides derived from Oppolzer’s sultam can becarried out in aqueous ethanol in high yield and de, providing a route to enantiopure �de

t-α-hydroxy acids.141

Pyranoside allyltins react with aldehydes, with BF3·OEt2 mediation, in a diastere-oselective coupling to give higher carbon sugars, but the corresponding furanosides �de

rearrange and eliminate tin before reacting with aldehyde.142

A chiral Lewis base (a binaphthylphosphoramide) has been combined with aweak Lewis acid (SiCl4) to produce a strong chiral Lewis acid. This acts as anenantioselective catalyst for allyation and allenylation of aldehydes in high yieldand ee.143 �ee

Other examples include a highly α-regioselective allylation of aldehydes medi-ated by indium in water144 (which apparently involves γ -allylation, followed by �de

rearrangement145), and a diastereoselective allylation of aldehydes employing 2-sulfinylallyl building blocks.146

Homoallyl alcohols have been cyclized with aldehydes, mediated by indiumtrichloride, to yield polysubstituted tetrahydropyrans. The reactions show highyields and excellent diastereoselectivities, with simultaneous control of up to five �de

stereogenic centres. Using the corresponding thiols to synthesize thiacyclohexanes,while giving the same major diastereomers, was somewhat complicated bycyclization–decyclization equilibria.147

Other Addition Reactions

General and Theoretical

Synthesis, properties, and reactions of 3,5,7-trimethyl-1-azatricyclo[3.3.1.13,7]decan-2-one (55), ‘the most twisted amide’, have been reported. With an ‘amide twist’ of90◦, (55) behaves as an amino ketone rather than an amide. Its pKa is 5.2 (forN -protonation), and the carbonyl reacts like a normal ketone. Not being stabilizedby resonance, it is hydrolysed rapidly to give zwitterionic amino acid (56) but,under mildly acidic conditions, this is reversible, with the ring closure exhibiting aneffective molarity of ∼1012 mol dm−3 for the amine nucleophile. (57), the hydrate ofthe conjugate acid (which would be a high-energy intermediate in a ‘normal’ amidehydrolysis), is stable both in acidic solution and as a crystalline hydrochloride.148

More electrophilic aldehydes and ketones typically react with nucleophiles muchfaster than less electrophilic analogues. However, this chemoselectivity can be


(57) (55) (56)

N

Me MeMe

OCO2

−NH2

+

Me MeMe

N

Me MeMe

H+H2OOH

OH

H

+

reversed by mediating the reaction with a Lewis acid catalyst. Examples of theexploitation of such reversal are reported.149

5-exo-Substituted bicyclo[2.1.1]hexan-2-ones (58) have been investigated as anew probe of long-range electronic effects on π-facial selectivity during hydride �de

reduction. Rapid calculation with a simple hydride model setup reproduces theobserved selectivities.150

O

(58) (59a) (59b)

O

H

Me

Me

MeO

Me

Me

Me

H

R

Ab initio gas-phase calculations on α-silyl aldehydes and ketones suggest thathydride attack is stereochemically controlled only by the bulk of the silyl sub-stituent and not by its electropositive nature. Thus hydride approaches syn to asilyl group, but anti (i.e. in the Felkin–Ahn sense) to a trimethylsilyl group.151 Thefinding has implications for the use of H-for-alkyl computational shortcuts in silylsystems.

Quantitative rearrangement of pivalaldehyde (59a) to methyl isopropyl ketone(59b) has been reported in highly acidic media, such as triflic acid, anhydrous HF,and BF3·2CF3CH2OH. The reaction, which involves formal H-for-methyl exchangeon adjacent carbons, apparently involves the O-diprotonated aldehyde. Analogieswith addition of CO to isobutane in HF–BF3, to give (59b), are discussed.152

Low-pressure FT-ICR mass spectrometry has been used to probe methyl cationtransfer between methanol and protonated methanol, protonated acetonitrile, andprotonated acetaldehyde: the enthalpies of activation (16.9, 16.5, and 18.4 kJ mol−1,respectively) are strikingly similar, indicating similar transition-state structures.153

The factors determining various outcomes in the base-catalysed reaction of cyclicand non-cyclic α-dicarbonyls, viz. (i) benzil–benzilic acid-type rearrangement, (ii)bond fission ‘outside’ the carbonyl system, and (iii) fission between the carbonyls,have been reviewed (23 references). The fate of cyclic substrates largely dependson the extent of ring strain.154


Hydrates and Hydrate Anions

Several quinone methides (60, R = H, Ph, p-MeOC6H4) have been generated byflash photolysis from the corresponding o-hydroxybenzyl alcohols. pH–rate profilesfor their hydration (back to the precursors) are reported, and also their reaction withnucleophiles such as bromide and thiocyanate. All additions are acid-catalysed,and inverse isotope effects indicate that they involve pre-equilibrium protonation toproduce benzyl carbocations.155

(61b)(60) (61a)

R

O

YX

O

H

YX

OH

H

O−HO−

In a computational study of substituent effects on five-membered heteroaromaticrings, the (X-to-carbonyl) transmission efficiency in the heterocyclic aldehyde (61a)increases in the order Y = NH > O > S > PH, but this is reversed for the hydroxideadducts (61b).156

A polarographic method has been developed for measuring the rate of dehydrationof ethane-1,1-diol, the hydrate of acetaldehyde. Due allowance for diffusional effectsbetween depolarizer and bulk solution allow the results to be compared with thoseobtained by other methods.157

For a hydrate of a ‘1-ammonium ketone’, see the ‘the most twisted amide’(55), above.

Addition of Organozincs

The current state of catalytic asymmetric organozinc additions to carbonyl com-pounds has been reviewed (233 references). The authors emphasize that althoughenormous efforts with dialkylzinc additions have brought it to a state of maturity,much remains to be done in the cases of aryl-, vinyl-, and alkynyl-zinc addi-tions. The scope for practical technologies exploiting macrocyclic and polymeric �de

chiral catalysts is examined, focusing on the advantages of ease of product isola-tion and catalyst recovery inherent in such methods and their scope for continuous �eeproduction.158 All reports below deal with enantioselection, mainly with diethylzinc.

Transition states for addition of dialkylzincs to aldehydes, promoted by chiralamino alcohols, have been characterized using two complementary computationalmethods: one (Q2MM) allows a rapid survey of conformational space, whereas aslower but more searching follow-up more thoroughly checks the results of thefirst.159

Amino acid-derived β-amino alcohols catalyse the enantioselective addition ofdiethylzinc to aldehydes. One case exhibits a strong non-linear effect (i.e. asymmet-ric amplification), in which a mere 20% ee (at 10% catalyst loading) gave 93% eefor addition.160 �ee


Et2Zn addition to N -diphenylphosphinoylimines, Ar−CH=N−P(=O)Ph2,is catalysed by diastereomeric 2-aminoethanols, and yields chiral amines, �eeAr−CH*(Et)−NH2, after acidic hydrolysis of the initial diphenylphosphinoylamideproducts.161

A fluorous β-amino alcohol derived from ephedrine acts as an enantioselectivecatalyst for addition to aldehydes; filtration through a fluorous reversed-phase silica �eegel allows for its recovery and re-use.162

Other papers report catalysis by a new chiral, C2-symmetric titanium diolcomplex,163 an azetidine derivative,164 a menthone-derived amino alcohol,165 β- �eeand γ -amino alcohols derived from (+)-camphor and (−)-fenchone,166 and a chiraldiamine the selectivity of which is reversed on methylation of the nitrogens.167

A pyrimidyl aldehyde has been reduced enantioselectively by addition ofdiisopropylzinc, using a chiral paracyclophane as the initiator of an autocatalytic �eesequence,168,169 and an enantioselective addition of an alkenylzinc to an aliphaticaldehyde has been reported.170

See Imines above for another addition of an organozinc.

Addition of Other Organometallics

Much of the focus was on diastereoselection: addition of organometallics to five-and six-membered cyclic ketones was achieved via prior incorporation of a (Z)-β-stannylvinyl group;171 methylmetal reagents were added to 2-methylaldehydes;172

and methyllithium was added to chiral (E)-aryl aldehyde oxime ethers to give �de

O-alkylhydroxylamines, which, after reductive N−O bond cleavage, gave (R)-1-(aryl)ethylamines.173

A chiral acetal derivative of tributylstannylmethanol, derived from L-valine, under-goes diastereoselective 1,2-addition to aldehydes, using butyllithium to transmetal-late; subsequent acid hydrolysis yields a chiral diol [HOCH2*CH(OH)R] derived �de

from the aldehyde and recovered chiral auxiliary.174

(2S)-O-(t-Butyldimethylsilyl)lactal (62) undergoes diastereoselective addition ofethylmagnesium bromide; the anti: syn ratio of the products shows a marked depen- �de

dence on the nature of the ethereal solvent employed, with an accompanying tem-perature dependence.175

1,4-Addition of bulky aryl groups (o,o,p-trisubstituted) to cyclic enones has beenachieved using BF3-promoted reaction of aryl cuprates to the α-iodoenone; subse-quent Grignard formation allows regular enolate chemistry to be pursued.176

All-trans-5-aminopenta-2,4-dienals (63) have been converted to pentamethinecyanine dyes (64). Addition of organometallics allows these to be chain extendedand elimination then yields a hexatriene.177

(62) (63)

O

OTBDMSR2N O

H

R2+N NR2

H

(64)


t-Butanesulfinyl ketimines derived from diaryl and aryl heteroaryl ketones undergoorganometallic addition to yield α,α-diaryl- and α-aryl-α-heteroaryl-alkylaminesdiastereoselectively. The facial selection is counterion dependent in some cases.178

�de

The reactions of phenylthiomethyllithium (PhSCH2Li) and cyanomethyllithium(NCCH2Li) with benzaldehyde and benzophenone have been investigated usingcarbonyl-carbon kinetic isotope effects. Comparison with results for other lithiumreagents in the literature suggest electron transfer as the dominant mechanism.179

The high diastereoselectivity of the condensation of lithiated (S)-(−)-N ,N -dimethyl-1-phenylethylamine with a range of dimethyl- and trimethyl- �de

benzophenones has been investigated.180

The Wittig Reaction and Variants

A Wittig reaction of 2,2-disubstituted cyclopentane-1,3-dione has produced an alco-holic rather than an olefinic product; a mechanism for this Grignard-like result hasbeen proposed.181

(R)-Piperidin-3-ol has been used as a new chiral auxiliary for stereoselectivesynthesis of α-hydroxyaldehydes.182

�de

A semi-stabilized ylid (65, R = Ph−CH=), readily prepared from the commer-cially available amine (65, R = H), gives quantitative E-selectivity in Wittig reac-tions with aldehydes.183

�de

NP

N

N

RMe Me

NMe

(65)

Pursuit of such stereoselectivity is also evident in papers on theHorner–Wadsworth–Emmons (HWE) modification of the Wittig reaction,184

including a review and computational study185 which looks at two transitionstates in the application of the reaction to stereoselective synthesis of α,β-unsaturated esters. The first involves the addition of the lithium enolate of a (model)trimethylphosphonoacetate to acetaldehyde, followed by oxaphosphetane formation.The second transition state is rate determining in the gas phase and in diethyl ethersolvent. On switching to methyl diphenylphosphonoacetate, the first step becomesrate determining; this is synthetically important, as it favours the trans product. �de

More generally, the calculations suggest that the trans-alkene will be favoured bynon-polar solvents and high temperatures, and vice versa for the cis-alkene.

A similar study of several mixed phosphonoacetates reacting with aromatic alde-hydes points to a switch from Z- to E-selectivity linked to the electron-withdrawing �de


ability of the phosphonoacetate substituents, and this in turn has been related to 31PNMR shifts.186

2-Substituted [1,8]naphthyridines (66) can be prepared from 2-aminopyridine-3-carboxaldehyde and an unsymmetrical ketone, MeCOCH2R. This transformation, theFriedlander reaction, is typically not regioselective, also giving the 2-methyl-3-alkylproduct. However, presenting the ketone with a phosphonate group on one side [i.e.(MeO)2P(=O)CH2COCH2R] makes the reaction up to 100% regioselective, whilemaintaining high yields.187 Essentially acting as an activating group, the phosphonateleaves in an HWE-type enone intermediate: apparently this species is trans-(67),with its isomerization to the ring-closable cis-isomer being achieved via addition ofmethanol (the reaction solvent) to the double bond, followed by its elimination.

(68)

N N NR

NH2

R

O

(67)(66)

OCH2P

Ph

O

Ph

O

Al O

Cl

H

Addition of Other Carbon Nucleophiles

Chiral aminoaldehydes have been cyanosilylated diastereoselectively, using a bifunc-tional catalyst (68) based on a sugar unit.188 A new series of bifunctional Lewis �de

catalysts has been reported. Using a 2,2′-binaphthol (BINOL) or carbohydrate scaf-fold, a Lewis-acidic metal site (Al or Ti) is juxtaposed with a Lewis base such asa phosphine oxide. Several enantioselective cyanosilylations are reported, and alsoStrecker- and Reissert-type transformations. Kinetic studies, together with catalyst �eecontrols, show that the reaction involves dual activation of substrate and trimethyl-silyl cyanide.189

For another enantioselective Strecker-type reaction of TMSCN, see Imines above. �eeEnantioselective cyanations have been carried out (i) on prochiral ketones, using

chiral Lewis bases derived from alkaloids as catalysts,190 and (ii) on ketones andaldehydes with TMSCN, using titanium(IV)–and vanadium(IV)–salen complexes, �eerespectively, as catalysts.191

A fast and diastereoselective cyanation of constrained ketones such as camphoradds TMSCN across the carbonyl; reductive desilylation then yields useful β-amino �de

alcohols. Catalysed by various lithium cation species, the reaction has also beenextended to α- and β-methylcyclohexanones.192 Another diastereoselective cyana-tion, this time of chiral α-amino aldehydes, uses Nagata’s reagent (Et2AlCN) toyield nitriles, which, on hydrolysis, give enantiopure β-amino-α-hydroxy acids.193


Counterion effects have been reported in the rhodium(I)-catalysed addition ofarylboronic acids to aldehydes.194 Stereocontrol of aryl transfer reactions by meansof chiral metal complexes has been reviewed (158 references).195

�eeArylaldehydes can be chloroalkylated by alkylboron dichlorides in the presence

of oxygen, apparently via an alkyl peroxide intermediate, followed by migration ofchloride.196

1,3-Dihalo-1,3-diarylpropanes, Ar1−CHX−CH2−CHX−Ar2, have been preparedusing the appropriate boron trihalide (X = Cl or Br) to promote addition of anarylaldehyde to a styrene.197

The mechanism of nucleophilic addition of unsaturated methyl lactones to pyri-dine aldehydes has been reinterpreted in the light of a quantum chemical study.198

Stannylated oxazolines add regiospecifically to 2-bromo-1,2-naphthoquinones.199

Miscellaneous Additions

γ ,δ-Acetylenic ketones can be hydrosilylated stereoselectively by exploiting σ –π-chelation control: subsequent reduction of the alkyne yields the anti-Felkin–Anh �de

products, not readily obtainable by other reductive methods.200 Copper(I)-catalysed �eeasymmetric hydrosilylation of aryl ketones has been reported.201

Ketones with an azido-containing alpha branch [CH2(CH2)nCH(N3)Ph, n = 1–3]can undergo two principal intramolecular reactions promoted by Lewis acids: (i)azido-Schmidt, involving azide addition to the ketone followed by rearrangementand ring expansion; and (ii) prior rearrangement to iminium ions, leading to aMannich pathway. For the four-carbon linker (n = 1), Schmidt reaction dominated,giving bicyclic lactams; longer tethers (n = 2, 3) favoured Mannich products.202

Danishefsky’s diene [trans-MeO−CH=CH−C(OTMS)=CH2] undergoes ahetero-Diels–Alder reaction with benzaldehydes, and with α,β-unsaturatedaldehydes, giving high ees using cationic metallosalen complexes as catalysts.203

�eeAppropriately substituted 2-norbornanones (69) undergo a stereoselective Leu-

ckart reaction to yield enantiopure 2-norbornylformamides when the bridgeheadsubstituent, R3, is H or Me. However, O- or N -acyl groups divert the reaction into �de

a pinacol-type skeletal arrangement, which is nevertheless still stereoselective.204

(69)

R2

R2

O

R1R1

R3

The possibility that hydrogen-bond interactions play an important role inPaterno–Buchi reactions (carbonyl–ene photocycloadditions) has been explored by


comparing the reaction of aldehydes with allylic alcohols and with the correspondingO-protected acetate esters. Both excited singlet and triplet states are considered.205

Enolization and Related Reactions

The kinetics and equilibria of tautomerization of 2-acetylcycloalkanones (70, R =Me; X = CH2), the corresponding triones (X = C=O), and cyclic β-keto esters(R = OMe; X = CH2, C=O), have been measured by a variety of methods forfive- and six-membered rings (i.e. n = 1, 2) with a particular emphasis on solventeffects.206

(70)

( )n X

R

OO

2-(Acylmethyl)quinolines (71a) can tautomerize to enaminone (71b) and eno-limine (71c) forms. The equilibria have been studied by 1H, 13C, and 15N NMRspectroscopy for a range of phenacyl and cinnamoyl compounds, with or with-out p-pyrrolidinyl substituents [i.e. R = (CH=CH)n C6H4X-p; n = 0, 1; X = H,N(CH2)4].207 Long-range effects include the cinnamoyl and pyrrolidinyl moietiesfavouring enolimine tautomers. Enaminone structures are favoured by low temper-atures.

(71b)

N N

HO R

H

O

R

H H

N

HO R

H

(71c)

(71a)

•••

•••

Thermolysis of vinylquinones (72-k) yields 2H -chromenes (73) via enolizationto a quinone methide (72-e), followed by 6π-electrocyclization.208

Computations on the acetaldehyde keto–enol system and on its radical cationanalogue (for which the enol is the stable tautomer) have elaborated the role ofsolvent molecules in the isomerizations of both systems.209


(72-k) (73)(72-e)

O

O

R4

R3

R1O

R2 O

OH

R4

R3

R1O

R2

OH

R4

R3O

R2

R1

O

Keto–enol tautomerization of acetylacetone has been computed by ab initiomethods.210

The kinetics of bromination of substituted acetophenones by phenyltrimethylam-monium tribromide have been measured in glacial acetic acid alone,211 and withcatalysis by sulfuric acid.212 Regioselective monohalogenation of bornane-2-thionesproceeds via thione–dihalogen complexes.213

Enolates

Brønsted acidities of a wide range of neutral C−H acids have been measured inthe gas phase and in DMSO solution, and compared with related literature data.214

Covering a large variety of aromatic structures and also nitriles, nitrile esters, andsome ketones, marked attenuations are observed in substituent effects on transferfrom the gas phase to solution, except for aromatics in which the conjugate baseexhibits very extensive delocalization, e.g. fluorenes, indenes, and aryl-substitutedcyclopentadienes.

Although benzocyclobutenone (74-KH) has been presumed to react in the pres-ence of bases via its enolate (74-E−), its low reactivity and unstable productshave hampered confirmation. 1H NMR observations on extracts from quinuclidene-catalysed reaction in D2O at 25 ◦C and pD = 12.5 clearly show the formationof the monodeuterated ketone (74-KD).215 Buffer plots confirm the reaction asbuffer-base-catalysed, and the very low reactivity is confirmed: correcting for theisotope, kOH ≈ 7.1 × 10−5 mol−1 dm3 s−1. This is comparable to ethyl acetate (1.2 ×10−4 mol−1 dm3 s−1; pKa = 25.6), and much lower than the structurally related 2-indanone (220; 12.2) or even acetone (0.11; 19.3). Ring strain and anti-aromaticityare likely factors destabilizing the enolate (74-E−).

House et al.’s conjecture216a that polyalkylation of alkali metal enolates isdue to greater aggregation of the less substituted enolate (with aggregation

(74-KD)(74-E−)(74-KH)

O O O

HD

kDO[DO−]

+ kB[B]

kD O

+ kBD[BD+]

2

−


lowering reactivity) has been confirmed216b in the case of 6-phenyl-α-tetralone(75, R = H). Its lithium enolate forms a tetramer (K1,4 = 4.7 × 1010 mol−3 dm9),whereas its monobenzyl product (75, R = Bn) forms a weaker dimer (K1,2 =3.8 × 103 mol−1 dm3). In both cases, kinetic studies show that reaction with benzylbromide is predominantly with the monomer. In one sample of synthetic conditionsconsidered, the second alkylation was already proceeding over 20 times faster thanthe first at the point when only 10% alkylation had been achieved.

(75)

Ph

O

R

(76)

O

A chiral lithium amide base has been employed to generate bridgehead enolatesfrom bicyclo[4.2.1]nona-2,4,7-trien-9-one (76); subsequent silylation gives the α-silyl ketone in 76% yield and >96% ee.217

Kinetic C-protonation of enolates by carbonyl-containing weak acids has beenreviewed.218 Oxazolinyloxiranes have been synthesized enantio- and diastereo- �eeselectively via azaenolates.219 A smooth, rapid cleavage of cyclic silyl enol ethersby potassium ethoxide yields enolates which can react kinetically with electrophiles �de

and oxidants.220

Oxidation and Reduction of Carbonyl Compounds

Regio-, Stereo-, Enantio-, and Diastereo-selective Reductions

Several reports are concerned with stereoselective reduction in constrained, cyclicketones, including model compounds selected to probe aspects of facial selectivityat the carbonyl group. The exterior frontier orbital extension (EFOE) model hasbeen used to interpret π-facial stereoselection in reduction of one and both carbonyl �de

groups of bicyclo[3.3.1]nona-2,9-dione (77, R = H) and its exo-methyl derivative.221�ee

(77)

O R

O

O

R

R(78)

Computations suggest that anti-selectivities in the lithium aluminium hydride(LAH) reduction of some 2,3-endo,endo-dialkylbicyclo[2.2.1]heptan-7-ones (78,


R = Me, Et) are inconsistent with the Cieplak hyperconjugative model, but canbe explained by antiperiplanar interactions with the carbonyl p-orbital.222

Theoretical studies of LAH reduction of formaldehyde and cyclohexanone suggestthat electronic effects are more important than torsional effects in controlling thestereoselectivity.223

Reduction of a series of 2-substituted-4-t-butylcyclohexanones with LAH yields(for equatorial substituents) increasing amounts of axial alcohol in the series H <

Me < Br < Cl < F << OMe.224 Steric or chelation arguments, or Felkin–Anh �de

or Cieplak approaches all fail to explain this trend, which apparently is due to anelectrostatic repulsion between the nucleophile and the 2-substituent. The results foraxial substituents (the axial proportion increases according to the series Cl < Br <

Me < OMe < H < F) are consistent with an electrostatic explanation and with theFelkin–Anh model.

Cyclic ketones are typically reduced to the more stable equatorial alcohol bydissolved metal and metal hydride reductions. However, aqueous titanium trichlo-ride–ammonia gives the opposite preference.225 The method depends on the basicmedium containing a mild Brønsted acid, i.e. ammonium cation. Kinetic and equi-librium studies suggest that the stereochemical preference is kinetic in origin: afterthe first electron transfer, the axial α-hydroxy radical formed is less stable than itsequatorial isomer, and reacts faster.

Borane in THF reduces cyclic ketones stereoselectively to the more thermody-namically stable alcohol: previous problems with poor selectivity at 0 ◦C have beenovercome by carrying out the reaction at reflux for protracted periods, which allowsthe initial boron adducts the opportunity to equilibrate.226

In other borane reductions, 2-benzyl-2-propioloyl-1,3-dithiane (79) has beenreduced with high enantioselectivity using an oxazaborolidine–BH3 complex,227

enantioselective borane reduction of ketones using chiral amino and diamino alcohol �eederivatives of squaric acid as catalysts has been reported,228 and the use of a chiraloxazaborolidine catalyst in effecting an enantioselective borane reduction has beenstudied quantum mechanically.229

S SPh

OCF3

OO

Ph

F3C O

Z

Y

O X

(81)(80)(79)

OMe

Stereoelectronic effects in the regioselectivity of reduction of aryl-1,2-ethanediolbenzylidene acetals [(E)- and (Z)-80] have been investigated.230

A range of hexoses were converted to keto sugars (81) via Swern oxidation.The carbonyl was then reduced with sodium borohydride, and the axial: equatorial


ratio of the products determined, and compared with other literature reports. Depar- �de

tures from expected behaviour are mainly explained by twisted-chair conformations,although the formation of an equatorial hydroxyl when Y = methoxymethyloxy issurprising, apparently arising from MOM participation.231

Diisopinocampheylborane reduces α-, β-, and γ -keto acids through an intramolec-ular mechanism, in high ee; in the case of the γ -hydroxy products, cyclization yieldschiral γ -lactones.232 �ee

Imines have been reduced to amines using trichlorosilane activated with N -formylpyrrolidine derivatives, and the reactions show selectivity over carbonyls.233

Optically active N -formylprolines give moderate ees. �ee

Other Reductions

A hydroxycyclopentadienyl ruthenium hydride (82), modelled on a similar systemdeveloped by Shvo et al.,234a reduces benzaldehyde to benzyl alcohol. Acetophe-none is reduced more slowly, whereas a simple imine, PhCH=NMe, is reduced morerapidly, to give a ruthenium adduct of the corresponding amine.234b Kinetic, ther-modynamic, and isotopic studies all point to a concerted hydride and proton transfermechanism. The moderately acidic nature of the hydroxy substituent (pKa = 17.5in MeCN) is highlighted as a critical feature of the reduction.

OHTol

Ph

Ru

HOC

OC

Tol

(82)

A wide range of aliphatic carboxylic groups, aldehydes, acyl chlorides, anhy-drides, and esters, and also carboxylic acids themselves, are reduced to methylgroups using trimethylsilane with B(C6F5)3 catalysis.235 Aromatic carboxylic func-tions, in contrast, stopped at the stage of the benzyl alcohol (as its SiEt3 derivative).

Atmospheric Oxidations

Several reactions of radicals and related species with carbonyl compounds in thegas phase have been reported, in particular those of relevance to combustion andprocesses occurring in the troposphere and the upper atmosphere. The role of ‘pre-reactive complexes’ in gas-phase molecule–radical reactions such as acetaldehydewith hydroxyl has been elucidated for formaldehyde and acetaldehyde: in eachcase, aldehydic hydrogen abstraction is substantially favoured over hydroxyl addi-tion to the double bond.236 A real-space ab initio molecular dynamics simulation


has been tested on the reactions of hydroxyl radical and hydroxide anion withformaldehyde.237

The HO2 radical reacts with formaldehyde to give a peroxy radical, HOCH2CO2.A recent study indicated ‘no’ reaction with a range of simple aliphatic ketones.238a

It is now suggested that both observations are consistent with the known thermo-chemistry of these systems.238b Taking an upper limit of 1 × 10−15 cm3 molecule−1

s−1 for the rate of reaction with ketones, it is proposed that this is consistent withthe evidence discounting direct addition as the mechanism. Rather, the reaction,such as it occurs, is proposed to proceed via a concerted, cyclic transition stateinvolving simultaneous H-transfer with 3 + 2-cycloaddition of the HO2 radical tothe carbonyl group.

Rate coefficients for the reaction of NO3 and OH radicals with 14 C2 –C6 aliphaticaldehydes in air have been reported at 298 K and 1 atm.239 Although the net resultof both reactions involves H abstraction (typically the aldehydic H), the reactivitiesfollow linear free-energy relationships typical of addition, a finding possibly relatedto the proposal for HO2 radical above. There is no correlation with reactivity ofsaturated organics.

An ‘abnormal’ increase in the rates of aldehydic H abstraction over a series ofaldehydes with NO3 radical in the gas phase has been explained, through computa-tions, as arising from an increase in the pre-exponential factor: the internal rotationpartition functions increase with the size of the aldehydes.240

Other Oxidations

Catalysis of chromium(VI) oxidation of formaldehyde by picolinic acid has beenstudied in acidic aqueous media.241 A series of chromium(VI → III)–picolinicacid complexes are proposed as intermediates. The catalysed reaction is first orderin picolinic acid, but zeroth order in H+; in contrast, the rate of the uncatalysedprocess in proportional to [H+]2. The mechanism has been further probed by kineticstudies in the presence of cationic and anionic surfactants.

The kinetics of the oxidation of substituted benzaldehydes by benzyltrimethylam-monium dichloroiodate, in the presence of zinc chloride, are explained in terms ofthe intermediacy of [PhCH2NMe3]+ [IZn2Cl6]−. A substantial kinetic isotope effectis observed for PhCDO, and the rates of oxidation of the substituted substrateshave been analysed using Charton’s tri- and tetra-parametric equations.242 Rates ofoxidation of a series of ortho-, meta-, and para-substituted benzaldehydes by pyri-dinium hydrobromide perbromide (PyH+Br3

−) in acetic acid have been correlatedusing the same analyses,243 and the kinetics and mechanism of this reaction, butwith NBu4

+Br3− as oxidant, have been reported for six aliphatic aldehydes in the

same solvent.244

Oxidation of benzaldehyde acetals by pyridinium chlorochromate, which is firstorder in both reactants and in the acetic acid catalyst employed, is accelerated byelectron-withdrawing substituents in the ring.245

A kinetic study of the oxidation of aliphatic aldehydes by 2,2′-bipyridiniumchlorochromate in DMSO indicates that the reaction is first order in oxidant, sub-strate, and protons; solvent effects are probed, and a large primary isotope effect


(5.90 at 298 K) is reported for MeCDO;246 a similar isotope effect (6.12) was foundusing pyridinium chlorochromate.247

Ebselen [83a, 2-phenylbenzisoselenazol-3(2H )-one] acts as a chemoselective oxy-gen-transfer catalyst in the conversion of aromatic aldehydes to arenecarboxylicacids by t-butyl hydroperoxide,248 with minimal formation of Baeyer–Villiger prod-uct, apparently because of steric hindrance in the actual oxidizing species (83b).

(83a)

SeN

O

PhSe

N

O

Ph

(83b)

HO2O But

Kinetic and thermodynamic parameters have been reported for the oxidation ofo-hydroxy- and p-methoxy-benzaldehyde by N -sodio-N -chlorotoluenesulfonamide(chloramine-T) in hydrochloric acid.249 Similar studies of several heterocyclicketones (piperidin-4-ones, oxan-4-ones, and thian-4-one-1,1-dioxides) in aqueousacetic–perchloric acid solution show second-order catalysis by hydronium ions.250

Oxidation of cyclohexanone by quinolinium dichromate in aqueous acetic–sulfu-ric acid, to produce adipic acid, proceeds via the enol: its reaction with the oxidantis rate determining.251

The oxidation of 2-heptylcyclopentanone by a hydrogen peroxide–urea complexin formic acid, to produce δ-dodecalactone, is rate determining in the step in whichperoxide is added to the carbonyl group.252

Several reports deal with sugars, including kinetics of the oxidation of D-fructoseby chromium(VI) in the presence and absence of both picolinic acid and of N -cetylpyridinium micelles,253 and palladium(II)-catalysed oxidation of D-glucose andL-sorbose254 (and of D-fructose and D-mannose255) by N -bromosuccinimide in acidicsolution. A range of tri-, tetra-, pent-, and hex-oses and their phosphates have beenoxidized in acetate buffers using gold(III):256 reactivity decreases in the order listed,with a variety of gold species implicated.

The kinetics of the oxidation of 1,2-dicarbonyl compounds, RCOCOR (R=H,Me, Ph), by permanganate have been measured in acetic–perchloric acid.257

Several studies of oxidative deoximation have been carried out. Kinetics of para-substituted benzophenone oximes with N -chloro-3-methyl-2,6-dimethylpiperidin-4-one in aqueous ethanolic hydrochloric acid are first order in each of thereactants and in hydronium and chloride ions.258 Rate-determining formation ofa cyclic intermediate is proposed in the reaction of aldo- and ket-oximes with(i) cetyltrimethylammonium permanganate,259 (ii) tetrabutylammonium tribromidein aqueous acetic acid (first order in both reactants), involving tribromide attack atcarbon,260 and (iii) pyridinium fluoro-261 or (iv) chloro-chromate262 as oxidant.


Other Reactions

Diacyldihydroxy[2.2]paracyclophane (84) was treated with sodium borohydride inrefluxing aqueous hydroxide, and refluxing methanol, in an effort to reduce thecarbonyl groups to methylenes. However, dideacylation occurred, in addition tosome mono-deacylation accompanied by reduction of the other acyl function to analkene. Neighbouring group participation by the phenolics has been established, anddeuterium labelling studies have implicated a solvated [2.2]paracyclophane anionas an intermediate.263

(85)(84)

OH

OH

Bu

O

O

Bu

O

ROAc

6-Acetoxycyclohexa-2,4-dienones (85, ‘quinol acetates’) have been found toundergo rapid ring opening in aqueous methanol, using carbonate base, to give anacyclic keto ester [RCOCH2CH(OMe)CH2CH2CO2Me] via an enone intermediate.Rates have been measured for R=Me and Ph, and the kinetic form and pHdependence suggest a benzene oxide–oxepin interconversion as part of the process.Implications for the mechanism of catechol dioxygenase enzymes are discussed.264

Organic modification of hydrogen-terminated silicon surfaces has been reviewed,with particular emphasis on the convergence of surface science and organic chem-istry, and the associated opportunity for physical organic chemists to help charac-terize the kinetics and mechanisms of such hybrid reactions.265 A wide variety ofreactions leading to Si−C bonds, including Grignard and alkyllithium transforma-tions, are covered.

Ring–chain tautomerism, shown for the examples of 3-oxoacrylic acids (86a,86b), has been studied computationally for the cases R3=Me and Ph, with R1, R2

varied between H, Me, and Ph.266 o-Oxobenzoic acids (87, R=H, Me, Ph) and8-formyl-1-naphthoic acid (88) were similarly examined, with due account takenof conformational interconversions in all cases, and also solvent effects. Conclu-sions include: (i) the ring tautomer is more favourable in acetyl (versus benzoyl)substrates; (ii) substitution at 2- or 3-positions in the acrylates favours the cyclic

(86a) (86b)

HO OO

R

O

OH

O

R3

O

OH

O

R1

R2

R3

O

R1

R2

O

(88)(87)


structure; and (iii) the open tautomer is favoured for benzoic acids, but the cyclicform predominates for (88).

1-Disilagermirene (89) reacts with benzaldehyde to give two isomeric cycload-dition products. One of them can add another benzaldehyde across the remainingSi−C bond.267

(89)

Si Si

Ge

R R

RR

Mass spectrometric studies of organic ion–molecule reactions have been reviewed(327 references).268 Emphasizing cases where mass spectrometry has made a contri-bution to understanding of fundamental organic processes, appropriate comparisonsand contrasts are drawn with condensed-phase studies, to tease out the precise roleof the solvent. Much of the focus is on carbanionic species, taking advantage oftheir lower propensity to rearrange, compared with carbocations.

Activation energies have been calculated for the competitive C- versus O-additionof radicals across the carbonyl bond of representative aliphatic and aromatic ketonesand aldehydes, and of acetic acid and its methyl ester.269

The mechanism of the ring-opening reaction of 4-benzylidene-2-methyl-5-oxazo-lone by butylamine may involve mixed first- and second-order roles for the amine.270

Flow-vacuum pyrolyses of three dibenzocycloalkenones appear to involve spiraneintermediates en route to anthracenes.271

(90a) (90b)

S+

H

H

S−

S

SH

H

Unsubstituted thioformaldehyde S-sulfide (thiosulfine, 90a) has been identified inan argon matrix at 10 K and characterized by IR and UV spectroscopy.272 The IRspectrum agrees with calculations assuming a planar, bent structure, confirming thatits nature is more dipolar (ylidic), rather than singlet diradical. Its photochemicaland thermal conversion to the unsubstituted dithiirane (90b) has been establishedand, at higher temperatures, both ultimately form dithioformic acid.

The mechanism of betaine formation in the reaction of thiones with a 1,2,4-triazoline-3,5-dione is proposed to involve a three-membered ring intermediate, fromelectrophilic addition of nitrogen to the C=S bond.273

The reactivity of α-cis-sulfanuric chloride and trichlorocyclotriazine towardsnucleophiles has been studied.274


Having considered five unimolecular reaction pathways for selenocarbonyls,HXC=Se (X=H, F, Cl, and Br), viz. (i) HX elimination, (ii) 1,2-H shift,(iii) 1,2-X shift, (iv) H and XCSe radicals, and (v) X and HCSe radicals, acomputational study concludes that the parent compounds should be both kineticallyand thermodynamically stable. Molecular parameters and IR spectra are alsopredicted.275

The synthesis and some intra- and inter-molecular nucleophilic additions of 3-(2-benzoylallyl)-4-hydroxy-6-methylpyran-2-one have been reported.276

1,10-Phenanthroline-5,6-dione undergoes a variety of different reactions withdiazomethane, depending on the type of solvent employed: aprotic media give amethylenedioxyphenanthroline, methanol gives C−C bond cleavage, and higheralcohols give a dispirodioxirane derivative.277

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