Formation and Reactions of Acetals and Related Species
A series of pyridinium cations with electron-withdrawing substituents on the ringcatalyse acetalization of aldehydes and other protection reactions, such as the forma-tion of dithianes, dithiolanes, dioxanes, and dioxolanes.1 The best catalyst works at0.1 mol%, outperforming a Brønsted acid with a pKa of 2.2.
DFT has been used in the development of a general equation relating the acti-vation energy of an intramolecular proton transfer to r (the distance between thereacting centres) and α (the hydrogen-bonding angle).2 The equation has been appliedto intramolecular general acid catalysis of five of Kirby’s acetals (e.g. 1; X = NH,O). Reaction rates correlate with r2 and sin (180◦ − α); that is, acetals with short r
values and α close to 180◦ (forming a linear hydrogen bond) are more reactive.3
The gas-phase elimination kinetics of several β-substituted acetals have been mea-sured in the range 370–441 ◦C and in the presence of a radical inhibitor.6 Two differentconcerted four-membered transition states are proposed, leading to either the alcoholand vinyl ether (the latter decomposing to alkene and aldehyde) or alkane and alkylester.
Iron(III) chloride or bromide has been used to catalyse Prins cyclization/halogenation of alkynyl acetals, using an acetyl halide as halogen source.8
1 Reactions of Aldehydes and Ketones and their Derivatives 3
(5)
OH
HPh OPh
EtO
Ph
(4)
PhCH(OEt)2
Sc(III), cat.
Deacetalization of acetals, R1CH(OR2)2, in the presence of trifluoroacetic acid hasbeen shown to be viable without water.9 Although water is a by-product, alcoholsare not, and a hemiacetal is not an intermediate. Rather, a hemiacetal TFA ester[R1–CH(OR2)–OCOCF3] is formed, followed by carbonyl production with two TFAester byproducts, F3CCO2R2. The latter process renders the reaction irreversible. Thetwo esters are produced at separate points in what is essentially a cascade mechanism.All intermediates have been identified by NMR. The new reaction has been dubbed‘acidolysis’ to distinguish it from the more familiar acid-catalysed hydrolysis.
Reactions of Glucosides
4,6-O-Benzylidene acetals of glycopyranosides (6) have been oxidatively cleavedto the corresponding hydroxy-benzoates (7a/b) using dimethyldioxirane under mildconditions, and in high yield.10 Appropriate choice of the neighbouring protectinggroup gives regioselectivity, with a preponderance of (7a) or (7b) of >99%, as desired.The balance of electronic and steric effects in the best groups – chloroacetyl and TBS(t-butyldimethylsilyl) – is discussed.
Glycoside hydrolases can give 1017-fold rate enhancements, and estimates of theirdissociation constants from their transition states are as low as 10−22 mol dm−3. Suchaffinity has encouraged mimicry, and a number of criteria have now been advancedto assess whether a natural or man-made glycosidase inhibitor is a true TS mimic.12
A new dicyanohydrin-β-cyclodextrin acts as an artificial glycosidase, hydrolyz-ing aryl glycosides up to 5500 times faster than the uncatalysed reaction.13
Michaelis–Menten parameters are reported and compared with other modifiedcyclodextrins.
Recent advances in understanding mechanisms of chemical O-glycosylation havebeen reviewed.15 pH-rate profiles have been constructed and analysed for glycosylationreactions of a range of aromatic amines.16
Oxime formation from sugars can be slow, but nucleophilic catalysis by aniline(at 100 mM) can increase rates up to 20-fold, and glycosylamine formation has to bewatched.17
DFT investigation of Staudinger 2 + 2-cycloaddition of a ketene and an imine,catalysed by NHCs, favour the ‘ketene-first’ mechanism, that is, it is the ketenethat is initially activated by the NHC. This mechanism persists even when varia-tion in the electrophilicity of the imine leads to stereodivergence in the experimen-tal results.24 NHCs also promote the chlorination of unsymmetrically disubstitutedketenes, R1R2C=C=O; the products are typically α-halo esters [R1R2C∗(Cl)–CO2R3]under the conditions employed. With chiral NHCs, modest ees of up to 61% are seen.25
The affinities of a wide-ranging array of imines for hydride, proton, and electron havebeen measured by titration colorimetry and by electrochemical methods, in acetoni-trile.27 Thermodynamic ‘characteristic graphs’ are then introduced, linking the energiesof the processes for each imine: each graph is intended to give the ‘molecular ID’ ofthe imine, facilitating prediction of likely reactions and mechanisms thereof.
The mechanism of Schiff base formation between pyridoxal analogues and aldehy-des has been studied by DFT.28
P –N–P ‘pincer’ complexes of ruthenium catalyse a new imine synthesis, from analcohol and an amine, with evolution of hydrogen.29
Formylpyridines react with tris(hydroxymethyl)aminomethane [(HOCH2)3CNH2,‘TRIS’], to give 1,3-oxazolidines (e.g. 11), which can equilibrate with their acyclictautomers, that is, Schiff bases. Anomeric and hydrogen-bonding effects have beenstudied in these systems, including the adduct derived from pyridoxal.30 Oxazolidinessuch as (12) – derived from TRIS and a benzaldehyde – have been prepared and then
6 Organic Reaction Mechanisms 2010
(11; Ar = 4-Py; 12; Ar = Ph-X)
(13)
O
HN Ar
HO
HO NH
SN
R1
R2
R3
ring-opened under acetylating conditions. X-ray crystal data and computations indicatea strong endo anomeric effect stabilizing a conformation that leads to regioselectivering opening to give imine (rather than N -acetyloxazolidine). Imine-oxazolidine equi-libria are also reported, and a per-O-acetylated imine, (AcOCH2)3–C−N=CHAr, inthe para-nitro case.31
An alkyl or aryl group, R1, in a 2-iminothiazole (13) can be exchanged with that inan isothiocyanate, R4–N=C=S, in toluene at 105 ◦C.32 The position of equilibriumin this reversible reaction is mainly dependent on the electronic properties of theexchanging groups (i.e. R1 and R4) and has been used to empirically compare theelectrophilicity of various isothiocyanates.
2-Substituted benzimidazoles have been prepared by condensation of various alde-hydes with 1,2-phenylenediamine, using copper(II) triflate catalyst, in refluxing ace-tonitrile.33
An anti -selective reaction of aldehydes with N -sulfonyl imines exploits hydrogenbonding involving a 4-hydroxypyrrolidine catalyst and an external Brønsted acid.39
Bench-stable α-amido sulfones have been used to generate N -Boc amino-protectedimines, which then undergo in situ Mannich reactions with glycine Schiff-bases,using a cinchonidine–thiourea catalyst, to give α,β-diamino acid derivatives withee/de close to 100%.42 In a similar strategy, a highly diastereo- and enantio-selective
DFT-calculated ees and des compare well with observed values for anti -Mannichand syn-aldol reactions catalysed by axially chiral amino sulfonamides.44
While chiral phosphoric acids such as 3,3′-disubstituted BINOLs have been knownto catalyse direct Mannich-type reaction of aldimines with 1,3-dicarbonyls, such cata-lysts can be contaminated by group I/II metal cations. Deliberate introduction of suchcations, especially calcium, confirms that the metal salts may be the ‘true’ catalysts,giving higher yields and ees in some cases.45
using chiral bifunctional organocatalysts give (β-aminoalkyl)fluoromalonates in93–97% ee,46 and bifunctional amine–thiourea catalysts derived from rosin give
N -Sulfonylcarboxamides of proline catalyse Mannich reaction of cyclic ketoneswith N -protected iminoglyoxylate, with de/ee up to 94/99%. Enamine intermediateshave been examined by DFT.48
The first catalytic, enantioselective vinylogous Mannich reaction of acyclic silyldienolates (17) has been reported. Using protected imines (16), ees up to 98% havebeen achieved (R1 = H), and more highly substituted products (18, R1 = Me) canbe prepared diastereoselectively. A second-generation BINOL-based phosphoric acidcatalyst developed for the process has been studied by NMR, and a crystal structureof the imine-bound catalyst was obtained, shedding light on the facial selectivity ofthe reaction.49
Nickel(II) and a spiro-chiral phosphine catalyse the three-component coupling ofimines, diethylzinc, and aromatic alkynes with ee up to 98%, and with good chemos-electivity, to give useful allylic amines.52
chiral aziridines with de/ee up to 96/98%; the stereoselectivity is opposite to that foundfor imines without the α-chloro substituents, presumably due to chlorine coordinationof the incoming Grignard.55
The reactions of Grignard reagents with imines have been contrasted for catalyticand stoichiometric amounts of titanium alkoxide reagents.56 The former favours alky-lation, while the latter gives reductive coupling, with distinctive mechanisms for each,as shown by studies using deuterium-labelled substrates.
Chiral phosphinoylimines have been prepared in high yield and good de by additionof Grignards to new P -chirogenic N -phosphinoylimines.57
In the triphenylphosphine-catalysed reaction of alkyl propiolates with N -tosylimines, a stable phosphonium-enamine zwitterion (21) of proven importancein the mechanism has been isolated and characterized by X-ray crystallography.60
Deuterium-labelling experiments have identified several hydrogen-specific processes,none of which limit turnover, but they are highly medium dependent.
Enantioselective addition of terminal alkynes to imines and their derivatives hasbeen reviewed, including in situ examples, that is, three-component reactions of ter-minal alkynes, aldehydes, and amines.62
Chiral 1,3-diamines have been accessed by diastereoselective reduction of enantiopureN -t-butanesulfinylketimines (23, prepared from the corresponding diaryl ketone).66
Advances in enantioselective reduction of C=N bonds have been reviewed,focussing on the use of metal-free chiral organocatalysts with Hantzsch esters ashydride source.68
Ammonia–borane (H3N–BH3) has been employed in a mild, metal-free trans-fer hydrogenation of imines.70 A concerted double-hydrogen-transfer mechanism isproposed, backed up by deuterium kinetic isotope effects, Hammett correlations,and ab initio calculations. Hydrogenation of other unsaturated systems is being fol-lowed up.
Iminium Species
Kinetics of the reactions of iminium ions (pre-generated from cinnamaldehyde and sec-ondary amines) with cyclic ketene acetals were studied by UV–visible spectroscopy.71
Second-order rate constants have been used to derive values of the electrophilicityparameter, E (−10 < E < −7), and these have been analysed using a correlationequation, log10k = S(E + N), where S and N are nucleophilicity parameters. Theequation is then found to predict rate constants for reactions of the iminium ions witha range of other species, such as pyrroles, indoles, and sulfur ylides.
The intermediacy of an iminium ion, Me2N+=CH2, in the nitrosative cleavageof triethylamine to N -nitrosodimethylamine (Me2N–NO) has been explored in aDFT study designed to elucidate how carcinogenic N -nitrosamines form from tertiaryamines.72
Reaction of dimethyl sulphate with DMF gives methoxymethylene-N ,N -dimethyliminium salt, Me2N+=CH(OMe) −O4S–Me.73 It acts as an acid promoter ofStaudinger synthesis of 2-azetidinones (β-lactams) from imines and substituted aceticacids. Under base catalysis, the carboxylate is proposed to react with the iminiumsalt to produce an activated ester, which breaks down (again with base catalysis) toyield the corresponding ketene, which is the immediate reactant with the imine.
A review surveys the development and potential of iminium ion catalysis, usingions formed by the condensation of chiral secondary or primary amines with α,β-unsaturated aldehydes or ketones, in a variety of cyclo- and conjugate-addition reac-tions.74
Palladium(II) and rhodium(I) catalysts and chiral disphosphane ligands allow additionof phenylboronic acid, and of phenylboroxine, to N -tosylimines, in up to 99% ee.75
1 Reactions of Aldehydes and Ketones and their Derivatives 11
(25)
N−
N OH
R
N NOH
O
R
(24)
OH+
the protocol, with generation of the chloromagnesium salt of the homoallylic alcoholbeing essential to the mechanism.
An unexpected reaction of aromatic aldimines (26) with a difluoroenoxysi-lane gives access to 2,2-difluoro-3-hydroxy-1-ones (28) – the Mukaiyama aldol-typeproduct – via an amine (27).77 Zinc triflate promotes the reaction, and 18O-labellingand other experiments suggest that water is required to form the product (28).
(28)
N
Ar1
Ar2
(27)(26)
NH
Ar1
Ar2
Ph
O
F F
OH
Ar1 Ph
O
F F
F
F OTMS
Ph
3,4-Dihydroisoquinoline (29) undergoes aza-Henry reaction with excess nitro-methane at ambient temperature to give the corresponding 1-(nitromethyl)tetrahydro-isoquinoline (30), an unstable species that is trapped by acylation or alkylation,leading to Reissert-like products via an overall one-pot three-component reaction.78
Evidence for reaction via the methyleneazinic acid tautomer of nitromethane (31) ispresented.
(30)(29)
NHN
NO2
OH
NO−
(31)
+
A vinylogous imine intermediate (33), generated in situ from an arylsulfonylindole (32), undergoes enantioselective Michael addition to malonitrile, using a chiralthiourea catalyst, to give useful 3-indolyl derivatives (34).79
trans-2,3-Disubstituted aziridines (36) have been prepared from N -sulfinylaldimines(37) and 2-(para-tolylsulfinyl)benzyl iodide (35) in high ee/de. Whether the inter-mediates are benzyl halocarbenoids or benzyl carbanions has been examined usingDFT.81
The previously reported reaction of diarylmethyl imines with diazoacetates to givecis-aziridines (using chiral VANOL or VAPOL ligands) has now been complemented
12 Organic Reaction Mechanisms 2010
(34)(33)(32)
NH
R1
R2
SO2Tol
NR1
NH
R1
R2R2
CN
CN
base
(35) (36)
R2 H
NS
O
Tol
SO
Tol
I
N
S
(37)
R1
H R2
H
O• •• •
by conversion of diazoacetamides to the corresponding trans-aziridines, again withhigh de, ee, and yield.82
Systematic investigation of aziridination of benzhydryl-type imines, R–CH=N–CHAr2, has been undertaken, varying the imine aryls and using VANOL-and VAPOL-derived chiral boroxinates.83 Typical ees of 96–97% were obtained
using 2,4-dimethyl-3-methoxy as the Ar groups, and for these substrates their highactivity allowed the conventional diazoacetate ester reagent to be replaced by adiazoacetamide, an option that is not really viable for simple benzhydryls (i.e. Ar= Ph). While varying the aryls varies the aziridine products, the latter are easilyconverted to N–H aziridines.
2-Methylazaarenes such as 2,6-lutidine (38) undergo palladium-catalysed benzylicaddition with N -sulfonyl aldimines, showing a powerful C−H activation effectand giving access to heteroarylethylamines (39); a stereoselective version is beingexplored.84
Chiral BINOLs and amino alcohols have both been used as enantioselective cat-alysts for Strecker reaction of achiral N -phosphinoyl imines with diethylaluminiumcyanide.86
Hydrolysis of the Schiff base, N -salicylidene-meta-chloroaniline, has been studiedfrom pH 3 to 12 at 303 K and also at other temperatures to yield thermodynamicparameters.89
Chiral phosphoric acids catalyse asymmetric peroxidation of imines, R2–CH=N–R1, to give amine-peroxides with the chiral centre between the functional groups(40), using organic hydroperoxides, R3–OOH.90
For a homocoupling of aromatic imines, see under ‘Benzoin Condensation andPinacol Coupling’ below . For a nucleophilic perfluoroalkylation of imines, see under‘Addition of Organozincs’ below .
Oximes, Hydrazones, and Related Species
FT-ICR mass spectrometry has been used to measure gas-phase acidities of ring-substituted (E)-acetophenone oximes.93 Substituent trends are the same as in DMSOsolution, indicating that solvation stabilization has a consistent effect, but that thereis no specific solvent effect on any particular substituent.
The use of O-substituted hydroxylamines and oximes as electrophilic amino-transferagents has been reviewed.94
2-Isoxazolines have been prepared enantioselectively by conjugate addition ofoximes to α,β-unsaturated aldehydes, with anilinium catalysis.95
regio- and stereo-specific addition of ketoximes (R1R2C=NOH) to acylacetylenes(Ph–C≡C−COR3) under mild conditions (DCM/r.t./10 mol% Ph3P).96 Slow build-upof the (Z)-material over time indicates that the (E)-isomer is a kinetic product.
A gold complex catalyses cyclization of O-propioloyl oximes (44), giving goodyields of 4-benzylideneisoxazol-5(4H )-ones (45) after transfer of the arylidene
14 Organic Reaction Mechanisms 2010
(45)(44)
ON
H Ph
O
Ph
NO
O
Ph
H
PhAu(PPh3)NTf2
MeCN/25 °C
(46)
NN
N
NR2
R1
group, but crossover experiments indicate that the arylidene ‘migration’ is in factintermolecular.97
Triphenylphosphine and carbon tetrachloride, together with catalytic DBU andBu4NI, effect oxime ether formation (from oxime and alcohol) in refluxing acetoni-trile.98
Among reports involving Beckmann rearrangement, N -imidoylbenzotriazoles (46)have been prepared in one pot in high yield from ketoximes, R1–C(R2)=NOH, byreaction with mesyl chloride in the presence of a base and subsequent addition ofbenzotriazole.99 A kinetic study of the rearrangement of cyclohexanone oxime toε-caprolactam in aprotic solvents has been carried out, using trifluoroacetic acid ascatalyst.100 Bromodimethylsulfonium bromide (Me2S+Br Br−) catalyses rearrange-ment of ketoximes in refluxing acetonitrile, in the presence of zinc chloride.101 Ratesof rearrangement of cyclohexanone oxime para-toluenesulfonate in eleven solventshave been described by a three-parameter linear correlation involving polarizabil-ity, electrophilicity, and solvent molar volume.102 Rearrangement of cyclododecanoneoxime into ω-laurolactam has been followed by an ‘in situ’ multinuclear solid-stateNMR method, and in a batch reactor process, using IL media.103
NiCl2·6H2O catalyses coupling of aldoximes with amines to give amides; the oximecan be prepared in situ from the corresponding aldehyde. 18O-Labelling studies havebeen used to probe the mechanism: a label in the oxime is not incorporated into theamide.104
The combination of triflic anhydride and a 30% excess of triphenylphosphinedehydrates aldoximes to nitriles at 0 ◦C in high yield in minutes, using 2 equiv. of tri-ethylamine base in DCM. 1H, 13C, 19F, and 31P NMR studies indicate that the reagentcombination equilibrates to a mixture of (Ph3P+) OTf Tf− and (Ph3P+)2O·2Tf−, withthe former acting as oxygen activation and dehydration reagent.105
Indium trichloride catalyses hydration of nitriles to amides: in refluxing toluene,acetaldoxime can be used as a water surrogate.106 The by-product – acetonitrile – isalready known to be required for some amide-to-nitrile protocols.
Reports of oxidative deoximation back to carbonyl include an account of the kineticsof deoximation of a series of oximes of 3-alkyl-2,6-diphenylpiperidin-4-one (47) bypyridinium fluorochromate, which indicate steric crowding as the major influence.107
Rates of deoximation of aldoximes and ketoximes by morpholinium chlorochromatehave been measured in DMSO, showing first-order dependence on both substrate andoxidant; for acetaldoxime, 19 solvents were examined.108 Quinolinium fluorochromatedeoximates ketoximes in aqueous acetic acid, with a first-order dependence on bothsubstrate and oxidant.109 Oximes have also been deoximated by aerial oxidation, using
1 Reactions of Aldehydes and Ketones and their Derivatives 15
(49)(47)
Ph NH
(48)
O
R
Ph
N
ON
R1
R2
O
a
R4R3
R2R1
manganese(I) porphyrins as catalysts and benzaldehyde as oxygen acceptor, in tolueneat 50 ◦C. A radical trap stops the reaction, and the presence of a manganese-oxoporphyrin was confirmed by UV–vis spectra. The oximes of 2-nitrobenzaldehyde andpyridine-2-carboxaldehyde gave nitrile product; that is, ‘benzaldehydes’ with electron-withdrawing groups in the ortho-position divert in this way.110
Organoceriums have been added diastereoselectively to chiral aldehyde hydrazonesderived from 1-aminoprolines; resulting hydrazines can be cleaved to give enantiomer-ically enriched amines in protected form.111 The advantages of organoceriums over
Grignards or organolithiums are discussed.Chiral N -amino cyclic carbonate hydrazones (‘ACC’ hydrazones, e.g. (48), with
a rigid carbamate derived from camphor) undergo α-alkylation via deprotonation byLDA.112 DFT has identified the features of the azaenolate intermediate that give rise
to stereoselectivity. The calculations predict higher stereoselectivity than previouslyreported by experiment, and a modified experimental method has now yielded thehigher values.
Chiral α-hydrazino acids (50) have been accessed by asymmetric hydrocyanationof hydrazones with TMSCN; an O-silylated BINOL-phosphate formed in situ acts asauxiliary, giving α-hydrazinonitriles in a Strecker-like process, with subsequent acidhydrolysis yielding (50).116
A range of α-amido-α-aminonitrones (51) can react to form three classes ofproducts – 1,2,5-oxadiazin-4-ones, amidines, and dibenzo[d,f ][1,3]diazepines – allof which retain the core structure. The products were identified by X-ray crys-tallography, which also pointed out unusual features, such as an exceptionallylong Csp2 –Csp2 single bond (arrowed), up to 1.54 A, and a very high ‘trigonal’angle of 131◦ for Nsp3 –Csp2 –Nsp2 , as well as NH· · ·O and NH· · ·N intramolecularhydrogen-bond-like interactions. These features, together with DFT calculations,have been used to help elucidate the operative mechanisms.117
For oxime formation from carbohydrates, see under ‘Reactions of Glucosides’above.
C−C Bond Formation and Fission: Aldol and Related Reactions
Reviews of Organocatalysts
General reviews include coverage of chemoselectivity in reactions involvingasymmetric aminocatalysis,118 the roots of asymmetric aminocatalysis over the past
niques are now being reassessed under high-temperature/pressure conditions.128
Asymmetric Aldols Catalysed by Proline and its Derivatives
Reviews of asymmetric aldol reactions include an account of those proceeding viaenamines using organocatalysts,129 their application to total synthesis of natural prod-
diates has been underlined by their direct observation by NMR. E-Configured s-transenamines (52) are detected: in DMSO, EXSY-NMR shows them arising from oxa-zolidinones rather than from iminium-type intermediates. The oxazolidinone-enamineequilibrium is not affected by additional water (in small amounts) or by the amountof catalyst.132 A computational study has compared the enamine (Houk–List) and
1 Reactions of Aldehydes and Ketones and their Derivatives 17
(53)(52) (54)
N
R
OH
O
NH HN
O
NH HN
O
NH
EWGR
oxazolidinone (Seebach) mechanisms, with the latter being found to be inadequatefor predicting the stereochemical outcome.133 Another DFT study has focussed on
List’s proline-catalysed stereoselective intramolecular aldols of 1,7-dicarbonyl com-pounds have been studied by DFT, with a polarizable continuum model employed forsolvent effects. The enantioselectivity is found to arise from a key electrostatic contactbetween the forming alkoxide and the proline. The origin of the diastereoselectivityis typically more complex, especially for dialdehydes.140
The possible roles of imidazolidinone intermediates or by-products in aldol reactionscatalysed by prolinamides (53; R = H, NO2) has been studied by NMR and X-raycharacterization of these species.142
Tf, and Ts) and the potential for multiple N–H· · ·O hydrogen bonding. The mesylategave the best performance in terms of yield/de/ee in a test aldol: 94/94/>98%, whilethe tosylate may involve an aryl-stacking stabilization of the transition state.143
Two new catalysts (alcohol 55, and the corresponding ketone) have been developedfor direct aldol addition in the presence of water.144 Prepared from trans-4-hydroxy-
l-proline and the steroid isosteviol, the strategy involves a hydrophilic catalytic group(the acid of proline), a lipophilic pocket (the isosteviol skeleton), and an assistingfunctional group (the remote alcohol/ketone). With only 1 mol% loading, yield/de/eeof up to 99/98/99% has been achieved for a cyclohexanone–araldehyde aldol at roomtemperature. Effects of solvent, water, temperature, and substrate structure have beenstudied.
18 Organic Reaction Mechanisms 2010
NH OH
O
NH HN
O
SO2
C12H25
O
O
OH
(56)
(55)
Ethylene and propylene carbonate, readily prepared from epoxides and carbondioxide, are effective solvents for proline-catalysed aldols, giving yields/de/ee up to99/100/99%. Choice of carbonate solvent and whether or not to use water co-solventhas to be matched to substrates, and in particular to their polarity.145
Intramolecular aldols of cyclic diketones are catalysed by proline, and List’s studiesof the effect of incorporation of a 4-fluoro substituent in the cis- or trans-positionhas been studied by DFT. It finds that fluorine changes pathways as well as transitionstates: a low energy epimerization (after the C−C bond forming process) affectsproduct distribution.146
N -(para-Dodecylphenylsulfinyl)-2-pyrrolidinecarboxamide (56) is one of the bestanti -aldol catalysts to date, with yields/ee/de up to 98/99/98%, low catalyst loading,mild conditions, and convenient solvents (or none). A DFT study has now identifiedthe origins of the diastereoselectivity in non-classical hydrogen bonds between thesulfonamide, the electrophile, and the catalyst enamine that favour the anti -Re aldoltransition state.147
Strong non-linear effects are observed in proline-catalysed aldols when an achiralthiourea catalyst is also employed in non-polar solvents: with an ee as low as 5%for the proline, 40% ee and 94% de are observed in the products.149 The role of the
thiourea co-catalyst in such reactions has been investigated. Examining the reactionof acetone with 4-substituted benzaldehydes, non-linear effects are observed (%eealdol
versus %eeproline), but these are markedly dependent on the nature of the aromatic sub-stituent. Results from 1H-NMR and ESI-MS suggest that the main role of the thioureais not that of producing a soluble proline-thiourea hydrogen-bonded complex.150
1 Reactions of Aldehydes and Ketones and their Derivatives 19
A chiral solvent effect has been seen in proline-catalysed aldols in aqueous propy-lene carbonate: when enantiopure (R)-propylene carbonate (57) is used with (R)-proline, they constitute a ‘matched pair’ with high de/ee, whereas (S)-proline/(57) isa mismatch.153
Racemic α-acylphosphinates undergo cross-aldol reaction with acetone to givediastereomeric α-hydroxyphosphinates (58), because of the phosphorous chiral centre.Using proline catalyst, high ees and des have been achieved.154
Efficient direct α-hydroxymethylation of ketones in homogenous aqueous solventshas been reported: a bis-prolinamide-zinc complex promotes aldol reaction with aque-ous formaldehyde in good yield and up to 94% ee.155
classes such as β-amino acids and hydrazides for testing.156 Amino amide catalyststhat exploit a double hydrogen-bonding activation of carbonyls give high ees.157 l-
Tryptophan catalyses reaction between cyclohexanone and aldehydes in water; DFThas been used to identify the precise role of the indole substituent in stabilizing thetransition state.158
A siloxy-serine facilitates syn-selective direct aldols in an IL: the recyclablecatalyst gives de/ee up to 88/94% under mild conditions.159 A simple chiral
The combination of a primary–tertiary diamine and a Brønsted acid enables syn-selectivity in cross-aldols of aldehydes: de = 92%. A chiral diamine (60), with triflicacid, renders it enantioselective too: ee = 87%, and it works for glycolaldehydedonors.161
Direct addition of enolizable aldehydes to α-halo thioesters gives β-hydroxythioesters via reductive soft enolization, with syn-selectivity, whereas conventional
Quinidine thiourea catalyses the asymmetric aldol reaction of unactivated ketoneswith activated carbonyl compounds via an enolate intermediate: it is suited to caseswhere the enamine-based organocatalysis does not work well.165
N ,N -Bis(trifluoromethanesulfonyl)squaramide (61) is a bench-stable and strongBrønsted acid. It catalyses a wide range of aldehyde reactions: Mukaiyama aldol,Mukaiyama Michael, Hosomi–Sakurai allylation, and an intramolecular carbonyl-enereaction of a 6-enol. In reactions with silylated substrates, it appears that (61) actsto directly protonate the carbonyl compound, rather than catalysing routes involvingsilylated Brønsted acid.167
An (R)-BINAP platinum(II) complex catalyses enantioselective reaction of alde-hydes with ketene silyl acetals, for example, Me2C=C(Me)OTMS in DMF.168 The
complex undergoes a dimer/monomer equilibrium in this solvent: the monomer isapparently more catalytic.
A new series of C2-symmetric chiral ligands (62; R=H, Me, But , etc.) has beensynthesized. Complexed with europium(III), aldehydes can be activated in aqueousmedia, with the lanthanide still having vacant sites for hydration.169 In addition, the
lanthanide complex facilitates luminescence-decay measurements. Tested as catalystsof Mukaiyama aldols in ethanolic water, β-hydroxy carbonyl products were obtainedin high yields and de/ee up to 96%, at temperatures as low as −25 ◦C. The use of lumi-nescence measurements allowed binding of benzaldehyde to be observed (indirectly)via decreases in the water-coordination number of the europium cation.
A stereoinduction model has been used to explain an unexpected syn-selectivity inthe Mukaiyama aldol addition of crowded enolsilanes to α-chloroaldehydes.170
+ −NTf2,promotes Mukaiyama aldol and Mannich reactions using ketene silyl acetals withketones and oxime ethers, respectively.171 1H-NMR and other investigations suggestin situ formation of trimethylsilyl bistriflimide, Tf2N(TMS), as the active catalyst.
A stereoinduction model has been used to explain the unexpected syn-selectivity inthe Mukaiyama aldol addition of sterically demanding enolsilanes to α-chloro alde-hydes.172
transfer from enol to aldehyde, shuttled across the non-bridgehead nitrogens of (67).Alternative nucleophilic and enamine mechanisms have been explicitly ruled out bythe calculations.
The aldol condensation of acetaldehyde in water has been studied under environ-mental conditions at high pH, as it may play a role in the degradation of organicmatter in hyperalkaline conditions.176 Analysis of the kinetics suggests that the reac-tion is first order in substrate, hydroxide, and carbonate, in contrast to earlier studiessuggesting a second-order base dependence, with the authors claiming that they havebetter avoided interference by a competing Cannizzaro process.
Benzamidine catalysis of an aldol reaction can be switched on and off reversiblywith carbon dioxide, without affecting substrate or products.177
Carbanions of 3-chloropropyl phenyl sulfones containing carbonyl and imino groups(e.g. 68) in the ortho-position add intramolecularly to these groups to give aldol-typeanions. Subsequent intramolecular 1,5-substitution of chlorine gives tricyclic tetrahy-drofurans, pyrrolidines, and cyclopentanes.178
Halogenotin hydrides, Bu2SnXH (X = Cl, I), catalyse a reductive aldol reactionof enones to give β-hydroxyketones in good de, using a Ph2SiH2/alcohol promotersystem.179
Enolizable aldehydes, R1R2CHCHO, undergo an asymmetric Meerwein–Ponndorf–Verley–Aldol etherification reaction in methanol, giving highly functionalized products(69) with defined configurations at adjacent quaternary and tertiary centres. (−)-Menthyl-TMS is used as auxiliary, and trifluoroacetic acid is required as a catalyst.182
Aldehyde ‘dimerization’ to Tishchenko esters is catalysed by sodium hydride. WhileNaH is usually considered a base, it can reduce aldehydes to sodium alcoholates, andthis is proposed as the first step; detection of alcohol by-product supports such amechanism.183
1 Reactions of Aldehydes and Ketones and their Derivatives 23
An asymmetric direct vinylogous aldol reaction of unactivated γ -butenolide (70)with aldehydes gives the corresponding 5-(1′-hydroxy) derivatives in high yield/ee(93/83%), using a cinchona-alkaloid-based thiourea organocatalyst.185
The complex mechanism involves an initial Breslow intermediate attacking the enoneto give an enol-enolate, the point where the trans-stereochemistry of (73) is deter-mined. An intramolecular aldol condensation, extrusion of the NHC, and eliminationof carbon dioxide feature in the later steps.
Homodimerization of 2-cyclohexanone, catalysed by l-proline, proceeds via a two-step imine/enamine addition or concerted Diels–Alder cycloaddition: the former ispreferred.188
The O-nitroso aldol reaction of nitrosobenzene with enolizable aldehydes is pro-moted by the TMS ether of diphenylprolinol, using para-nitrobenzoic acid as aBrønsted acid co-catalyst, with ee of about 100%. The α-oxyaldehyde adducts pro-duced are readily converted in situ to α-oxyimines, and thence to 1,2-aminoalcoholsvia treatment with Grignards, the latter process exhibiting des > 90%.190
A supramolecular chiral host, per-6-amino-β-cyclodextrin, gives ‘all-99s’ performance(yield, de, ee) for a Henry reaction in aqueous acetonitrile, and is readily recy-clable without loss of activity.191 Thiourea, flanked by proline and cinchonidine
Copper catalysis is widely used. A high level of stereocontrol of three contiguousstereogenic centres has been achieved using a complex of copper(I) chlorideand a chiral sulfonyldiamine in a Henry reaction of (R)-2-phenylpropanal andnitroethane.193 Copper(II) complexes of chiral secondary diamines derived from
1,2-diaminocyclohexane catalyse reaction in 2-propanol at −30 ◦C in the presence ofHunig’s base, i-Pr2NEt: examples of high yield/ee/de are recorded.194 Combining
The Baylis–Hillman Reaction and its Morita-variant
The titanium-tetrachloride-promoted Baylis-Hillman reaction of methyl vinyl ketoneand acetaldehyde in the absence of base has been studied by DFT, carefully dissectingthe alternatives at each of the three main steps: chloride transfer to give a chloro-enolate, titanium-mediated aldol, and elimination of HCl or HOTiCl3.200
Brucine N -oxide and proline have been developed as a dual-catalyst system forasymmetric MBH reactions of vinyl ketones: the former activates the vinyl ketones toprovide enolates via conjugate addition, while the proline forms iminium intermediateswith electron-deficient aryl aldehydes.202
methyl vinyl ketone has been investigated by DFT for N -methylprolinol (75), a bifunc-tional catalyst. Of the two steps – C−C bond formation and hydrogen migration – thelatter is accelerated by water, leaving the former determining the rate and the stereo-chemistry.204
B3LYP calculations for this reaction and substitutes the MO6-2X DFT computationalmethod.205 The failure to accelerate the reaction with higher temperatures has beenexplained by VT (variable temperature) experiments and MP2 calculations: theequilibrium shifts towards the reactants even with moderate increases in temperature.The authors also examine two key alternative mechanisms for proton transfer:Aggarwal’s protic route and McQuade’s aprotic one. They are found to be typically
1 Reactions of Aldehydes and Ketones and their Derivatives 25
in competition, with the mechanistic balance depending on both the amount ofprotic species present and on the reaction progress (early or late stage). Phenol- andauto-catalysis are also accurately modelled.
A highly enantioselective reaction of isatins (76) yields 3-substituted 3-hydroxy-2-oxindoles (77): this is the first ketone/acrolein example of a catalytic asymmetricMBH. A chiral β-amino ether auxiliary with a pendant hydroxyquinoline gives eesup to 98% and high yields, in dichloromethane at −20 ◦C.206
A primary–tertiary diamine catalyses reaction of vinyl acetate with araldehydes,apparently via a bifunctional cooperative catalysis involving an enamine-quaternaryammonium intermediate.209
Amphiphilic N -alkylimidazoles catalyse reactions in water, without organicsolvent.210
An account of the roles of chiral phosphine organocatalysts of asymmetric MBHand related reactions emphasizes their multifunctionality.211
A chiral dinuclear cadmium amino acid complex is an efficient water-compatibleLewis acid catalyst for chemo-, regio-, and diastereo-selective allylation ofaldehydes.212
aldehydes with allyl trichlorosilanes, giving high ee and de and non-linear effects; thelatter suggest that two sulfoxides are coordinated to silicon in the transition state.213
A mild indium-mediated Barbier-type allylation of aldehydes using an allyl halidehas been reported using a simple chiral amino-alcohol: high yields and ees are obtained(and des when extended to crotylation), and a wide variety of other functionalityis tolerated. Carried out in dipolar aprotic media such as THF, with a pyridine asLewis base, the active allylating intermediate appears to be an allylindium(III) species.Indium(0) persists throughout the reaction, indicating that the indium halide by-productdisproportionates.218
The samarium Barbier reaction – the coupling of alkyl halides and ketones bySmI2 – is dramatically accelerated by HMPA. A kinetic and computational inves-tigation has been undertaken to pin down the cause. Although addition of HMPAincreases the reducing power of samarium(II), the key finding is that it activates thecarbon–halide bond.219
NMR and deuterium-labelling experiments have been used to explore themechanism of rhodium-catalysed coupling of allylic, homoallylic, and bishomoallylicalcohols with aldehydes and N -tosylimines.220 The reactions, which can involveisomerization of the alkenols and then give aldol- and Mannich-type products, requireactivation by a strong base (t-BuOK), which promotes routes via alkoxides ratherthan via rhodium hydrides.
An ene-type coupling of aldehydes and conjugated dienes gives dienyl homoal-lyl alcohols, using a Pd/diphosphine/Et3B catalytic system.221 The reaction occursselectively at the more electron-rich double bond of the diene.
Chiral benzylic trifluoroborate salts, Ar1Ar2C*(Me)–BF3− K+, react with aldehydes
A new compound, difluoromethyl 2-pyridyl sulfone (78) acts as a gem-difluoro-olefination agent for aldehydes and ketones.226 A fluorinated sulfinate intermediate(79) in the reaction is relatively stable: it is observable by 19F NMR and trappable withmethyl iodide. It loses sulfur dioxide to give the gem-difluoro-alkene and 2-pyridone.
N
SOO
F
H
FN
OS
O
OR1 R2
F FFF
R1 R2
O
R1 R2
(79)(78)
−
Formaldehyde and propene, and substituted variants thereof, are the subject ofa DFT study of carbonyl-ene reactions examining 12 Lewis acid catalysts.227 Thesubstituent effects observed are very different from those seen for the Diels–Alderreaction.
For a review of the HWE and Wittig reactions, see under ‘The Wittig Reaction’below .
Alkynylations
Reviews of asymmetric alkynylation cover enantioselective addition of terminalalkynes to aldehydes,228 catalysis by zinc triflate and two-point chiral ligands,229 and
Deuterium-labelling NMR studies have been used to explore the catalysis of directalkynylation of aldehydes using chiral ruthenium-bis(oxazolinyl)phenyl complexes.231
and alkynes has been achieved: a cyclopropenylidene ligand favours reaction at the lesshindered end of the alkyne, while use of an NHC reverses this,234 and a DFT studyhas examined nickel-catalysed reactions of this type: steric effects predominate forsimple alkynes, but a more complex behaviour is observed for enynes and conjugated1,3-diynes.235
The dilithium salt of a chiral BINOL catalyses alkynylation of ketones bytrimethoxysilyl-alkynes in fair to good ee.236
Benzils have been prepared from benzaldehydes using an NHC catalyst under metal-free conditions.237 The one-pot method uses an azolium salt and DBU in DMF at
28 Organic Reaction Mechanisms 2010
room temperature or below to form the benzoin, followed by addition of ethyl acetateand heating under air at 70 ◦C to oxidize to the benzil.
Viability of cyanide-catalysed benzoin condensation without protic assistance hasbeen shown in a DFT study to follow a mechanism similar to the original Lapworthproposal.238
As part of a mechanistic investigation of aldehyde umpolung via the use of NHCs,the keto form of the Breslow intermediate (80) has been synthesized, isolated, andpurified, being formed from a triazolylidene and propanal.239 With rigorous exclusionof oxygen, it can be studied by NMR, and addition of catalytic amounts of acid (TFAor para-tosic acid) do not result in detectible tautomerization to either its enaminolor enol forms. A second aldehyde can convert the intermediate (80) to a spirocyclicdioxolane (81), a ‘resting state’ in the catalysis. Although this reaction is reversible, theactivation energy of 67 kJ mol−1 (for the reverse) helps account for the sluggishnessof aliphatic aldehydes.
The asymmetric Michael addition continues as a very active field, particularly withproline-derived catalysts. An ‘amphibian’ organocatalyst (82), containing prolineincorporated into a hexahydropyrrolo[2,3-b]indole skeleton, catalyses addition ofaldehydes to nitroalkenes with high yield and de/ee up to 98/99%.242 Compound
(82) features a bowl-shaped conformation, high geometry control over an enaminewith efficient face-shielding, and a chiral pocket, allowing asymmetric reaction inboth water and organic solvents.
Complete enantio-pair sets of diastereomeric spiro-lactams and spiro-diamines (83;X = C=O, CH2; R = H, Boc, and the enantiomers at the spirocentre) have been
1 Reactions of Aldehydes and Ketones and their Derivatives 29
NH
N
NH
CO2HN
EtO2C
H
H
R
XN Ph
Me
N
Boc
NN
BF4−
S
O
O
(83)
(84)
(85)
(82)
+
prepared and isolated, all from l-proline, with absolute stereochemistry being deter-mined by X-ray crystallography. High yields and de/ee have been obtained for thetest reaction of addition of valeraldehyde to β-nitrostyrene. Thus the catalysts alloweither enantiomer of the syn-Michael product to be favoured, even though all catalystsare sourced from the one (readily available) enantiomer of proline.243
Recyclable chiral IL (84), derived from DABCO and l-prolinol, gives yields/de/eeup to 100/98/97% for both aldehyde and ketone substrates,244 while pyrrolidinyl sul-
(S)-Prolinol silyl ether (87) acts as a surfactant-organocatalyst at room temperaturein water containing 20 mol% formic acid and a catalyst loading of 2 mol%: the goodde/ee results achieved fall sharply if the dodecyl chain is omitted.247 Silylation closer
to the pyrrolidine (e.g. 88) is also highly effective.248
Mentions of other proline-based catalysts include (with de/ee): C3-symmetrictris-prolinamines (98/98%),249 proline-BINAP-sulfonimides with Brønsted acid co-
catalysis for addition to ketones (98/96%),250 a proline-BINOL thiophosphoramidite(98/99%),251 pyrrolidinyl-camphors in direct addition to aldehydes and ketones
30 Organic Reaction Mechanisms 2010
(96/99%),252 and a series of proline-derived catalysts optimized for addition ofoxyaldehydes (66/96%).253
As seen for aldols, the urea or thiourea moiety has been extensively used, oftenwith proline; for example, bifunctional catalyst (89a) can potentially donate two ureahydrogen bonds during addition of ketones to nitroalkenes, but it proved to be apoorer catalyst than benzyl-catalyst (89b) with only one urea NH.254 A DFT study
suggests that (89a) does indeed form a rigid complex with the nitro group of thesubstrate, but that this retards the approach of the enamine intermediate. The resultserves as a caution for approaches to catalyst design that merely maximize the numberof hydrogen bonds to the catalyst.
NNNH
O
R
(89a; R = H; 89b; R = Bn)
CF3
CF3H
Thiourea examples include (with yield/de/ee) a thiourea incorporating BINOL anda prolinamide for conjugate addition of ketones to alkylidene malonates without sol-vent at ambient temperature (95/98/99%),255 a thiourea with a chiral amine attached
case of [(diphenylmethylene)amino]acetonitrile (Ph2C=N–CH2–CN), a representativeC−H acidic Schiff base, and for benzylideneacetophenone (Ph–CH=CH–CO–Ph).263
A domino Michael/Henry reaction has allowed preparation of medicinally impor-tant bicyclo[3.2.1]octanes (e.g. 90) from achiral reactants, for example, β-nitrostyreneand phenyl cyclohexylcarboxylate-2,4-dione.264 The example contains four contiguous
stereocentres, including two quaternaries. Prepared with yield/de/ee of 93/98/94%, thereaction is catalysed by a thiourea (91) bearing a chiral cinchona alkaloid on one sideand a substituted phenyl on the other. Evidence for multiple activation of the reactants
1 Reactions of Aldehydes and Ketones and their Derivatives 31
(90)
(92)
O
PhO2C
NO2Ph HN
HN
S
N
N
OMe
H
F3C
CF3
N
R2
CHOR1
(91)
suggests hydrogen bonding between (i) the conjugate acid of the amine and the nitrogroup of the styrene, (ii) the thiourea and the Michael donor, and (iii) unusually, aphenyl C−H (arrowed) and the Michael donor.
A synthesis of Troger’s base from anilines and formaldehyde in an IL at ambienttemperature has thrown up two new putative intermediates, bicycle (93) and tricycle(94), both being identified by X-ray crystallography.267
1,1,3,5-Tetramethyl-4-oxo-2,6-diphenylpiperidinium triflate (95) has been preparedin four steps, starting with a Mannich reaction of benzaldehyde.268 It is an excellentcatalyst for Biginelli synthesis of hydropyrimidines from the building blocks of analdehyde, a β-dicarbonyl, and a (thio)urea. The possible intermediacy of N -acyliminesis discussed.
Anthranilic acids, salicylaldehydes, and alkyl isocyanides undergo a novel Ugi-type process to give 2-[{2-(alkylamino)-1-benzofuran-3-yliden}amino]benzoic acids(96).269 The high-yielding one-pot reaction, carried out in water, is proposed to involveinitial salicylidenimine production followed by isocyanide attack, leading to forma-tion of a nitrilium-amino-carboxylate intermediate, attack by phenol, and final aerialoxidation.
Multi-substituted cyclohexa-1,3-dienamines (97) have been prepared via amulti-component domino reaction of aryl ketones (Ar1COMe), aromatic aldehydes
32 Organic Reaction Mechanisms 2010
(94) (95)(93)
N+
N
Me
BF4−
N+
N BF4−
R
R
N
Me
Me
Me
N
O
Ph
Me
Ph
Me
MeMe
TfO−
+
ON
Y
N
OH
OX
R Ar2
NC
NH2
Ar1
CNCN
(96) (97)
(Ar2CHO), and malononitrile (NC−CH2–CN).270 Primary 1,2-diamine catalysis wasachieved with the simplest possible catalyst, 1,2-diaminoethane.
Pictet–Spengler condensation of phenethylamines (98; R = H, OMe) with car-bonyls has been achieved under mild conditions (DCM/ambient) to give tetrahy-droisoquinolines (99). Catalysed by calcium bis-1,1,1,3,3,3,-hexafluoroisopropoxide,Ca[OCH(CF3)2]2, the reaction is unremarkable for aldehydes but is unprecedented forunactivated ketones, which have previously required two steps: imine formation, thencyclization.271
(98) (99)
HO
R1
NH
HO
R1
R2 R3
O
R3R2
NH2
Ca[OCH(CF3)2]
Cyclic vinylogous acyl triflates (‘VAT’s’, e.g. 100) undergo addition of stabilizedcarbanionic nucleophiles to give a ketone aldolate intermediate (101), which under-goes ring opening to give an alkynyl-tethered ketone (102), still activated for furtherreaction via α-deprotonation.272 The process – dubbed ‘VAT-Claisen’ – differs fromthe classic Claisen because C−C bond cleavage is irreversible. Some labelling studies
1 Reactions of Aldehydes and Ketones and their Derivatives 33
(100) (102)(101)
TfO
O
TfO
O
O-
EWG EWG[1,2-addition]
EWGLi
(fast)
[fragmentation]
(slow)
and preliminary mechanistic details are reported in addition to practical examples thatshow the ease of the reaction when the electron-withdrawing group is an ester, aphosphonate, a phosphine oxide, etc.
Modified Knoevenagel condensation of malonic acid and aldehydes, usingN -methyl-morpholine as catalyst, gave (E)-β,γ unsaturated acids with high β,γ -regioselectivity and exclusive (E)-stereoselectivity.273
Other Addition Reactions
A computational study has compared hydration of acetone in the gas phase and inwater solvent: the former involves concerted processes avoiding zwitterionic transitionstates, whereas solvation in the latter allows hydrogen transfers to be asynchronous.274
Further investigations of Soai’s autocatalytic addition of diisopropylzinc to pyrim-idine aldehydes (103) to give highly enantiopure alcohol (104) in high ee from acatalytic quantity of (104) in very low initial ee, show intriguing results. An inversetemperature dependence on reaction rate is accompanied by a very long inductionperiod, which is longer at higher temperature. Changing from 298 to 263 K, the rateincreases 20-fold. A similar behaviour is observed over a range of concentrations,starting enantio-purities, and R groups and when the zinc alkoxide of (104) is usedas catalyst. Low-temperature NMR techniques including COSY, ROESY, and DOSY(diffusion spectroscopy) have been used to probe the species present, with the lasttechnique suggesting that a tetrameric zinc alkoxide and equilibria related to it can
New enantiopure pyridyl alcohols derived from terpenes contain conformationallyflexible biaryl axes: alkylzincation of the hydroxide then freezes the conformer equi-librium to give enantioselective catalysts of addition of dialkylzincs to benzaldehyde.2D-NMR and computations support the analysis.281
In a novel aryl coupling reaction, 2-phenylpyridine can be arylated (in the 2′-position:see 107)byanoxidativedecarbonylativecouplingofanaromaticaldehyde,ArCHO,usinga rhodium(I) catalyst and t-butyl peroxide as oxidant.295
DFT has been used to investigate intermediates in organo- singly occupied molecularorbital (SOMO) catalysis of α-arylation of aldehydes, focussing on the cyclized radicalcation intermediates.296 Metal-catalysed α-arylation of carbonyl compounds has beenreviewed (130 references).297
(F3C−SO3H), giving 1,1,1-triaryl-2,2,2-trifluoroethanes.298 The mechanism andsynthetic scope of the reaction has been studied, including competing side andintramolecular reactions.
For enantioselective addition of alkenyl and aryl boronates to chromene acetals, seeunder ‘Formation and Reactions of Acetals and Related Species’ above.
Addition of Other Organometallics, Including Grignards
While des in addition of chiral oxiranyllithiums to arylaldehydes are often low,completely stereoselective reactions can be achieved in suitably matched pairs oforganolithium and a ‘remote’ sulfinyl group on (S)-2-para-tolylsulfinylbenzaldehyde(108) to give 2,3-epoxy alcohols.299
1,3-dioxa-BF2 complexes (110) under mild conditions.300 Starting from an ethyl 3-oxopropanoate, the process yields 1,3-diketones (after cleavage of the boron).
(110)
N
O
NO OB
F F
OEtR1
O OB
F F
R2R1
R2-Li
(109) (111)
36 Organic Reaction Mechanisms 2010
A DFT study of the reaction of 1-propynyllithium (as a model for an sp organo-lithium) with formaldehyde has considered aggregation of the lithium reagent up tothe hexamer and the relative nucleophilicity of the sp/sp2/sp3 lithiated carbons bycomparing vinyl- and methyl-lithium.301 Nucleophilicity order may not follow theacidity order (sp > sp2 > sp3).
The possibility that Grignard reactions with carbonyl compounds can compete inthe presence of water, phenols, carboxylic acids, and other protic reagents has beentested, and moderate yields of Grignard adducts can be achieved, especially withallylmagnesium bromide and benzylmagnesium chloride.303 Although the effect maybe partly due to the protic species being scavenged by electrophilic magnesium species,this effect can be obviated by carrying out intramolecular competitions, that is, byhaving a carbonyl and hydroxyl present in one substrate.
Clean addition of Grignards, RMgX, to ketones has been achieved using a triplecatalyst/reagent system, ZnCl2·Me3Si–CH2MgCl·LiCl (10/20/110 mol%). Mechanis-tic investigation suggests that stabilized mixed salts [R(Me3Si–CH2)2Zn]− [Li]+[MgX2]m[LiX]n form in situ . These can act as catalytic alkylating agents throughincreased nucleophilicity in their anions, while the cation can act as a Lewis-acidicactivator of carbonyls. High yielding in THF at 0 ◦C in a few hours with minimalby-products, the reaction can be used not only for aldehydes (unsurprisingly) but alsofor aldimines (to give secondary amines).304,305
A 1 : 2 mole ratio of a Grignard and titanium tetraisopropanoxide has been used toalkylate or arylate aldehydes, with a BINOL catalyst giving ees >90%; the methodmay be a useful alternative to use of organozincs.306
Stepwise and concerted mechanisms have been examined by DFT for a simplediastereomeric aldehyde (112) undergoing Wittig reaction with triphenylphosphoniumylide (Ph3P=CH2) in THF, and in vacuo.310
A scandium carbene complex (113) has been prepared from a geminal dianionprecursor, [Ph2(S=)P–]2C2− (Li+)2, by salt metathesis on ScCl3(THF)3. TheX-ray structure and Natural Bond Orbital (NBO) analysis suggest it shouldbehave as a nucleophilic carbene, with double σ + π donation towards the metalcentre. Addition of benzophenone to the complex gives the expected alkene viaa ‘scandia-Wittig’ reaction, further confirmed by the trapping of a rare μ3-oxo-Sc
1 Reactions of Aldehydes and Ketones and their Derivatives 37
(112)
∗ ∗ H
ON
PS
Sc
S P
Cl
Ph
Ph
Ph
Ph
Py
Py
PN
Y
N P
Ph
Ph
Ph
Ph
TMS
TMS
(114)(113)
THF
R
species.311 A new but related yttrium carbene (114; R = CH2SiMe3) has beencharacterized by X-ray crystallography. Reaction with benzophenone gives anadduct (114; R = OC(CH2SiMe3)Ph2). However, it does not quite behave as an‘yttria-Wittig’ intermediate, . . . but it does effect regioselective ortho-C−H activationand subsequent C−C and C−O bond-forming steps give iso-benzofurans andhydroxymethyl-benzophenones.312
An equilibrium between a phosphonium dienolate (115a) and a vinylogous ylide(115b) has been described. In reactions between ethyl 2-methyl-2,3-butadieneoate[H2C=C=C(Me)–CO2Et] and aryl aldehydes using 1 equiv. of a trialkylphosphine,these intermediates are formed, with the balance depending on the presence or absenceof a Lewis acid and on the nature of the phosphine. In one case, a rare vinylogousWittig olefination is observed, while the other proceeds to vinylogous aldol additionvia an unusual 1,2-aryl phosphorus-to-carbon migration.313
(115a) (115b)
CO2EtR3P CO2EtR3P+
−
+
−
Ruthenium-catalysed synthesis of the alkenes by decarbonylative coupling of alde-hydes with alkynes has been described in both inter- and intra-molecular versions.314
Hydrocyanation, Cyanosilylation, and Related Additions
An unusual reversal of enantioselectivity in the proline-catalysed α-amination of alde-hydes with diethylazodicarboxylate (DEAD) is observed on addition of tertiary aminessuch as DBU, but the mechanistic cause is as yet unclear.315
Amination of aldehydes in water has been modelled using MO moleculardynamics simulations on the formaldehyde/ammonia reaction: H2C=O + NH3 →[H3N+–CH2–O− ?] → H2N–CH2–OH.321 Two hundred water molecules have beenexplicitly used in the calculations, comparing the direct (concerted) versus stepwisemechanisms, with the results favouring the latter (i.e. reaction does occur via thezwitterion, H3N+–CH2–O−).
A kinetic study of three aluminium-based BINOL catalysts of asymmetric additionof TMSCN to benzaldehyde shows orders of one and zero in reactants, respectively.326
1 Reactions of Aldehydes and Ketones and their Derivatives 39
reactants is outlined and extended to a magnesium-based catalyst. Control experimentsmonitored by NMR indicate that the rate independence of the aldehyde concentration isdue to its involvement only after the rate-determining step rather than the alternativepossibility of a catalyst-aldehyde complex at constant concentration (i.e. saturationkinetics).
Chiral manganese(II) bis-salen complexes catalyse cyanohydrin formation fromaldehydes with sodium cyanide in up to 99% ee.327
linked, allow asymmetric cyanation of aldehydes with catalyst loadings as low as0.005 mol%328,329; the latter reports up to 99% yield and 97% ee and turnovers
A simple NHC catalyst promotes a new intramolecular cross-coupling of aldehyde-nitriles (121) to give access to 3-aminochromones (122).331
(121) (122)O
O
R
O
O
R
NH2N
Hydrosilylation, Hydrophosphonylation, and Related Reactions
Progress in the application of NHC complexes of metals to the hydrosilylation ofketones has been reviewed.332
In a copper-catalysed hydrosilylation, a bowl-shaped phosphorane catalyst accel-erates reduction of bulky ketones preferentially, to the point of leaving aldehydesuntouched.333
α-Aminophosphonic acid derivatives have been prepared diastereoselectively byhydrophosphonylation of N -diphenylphosphinylimines, R–CH=N–P(=O)Ph2, using(R,R)-TADDOL-phosphite (123), derived from tartaric acid.341
In a kinetic study of the effect, if any, of the critical phenomena on reaction mecha-nism, iodination of acetone in isobutyric acid–water mixtures shows pseudo-zero-orderkinetics and a critical slowing down, but the mechanism is not affected by criticality.342
2-Adamantanone (124), when deprotonated in the gas phase, gives its β-enolateanion (125), a species that can also be independently prepared if the 4-TMS deriva-tive of the ketone is desilylated with fluoride.343 DFT studies suggest that the orderof stability of the conjugate bases of (124) – that is, the ‘positional’ anions – isβ > γ > α > δ. An attempt to generate the γ -enolate (by loss of carbon dioxide froma carboxylate in the γ -position) only yielded the ring-opened α-enolate isomer (126).
A review examines the scope for extending the reactivity of enolates from viny-logation to alkynylogation.344 A wide-ranging review examines metal enolates: theirstructure and spectroscopy and their role in many reaction types.345
A DFT study of keto-enol tautomerism of 1-phenylazo-2-naphthol and related com-pounds indicates that the quinone form is generally more stable and is further stabilizedby electron-withdrawing groups. Solvent effects are small.346
A new protocol for intramolecular stereoselective protonation of enolates derivedfrom aldehydes has been reported.347
has been accessed via vacuum-UV photo-ionization. Gas-phase IR spectra of clusterscontaining a few molecules generated in this way have been correlated with IR spectracalculated using Gaussian™. Both proton-relay and ‘catch-and-release’ mechanismsare considered, with calculations favouring the latter.348
α-Halogenation, α-Alkylation, and Other α-Substitutions
A proline-functionalized chiral IL has been employed in asymmetric α-alkylation ofketones, giving yield/de/ee up to 99/98/87%.349
Levulinic acid and its esters (MeCOCH2CH2CO2R; R = H, Me, Pr, Bu) brominatein the 3-position, predominantly, in imidazolium ILs, using molecular bromine. Inorganic solvents, 5-bromination is the major route.350 Small, variable amounts of
1 Reactions of Aldehydes and Ketones and their Derivatives 41
3,5-dibromo-product are isolated in both solvent types. The IL may help equilibratetowards the thermodynamically stable 3-product: transferring a product mixture fromorganic solvent to IL causes a net shift (in the absence of bromine). The IL cation mayalso favour equilibration towards the more stable internal enol. Addition of urea to theIL switches the balance back towards the 5-product, possibly by hydrogen bonding tothe carbonyl, causing disruption of interactions with the IL.
The use of molecular iodine to effect mild and metal-free α-iodination of carbonylsystems has been reviewed, emphasizing its dual role: it can catalyse enolization, aswell as the more well-known subsequent reaction with the enol.351
Functionalized chiral ILs derived from proline catalyse SN1 α-alkylation of alde-hydes and ketones with yield/de/ee up to 99/98/97% over a wide range of carbonyltypes.354
Aldehydes have been α-alkylated by propargylic alcohols using a cooperative strat-egy of organocatalyst and ruthenium complex, in high ee.359
A useful preferential activation of a C−F bond over a C−I bond has been achieved,reacting trifluoromethyl iodide with the lithium enolate of an α-substituted carbonylcompound. The latter can be a ketone, ester, or amide, and −CF2I is added exclusivelyat the α-carbon (in preference to −CF3) in most cases.360
Oxidation and Reduction of Carbonyl Compounds
Regio-, Enantio-, and Diastereo-selective Reduction Reactions
A dynamic kinetic resolution in the hydrogenation of racemic α-aryloxyketonesgives ee/de up to 99/98%, using a chiral ruthenium complex as catalyst.364
The kinetics of the Meerwein–Ponndorf–Verley reduction of a range of aldehydesand ketones have been measured, using boron triethoxide catalyst.370 Aliphatic sub-strates, but not aromatics, were reduced at room temperature. The reaction is alsochemoselective, in that unsaturation in the substrates is not reduced.
Ketones have been reduced under hydrothermal conditions in the presence ofNaOH at 300 ◦C, using formic acid for transfer hydrogenation; catalysis by water isconsidered.371
Oxidation Reactions
Sulfides are poor catalysts of sulfonium-ylide-mediated methylene transfer to aldehy-des, for example, conversion of benzaldehyde to styrene oxide. Ylide formation is theproblematic step, and a new protocol uses methyl triflate to alkylate cyclic thiolanes,to allow aldehyde epoxidation. An asymmetric version has also been trialled.372
example, they are oxidized to esters organocatalytically under mild conditions, usingcooperative catalysis by an NHC to chemoselectively acylate in the presence of amines.Yields are high, and typically ester formation exceeds amide by >99 : 1.373 Aldehydes
1 Reactions of Aldehydes and Ketones and their Derivatives 43
with electron-withdrawing groups, including heterocyclic aldehydes, can be directlyconverted to esters in aqueous alcoholic solution, using I2/NaNO2.374 Lanthanide metalamides catalyse convenient direct synthesis of amides from aldehydes; cyclopentadi-enyl ligands are not required.375
1,3-Dicarbonyls have been oxidized by hydrogen peroxide, using a quaternaryammonium iodide catalyst.376 Cerium(IV) catalyses oxidative coupling of 1,3-dicarbonyls in acetonitrile/methanol/water mixtures, giving 1,4-diketone derivativesin high yield.377
conditions, performing 1,2-dihydroxylation of alkenes, oxidation of aldehydes andketones, and also regeneration of such carbonyl functionalities from their oximes.378
A supramolecular micellar effect has been claimed to explain a diastereo- andenantio-selective Baeyer–Villiger oxidation of cyclobutanones with hydrogen peroxideand a cobalt(salen) catalyst in water: the system is inactive in organic solvents.379
Kinetics of the oxidation of 36 monosubstituted benzaldehydes by morpholiniumchlorochromate has been studied in a range of organic solvents.380
The kinetics of oxidation of substituted benzaldehydes by benzyltrimethylammo-nium fluorochromate has been studied in protic solvents at 303 K.381 Rates are firstorder in substrate, oxidant, and hydronium, and Exner and Hammett plots have beenconstructed and thermodynamic parameters extracted from results at four temperatures.
For an oxidative decarbonylative coupling of aldehydes, see under ‘Arylations’above.
Atmospheric Reactions
For the reaction of ozone with formaldehyde, the singlet and triplet potential energysurfaces have been explored by DFT.382 Reaction proceeds mainly via singlet states,leading to HCO and HO3.
The possibility that a single water can catalyse reaction of acetaldehyde andhydroxyl radical under tropospheric conditions has been contraindicated bycomputation.383
Quadropole MS and FT-IR techniques have been used to measure the rates ofreaction of chlorine atoms with acetone in the gas phase over a range of temperatureand pressure.384 Hydrogen abstraction to give HCl predominates, with formation ofacetyl chloride contributing >0.1% of the reaction flux.
Other Reactions
In a rhodium-catalysed C−H activation/β-carbon elimination strategy, the strainenergy of cyclobutanes and azetidines has been exploited to insert a tetheredaldehyde, expanding four-membered rings to eight-membered enones.385
Claims for synthesis of diazirinone (128) – a metastable adduct of N2 and CO –have been challenged.386
O-protected glycolate derivatives of N -1-(1′-naphthyl)ethyl-O-t-butylhydroxyl-amine (129) have been alkylated to give α-substituted derivatives in high de;
44 Organic Reaction Mechanisms 2010
(128)
(130; R3 = H, Me)(129)
(131)
N
NO
NO
OR1
But
(i) KHMDS, R2-X;R3 ∗∗ R1
R2
O
O
N
N
(ii) LAH (or MeLi)
subsequent reduction cleaves off enantiopure α-alkoxy-, α-substituted-β-alkoxy-, andα,β-dialkoxy-aldehydes (130; R3 = H).387 Useful alternative products have also been
obtained via methyllithium cleavage or aldol sequences.A new pentacycle, chromeno[2′,2′ : 4,5]imidazo[2,1-α]isoquinoline (131), has been
prepared from an immonium salt (isoquinoline quaternized with chloroacetonitrile)and salicylaldehyde, via a novel cascade Krohnke condensation.388
Vinylidenecyclopropanes (132) undergo a novel domino carbolithiation with conju-gated ynones when treated with LDA in THF, to give hydroxy-diyne-dienones (133).Control experiments have been used to probe the mechanism.389
(132) (133)
R3
R4
R2
R1
O
R5
R5HO
•
R2
R1R3
R3
O
R5
LDA/THF/−78 °C
β-Hydroxy and β-amino esters, R1–∗CH(X)–CH2–CO2R2 (X = OH, NHTs) havebeen prepared in high yield and ee from enals, R1–CH=CH–CHO, using a combina-tion of amino- and NHC-catalysis, with low loadings of the two catalysts, in a one-potprocedure tolerant of air and moisture.390
5-Hydroxy-1,3-diketones (134) have been prepared from reaction of an acid chlo-ride (RCOCl) with 2 equiv. of acetone in the presence of LiHDMS.392 Subsequentcyclization yields 2,3-dihydro-4H -pyran-4-ones (135) when mediated by anhydrous
1 Reactions of Aldehydes and Ketones and their Derivatives 45
(135)(134)
R
O O OH
O
R
O
indium(III) chloride. In situ FT-IR spectroscopy has proved useful in exploring thelatter reaction. Dry conditions are essential, or else InCl3 precipitates as its trihydrate.
Smiles rearrangements of PhO(CH2)nO− anions, including the n = 3 case that pro-duces phenoxide, ethylene, and formaldehyde, have been studied in the gas phase by18O-labelling studies and by computation.393
Natural secondary α-amino acids (136) have been coupled with alkynes in analdehyde- or ketone (137)-induced tandem decarboxylation, with the loss of CO2
and H2O.394 In formation of the amine-alkyne products (138), the carboxylate carbonhas been replaced by the alkyne, and the nitrogen has been ‘alkylated’ by the car-bonyl reactant. Copper(I) iodide is a catalyst, presumably via a copper acetylide. Theregioselectivities observed have been investigated by computation.
(137)(136) (138)
R1
NH
CO2H
R2
+O
R4R3
R1
N
R2
R3 R4Ar
H Ar
Favorskii rearrangement of α,α′-dibromodibenzyl ketone has been studied in thegas phase by tandem MS and theoretical methods, using alkali cations.395
Metal triflates catalyse the oxa-Pictet–Spengler reaction of aldehydes withβ-arylethanols to give isochroman rings.396
A rhodium-catalysed hydroacylation of cyclopropenes with aldehydes, catalysed bychiral ferrocenyl-phosphine auxiliaries, efficiently desymmetrizes them. This use ofcyclopropyl strain energy to activate a C−H bond proceeds with ees often >99% anddes of up to 95%, and high yields.397
An attempted hydroamination reaction between 2-(2-phenylethynyl)aniline and ace-tone catalysed by an iridium complex yielded an unexpected vinyl indole derivative.398
Labelling studies, isolation of an intermediate, and DFT calculations have been usedto identify a likely mechanism via an imine intermediate.
A DFT study of the reactions of representative aromatic and aliphatic nitroso com-pounds with formaldehyde to give hydroxamic acids has looked at the gas phase(where a stepwise mechanism predominates), and at acetonitrile and water solvents,where solvent effects are found to be modest.399
A kinetic study of the reaction of arylnitroso oxides and methyl vinyl ketone inacetonitrile at 295 K finds that only the trans-oxides react; a Hammett ρ value of1.11 ± 0.08 was determined.400
46 Organic Reaction Mechanisms 2010
A DFMBA (a difluoromethylbenzylamine such as 3-tolyl-CF2–NEt2), facilitatesregioselective synthesis of β-fluoro-α,β-unsaturated ketones by deoxyfluorination ofunsymmetrical β-diketones.401
Pyrrolo[a]indoles can be prepared by acid-catalysed condensation of acetone oracetophenones with activated 3-substituted-4,6-dimethoxyindoles (139).402
For other mentions of Prins-type reactions, see under ‘Formation and Reactions ofAcetals and Related Species’ above.
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