Imines and their N-Substituted Derivatives: Oximes and their O-R Substituted Analogues

3.11 Imines and their N-Substituted Derivatives: Oximes and their O-R Substituted Analogues GRAEME M. ROBERTSON Glaxo Research and Development, Stevenage, UK 2[00[0 OXIMES AND THEIR DERIVATIVES 2[00[0[0 Oximes of Aldehydes and Ketones 2[00[0[0[0 Preparations of oximes from carbonyl compounds 2[00[0[0[1 Preparations of oximes from noncarbonyl compounds 2[00[0[0[2 Miscellaneous methods for the preparation of oximes 2[00[0[0[3 a\b!Unsaturated oximes 2[00[0[0[4 Cyclic oximes 2[00[0[1 O!Carbon!substituted Oximes 2[00[0[2 Nitrones and Related Derivatives 2[00[0[2[0 Acyclic nitrones 2[00[0[2[1 Cyclic nitrones 2[00[0[2[2 Miscellaneous nitrone derivatives 2[00[0[3 O!Chalco`en!substituted Oximes 2[00[0[4 O!Arsenic!substituted Oximes 2[00[0[5 O!Silicon!substituted Oximes

314 314 314 315 316 318 329 329 320 320 323 324 324 324 325

2[00[1 N!HETEROATOM ANALOGUES OF OXIMES 2[00[1[0 Sulfur Analo`ues 2[00[1[0[0 Sulfenimines 2[00[1[0[1 Sul_nimines 2[00[1[0[2 Sulfonimines 2[00[1[1 Phosphorus Analo`ues 2[00[1[2 Nitro`en Analo`ues 2[00[1[3 N!Silicon!substituted Imines

325 325 325 326 326 328 328 328

2[00[0 OXIMES AND THEIR DERIVATIVES 2[00[0[0 Oximes of Aldehydes and Ketones Oximes are important functional groups in organic chemistry\ but in particular they feature as protecting groups for carbonyl groups and as intermediates in the Beckmann rearrangement ð77OR"24#0\ B!78MI 200!90Ł[ Unlike imines the geometric isomers of oximes are isolable and the measurement of syn! and anti!oximes by chemical and especially NMR methods has been reviewed ð63MI 200!90Ł[ 2[00[0[0[0 Preparations of oximes from carbonyl compounds Oximes are customarily prepared from the corresponding carbonyl compound\ and the prep! aration of oximes by the addition of hydroxylamine to aldehydes or ketones has been reviewed 314

315

Oximes and their O!R Substituted Analo`ues

ðB!61MI 200!90Ł[ Derivatives of hydroxylamine\ e[g[\ NH1OSO2H and HON"SO2Na#1\ have also been used[ For hindered ketones\ such as hexamethylacetone\ high pressures ð48JA1040Ł or prolonged reaction times may be necessary[ It has also been shown ð48JA362\ 53MI 200!90Ł that the rates of formation of oximes are at a maximum when the acidity of the mixture is about pH3[ Ketones can also be converted into their oximes by a trans!oximation reaction[ Other oximes such as ethyl a!"isopropylidene#aminooxylpropionate ð54JOC0296\ 62OSC"4#0920Ł\ and aldehydes or ketones can be converted into oximes using acetone oxime in acetic acid ð78JPR769Ł[ 2[00[0[0[1 Preparations of oximes from noncarbonyl compounds Oximes may be prepared from noncarbonyl compounds via redox reactions of other N0O species[ Thus the reduction of nitroalkenes is a useful method for the preparation of oximes\ and a wide range of reagents "typically transition metal!based catalysts#\ and conditions have been developed[ Some of the methods are quite general\ whereas others such as reductions with zinc in acetic acid ð33JA241Ł\ or Na1SnO1 ð74TL5902Ł are restricted to the synthesis of ketoximes[ a\b!Unsaturated nitroalkenes are readily reduced to aldoximes in high yield by tin"II# chloride at room temperature ð77SC582Ł[ Ketoximes can be formed similarly by the reduction of a\b!unsaturated nitroalkenes with Na1SnO1 "produced in situ from aqueous SnCl1 and aqueous NaOH# ð74TL5902Ł[ However\ these conditions are not suitable for the preparation of aldoximes[ Corresponding reac! tions carried out under acidic ð59CB21Ł or neutral ð74CL132Ł conditions result in the formation of a!substituted oxime derivatives[ Thus SnCl1 in the presence of an alcohol or thiol gives high yields of the corresponding a!alkoxy! and a!alkylthiooximes\ respectively ð74CL132Ł[ The latter compounds can also be prepared by metallation of saturated oximes with lithium diisopropylamide\ followed by reactions of the resulting O\C!dianions with diphenyl disul_de ð74OPP072Ł[ a\b!Unsaturated nitroalkenes are also readily converted into ketoximes\ by reduction with chro! mium"II# chloride ð74SC0214Ł[ Unfortunately the corresponding reductions of a!unsubstituted nitroalkenes to aldoximes are accompanied by signi_cant polymerization[ a\b!Unsaturated nitro! alkenes are reduced to the corresponding oximes by sodium hypophosphite in the presence of palladium ð75SC80Ł whereas a\b!unsaturated nitroalkanes are readily reduced to the corresponding oximes via palladium!assisted transfer hydrogenation with ammonium formate ð89SC1342Ł[ a\b! Unsaturated nitroalkanes can also be reduced to oximes with leadÐacetic acid in DMF ð89SL366Ł[ Reductions of nitroalkenes with hydride reagents can be capricious\ leading to over!reduction and to mixtures of products ð74JOC022Ł[ However\ zinc borohydride reduces a!substituted conjugated nitroalkenes to the corresponding a\b!unsaturated oximes ð80TL2468Ł\ although nona!substituted analogues undergo 0\3!reduction to the corresponding nitroalkanes[ Electroreductions of nitroalkenes are also possible using an aqueous perchloric acidÐdichloro! methaneÐdioxaneÐlead electrode system followed by a hydroxylamine hydrochlorideÐsodium acet! ate workup to yield mixtures of ketoximes and ketones ð72CL596Ł\ or ketoximes and ketals ð72JOC1092Ł depending on the conditions used[ Examples of conjugate additions to a\b!unsaturated nitro compounds are rare[ However\ the conjugate addition of lithium organocuprates has been observed in the reactions of both 0!"3! chlorophenyl#!1!nitropropene ð64TL2480Ł and 2b!acetoxy!5!nitrocholest!4!ene ð72CC49Ł[ Aliphatic nitro compounds that contain an a!hydrogen can be reduced to oximes with a range of reagents\ such as zinc dust in AcOH ð28JA2083Ł\ Co0CuII salts in alkanediamines ð62JOC2185Ł\ CrCl1 ð69JCS"C#0071\ 63S0Ł\ and "for a!nitro sulfones# NaNO1 ð63S38Ł[ Tin"II# complexes prepared by treatment of SnCl1 or Sn"SR#1 with appropriate amounts of RSH and Et2N reduce primary and secondary aliphatic nitro compounds to oximes ð89CL524Ł[ Secondary nitro compounds are also converted into oximes by reaction with KH and TMS!TMS or MeS!TMS in THF or 0\3!dioxane "Equation "0## ð89T6302Ł[ Primary nitro compounds are converted into the corresponding thio! hydroximates under these conditions[ Secondary nitroalkanes are deoxygenated to the cor! responding ketoximes\ under mild and neutral conditions\ by treatment with iodotrimethylsilane and hexamethyldisilazane ð72JOC1655Ł[ In contrast\ primary nitroalkanes are converted into nitriles\ and tertiary nitroalkanes give the corresponding iodoalkanes via cleavage of the carbonÐnitrogen bond[ NO2 R1

R2

KH, (TMS)2S, THF, ∆

N R1

OH (1) R2

316

Oximes

Methods available for the direct conversion of aliphatic nitro compounds into oximes in the presence of acid!sensitive groups\ or other reducible functionalities\ are relatively rare[ The best conditions for such systems is reduction in carbon disul_de\ in the presence of triethylamine ð76T440\ 89S222Ł[ Alternatively\ nitro compounds can be converted into oximes photochemically by irradiation in acetone in the presence of Et2N "Equation "1## ð78S195Ł[ a!Nitroketones can also be converted into the corresponding oxime\ by irradiation in 1!propanol ð62BCJ2087Ł[ Primary aliphatic amines that lack an a!hydrogen can be oxidized to oximes under acidic conditions\ via an inter! mediate nitroso compound ð59CB021Ł[ NO2 R2

R1

N

hν, Et3N, acetone

R1

OH (2) R2

Homologated oximes can be obtained in good yields from nitro compounds after activation with N\N!dimethylchloromethyleniminium chloride followed by treatment with a Grignard reagent "Scheme 0# ð72CL0426Ł[ Alternatively\ homologated ketoximes can be prepared via carbonÐcarbon bond formation by regioselective attack of Grignard reagents at the a!position of aci!nitro com! pounds activated by Vilsmeier|s salt in the presence of copper"I# iodide as a catalyst ð72CL0426Ł[ Since aci!nitro compounds are available by the treatment of nitro compounds with n!butyllithium\ this method provides an indirect route for the conversion of nitro compounds into homologated ketoximes[ +

BuLi, THF

R1

R1

NO2

O–

DMF, (COCl)2, CH2Cl2

O– Li+ R2

Me R1

N

N

O

N

CuI, R2MgX, THF

+

Me

Cl–

R1

N OH

Scheme 1

2[00[0[0[2 Miscellaneous methods for the preparation of oximes Metallations of oximes\ and in particular aldoximes\ have been the subject of several studies\ and the resulting anions can be alkylated in high yield ð73TL152Ł[ Anions generated from trimethylsilyl ethers of methyl ketoximes undergo rearrangement with 0\3!migration of the silyl moiety^ this sequence is reversed in a thermal 0\3!migration of silicon from carbon to oxygen ð73TL2382Ł[ Nontertiary carbon atoms that are activated by an electron!withdrawing group can be nitrosated to provide oximes ðB!77MI 200!90Ł[ The initially formed C!nitroso compound is not stable and isomerizes rapidly to give the more stable imine[ The formation of an oxime is a classical means of derivatizing a carbonyl compound[ This transformation can also be applied to a!ketocarboxylate systems\ and an example is found in the synthesis of a!alkoximinocarboxylic acids from a!keto!thiolic acid esters and alkoxyamines ð73JAN421Ł[ Alkylnitriles can be converted into the corresponding a!"tosyloxyimino#alkylnitriles by nitrosation with freshly distilled nitrosyl chloride in chloroform\ and subsequent O!tosylation ð72OPP30Ł[ Quinone monooximes can be prepared from phenols by photolysis of equimolar amounts of the phenol and N!nitrosodimethylamine in dioxane ð74JA2227Ł[ This procedure involves a dual proton and energy transfer process utilizing the enhanced acidity of single!state phenols to cause photo! dissociation of the N!nitrosodimethylamine[ The di}erent methods for the synthesis of a!hydroxylaminooximes\ their properties and their use in heterocyclic synthesis\ have been reviewed ð75S693Ł[ a!Hydroxylaminooximes have a number of distinctive properties associated with the vicinal reactive groups[ They have been utilized in the synthesis of four!\ _ve!\ and six!membered heterocyclic compounds\ with a special emphasis on N!oxide analogues and are also important as metal chelators[ Chiral a!hydroxyoximes are available in high optical purity via resolution using "0R\ 1R#!"−#!0\1!cyclohexanediamine as the resolving

317

Oximes and their O!R Substituted Analo`ues

agent ð80CL652Ł[ a\b!Unsaturated carbonyl compounds are converted directly into the cor! responding a!hydroimino carbonyl compounds upon treatment with butyl nitrite and phenylsilane in the presence of a catalytic amount of N\N?!bis"1!ethoxycarbonyl!2!oxobutylidene# ethylenediaminatocobalt"II# complex "eobe# "Equation "2## ð80BCJ1837Ł[ O

O

Co(eobe)2, PhSiH3, BuONO, THF

R

N

OH (3)

R

The synthesis of aldohydroximino lactones via oxidations of sugar oximes have been reported ð74HCA1143Ł[ The oxidations were e}ected by manganese dioxide\ or by mercury"II# acetate and oxygen in the presence of cuprous chlorideÐpyridine[ Oximes have been generated by electrocyclic ring!opening reactions involving four!membered cyclic nitrones "N!hydroxy!0\1!dihydroazetes# following treatment with potassium t!butoxide "Scheme 1# ð75RTC092Ł[ R1

+

O–

R1

N

O– N

KOBut

R2

R2

R3

R1

R3

R1

NOH CONEt2

R2

NH4Cl (aq.)

+ CONEt2 K

CONEt2

+

NOH R3

R2

R3

CONEt2 Scheme 2

In the steroid series\ 5!nitro!alkene derivatives have been shown to undergo facile reactions with ammonia\ methanol\ and zinc to a}ord exclusively the oximes of the corresponding 5!keto!steroids ð73IJC"B#790Ł[ Cyclic ketones can be cleaved by treatment with NOCl and an alcohol in liquid SO1 to give v!oximinocarboxylic acids "Equation "3## ð48JA4140Ł[ O

CO2Et

NOCl, EtOH, SO2

(4)

N

HCl

OH

C!Alkylations or arylations of aldoximes have not been widely reported[ The only examples of both alkylation ð75S352Ł and arylation ð43JCS0186Ł involve homolytic reaction of free C!radicals[ Thus aldoximes are C!arylated e.ciently by decomposition of arenediazonium salts ð75S352Ł\ and aldoximes are converted into ketoximes using a mixture of a peroxy ester and a cycloalkane or ether as the C!alkylating agent ð75S352Ł[ Monosubstituted ketene O!alkyl!O?!silylacetals\ unlike their disubstituted analogues\ react with nitric oxide or isoamyl nitrite in the presence of TiCl3\ to give a!ketoxime esters "Equation "4## ð77S794Ł[ This method permits the introduction of a nitrogen substituent at the a!carbon of the parent carboxylic ester[ a!Ketoxime esters can also be prepared from electron!de_cient nitroalkenes via formation of cyclic nitronic esters intermediates followed by their fragmentation by a catalytic amount of base "Equation "5## ð77BCJ350Ł[ O

R1

R2

N

C5H11ONO, TiCl4, CH2Cl2

(5)

O-TMS

Ar CO2Me

O

CO2R2

R1

Ar R1 R2O

OH

N

+

O–

NaOMe, THF

R1

CO2Me N

OH

(6)

318

Oximes

Nitronate salts "RCHNO1Na# act as precursors of hydroxynitrilium ion equivalents\ and react with aromatic compounds under acidic conditions to give the corresponding oximes via protonated nitronic acids ð78TL4652Ł[ The a!methyl groups of oximes can be functionalized regiospeci_cally via a cyclopalladation reaction with sodium tetrachloropalladate to form the dimeric organopalladium species "0# ð74CC015\ 74T588Ł[ A variety of b!functionalized products can then be prepared via subsequent func! tionalization of the C0H bond "Scheme 2#[ For 1!disubstituted cyclohexanone oximes\ A"0\1# strain dominates and subsequent reactions lead to the selective functionalization of the smaller 1!substituent[ HO

N

Na2PdCl4, NaOAc, EtOH

R1 R2

HO

Cl N

Pd

R2

R3

HO

PPh3

R1

R3

Cl N

Pd PPh3

R1 R3

R2

2

(1) i, Ac2O, pyridine ii, Pb(OAc)4 iii, NaBH4

pyridine

HO

N

Cl

R2

R3

R1

HO i, Cl2, CCl4 ii, NaCNBH3

Cl N

Pd py

R1

HO

OAc

R1

ii, NaBH4, 1M NaOH

R2

N

i, Pb(OAc)4, AcOH

R2

R3

R3

Scheme 3

The initial product of the addition of NOCl to alkenes is a b!chloro nitroso compound\ and\ if the carbon bearing the nitroso group also has a hydrogen atom\ isomerization occurs to give a!halo oximes ð57RCR432Ł[ Procedures for the synthesis of 0\2!dioximes have been reviewed ð80OPP482Ł[

2[00[0[0[3 a\b!Unsaturated oximes Substituted styrenes are converted regiospeci_cally into ketoximes through reaction with ethyl nitrite in the presence of a cobalt complex and BH3− ion "Equation "6## ð77JOC3786Ł[ The reaction proceeds via the formation of an alkylcobalt intermediate and subsequent reaction with ethyl nitrite[ Catalytic nitrosations of styrene derivatives could become a useful method for the synthesis of oximes following the report that the catalyst ðCo"DMGH#1"py#ClŁ promotes the regioselective hydronitrosation of styrene to give acetophenone oxime ð73CC178Ł[ Nitronate salts\ from nitro! methane or nitroethane\ react with aromatic compounds in acidic media to yield aromatic oximes ð80BSF629Ł[ Reductive condensations of trichloromethylarenes with hydroxylamines in pyridine also provide a route to aryl oximes "Equation "7## ð80T336Ł[ N R

EtONO, ClCo(DH2)py, Et4NBH4, C6H6

OH (7)

R

CCl3

NH2OH, py, ∆

N

OH (8)

1\2!Dioximinopiperazines are formed from the additions of 0\1!diamines to dichloroglyoxime in methanol ð74H"49#4012Ł[

329

Oximes and their O!R Substituted Analo`ues

Allylic nitro compounds are converted into allylic oximes using CS1 under solidÐliquid phase! transfer conditions with K1CO2 as the base "Equation "8## ð89S222Ł[ This method complements the related procedure of Barton et al[ for the reduction of aliphatic nitro compounds to oximes in CS1 with Et2N as the base ð76T440Ł[ R

NO2

CS2, K2CO3, PhCH2NEt3Cl

R

N

H2O, CH2Cl2

(9)

OH

"E#!1!Hydroxyimino!1!arylacetonitriles\ which are useful as synthetic blocks in peptide protecting group chemistry\ can be synthesized from styrenes via cycloaddition reactions to 3!azido!2!aryl! furazan!1!oxides\ followed by stereoselective photolysis in EtOH:CH1Cl1 "Scheme 3# ð89BCJ0732Ł[ Ar Ar

hν, EtOH, CH2Cl2 +

18-crown-6, AcOH

Ar

N3

NaNO2, NaN3 –O

N

NC

N O

N OH

Scheme 4

2[00[0[0[4 Cyclic oximes Relatively hindered a!chloronitroso compounds\ such as "1#\ can undergo fragmentation followed by ring closure in an overall sequence which leads to a ring expansion and the formation of cyclic oximes "Scheme 4# ð75RTC11Ł[ Cl

O N

Cl

Me3Al, n-C6H14, –80 °C

HO

N

H2O

Me3Al, n-C6H14, –80 °C H2O

N OH

(2) Scheme 5

2[00[0[1 O!Carbon!substituted Oximes Oximes can be smoothly alkylated using alkyl halides or sulfates[ N!Alkylation is a possible side reaction\ leading to a nitrone ðB!77MI 200!90Ł[ The relative yields of oxime ether versus nitrone depend on the nature of the reagent used\ the con_guration of the oxime\ and on the reaction conditions ðB!72MI 200!90Ł[ For example\ anti!benzaldoximes give nitrones\ while the syn!isomers lead to oxime ethers ð56JOC150Ł[ The syntheses of the four isomers of benzylideneacetone oxime O! methyl ether is possible via direct or sensitized irradiation of the "E\E#!isomer or the "Z\E#!isomer and subsequent equilibration ð75JCS"P0#0580Ł[ Alkylations of pyridine aldoximes with alkyl and benzyl halides\ under phase!transfer conditions in a benzeneÐ09) aqueous NaOH system\ proceed regiospeci_cally to give O!alkylated oxime ethers ð78SC2018Ł[ Alternatively\ alkali metal alkoxides in the corresponding alcohols ð65MI 200!90Ł\ or sodium hydride in DMF ð77LA0980Ł\ can be used to generate the necessary anion[ Oximes can be converted into their O!"0!butoxyethyl#oximes analogues by O!alkylation with butyl vinyl ether catalyzed by either Lewis acids\ such as ZnCl1\ or with mild protic acids such as p!TSA "para!toluene sulfonic acid# ð74ZOR655Ł[ a!Chloro nitroso compounds react with ether complexes of trialkylaluminum compounds to give oxime ethers via a radical reaction ð75RTC050Ł[ O!Aryloximes can be prepared from arenetricarbonyl chromium"9# complexes followed by reac! tion under phase!transfer conditions "KOH\ tetraoctylammonium bromide# with oximes and sub! sequent decomplexation with iodine ð74CC306Ł[ O!Methyl aldoximes can be prepared from the corresponding carboxylic acid via hydrogenation of N!methoxyimidoyl halides ð80S649\ 81JOC2134Ł\ or by the one!pot reaction of the carboxylic acid with methoxyamine and Ph2P0CBr3[ As O!methyl aldoximes can be converted into aldehydes or

320

Oximes

ketones by deoximation with paraformaldehyde and Amberlyst!04 in aqueous acetone ð82S452Ł\ this procedure not only protects the carbonyl functionality\ but also provides a mild route for the conversion of carboxylic acids into aldehydes[ O!Allyl ethers have been developed as an acid! and base!stable protecting group for oximes ð76TL3446Ł[ O!Oxime alkylation is selective in the presence of hydroxyl and amino groups\ whilst palladium!catalyzed deprotection using triethylammonium formate as the reducing agent is straight! forward even in the presence of acid! or base!sensitive functional groups "Scheme 5#[ N R1

OH

allyl bromide, KOH, DMF, 0 °C to 40 °C

N

Pd(OAc)2, PPh3, HCO2HNEt3, EtOH (aq.), ∆

R2

R1

O R2

Scheme 6

Oximes can be prepared directly from carbonyl compounds via a Peterson!type reaction with the bissilyl derivative "2# ð76S720Ł\ proceeding via an intermediate adduct which can be quenched directly to the parent oxime\ or trapped with a range of electrophiles to give O!substituted oxime derivatives "Scheme 6#[ O R1

TMS-(TMS-O)N– K+ (3), THF, –78 °C to 25 °C

R2

O– K+

N

R1

R2

R1

N

ECl, –78 °C

OE R2

Scheme 7

O!Alkyloximes are deprotonated regiospeci_cally by n!butyllithium to give the corresponding syn!a!lithium species\ which then undergo regiospeci_c carbonÐcarbon and carbonÐhalogen bond! forming reactions leading to syn!functionalized oximes ð78IJ076Ł[ Oxime esters are important as chemoselective acylating reagents\ particularly for bifunctional substrates such as amino alcohols ð80S602Ł[ They can be prepared from the parent oxime either chemically ð80S602Ł\ or using lipases biocatalysts ð82S61Ł\ via reaction with vinyl esters or di!t!butyl carbonate to give O!acyloximes and O!"t!butoxycarbonyl#oximes\ respectively[

2[00[0[2 Nitrones and Related Derivatives 2[00[0[2[0 Acyclic nitrones Nitrones are extremely versatile synthetic intermediates ð74OPP12Ł\ and they are of particular importance as 0\2!dipoles in cycloaddition reactions with multiple bond systems leading to the production of a wide variety of _ve!membered heterocyclic ring systems[ A range of reviews is available covering this area ð64S491\ B73!MI 200!90\ 75MI 200!90\ 77OR"24#0\ 78G142\ 80G174Ł[ The traditional method for the preparation of nitrones is by the condensation of carbonyl compounds with hydroxylamines ð68COC"1#499Ł\ or by direct oxidation of hydroxylamines[ For example\ nitrones of the type "3# were prepared by the reaction of the corresponding hydroxymethylene compounds with hydroxylamines "Equation "09## ð75CB1645Ł[ With the exception of the N!phenyl nitrone derived from indanone\ the nitrones formed were found to exist in the enolic form[ O HO

+

RNHOH

( )n

O– OH

R N

(10) ( )n

(4) R = Ph, Me or Bu; n = 1 or 2

The treatment of N\N!disubstituted hydroxylamines with palladium black results in formation of nitrones ð72TL0938Ł[ Furthermore\ if this reaction is carried out in the presence of an alkene\ a regio!

321

Oximes and their O!R Substituted Analo`ues

and stereoselective heterocycle formation is possible "Scheme 7#[ Hydroxylamines are also oxidized to nitrones by a suspension of Ag1O in ether ð68OPP138Ł[ The oxidations of hydroxylamines with PbO1 in dichloromethane a}ord 0\3!dinitronesdehydrodimers of vinylaminyl oxides ð74CB0094Ł presumably via isomerization of initially formed mononitrones to vinyl!substituted hydroxylamines\ followed by abstraction of a hydrogen radical[ R3

R1 HO

Pd black, 80–110 °C

N

R2

–O

R1

X

R1

X

N

+

N

R3

R2

O

R2

Scheme 8

Both these methods are controlled by the availability of the appropriate hydroxylamine[ An alternative general synthesis of nitrones from aldimines and ketimines is their reaction with the hydroxylamine derivative\ MeNHOSO2H[ This method has been employed in a convenient prep! aration of ~uorenone methylnitrone\ a previously di.cult compound to prepare "Equation "00## ð68OPP84Ł[ Me

NPh

+

N

O–

MeNHOSO3H, MeOH, 0 °C

(11)

Nitrones have been obtained from secondary amines in one step by sodium tungstate catalyzed oxidation with hydrogen peroxide ð73CC763\ 73H"10#372Ł\ or by oxidation with hydrogen peroxide in the presence of selenium dioxide as catalyst ð76TL1272Ł[ The latter method is also suitable for the preparation of nitrones in the presence of alkenes[ Imines can be converted into nitrones by treatment with potassium permanganate under phase!transfer conditions\ via a ð2¦1Ł cycloaddition type reaction "Equation "01## ð78JOC015Ł[ R3

R3 R1

KMnO4, CH2Cl2, H2O, pH 4.1

N

R2

+

R1

Bu4NCl, NaHSO3, H2O

N

R2

(12)

O–

Nitrones are also available via the electrochemical oxidation of N!hydroxy secondary amines using a supporting electrolyte such as sodium iodide ð75JOC438Ł[ Ene!type reactions of alkenes ð68T036Ł or allenes ð68RTC07Ł with a!chloronitroso compounds lead to the formation of N!a!chloroalkyl!N!alkenylhydroxylamine intermediates[ Rearrangement then provides access to aliphatic ketonitrones\ in excellent yields[ An investigation of the reaction of a!chloronitrosoadamantane with Grignard reagents has shown that adamantylidene nitrones "4# are formed in yields that vary widely with the nature of the Grignard reagent "Equation "02## ð79RTC135Ł[ With MeMgX and PhMgX\ the N!methyl! and N!phenylnitrones can be obtained in 48) and 76) yield\ respectively\ but with all other Grignard reagents nitrone yields are much lower[ Similarly\ methyl and phenyl Grignard reagents react with simple a!chloronitroso compounds to give the expected nitrones "5# "Equation "03## ð79RTC167Ł[ O–

NO Cl

N+

RMgX

R

(13)

(5)

Cl

NO

R1

R2

R1

R3MgX

+

R2

N R3 (6)

O–

(14)

322

Oximes

The reaction between N!chlorosuccinimide and benzil "E#!monooxime\ in the presence of dimethyl sul_de and Et2N\ a}ords a 3 ] 0 mixture of "E#! and "Z#!isomers of C!benzoyl!C!phenyl!N!methyl! thiomethylnitrone ð79JCR"S#255Ł[ These methylthiomethylnitrones undergo cyclization under ther! mal or photochemical stimulation\ leading to oxazoles[ C!t!Butyl!N!phenylnitrone has been prepared\ and its chemistry has been investigated in some detail ð79JCR"S#011Ł[ Functionally modi_ed cyclic nitrones appear to o}er synthetic potential[ However\ the fact that such nitrones have not been so utilized re~ects the problems associated with their preparation[ Nitrones of type "6# have now been prepared in high yield\ and their 0\2!dipolar cycloaddition reactions investigated "Scheme 8# ð79JA262Ł[ O HC(OMe)3, HCl, MeOH

OMe OMe

OMe OMe

OMe OMe

HgO

N

N

N

N+

Et

Et

OH

O– (7)

Scheme 9

Treatment of methyl 2\4!dimethoxybenzoate with thallium"III# nitrate in TFA at low temperature has been shown to lead to the formation of 3!"1!methoxycarbonyl!3\5!dimethoxyphenyl#imino!2! methoxycarbonyl!4!methoxycyclohexa!1\4!dien!0!one N!oxide "7# ð72SC538Ł[ MeO OMe MeO

O +

N CO2Me

O–

CO2Me

(8)

N!Alkylations of oximes by alkyl halides or sulfonates yield nitrones ðB!77MI 200!90Ł[ Nitrones have also been obtained by alkylation of O!trimethylsilyloximes with either trialkyloxonium tetra! ~uoroborates or alkyl tri~ates in dichloromethane solution ð74TL3220Ł[ The same research group also prepared medium!ring cyclic nitrones by heterolytic fragmentation reactions of bicyclic g!N!hydroxylaminosulfonates[ This procedure enabled the conversions of decahydroquinolines to perhydroazulenes to be performed ð74JOC2827Ł[ N!Methylnitrones have been generated in excellent yields by reacting carbonyl compounds with N!methyl!N\O!bis"trimethylsilyl#hydroxylamine ð74JOC4802Ł\ and a!aroyl!N!phenylnitrones have been obtained upon oxidation of the adducts derived from silyl enol ethers and nitrosobenzene with silver oxide ð74S168Ł[ The addition of 1!methyl!1!nitropropane and activated zinc dust to a cold ethanolic solution of a p!substituted benzaldehyde a}ords derivatives of phenyl!t!butylnitrone in high yields ð74JOC0420Ł[ A nitrone derived from an N!hydroxytryptophan ester and methyl ortho!formate provides a route to b!carbolines via nitrone cycloadditions ð75JOC298Ł[ Sterically unhindered and certain moderately hindered a!chloronitroso compounds "8# react with trimethylaluminum to give methyl nitrones "09# "Scheme 09# ð75RTC11Ł[ N R

R

Me

O Me3Al, n-C6H14, –80 °C

Cl

R

N R

(9)

O Cl

AlMe2

H2O

+

Me

N

R

O– R

(10) Scheme 10

As part of a mild\ multistep procedure for the oxidative deamination of benzylamines\ 3\5! diphenylpyridinium!1!carboxylates have been converted into nitrones by reaction with p!nitroso! N\N!dimethylaniline in re~uxing dichloromethane "Equation "04## ð72MI 200!90Ł[

323

Oximes and their O!R Substituted Analo`ues Ph

NMe2 p-Me2NC6H4NO

Ph

N

–O

–

+

CO2

+

(15)

N

Ar

Ar

A selection of methods for the stereocontrolled preparation of "Z#!nitrones is available[ Thus\ "Z#!nitrones have been synthesized under mild conditions by addition of alkoxyamines to aldehydes in the presence of sodium bicarbonate and calcium chloride ð73JOC2310Ł\ and the adamantone! derived nitrone "00# reacts with aromatic and aliphatic aldehydes to give the corresponding "Z#! aldonitrone selectively\ via the fragmentation of an initially formed 0\3\1!dioxazolidine to an oxazi! ridine intermediate\ which then rearranges to the "Z#!nitrone "Equation "05## ð89HCA058Ł[ Me N+

+

RCHO, THF, ∆

O–

N

R

Me (16)

O– (11)

C!Aryl!N!"0!carboxyalkyl#!nitrones are prepared by alkylation of aromatic "Z#!aldoximes or by condensation of a!hydroxyiminocarboxylic acids with aromatic aldehydes ð73LA0434Ł[ N!Carbamoylnitrones were prepared by low!temperature addition of isocyanates to aldoximes ð73ZOR877Ł[ The rearrangements of 1!chloro!1!nitrosofenchane and 1!chloro!1!nitrosocamphane to chloro! nitrones have been recorded ð73RTC217Ł[ Acyclic a!heteroatom!substituted nitrones are available via the regioselective alkylation of hy! droxamic acids\ under neutral conditions\ with alkyl tri~ates to give nitrone hydrotri~ates[ Subsequent displacement of the a!O!alkyl group from these highly reactive nitrones by heteronucleophiles then produces new nitrones with amino\ thio\ and cyano groups in the a!position "Scheme 00# ð78JOC0625Ł[ R3

O R1

N

R3OTf,

OH

CH2Cl2

O +

R1

R2

N

Et3N, MeCN

R2 –OTf

OH R3

Nuc

O +

R1

N

R2

NucH, Et3N, MeCN

+

R1

N

R2

O–

O– Scheme 11

1!Butenylmagnesium chloride undergoes 0\1!addition to both aryl and alkyl nitro compounds to give\ after workup\ the corresponding "E#!nitrone "Equation "06## ð89JOC3345Ł[ MgCl, THF, –70 °C

R

NO2

+

R

N

(17)

O–

2[00[0[2[1 Cyclic nitrones The syntheses and reactivity of four!membered cyclic nitrones have been reviewed ð89BSF693Ł[ An e.cient synthesis of _ve!ring cyclic nitrones has been achieved by the reduction of g!nitro ketones with ammonium formate:Pd!on!carbon "Equation "07## ð77TL0574Ł[

324

Oximes N

OH

–O

HCO2NH4, Pd/C, MeOH, 60 °C

R

N

+

CO2Me

R

CO2Me

(18)

NO2

The treatment of N!"benzyloxy#amines with concentrated hydrogen peroxide solution in AcOH enables the one!pot preparation of seven!membered cyclic nitrones in respectable yields ð71CB1568Ł\ and o}ers some advantages compared with conventional routes[ Four!membered cyclic nitrones are the major products of the reaction between nitroalkenes and 0!aminoalkynes[ In all cases only one of the two possible diastereomers is formed "Equation "08## ð72JOC0705Ł[ R4 R1

R4

N

NO2

–O

CONR42

+

R3

N

+ R2

R2

R1

R3

(19)

2[00[0[2[2 Miscellaneous nitrone derivatives Acetic nitronic anhydrides are readily prepared via reaction between aliphatic nitroalkenes and lithium enolates in the presence of acetic anhydride "Equation "19## ð89T6458Ł[ Thioimidate N!oxides "nitrones of thio esters# have been prepared by S!alkylations of N!alkylthiohydroxamic acids with alkyl iodides\ followed by treatment of the resulting hydroiodide salts with base "Scheme 01# ð75JOC4087Ł[ NO2

R1

LDA, Ac2O, THF, –78 °C

R1NHOH

S

CO2H

+ –O

R2

N

R2

(20)

R1

R2

S

O Ph

+

O

OAc

O

(aq.)

Ph

N

R2I,

OH

N R1

NaHCO3

OH I–

S +

Ph

S +

Ph

R1 R2

Me2CO

N

O–

R1 Scheme 12

2[00[0[3 O!Chalcogen!substituted Oximes The Neber rearrangement involves the base!catalyzed conversion of oxime tosylates "or quat! ernary salts of hydrazones or N!chloroimines# into a!amino ketones via isolable azirine intermediates ð53CRV70\ B!69MI 200!90\ 60MI 200!90\ B!62MI 200!90Ł[ For a review of the conversion of ketoxime sulphonates into a!amino ketones via the Neber rearrangement the reader is referred to Maruoka and Yamaoto\ {{Functional Group Transformations via Carbonyl Derivatives|| ð80COS"5#675Ł[

2[00[0[4 O!Arsenic!substituted Oximes The chemistry and physical properties of arsinooximes have been reviewed ð66C125\ 66CZ022Ł[

325

Oximes and their O!R Substituted Analo`ues

2[00[0[5 O!Silicon!substituted Oximes Silylations of a!ketoximes leading to O!silylated ketoximes "i[e[\ no silylation of the ketone function# have been achieved using mixtures of zinc chloride and triethylsilane in dioxane at 099>C ð74ZOB1966Ł[ 1!"Trialkylsilyloxy#oxime O!trialkylsilyl ethers can be formed from nitroalkanes by reaction with trialkylsilyl tri~ates\ via a 0\2!trialkylsiloxy migration "Scheme 02# ð75LA317Ł[ R2

R2 R3

R1

R2

TMS-OTf, Et3N

R3

R1

NO2

N

R1

O-TMS

R3

N(O-TMS)2

Scheme 13

2[00[1 N!HETEROATOM ANALOGUES OF OXIMES N!Heteroatom substituted aldimines "e[g[\ sulfenimes RCH1NSAr\ silylimines R0CH1N SiR12\ sulfonylimines R0CH1NSO1R1\ and the corresponding oximes# are useful synthons for the unstable N0H aldimine anions\ especially in the synthesis of a!branched primary amines ð80COS"1#883Ł[ Oximes\ oxime ethers\ and sulfenimines have been the most widely studied compounds[ Silylimines and sulfonimines have similarly been used to prepare a!aryl!substituted homoallylamines[ The corresponding ketimine analogues are also known\ but are much less common[ 2[00[1[0 Sulfur Analogues 2[00[1[0[0 Sulfenimines The preparations of sulfenimines "also known as sulfenylimines and N!alkylidenesulfenamides#\ together with their structural characteristics\ their reactions\ and the methods for their conversion into sul_nimines have been reviewed previously\ and the interested reader is directed to these comprehensive articles ð75JOC4913\ 78CR578\ B!89MI 200!90Ł[ Unlike imines and oximes\ sulfenimines undergo relatively facile stereomutation\ but examples of stereoisomers of sulfenimines are limited to constrained analogues ð78CR578Ł[ Sulfenimines are available from sulfenamides by three main routes\ namely] "i# via condensation reactions with carbonyl compounds^ "ii# from disul_des via reactions with metal salts and carbonyl compounds\ and "iii# via the condensation reactions between sulfenyl halides and imines ð78CR578\ B!89MI 200!90Ł[ They can also be prepared directly from the corresponding sulfenamide\ by treatment with N!chlorosuccinimide and Et2N ð83SL056Ł[ Application to glycine provides an electrophilic glycine equivalent for amino acid synthesis[ Sulfenimines are versatile synthetic intermediates\ and undergo nucleophilic additions at the iminyl carbon\ electrophilic additions at the nitrogen centre\ and alkylation reactions at sulfur ð78CR578\ B!89MI 200!90Ł[ They have also been reduced to N!sulfur!substituted amines by treatment with NaBH2CN in TFA ð72JOC2420Ł[ Sulfenimines undergo oxidation to both sul_nimines "sul_nyl imines# and sulfonimines "sulfonyl imines# "see Sections 2[00[0[1 and 2[00[1[0[2#[ The focus in the 0889s has been on the preparation of chiral sulfenimines ð83MI 200!90Ł and their utilization as electrophilic glycine equivalents in the synthesis of amino acids "Scheme 03# ð83SL056Ł[ CO2But

R R

O

i, LiN(TMS)2, THF, –20 °C

O

ii,

ButO2CCH=NS(o-NO2C6H4),

H

THF, 0 °C

N

TFA-H2O

S NO2

Scheme 14

CO2H

R O

NH2

N!Heteroatom Analo`ues

326

2[00[1[0[1 Sul_nimines Sul_nimines are more reactive than their sulfenyl analogues\ and they act as ammonia imine synthons[ Thus\ reduction of the C1N bond with either LAH or NaBH3 a}ords the corresponding sul_namides\ which readily undergo cleavage at the S0N bond with TFA to give the parent amino compound ð78CR578\ B!89MI 200!90Ł[ Alternatively\ the intermediate sul_namide can be oxidized to the corresponding sulfonamide ð71JCS"P0#228Ł[ Chiral sul_nimines are therefore valuable as chiral ammonia imine synthons in the synthesis of nonracemic amines ð71JCS"P0#228Ł[ They are also valuable in the synthesis of a!\ b!\ or g!amino acid derivatives\ via either reaction with diethyl! aluminum cyanide to form a!amino nitriles\ which are readily hydrolyzed to the corresponding amino acids ð80JOC3\ 83TL8240Ł\ or reaction of nitriles with an alkyllithium followed by reaction with "−#!L!menthyl "S#!p!tolylsul_nate ð80JOC3Ł[ They also undergo Darzen|s!type reactions with lithium enolates to form cis!aziridine!1!carboxylic acids ð83JOC2132Ł[ Sul_nimines are generally accessed by asymmetric oxidations of the corresponding sulfenimines with reagents such as chiral N!sulfonyloxaziridines ð81JOC5276\ 82PAC522Ł\ or by Andersen!type procedures from metalloimines and menthyl p!tolyl sul_nate "Scheme 04# ð82TL5118Ł\ although this procedure is limited to the formation of alkyl aryl sul_nimines[

:

p-Tolyl

R CN

dibal

R

N

AlBui

2

MeLi

R

2

O

Li+

:

O p-Tolyl

N

–

AlBui

O S

S

N

R

Scheme 15

2[00[1[0[2 Sulfonimines As with most N!heteroatom!substituted oxime derivatives\ sulfonimines are known by a range of titles such as sulfonyl imines or oxime sulfonates[ They are highly versatile and reactive reagents and are readily available from oximes by reaction with sulfonyl halides in the presence of base ð64S491Ł[ An alternative and general procedure for the preparation of sulfonimines\ even in systems prone to tautomerization\ is the treatment of carbonyl compounds with sulfonyl chlorides in the presence of tertiary amines\ such as Et2N ð81JOC3666Ł[ Sulfonimine formation results from a reaction cascade of amine!catalyzed rearrangement of the initial sulfonyl chloride to a sul_nyl cyanate\ followed by oxime O!sul_nylate formation and subsequent homolytic rearrangement to the sul! fonimine[ Sulfonimines have proved to be highly useful precursors ð81BSB270Ł[ In particular\ they readily undergo Beckmann!type rearrangements under a variety of conditions to give a number of compounds\ e[g[\ in the presence of dialkylaluminum thiolates or selenoates to give iminothioethers "valuable as activated amide surrogates# and iminoselenoethers\ respectively ð72JA1720Ł[ A similar reaction with cyanotrimethylsilane and diethylaluminum chloride has a}orded iminonitriles and a! alkylated amines are available via organoaluminum!promoted Beckmann rearrangement of sul! fonimines ð72JA1720Ł[ Rearrangement in the presence of TMS!I or Et1AlI gives imidoyl iodides ð72TL2144Ł[ Regio! and chemospeci_c carbonÐcarbon bond formation results from the Lewis acid promoted reaction of sulfonimines with silyl enol ethers and provides an e.cient method for the synthesis of enaminones\ which are useful building blocks for the synthesis of fused carbocycles and polyheterocycles\ in addition to their reduction to functionalized amino alcohols ð72JA5201Ł[ Alkenic cyclizations promoted by Beckmann rearrangement of sulfonimines provide access to a range of ring systems\ via four distinct cyclization modes "Scheme 05#\ controlled by the Lewis acid employed as the initiator and the migratory aptitude of the rearranged group ð72JA561\ 72TL832Ł[ Natural product applications of these reactions have included syntheses of solenopsin B and

327

Oximes and their O!R Substituted Analo`ues

muscopyridine ð72JA561Ł[ Beckmann rearrangement of sulfonimines by reaction with Grignard reagents gives functionalized imines\ which upon reduction give a!alkylamines ð71TL2284Ł[

endo(B)–endo mode

R

R

N

OMs

N H

R2 R2 endo(B)–exo mode

R1

R1

R1 N

R1

N

OMs

( )n

( )n

exo(B)–endo mode

Ph MsO

NHPh

N

exo–exo mode

R MsO

N R

N Scheme 16

The C1N bond of sulfonimines is readily reduced under mild conditions with NaBH3 ð70JCS"P0#1332Ł or LAH ð76S608Ł to give the corresponding sulfonamide[ N!Aryl sulfonimines were used as dienophiles in some of the earliest examples of heterocycle formation via imino DielsÐAlder reactions ðB!56MI 200!90Ł[ Sulfonimines can also be generated in situ for use in both inter! and intramolecular DielsÐAlder reactions by treatment of an aldehyde and 0\2!diene with N!sul_nyl!p! tolylsulfonamide and BF2 = Et1O ð89JOC2926Ł[ Sulfonimines are e.cient acceptors and they readily undergo nucleophilic reactions with organo! metallic reagents ð72S443\ 73TL4840\ 76TL4004Ł to give a!functionalized N!arylsulfonamides[ Hitherto the reaction has been of little use for amine synthesis however\ due to the problems of removal of the sulfonyl group[ This problem has now been overcome by the use of diarylsulfamylimines as the masked amine functionality\ as these groups are readily hydrolyzed in re~uxing aqueous pyridine "Scheme 06# ð75TL2846Ł[ O Ar

N

O S

N

R O

RM

Ar

Ar

N H

O R S

N H

R

i, pyridine, H2O

Ar

ii, NaOH

Ar

NH2

Scheme 17

In situ generation of the sulfonimine has also been used for the generation of aldehyde derived sulfonimine examples\ thus treatment with N!sul_nylsulfonamides a}ords sulfonimines which react with Grignard reagents to give N!sulfonylamines ð89JOC282Ł[ N!Tosylimines have been synthesized in variable yields by a diisobutyl telluride:copper powder! induced reaction of aldehydes with tosylazide ð74CL568Ł which does not react even under forcing conditions[ An organotellurilimine has been proposed as an intermediate "Scheme 07#[

N!Heteroatom Analo`ues

328 Ts

TsN3 + R2Te

R2Te

NTs

R2Te+

R1CHO

–R2TeO

N

R1

–O

NTs R1

Scheme 18

2[00[1[1 Phosphorus Analogues N!Phosphinoyl imines are highly electrophilic imines[ They are usually prepared by the reactions of oximes with chlorophosphorus"III# reagents in the presence of Et2N "Scheme 08# ð71S169\ 74CC471Ł[ N!Phosphinoyl imines can be reduced by a variety of hydride reagents under mild conditions ð67S410Ł to N!phosphinylamines\ which are then cleaved under mild acidic conditions to the parent amines[ Diastereoselective reductions have also been performed using LiBHBus2 ð76TL4508Ł\ and enantioselective reductions of N!diphenylphosphinylimines are also possible ð71S169\ 76JOC691Ł[ Ar

Ar ArCHO

Ar

R2PCl

[O]

O

N

N

N

OH

P(O)R2

P(O)R2

Scheme 19

N!Phosphinoyl imines serve as precursors to N!phosphinoyloxaziridines\ the phosphorus equiv! alents of the Davis reagents N!sulfonoyloxaziridines "Scheme 08# ð74CC471Ł\ and can also be converted into primary amines in a stereoselective manner ð76JOC691Ł[ Reactions of phosphinamides or sulfonamides with aryl aldehydes in the presence of TiCl3 and Et2N provide a simple one!step synthesis of N!phosphinoyl! and N!sulfonoyl imines\ respectively ð77TL2614\ 80T4450Ł[ Extension of this reaction to ketone examples failed owing to competing aldol condensation reactions\ although nonenolizable ketones or bulky ketones\ such as camphor\ can form both N!phosphinoyl! and N!sulfonoyl imines under more forcing conditions of re~ux in toluene[

2[00[1[2 Nitrogen Analogues The chemistry of N!nitrosoimines and N!nitrosamines has been reviewed in depth ðB!71MI 200!90Ł[ The chemistry of N!nitrosoimines\ and especially their use in the preparation of heterocycles\ has also been reviewed ð66H"6#0020Ł[ The formation of sterically hindered nitroimines is possible via the direct treatment of the parent oxime with NOCl\ although concomitant formation of the parent ketone via intramolecular reaction of the intermediate N!nitrosonitrone can be a problem ð73S368Ł[ The chemistry of N!nitrosoimines as synthetic intermediates\ for example\ in the preparation of azamonomethinecyanines ð67BCJ424Ł\ or their reduction with LAH ð65BCJ0802Ł\ has been studied in a series of papers by Akiba et al[ ð65BCJ449Ł[ As for the other N!heteroatom!substituted oximes derivatives\ N!nitroimines "also known as nitrimines# are also reduced by NaBH3 in this case to N!nitroamines "nitramines# ð66JOC2335Ł[ However\ in this series\ the reduction must be carried out in AcOH in order to be successful[

2[00[1[3 N!Silicon!substituted Imines Like their sulfur counterparts\ N!silylimines have been employed as masked N!H imines\ since the labile silyl group is readily removed even in situ[ Thus nonenolizable carbonyl compounds can be converted into primary amines by reaction with lithium hexamethyldisilazide to give N!trimethylsilylaldimines\ which spontaneously lose trimethyl silyl oxide\ in analogy to the Peterson alkenation\ to give the target amine "Scheme 19# ð72JOC178Ł[ Trimethylsilylimines also

339

Oximes and their O!R Substituted Analo`ues

react with organolithium and Grignard reagents to give primary amines\ after hydrolysis ð71S350Ł[ Attempts to prepare N!silylimines from enolizable carbonyl compounds have largely been thwarted by the problems of competing enolization and tautomerization to the corresponding enamines ð71S350Ł[ N!Silylimines from enolizable aldehydes have nevertheless been prepared and reacted in situ with ester enolates to provide b!lactams ð76TL4258Ł[ The temperature at which the N!silylimine is generated\ −29>C\ may be the key to success\ since nonenolizable N!silylimines are normally generated at −69>C[ Enolizable N!trimethylaldimines can also be prepared by the reaction of bis"trimethylsilyl#formamide with organolithium reagents ð78TL3164Ł[ Again this method was developed as a route to b!lactams "Scheme 10#[ O– LHMDS

RCHO

R

N

TMS

R

TMS

N

TMS

Scheme 20

O R1

OH N

BuLi, THF, –78 °C

TMS

R1

TMS

R1

N

TMS

TMS

N

TMS

R2CH2CO2Et, LDA

R2

R1 NH

THF, < –70 °C

O Scheme 21

A detailed coverage of the methods available for the preparation of N!silylimines\ their mechanism of formation\ and their structure\ is presented in an article by Colvin et al[ on the condensations of silyl ketene acetals with N!silylimines ð77T3046Ł[ N!Silylimines are also available via the condensation reactions between N!"trimethylsilyl#phosphimines and carbonyl compounds ð65CB0380Ł and the reaction of nitriles with organometallic reagents when quenched with TMS!Cl ð56JOM"8#120Ł[ As mentioned earlier\ N!silylimines provide a valuable alternative to oxime ethers for the synthesis of N!unsubstituted b!lactams\ as the silyl group is readily removed by protodesilylation during workup[ N!Silylimines are similar in reactivity and stereoselectivity to N!arylimines in their reactions with enolates and silyl ketene acetals[ Like acyclic imines\ they exist in one geometrical form\ presumably the "E#!isomer[ Pioneering investigations by Hart et al[ have provided much insight into the scope and stereo! selectivity of enolate!N!silylimine condensations[ In their original paper\ the viability of these reactions was demonstrated using mainly a\a!disubstituted esters\ which add via their lithium enolates to nonenolizable N!silylimines to a}ord mixtures of diastereomeric N!unsubstituted b!lactams\ following aqueous workup "Equation "10## ð72JOC178Ł[ For a review of this aspect of N!silylimine chemistry\ see Kleinman and Volkman ð80COS"1#823Ł[ R2

R2 R1

LDA, THF, –78 °C; R3CHN-TMS

R3

R1

(21) NH

CO2Et O

A simple route to N!"trimethylsilylmethyl#imines\ which are useful as precursors to {{non! stabilized|| azomethane ylides\ involves the reduction of trimethylsilylmethylazide using LiAlH3\ followed by standard imine formation with carbonyl compounds "Scheme 11# ð77SC0864Ł[

330 O LiAlH4, Et2O, < 10 °C

TMS

N3

TMS

NH2

R1

R1

R2

Na2SO4 40nm molecular sieves

TMS

N

R2

Scheme 22

Copyright

#

1995, Elsevier Ltd. All R ights Reserved

Comprehensive Organic Functional Group Transformations