The Chemistry of Heterocycles
Structure, Reactions, Syntheses, and Applications
Mohammad Jafarzadeh Faculty of Chemistry, Razi University
The Chemistry of Heterocycles, (Second Edition). By Theophil Eicher and Siegfried Hauptmann, Wiley-VCH Veriag GmbH, 2003 1 24 3 Three-Membered Heterocycles
3.2 Thiirane
24 3 Three-Membered Heterocycles 3.2 Thiirane Thiiranes are also known as episulfides. As a result of the greater atomic radius of the S-atom, the three atoms form an acute-angled triangle (see Fig. 3.2). [A] Thiiranes are also known as episulfides. As a result of the greater atomic radius of the S-atom, the 3.2 Thiirane three atoms form an acute-angled triangle.
Fig. 3.2 Structure of thiirane (bond lengths in pm, bond angles in degrees)
The thermochemically determined strainThenthalpye thermochemicallof thiiraney determineof 83 kJd molstrai-1n isenthalplessythan of thiiranthateof ofoxirane 83 kJ mo. H is less than that of oxirane. The ionization potential amounts to 9.05TheV,e ionizatiothe dipolen potentiamomentl amountto 1.66s toD 9.0. Both5 eVvalues, the dipolaree belowmomenthoset to 1.66 D. Both values are below Thiiranes are also known aofsoxirane episulfides. The chemical. Ashiftss a resulin the NMRt thosofspectrae thof oxiranee greateare. �ThH e= chemica2r. 27atomi, �l Cshift= 18sc i .n1radiu .the NMRs spectrof ath are S ^S-atom = 2.27, Sc ,=18.1. the three atoms form an acute-angled triangle (see Fig. 3.2)Th.e properties of the thiiranes are primarily due to ring strain. In spite of the smaller strain en- [B] The properties of the thiiranes are primarilythalpydue, tothiiranringestrain is thermall. In spitey lessof stabltheesmaller than oxiranestrain. Eveenthalpy,n at room temperature, linear macro- thiirane is thermally less stable than oxiranemolecule. Evens are atformeroomd becaustemperature,e of polymerizatiolinear macromoleculesn of ring-opened productsare . Substituted thiiranes are formed because of polymerization of ringthermall-openedy morproductse stable.. The following reactions are typical for thiiranes [13]:
Substituted thiiranes are thermally moreRing-openingstable. The following by nucleophilesreactions are typical for thiiranes: 2 Ammonia, or primary or secondary amines, react with thiiranes to give /?-amino thioles:
S R—NH2 + / \ +• R—NH—CH2-CH2-SH
The mechanism is the same as described on p 18 for oxiranes. However, the yields are lower, due to competing polymerization. Concentrated hydrochloric acid reacts with thiiranes to give /?-chlorothioles Fig. 3.2 Structure of thiirane (protonation on the S-atom and ring-opening by the nucleophilic chloride ion).
(bond lengths in pm, bond angles in degrees) Oxidation Thiiranes are oxidized by sodium periodate or peroxy acids to give thiirane oxides. They decompose at The thermochemically determined strain enthalpy of thiiranehighe ofr temperatur83 kJ emo into alkeneH iss an lesd sulfus rtha monoxiden tha: t of oxirane. The ionization potential amounts to 9.05 eV, the dipole moment to 1.66 D. Both values are below A Nal04 s those of oxirane. The chemical shifts in the NMR spectra are S^ = 2.27, Sc =18.1. *• H2C=CH2 + S=0
The properties of the thiiranes are primarily due to ring strain. In spite of the smaller strain en- thalpy, thiirane is thermally less stable than oxirane. Even at room temperature, linear macro- molecules are formed because of polymerization of ring-opened products. Substituted thiiranes are thermally more stable. The following reactions are typical for thiiranes [13]:
Ring-opening by nucleophiles Ammonia, or primary or secondary amines, react with thiiranes to give /?-amino thioles:
S R—NH2 + / \ +• R—NH—CH2-CH2-SH
The mechanism is the same as described on p 18 for oxiranes. However, the yields are lower, due to competing polymerization. Concentrated hydrochloric acid reacts with thiiranes to give /?-chlorothioles (protonation on the S-atom and ring-opening by the nucleophilic chloride ion).
Oxidation Thiiranes are oxidized by sodium periodate or peroxy acids to give thiirane oxides. They decompose at higher temperature into alkenes and sulfur monoxide:
A Nal04 s *• H2C=CH2 + S=0 24 3 Three-Membered Heterocycles 24 3 Three-Membered Heterocycles 3.2 Thiirane 3.2 Thiirane
Thiiranes are also known as episulfides. As a result of the greater atomic radius of the S-atom, the Thiiranethree atoms ars efor alsmo a known acute-anglen as episulfidesd triangl.e A (ses ae resulFig. 3.2)t of .the greater atomic radius of the S-atom, the three atoms form an acute-angled triangle (see Fig. 3.2).
Fig. 3.2 Structure of thiirane Fig. 3.2 (bonStructurd lengthe so fin thiiran pm, bone d angles in degrees) (bond lengths in pm, bond angles in degrees) The thermochemically determined strain enthalpy of thiirane of 83 kJ moH is less than that of oxirane. TheTh ionizatioe thermochemicalln potentialy amountdetermines tdo strai9.05n eVenthalp, the ydipol of thiirane momene of t8 t3o k J1.6 mo6 HD . isBot leshs valuethan thas art eo fbelo oxiranew . thosThe eo fionizatio oxirane.n Th potentiae chemical amountl shifts itno th9.0e NM5 eVR, spectrthe dipola aree Smomen^ = 2.27t ,t oS c 1.6=18.16 D. .Both values are below those of oxirane. The chemical shifts in the NMR spectra are S^ = 2.27, Sc =18.1. The properties of the thiiranes are primarily due to ring strain. In spite of the smaller strain en- thalpyTh,e thiiranpropertiee is thermallof the thiiraney less s stablare eprimaril than oxiraney due t.o Everingn strainat roo. mIn temperaturespite of the , smallelinearr macrostrain -en- moleculesthalpy are ,forme thiirand ebecaus is thermalle of polymerizatioy less stable ntha onf ring-openeoxirane. Eved productsn at room. Substitutetemperatured thiirane, linear smacro are - thermallmoleculey mors ear stablee forme. Thd ebecaus followine ogf reactionpolymerizatios are typican of l ring-openefor thiiraneds products[13]: . Substituted thiiranes are thermally more stable. The following reactions are typical for thiiranes [13]: Ring-opening by nucleophiles Ring-opening by nucleophiles Ammonia, or primary or secondary amines, react with thiiranes to give /?-amino thioles: AmmoniaRing-opening, or primarby nucleophilesy or secondary amines, react with thiiranes to give /?-amino thioles: Ammonia, or primary or secondary amines, react with thiiranes to give �-amino thioles: S R—NH2 + / \ +• R—NH—CH2-CH2-SH S R—NH2 + / \ +• R—NH—CH2-CH2-SH The mechanism is the same as described on p 18 for oxiranes. However, the yields are lower, due to competinThThee mechanismechanismg polymerizationm isis ththee .samesam Concentratee asas describeddescribed hydrochlorid foronoxiranes p 18c fo aci.rHowever, doxiranes reacts .witthe Howeverhyields thiiraneare, thslower, et oyield givduees /?-chlorothiole artoe competinglower, duse to (protonatiocompetinpolymerizationn go polymerizationn the. ConcentratedS-atom an. dConcentrate ring-openinhydrochloricdg hydrochlori acidby threactse nucleophilicwith acithiiranesd reactc chlorids witto giveeh ion)thiirane�-.chlorothioless to give (protonation/?-chlorothioles on the S-atom and ring-opening by the nucleophilic chloride ion). (protonation on the S-atom and ring-opening by the nucleophilic chloride ion). Oxidation ThiiraneOxidations are oxidized by sodium periodate or peroxy acids to give thiirane oxides. They decompose at Oxidation higheThiiraneThiiranesr temperaturs araree oxidizeeoxidized into dalkene bbyy sodiumsodius anmd sulfuperiodateperiodatr monoxideeor orperoxy perox: yacids acidtos tgiveo givthiiranee thiiranoxidese oxides. They. Thedecomposey decomposat e at highehigherr temperaturtemperaturee intintoo alkenealkeness anandd sulfursulfur monoxidemonoxide: :
A Nal04 s A*• H2C=CH2 + S=0 Nal04 s *• H2C=CH2 + S=0 3 3.2 Thlirane 25
Desulfurization to alkenes Triphenylphosphane, as well as trialkyl phosphites, have proved to be reliable reagents for this pur- pose. The reaction is stereospecific. Czs-thiiranes yield (Z)-olefms and trans-thiirones yield (£)-olefins. The electrophilic attack of the trivalen3.2t phosphoruThlirans on eth e heteroatom is different from that describe25 d on p 20. Desulfurization to alkenes
DesulfurizationTriphenylphosphaneto alkenes, as well as trialkyl phosphites, have proved to be reliable reagents for this pur- Triphenylphosphane,pose. The reactionas is wellstereospecificas trialkyl. Czs-thiiranephosphites,s yielhaved (Z)-olefmprovedPh3top=s sanbed trans-thiironesreliable reagents yielford (£)-olefinsthis . purposeThe. electrophiliThe reactionc attacis stereospecifick of the trivalen. Cist phosphoru-thiiranes syield on th(Ze )heteroato-olefins andm istrans differen-thiiranest fromyield that (describeE)- d olefinson. pThe 20. electrophilic attack of the trivalent phosphorus on the heteroatom is different from that described previously. Metallic reagents, e.g. n-butyllithium, also bring about a stereospecific desulfurizationMetalliofc reagentsthiiranes,. e.g. w-butyllithium, also bring about a stereospecific desulfurization of thiiranes.
The synthesis of thiiranes starting from /^-substitutePh3p=s d thioles and oxiranes can be achieved as follows.
[C] The (1synthesis) Cyclizationof thiiranes of ß-substitutedstarting from thioles�-substituted thioles and oxiranes can be achieved as followsMetalli. c reagents, e.g. w-butyllithium, also bring about a stereospecific desulfurization of thiiranes. By analogy with the oxirane synthesis described on p 20, halothiols react with bases to give thiiranes. (1) Cyclization/?-AcetoxythiolThe ofsynthesi�-substitutedss alsofo thiirane yielthiolesd thiiranes startins gunde fromr simila/^-substituter conditionsd thiole. 2-Sulfanylethanos and oxiranes cal nreact be sachieve with phosgend as e By analogy with the oxirane synthesis, halothiols react with bases to give thiiranes. �-Acetoxythiols also in followsthe presenc. e of pyridine to give l,3-oxathiolan-2-one, which on heating to 200°C decarboxylates to yield thiiranesgive thiiraneunder. similar conditions. 2-Sulfanylethanol reacts with phosgene in the presence of pyridine to give 1,3-oxathiolan-2-one, which on heating to 200 °C decarboxylates to give thiirane. (1) Cyclization of ß-substituted thioles .SH By analogy with the oxirane synthesis described on p 20, halothiols react with bases to give thiiranes. /?-Acetoxythiols also yield thiiranes under similar conditions. 2-Sulfanylethanol reacts with phosgene cOH in the presence of pyridine to give l,3-oxathiolan-2-one, which on heating to 200°C decarboxylate4 s to give thiirane. (2) Ring transformation of oxiranes .SH Conversion of one heterocyclic system into another is known as ring transformation. Oxiranes react with aqueous ethanolicc potassiuOH m rhodate to give thiiranes, probably according to the following mechanism:
(2) Ring transformation of oxiranes N=C-SI+ Conversion of one heterocyclic system into another is known as ring transformation. Oxiranes react with aqueous ethanolic potassium rhodate to give thiiranes, probably according to the following mechanism: '
N=C-SI+
' 3.2 Thlirane 25
Desulfurization to alkenes Triphenylphosphane, as well as trialkyl phosphites, have proved to be reliable reagents for this pur- pose. The reaction is stereospecific. Czs-thiiranes yield (Z)-olefms and trans-thiirones yield (£)-olefins. The electrophilic attack of the trivalent phosphorus on the heteroatom is different from that described on p 20.
Ph3p=s
Metallic reagents, e.g. w-butyllithium, also bring about a stereospecific desulfurization of thiiranes.
The synthesis of thiiranes starting from /^-substituted thioles and oxiranes can be achieved as follows.
(1) Cyclization of ß-substituted thioles By analogy with the oxirane synthesis described on p 20, halothiols react with bases to give thiiranes. /?-Acetoxythiols also yield thiiranes under similar conditions. 2-Sulfanylethanol reacts with phosgene in the presence of pyridine to give l,3-oxathiolan-2-one, which on heating to 200°C decarboxylates to give thiirane.
.SH
cOH
(2) Ring transformation of oxiranes Conversion of one heterocyclic system into another is known as ring transformation. Oxiranes react with aqueous ethanolic potassium rhodate to give thiiranes, probably according to the following mechanism:
(2) Ring transformation of oxiranes Conversion of one heterocyclic system into N=C-SI+ another is known as ring transformation. Oxiranes react with aqueous ethanolic potassium rhodate to give thiiranes, probably according to the following mechanism: ' 26 3 Three-Membered Heterocycles
[D] Thiirane (ethylene sulfide) is a colorless liquid,Thiiransparinglye (ethylene sulfidesoluble) is ina colourleswater sand liquidof, sparinglbp 55y° solublC. e in water and of bp 55°C.
[E] A method for C-C coupling, which isAbased method foonr C-Cclosing coupling,a whicthiiraneh is basedring on closinandg a openingthiirane ring itandby opening it by desulfu- desulfurization, is known as sulfide contractionrizationafter, isESCHENMOSER known as sulfide contractio. n after ESCHENMOSER, e.g.:
COOEt V KHCÜ3
Pyrrolidine-2-thione is S-alkylated with bromomalonic diethyl ester. On treatment with a solution of KHCO3, the resulting iminium salt COOEt 1 yields a thiirane 2 which desulfurizes at 60 °C COOEt Ä /V $ S to give 3. H COOEt " H COOEt
2 35
Pyrrolidine-2-thione is S-alkylated with bromomalonic diethyl ester. On treatment with a solution of KHCO3, the resulting iminium salt 1 yields a thiirane 2 which desulfurizes at 60°C to give 3 [14].
3.3 2//-Azirine
Unlike l//-azirine, 2//-azirines can be used preparatively, although the ring strain is substan- tially greater than that of the saturated three-membered heterocycles. The ring strain enthalpy amounts to approximately 170 kJ mol"1.
TI 2/f-Azirine is thermally unstable and has to be stored at very low temperatures. Substituted 2H- azirines are more stable. They are liquids or low melting solids. Their basicity is substantially lower than that of comparable aliphatic compounds. For instance, 2-methyl-3-phenyl-2//-azirine is not soluble in hydrochloric acid. The ring strain endows the ON double bond with an exceptionally high reactivity. Electrophilic re- agents attack the N-atom, nucleophilic reagents the C-atom. For example, methanol added in the pres- ence of a catalytic amount of sodium methoxide produces 2-methoxyaziridines:
K MeOH + A\ " MeO
R
Carboxylic acids also add to the C=N double bond and the products rearrange to more stable com- pounds with opening of the aziridine ring. A method for peptide synthesis is based on these reactions [15]: 26 3 Three-Membered Heterocycles
Thiirane (ethylene sulfide) is a colourless liquid, sparingly soluble in water and of bp 55°C.
A method for C-C coupling, which is based on closing a thiirane ring and opening it by desulfu- rization, is known as sulfide contraction after ESCHENMOSER, e.g.: 26 3 Three-Membered Heterocycles
COOEt V KHCÜ3 Thiirane (ethylene sulfide) is a colourless liquid, sparingly soluble in water and of bp 55°C.
A method for C-C coupling, which is based on closing a thiirane ring and opening it by desulfu- rization, is known as sulfide contraction after ESCHENMOSER, e.g.:
COOEt V KHCÜ3
COOEt COOEt Ä /V
$ S H COOEt " H COOEt
COOEt 2 COOEt Ä /V 3
$ S H COOEt " H COOEt
Pyrrolidine-2-thione is S-alkylated with bromomalonic diethy2 l ester. On treatmen3t with a solution of KHCO3, the resulting iminium salt 1 yields a thiirane 2 which desulfurizes at 60°C to give 3 [14]. Pyrrolidine-2-thione is S-alkylated with bromomalonic diethyl ester. On treatment with a solution of KHCO3, the resulting iminium salt 1 yields a thiirane 2 which desulfurizes at 60°C to give 3 [14].
3.3 2//-Azirin3.3 2//-Azirine e 3.3 2H-Azirine
[A] Unlike 1H-azirine,Unlike 2l//-azirineH-azirines, can2//-azirinebe useds capreparativelyn be used preparatively, although the, althougring strainh theis rinsubstantiallyg strain is substan- greater than thattiallofy thegreatesaturatedr than thathreet o-fmembered the saturateheterocyclesd three-membere. The dring heterocyclesstrain enthalpy. The amountsring straiton enthalpy Unlike l//-azirine, 2//-azirines can be 1 used preparatively, although the ring strain is substan- tially approximatelygreateamountr tha170ns tothakJ approximatelmolt o-1f. they saturate170 kJ mol"d .three-membered heterocycles. The ring strain enthalpy 1 amounts to approximatel[B] 2H-AzirineTI is2/f-Azirinythermally 170e k iJunstables thermallmol" and.y unstablhas toe beandstored has to atbe verystorelowd at temperaturesvery low temperatures. Substituted. Substitute2H- d 2H- azirines are moreazirinestables ar.eThey moreare stableliquids. Theory loware liquidmeltings osolidsr low .meltinTheir gbasicity solids. isTheisubstantiallyr basicity ilowers substantially than thatloweof rcomparable than that of comparablaliphatic compoundse aliphatic .compoundsFor instance,. For 2instance-methyl,- 32-methyl-3-phenyl-2//-azirin-phenyl-2H-azirine is not e is not soluble in hydrochloric acid. TI 2/f-Azirine solublis thermalle in hydrochloriy unstablc acid.e and has to be stored at very low temperatures. Substituted 2H- azirineThes arringe morstrainThe erin endowsstableg strain .theendow TheC=Nsy th ardoublee Oe Nliquid doublbondsewith bonor danlo witwexceptionallyh meltinan exceptionallg solidshighy reactivityhig. hThei reactivity. rElectrophilic basicit. Electrophiliy is csubstantiall re- y lower than thareagentst of agentcomparablattacks attacthe kN -thatom,ee N-atomaliphatinucleophilic, nucleophilic compoundsreagentsc reagentthe.s CFo th-atomer C-atom instance. For. example,For, example 2-methyl-3-phenyl-2//-azirinmethanol, methanoaddedl addeindthe in the pres- e is not soluble in hydrochloripresenceencofea occatalyticf acida catalyti. amountc amounof tsodium of sodiumethoxidem methoxidproducese produce2-methoxyaziridiness 2-methoxyaziridines: : The ring strain endows the ON double bond with an exceptionallKy high reactivity. Electrophilic re- MeOH + A\ " MeO agents attack the N-atom, nucleophilic reagents the C-atom. For example, methanol added in the pres- R ence of a catalytic amount of sodium methoxide produces 2-methoxyaziridines: 6 Carboxylic acids also add to the C=N double bond and the products rearrange to more stable com- pounds with opening of the aziridine ring. A method for peptide synthesiK s is based on these reactions [15]: MeOH + A\ " MeO
R
Carboxylic acids also add to the C=N double bond and the products rearrange to more stable com- pounds with opening of the aziridine ring. A method for peptide synthesis is based on these reactions [15]: 3.3 2H-Azirine 27 Carboxylic acids also add to the C=N double bond and the products rearrange to more stable compounds with opening of the aziridine ring. A method for peptide synthesis is based on these reactions: Z NH zNH e x
- - ^OH + >X 2 « - V4i J ^ ! MezKT ^R 2 L Me 2 M^^R 2
Z_NH H
R 2 Me2l/ Me2N^ R
0
NH Z_NH- ^^ANMe2 "2°'"®. dipeptide
° ?\ Z = Ph—CH2-O-C— For instance, when the carboxyl group of an N-(benzoyloxycarbonyl)amino acid reacts with a 2- substituted or a 2,2-disubstitutedFor instance, whe3n- (thdimethylaminoe carboxyl group) -o2f Han-azirine 7V-(benzoyloxycarbonyl)aminin diethyl ether ato aciroomd reacttemperature,s with a 2- the substituted or a 2,2-disubstituted 3-(dimethylamino)-2//-azirine in diethyl ether at room temperature, N,N-dimethylamide of the dipeptide is obtained quantitatively. Its hydrolysis with 3N hydrochloric acid the Af,7V-dimethylamide of the dipeptide is obtained quantitatively. Its hydrolysis with 3N hydrochloric yields the N-(benzyloxycarbonylacid yields the )dipeptide^/-(benzyloxycarbonyl)dipeptide. . 2//-Azirines undergo cycloadditions. They react, for instance, as dienophiles in [4+2] cycloaddi- 2H-Azirines undergotionscycloadditions. . They react, for instance, as dienophiles in [4+2] cycloadditions. 7
2//-Azirines are prepared by thermolysis or photolysis of vinyl azides, which are obtainable from alkenes.
3 Br2 NaN3 V R—CH=CH2 *> R—CH—CH2-Br *> R—CH—CH2-Br Br
6_ ®_ NaOH N—N=N A N ^ N
*- R—CH=CH2 *- R—CH=CH2 *> // \ -N2 S*-^ vinyl azide vinyl nitrene
The dediazoniation of the vinyl azide proceeds via vinyl nitrene. A variant of this synthesis enables the preparation of 3-(dialkylamino)-2//-azirines starting from AyV-disubstituted acid amides [15]:
Cl COCI2, NEt3 \ 3.3 2H-Azirine 27 3.3 2H-Azirine 27
Z NH zNH e x
- Z-NH ^OH + >X 2 « - zV4iNH e J ^x! MezKT ^R 2 L Me 2 M^^R 2 - - ^OH + >X 2 « - V4i J ^ ! MezKT ^R 2 L Me 2 M^^R 2
Z_NH H
Z_NH H
R 2 Me2l/ Me2N^ R R 2 Me2l/ Me2N^ R
0 0 NH Z_NH- ^^ANMe2 "2°'"®. dipeptide NH Z_NH- ^^ANMe2 "2°'"®. dipeptide ° ?\ Z = Ph—CH2-O-C— ° ?\ Z = Ph—CH2-O-C— For instance, when the carboxyl group of an 7V-(benzoyloxycarbonyl)amino acid reacts with a 2- substituteFor instanced or a 2,2-disubstitute, when the carboxyd 3-(dimethylamino)-2//-azirinl group of an 7V-(benzoyloxycarbonyl)amine in diethyl ether ato rooacidm reacttemperatures with ,a 2- the Af,7V-dimethylamidsubstituted or a 2,2-disubstitutee of the dipeptidd 3-(dimethylamino)-2//-azirine is obtained quantitatively. Ite si nhydrolysi diethyl sethe witrh a 3t Nroo hydrochlorim temperaturec , acid thyielde Af,7V-dimethylamids the ^/-(benzyloxycarbonyl)dipeptidee of the dipeptide is .obtained quantitatively. Its hydrolysis with 3N hydrochloric 2//-Azirineacid yieldss thunderge ^/-(benzyloxycarbonyl)dipeptideo cycloadditions. They react., for instance, as dienophiles in [4+2] cycloaddi- tions. 2//-Azirines undergo cycloadditions. They react, for instance, as dienophiles in [4+2] cycloaddi- tions. 2//-Azirines are prepared by thermolysis or photolysis of vinyl azides, which are obtainable from 2//-Azirinealkenes. s are prepared by thermolysis or photolysis of vinyl azides, which are obtainable [C] 2H-froAzirinesm alkenesare prepared. by thermolysis or photolysis of vinyl azides, which are obtainable from alkenes. The dediazoniation of the vinyl azide proceeds via vinyl nitrene. 3 Br2 NaN3 V R—CH=CH2 *> R—CH—CH2-Br *> R—CH—CH3 2-Br Br2 NaN3 V R—CH=CH2 *> BR—CH—CHr 2-Br *> R—CH—CH2-Br Br 6_ ®_ NaOH N—N=6_ N® _ A N ^ N
NaO*- H R—CH=CHN—N=2 N *-A R—CH=CHN ^2 *> // \ N -N2 S*-^ *- R—CH=CH2 *- R—CH=CH2 *> // \ -N S*-^ vinyl azide 2 vinyl nitrene vinyl azide vinyl nitrene The dediazoniation of the vinyl azide proceeds via vinyl nitrene. A variant of this synthesis enables the preparatioThA variante dediazoniation ofof 3-(dialkylamino)-2//-azirinethis synthesisn of the enablesvinyl azidthee spreparationproceed startinsg vi froaof mviny3 -AyV-disubstitute(dialkylamino)l nitrene. A -varian2Hd-azirines acit do famide thistartings synthesis [15]from: s enableN,N- s the preparatiodisubstitutedn oacidf 3-(dialkylamino)-2//-azirineamides: s starting from AyV-disubstituted acid amides [15]:
Cl COCI2, NEt3 \ Cl COCI2, NEt3 \
8 28 3 Three-Membered Heterocycles
28 3 Three-Membered Heterocycles
The methyl iodides of dimethyl hydrazones furnish 2//-azirineThe methys whel iodidens o ftreate dimethyl dhydrazone withs furnisbaseh 2//-azirines sucsh whe ans treate sod- with bases such as so- 28 3 Three-Membered Heterocycles dium propoxide: dium propoxide: The methyl iodides of dimethyl hydrazones furnish 2//-azirines when treated with bases such as so- The methyldiumiodides propoxideof :dimethyl hydrazones furnish 2H-azirines when treated with bases such as sodium propoxide:
3.4 Aziridine
3.4 Aziridine Aziridine was once known as ethylene imine. Bond lengths and bond angles are essentially the [A] Aziridine was once known as ethylene imine. Bond lengths and bond angles are essentially the 3.4 Aziridine same as those in oxirane. The plane in which the N-atom, its nonbonding electron pair and the same as those in oxirane. The plane in which theN-NH- atom,bond aritse situatenonbondingd is perpendiculaelectronr to thpaire planande of ththee aziridinN-H e ring (see Fig. 3.3). 3.4 Aziridine bond are situated is perpendicular to the plane of the aziridine ring.
Aziridine was once known as ethylene imine. Bond lengths and bond angles are essentially the same as those in oxirane. The plane in which the N-atom, its nonbonding electron pair and the
N-H bond are situated is perpendicular toFig th. e3. plan3 eStructur of thee o aziridinf aziridine e ring (see Fig. 3.3). (Bond lengths in pm, bond angles in degrees) 9
Aziridine was once known as ethylene imine. Bond length2-Methylaziridins ane would bond be expectedd angle, therefores ar, toe displa essentially diastereoisomerismy the. Trivalent N-atoms are, same as those in oxirane. The plane in which the N-atomhowever, it, liabls nonbondine to pyramidal inversiong electro. n pair and the N-H bond are situated is perpendicular to the plane of the aziridine ring (see Fig. 3.3).
'CH3
Although the activation enthalpy of this process AG* = 70 kJ mol"1, i.e. substantially greater than with Fig. 3.3 Structure of aziridine a secondary aliphatic amine, inversion occurs so rapidly at room temperature that the diastereo- (Bond lengths in pm, bond angleisomers in degreess are no)t separable. However, in the case of l-chloro-2-methylaziridine, where AG* = 112 kJ mol"1, the mixture of stereoisomers can be separated. The strain enthalpy of aziridine determined thermochemically amounts to 113 kJ mol"1 and is, there- 2-Methylaziridine would be expected, thereforefore, almos, tot identicadisplaly t odiastereoisomerism that of oxirane. The ionizatio. Trivalenn potentiat N-atoml was founs ared to, be 9.8 eV and the ex- however, liable to pyramidal inversion. cited electron derives from the nonbonding electron pair of the N-atom. The dipole moment of 1.89 D is almost the same as that of oxirane. The chemical shifts in the NMR spectra are S^ = 1.5 (CH), 1.0 (NH) and Sc= 18.2.
'CH3 Fig. 3.3 Structure of aziridine (Bond lengths in pm, bonAlthougd angleh the activatios in degreesn enthalp)y of this process AG* = 70 kJ mol"1, i.e. substantially greater than with a secondary aliphatic amine, inversion occurs so rapidly at room temperature that the diastereo- isomers are not separable. However, in the case of l-chloro-2-methylaziridine, where AG* = 112 kJ 2-Methylaziridine would be expected1 , therefore, to display diastereoisomerism. Trivalent N-atoms are, mol" , the mixture of stereoisomers can be separated. however, liable to pyramidal inversionThe strai. n enthalpy of aziridine determined thermochemically amounts to 113 kJ mol"1 and is, there- fore, almost identical to that of oxirane. The ionization potential was found to be 9.8 eV and the ex- cited electron derives from the nonbonding electron pair of the N-atom. The dipole moment of 1.89 D is almost the same as that of oxirane. The chemical shifts in the NMR spectra are S^ = 1.5 (CH), 1.0 (NH) and Sc= 18.2.
'CH3
Although the activation enthalpy of this process AG* = 70 kJ mol"1, i.e. substantially greater than with a secondary aliphatic amine, inversion occurs so rapidly at room temperature that the diastereo- isomers are not separable. However, in the case of l-chloro-2-methylaziridine, where AG* = 112 kJ mol"1, the mixture of stereoisomers can be separated. The strain enthalpy of aziridine determined thermochemically amounts to 113 kJ mol"1 and is, there- fore, almost identical to that of oxirane. The ionization potential was found to be 9.8 eV and the ex- cited electron derives from the nonbonding electron pair of the N-atom. The dipole moment of 1.89 D is almost the same as that of oxirane. The chemical shifts in the NMR spectra are S^ = 1.5 (CH), 1.0 (NH) and Sc= 18.2. 28 3 Three-Membered Heterocycles
The methyl iodides of dimethyl hydrazones furnish 2//-azirines when treated with bases such as so- dium propoxide:
3.4 Aziridine
Aziridine was once known as ethylene imine. Bond lengths and bond angles are essentially the same as those in oxirane. The plane in which the N-atom, its nonbonding electron pair and the N-H bond are situated is perpendicular to the plane of the aziridine ring (see Fig. 3.3).
Fig. 3.3 Structure of aziridine (Bond lengths in pm, bond angles in degrees)
2-Methylaziridine would be expected, therefore, to display diastereoisomerism. Trivalent N-atoms are, 2-Methylaziridinehowever, liablwoulde to pyramidabe expected,l inversiontherefore,. to display diastereoisomerism. Trivalent N-atoms are, however, liable to pyramidal inversion.
'CH3
-1 AlthoughAlthougtheh activationthe activatioenthalpyn enthalpof thisyprocess of this �procesG* = 70s AGkJ mol* = ,7i0.e k. Jsubstantially mol"1, i.e.greater substantiallthan withy greatea r than with secondary aliphatic amine, inversion occurs so rapidly at room temperature that the diastereoisomers area notsecondarseparabley aliphati. However,c aminein the, inversiocase of n1- occurchloro-s2 -smethylaziridine,o rapidly at roowherem temperatur�G* = 112e thakJ tmol the-1 ,diastereothe - mixtureisomerof sstereoisomers are not separablecan be .separated However. , in the case of l-chloro-2-methylaziridine, where AG* = 112 kJ 1 mol" , the mixture of stereoisomers can be separated. -1 The strain enthalpy of aziridine determined thermochemically amounts to 113 kJ mol and is, there- fore,1 almostThidenticale strain toenthalpthat ofy oxiraneof aziridin. Thee ionizationdeterminepotentiald thermochemicallwas found toy beamount9.8 eVs tando 11the3 kJexcited mol" and is, there- electronfore, derivesalmost fromidenticathe nonbondingl to that oelectronf oxiranepair. Thof thee ionizatioN-atom. n potential was found to be 9.8 eV and the ex- cited electron derives from the nonbonding electron pair of the N-atom. The dipole moment of 1.89 D The dipole moment of 1.89 D is almost the same as that of oxirane. The chemical shifts in the NMR is almost the same as that of oxirane. The chemical shifts in the NMR spectra are S^ = 1.5 (CH), 1.0 spectra are �H = 1.5 (CH), 1.0 (NH) and �C= 18.2. (NH) and Sc= 18.2. 10 3.4 Aziridine 29
Care is advisable when handling3. 4aziridines Aziridin, because e many show considerabl29 e toxicity. The fol- lowing reactionCare is advisabls are eo whef importancen handling aziridines: , because many show considerable toxicity. The fol- [B] Care is Acidadvisable basewhen reactionshandlinglowing reactionaziridines,s are of importancebecause :many show considerable toxicity. The following reactions are of importanceAcid: base reactions AziridinesAziridine unsubstitutes unsubstituted ond othn eth eN-ato N-atomm behav behave likee secondarlike secondary amines; yTV-substitute aminesd; aziridineTV-substitutes behaved aziridines behave Acid base reactions like tertiary amines. They react with acids to give aziridinium salts: Aziridines unsubstitutedlike tertiaryon aminesthe N-.atom Theybehave react witlikehsecondary acids to givaminese aziridiniu; N-substitutedm saltsaziridines: behave like tertiary amines. They react with acids to give aziridinium salts: + HA A + H A*=* The pKa value of the aziridiniuAm ion is 7.98. Aziridin *=e is thu*s a weaker base than dimethylamine (pKa = 10.87), but stronger than aniline (pKa = 4.62). The pKa value of the aziridinium ion is 7.98. Aziridine is thus a weaker base than dimethylamine (pKa = 10.87), but stronger than anilineThe aziridin(pKe rin= 4g .i62s destabilize). d by salt formation, and ring-opening by nucleophiles is favoured. The pK valuAziridine oef itselthef areactaziridinius with acidms explosivelion is 7.98y to giv. Aziridine polymerice productsis thus. a weaker base than dimethylamine (pK The aziridine ring is adestabilized by salt formation, and ring-opening by nucleophiles is favored. Aziridine a itself reacts =with 10.87)acids, explosivelybut strongetorgive thanpolymeric aniline products (pKa =. 4.62). Reactions with electrophilic reagents The aziridine ring is destabilized by salt formation, and ring-opening by nucleophiles is favoured. Aziridines, like amines, are nucleophiles and react with electrophiles. A nucleophilic substitution on a Reactions withAziridinelectrophilice itself reactreagentss with acids explosively to give polymeric products. Aziridines, like amines,saturateare nucleophilesd C-atom and aand nucleophilireact withc additioelectrophilesn to an alken.eA bearinnucleophilicg an acceptosubstitutionr group serveon as exama - saturated C-atom andplesa :nucleophilic addition to an alkene bearing an acceptor group serve as examples: Reactions with electrophilic reagents NEt3 Cl— C H 2COOEt » £>-CH2COOEt Aziridines, like amines, are nucleophiles and react with electrophiles. A nucleophilic substitution on a saturated C-atom and a nucleophilic addition to an alkene bearing an acceptor group serve as exam- H2C=CH-CN - *• £>-CH2-CH2-CN 11 ples: Ring-opening by nucleophiles Ammonia and primary amines Clreac—t Cwit HhCOOE azirdinet s to givNEte 31,2-diamines » £>-CH. The mechanisCOOEmt and the stereochemistry of this reaction are similar 2to the corresponding reactions of the oxiranes2 . The ring-opening of the aziridines is catalyzed especially effectively by acids (A2 mechanism, see p 19). The acid-catalysed hydrolysis to give amino alcohols serves as an example:
© H2C=CH-CN - H2*(X• £>-CHHO,2-CH2-CN
H30 *=* NH2 + H 20 - * ^
H3 Ring-opening by nucleophiles Such reactions can also be interpreted as alkylation of the nucleophile. This explains the cytostatic and Ammonia antitumouand primarr actiony o famine aziridiness anreacd oft bis(2-chloroethyl)aminwith azirdines et o1. Agivn equilibriue 1,2-diaminesm exists betwee. Thn 1e an dmechanism and the stereochemistr1 -(2-chloroethyl)aziridiniuy of this reactionm car h l oe r i dsimilae 2. r to the corresponding reactions of the oxiranes. The ring-opening of the aziridines is catalyzed especially effectively by acids (A2 mechanism, see p 19). The acid-catalysed hydrolysis to give amino alcohols serves as an example:
© H2(X HO,
H30 *=* NH2 + H 20 - * ^
H3
Such reactions can also be interpreted as alkylation of the nucleophile. This explains the cytostatic and antitumour action of aziridines and of bis(2-chloroethyl)amine 1. An equilibrium exists between 1 and 1 -(2-chloroethyl)aziridiniu m c h l o r i d e 2. 3.4 Aziridine 29
Care is advisable when handling aziridines, because many show considerable toxicity. The fol- lowing reactions are of importance: Acid base reactions Aziridines unsubstituted on the N-atom behave like secondary amines; TV-substituted aziridines behave like tertiary amines. They react with acids to give aziridinium salts:
A + HA *=*
The pKa value of the aziridinium ion is 7.98. Aziridine is thus a weaker base than dimethylamine (pKa = 10.87), but stronger than aniline (pKa = 4.62). The aziridine ring is destabilized by salt formation, and ring-opening by nucleophiles is favoured. Aziridine itself reacts with acids explosively to give polymeric products.
Reactions with electrophilic reagents Aziridines, like amines, are nucleophiles and react with electrophiles. A nucleophilic substitution on a saturated C-atom and a nucleophilic addition to an alkene bearing an acceptor group serve as exam- ples:
NEt3 Cl— C H 2COOEt » £>-CH2COOEt
H2C=CH-CN - *• £>-CH2-CH2-CN
Ring-opening by nucleophiles Ammonia and primary amines react with azirdines to give 1,2-diamines. The mechanism and the Ring-opening by nucleophiles Ammoniastereochemistrand yprimary of this aminesreaction reactare similawith razirdines to the correspondinto give 1,g2 -diaminesreactions. oThef themechanism oxiranes. and the stereochemistryThe ring-openinof thisg ofreaction the aziridineare similars is catalyzeto the correspondingd especially effectivelreactionsyof bthey acidoxiraness (A2. mechanism, see Thep 19)ring. Th-openinge acid-catalyseof the aziridinesd hydrolysiis catalyzeds to give aminespeciallyo alcoholeffectivelys servebys aacidss an example(A2 mechanism): . The acid- catalyzed hydrolysis to give amino alcohols serves as an example: © H2(X HO,
H30 *=* NH2 + H 20 - * ^
H3 30 3 Three-Membered Heterocycles Such reactions can also be interpreted as alkylation of the nucleophile. This explains the cytostatic and antiSuc-htumor reactionactions caofnaziridines also be interpreteand of bisd( 2a-schloroethyl)amine alkylation of the1 nucleophile. An equilibrium. Thiexistss explainbetweens the 1cytostatiand 1- c and (antitumou2-chloroethyl)aziridiniumr action of aziridinechlorides an2.d of bis(2-chloroethyl)amine 1. An equilibrium exists between 1 and 1 -(2-chloroethyl)aziridiniu m c h l o r i d e 2.
H
1 2 Nucleophilic cell components, e.g. the amino groups of the guanine bases in DNA, are alkylated by the aziridinium ionNucleophilias a resultc celofl componentsa nucleophilic, e.gring. the-opening amino group. In thes ofcase the guaninof bise( 2base-chloroethyl)amine,s in DNA, are alkylatethe d by the reaction can aziridiniube repeatedm ioonn aas guaninea result baseof a nucleophiliof the otherc ring-openingDNA strand .of Inthe thedouble case ohelixf bis(2-chloroethyl)amine. This results in , the cross-linkingreactioof the ntwo canDNA be repeatestrandsd andon aconsequently guanine base blocksof the othereplicationr DNA .strand of the double helix. This results in cross-linking of the two DNA strands and consequently blocks replication (see p 31). 12
Deamination to alkenes Aziridines with an unsubstituted N-atom are stereospecifically deaminated by nitrosyl chloride via the corresponding 7V-nitroso compound:
H n -R 0=N-CI + H
The synthesis of aziridines can be achieved from substituted amines or alkenes.
(1) Cyclization of ß-substituted amines /?-Amino alcohols, which are conveniently made from oxiranes with ammonia or amines, react with thionyl chloride to give chloroamines, which can be cyclized to aziridines by alkali hydroxide (GABRIEL 1888).
SOCI2 e KOH -— Cl -S02, -HCI { _ , V u Mitsunobu-reagent N
-H20
H2SO4 HoN ^ SQ KOH .Q/ 3 -H2O
Sulfate esters, obtained from amino alcohols and sulfuric acid, when treated with alkali also form aziridines (WENKER 1935). In both cases, the amine is liberated from the ammonium salts by the base. The leaving group Cl or OSCV is substituted intramolecularly by the amino group on the /?-C-atom. The direct cyclodehydration of /?-amino alcohols can be effected with the MITSUNOBU reagent (triphenylphosphane/diethyl azodicarboxylate) [16]. 30 3 Three-Membered Heterocycles
H
1 2
Nucleophili30 c cell components3 , e.g.Three-Membere the amino groupd Heterocycles of the guanins e bases in DNA, are alkylated by the aziridinium ion as a result of a nucleophilic ring-opening. In the case of bis(2-chloroethyl)amine, the reaction can be repeated on a guanine base of the other DNA strand of the double helix. This results in cross-linking of the two DNA strands and consequently blocks replication (see p 31).
Deamination to alkenes H Aziridines with an unsubstituted 1N-ato m are stereospecificall2y deaminated by nitrosyl chloride via the corresponding 7V-nitroso compound: Nucleophilic cell components, e.g. the amino groups of the guanine bases in DNA, are alkylated by the aziridinium ion as a result of a nucleophilic ring-opening. In the case of bis(2-chloroethyl)amine, the reaction can be repeated on a guanineH base of the other DNA strand of then double helix. This results in -R cross-linking of the two DNA strands and consequently blocks replication (see p 31). 0=N-CI + H
H2SO4 HoN ^ SQ KOH Sulfate esters, obtained from amino alcohols an.Q/ d sulfuri3 c acid, when treated with alkali also form -H2O aziridines (WENKER 1935). In both cases, the amine is liberated from the ammonium salts by the base. The leaving group Cl or OSCV is substituted intramolecularly by the amino group on the /?-C-atom. SulfatThe e direcesterst, obtainecyclodehydratiod from aminn o oalcoholf /?-amins anod sulfurialcoholc acids ca, nwhe bne treateeffected witd hwit alkalh ith alse oMITSUNOB form U reagent (triphenylphosphane/diethyaziridines (WENKER 1935). In botl azodicarboxylateh cases, the amine) is [16]liberate. d from the ammonium salts by the base. The leaving group Cl or OSCV is substituted intramolecularly by the amino group on the /?-C-atom. The direct cyclodehydration of /?-amino alcohols can be effected with the MITSUNOBU reagent (triphenylphosphane/diethyl azodicarboxylate) [16]. In both cases, the amine is liberated from the ammonium salts by the base. The leaving group Cl or - OSO3 is substituted intramolecularly by the amino group on the �-C-atom.
The direct cyclodehydration of �-amino alcohols can be effected with3.4 the MITSUNOBUAzlridine reagent 31 (triphenylphosphane/diethyl azodicarboxylate). (2) Thermal or photochemical reaction ofazides with alkenes (2) Thermal or photochemical reactionPhenylof azidazidese reactwiths withalkenes alkenes to give 4,5-dihydro-l,2,3-triazoles (1,3-dipolar cycloaddition, see Phenyl azide reacts with alkenes top 204)give, whic4,5-dihydroh are thermall-1,2,3y- triazolesor photochemicall(1,3-dipolary convertecycloaddition),d into aziridinewhichs through loss of nitrogen: are thermally or photochemically converted into aziridines through loss of nitrogen:
R1= Ph
Thermolysis of ethyl azidoformate, however, + R2CH=CHR3 R1-—/fS A produces ethoxycarbonylnitrene, which by a [2+1] cycloaddition reacts with alkenes to form aziridines. The mechanism is thus influenced by the azide
1 1 substituent R . R —N3
2 : A 1 _ + R CH=CHR
-N2
14 R1 = COOEt
Thermolysis of ethyl azidoformate, however, produces ethoxycarbonylnitrene, which by a [2+1] cycloaddition reacts with alkenes to form aziridines. The mechanism is thus influenced by the azide substituent R1.
Aziridine, a colourless, water-soluble, poisonous liquid (bp 57°C) of ammoniacal odour is rela- tively stable, thermally, but is best stored in a refrigerator over sodium hydroxide. Some natural products contain an aziridine ring, e.g. mitomycins (3: mitomycin C). This is responsi- ble for the cytostatic and antitumour activity of these antibiotics. Many synthetic aziridines have been screened for their antitumour activity. Some have reached the clinic, especially as antileukaemic agents, e.g. 4 and 5.
J A AIN NN NA JI^M—A \^ \xx II I II
Aziridines with C2 symmetry have been used successfully as chiral auxiliaries for alkylations and aldol reactions [17]. 3.4 Azlridine 31
(2) Thermal or photochemical reaction ofazides with alkenes Phenyl azide reacts with alkenes to give 4,5-dihydro-l,2,3-triazoles (1,3-dipolar cycloaddition, see p 204), which are thermally or photochemically converted into aziridines through loss of nitrogen:
R1= Ph
+ R2CH=CHR3 R1-—/fS A
1 R —N3
2 : A 1 _ + R CH=CHR
-N2
R1 = COOEt
Thermolysis of ethyl azidoformate, however, produces ethoxycarbonylnitrene, which by a [2+1] cycloaddition reacts with alkenes to form aziridines. The mechanism is thus influenced by the azide substituent R1.
[D] Aziridine, aAziridinecolorless,, a colourlesswater-soluble,, water-solublepoisonous, poisonouliquids liqui(bpd57 (bp° 57°CC) of) oammoniacalf ammoniacal odouodorr isis relarelatively- stable, thermally,tivelbuty stableis best, thermallystored, buinta isrefrigerator best stored inover a refrigeratosodiumr ovehydroxider sodium. hydroxide. Some natural products contain an aziridine ring, e.g. mitomycins (3: mitomycin C). This is responsi- Some naturalble forproducts the cytostaticontainc and antitumouan aziridiner activitring,y oef .thesg. mitomycinse antibiotics. (Man3: mitomyciny synthetic aziridineC). Thiss havis responsiblee been for the cytostaticscreened foandr theiantir antitumou-tumor ractivity activityof. Somthesee havantibioticse reached .thManye clinicsynthetic, especiallyaziridines as antileukaemihavec been screenedagentsfor their, e.g. anti4 and-tumor 5. activity. Some have reached the clinic, especially as anti-leukaemic agents, e.g. 4 and 5.
J A AIN NN NA JI^M—A \^ \xx II I II
[E] Aziridines withAziridineC2 symmetrys with C2 symmetrhave beeny haveused been successfullyused successfullasy chiralas chiraauxiliariesl auxiliaries forfor alkylationsalkylations and aldol reactions.and aldol reactions [17].
15 32 3 Three-Membered Heterocycles
32 3.5 Dioxiran3e Three-Membered Heterocycles 3.5 Dioxirane
Dioxiranes have been available only since the mid-eighties [18]. They are synthesized by 3.5 Dioxiraneoxidation of ketones with potassium hydrogenperoxysulfate (oxone®), e.g.: 32 3 Three-MembereDioxiraneds Heterocyclehave been availabls e only since the mid-eighties [18]. They are synthesized by [A-C] Dioxiranes have been available only since theO mid-eighties. They are synthesized°by oxidation of oxidation of ketones with potassiu// m hydrogenperoxysulfatKHSO5 Hur C e/ (oxone®)\ , e.g.: ketones with potassium hydrogen peroxysulfateH3C-C(oxonex ®),- e.g.: —* - 3 ^/— O
3.5 Dioxirane CH3 H3C O ° // KHSO5 Hur C / \ H3C-Cx - —* - 3 ^/— O Dimethyldioxirane, together with acetone, is removed from the reaction vessel by distillation. The yel- CH3 H3C low 0.1-0.2 M solution can be used as an oxidizing agent, e.g. for the epoxidation of olefins [19], for Dimethyldioxiranethe oxidatio, togethern of enolatewith acetone,s to or-hydroxycarbonyis removed from thel compoundreaction vessels and fobyr distillationthe oxidatio. n of primary amines Dioxiranes have been availablTheDimethyldioxiraneyellowe onlinty0o .1 sincnitr-0.2oe M compoundsthsolution,e togethe mid-eightiecan:r witbe huseds acetone[18]as .an ,The oxidizingis removey areagent, synthesized froem.g .thfored reactiothebyepoxidationn vesselof byolefins, distillationfor . The yel- oxidation of ketones with potassiuthelooxidationw 0.1-0.m hydrogenperoxysulfat2of Menolates solutioton� ca-hydroxycarbonyln be usee (oxone®)d as acompoundsn ,oxidizin e.g.: gand agentfor the, e.goxidation. for theof epoxidatioprimary aminesn of intoolefins [19], for nitrothecompounds oxidation : of enolates to or-hydroxycarbonyl compounds and for the oxidatioO n of primary amines jf into nitro compounds: O R— N H 2 +° 3 H3 C^JO - *> R— N O 2 + 3 H3C CH3 + H2O // KHSO5 ur / \ H C-C - —* - H3C^/— O 3 x H3C O BoronCH3 trifluoride catalyzes the Hisomerization3C of dimethyldioxiranes to methyl acetatejf. Difluorooxirane is formed as a pale-yellow, normally stable gas when an equimolar mixture of FCO F Boron trifluoridR— N He2 catalyse+ 3s Hthe3 C^JisomerizatioO - n of dimethyldioxirane*> R— N O 2 + 3s toH methy3C lCH acetate3 . +2 H2O and CIF is passedDifluorooxiranover a CsFe icatalysts forme. d as a pale-yellow, normally stable gas when an equimolar mixture of Dimethyldioxirane, together with acetone, is removed from the reactioHn3 Cvessel by distillation. The yel- 16 low 0.1-0.2 M solution can be used as an oxidizinFCO2Fg anagentd GIF, e.gis passe. ford thovee repoxidatio a CsF catalysn to f[20] olefin. s [19], for the oxidation of enolates to or-hydroxycarbonyBoron trifluoridl compounde catalyses ans dth efo isomerizatior the oxidation onf dimethyldioxiraneof primary aminess to methyl acetate. into nitro compounds: Difluorooxiran3.6 Oxaziridine is formed aes a pale-yellow, normally stable gas when an equimolar mixture of FCO2F and GIF is passed over a CsF catalyst [20]. O jf R— N H 2 + 3 H3 C^J3.O6 - Oxaziridin*> R— N O 2e + 3 H3C CH3 + H2O H3C Oxaziridines are structural isomers of oximes and nitrones. Trialkyl oxaziridines are colour- less liquids, sparingly soluble in water. The following reactions are typical for oxaziridine. Boron trifluoride catalyses the isomerization of dimethyldioxiranes to methyl acetate. Isomerization to nitrones Difluorooxirane is formed as a pale-yellow, normally stable gas when an equimolar mixture of As aOxaziridine reversal to ths ear photoisomerizatioe structural isomern so fo nitronef oximes s(se ane dp nitrones 33), oxaziridine. Trialkys l caoxaziridinen be convertes arde intcolouro ni-- FCO2F and GIF is passed over a CsF catalyst [20]. troneless sb yliquids thermolysis, sparingl. They require solublde temperaturin water. The depende followins on gth ereaction type ofs oxaziridin are typicae lsubstituents for oxaziridine. .
IsomerizationRing-opening to nitrones by nucleophiles 3.6 Oxaziridine As a reversaOn acid-catalysel to the photoisomerizatiod hydrolysis, 2-alkyl-3-phenyloxaziridinen of nitrones (see p 33)s ,yiel oxaziridined benzaldehyds cane bane dconverte A^-alkylhydroxyld into ni-- trones baminesy thermolysis, e.g.: . The required temperature depends on the type of oxaziridine substituents.
Ring-opening by nucleophiles
Oxaziridines are structural isomerOn acid-catalyses of oximeds hydrolysisand nitrones, 2-alkyl-3-phenyloxaziridine. Trialkyl oxaziridines ares colouryield benzaldehyd- e and A^-alkylhydroxyl- amines, e.g.: less liquids, sparingly soluble in water. The following reactions are typical for oxaziridine.
Isomerization to nitrones As a reversal to the photoisomerization of nitrones (see p 33), oxaziridines can be converted into ni- trones by thermolysis. The required temperature depends on the type of oxaziridine substituents.
Ring-opening by nucleophiles On acid-catalysed hydrolysis, 2-alkyl-3-phenyloxaziridines yield benzaldehyde and A^-alkylhydroxyl- amines, e.g.: 32 3 Three-Membered Heterocycles
3.5 Dioxirane
Dioxiranes have been available only since the mid-eighties [18]. They are synthesized by oxidation of ketones with potassium hydrogenperoxysulfate (oxone®), e.g.:
O ° // KHSO5 Hur C / \ H3C-Cx - —* - 3 ^/— O
CH3 H3C
Dimethyldioxirane, together with acetone, is removed from the reaction vessel by distillation. The yel- low 0.1-0.2 M solution can be used as an oxidizing agent, e.g. for the epoxidation of olefins [19], for the oxidation of enolates to or-hydroxycarbonyl compounds and for the oxidation of primary amines into nitro compounds:
O jf
R— N H 2 + 3 H3 C^JO - *> R— N O 2 + 3 H3C CH3 + H2O
H3C
Boron trifluoride catalyses the isomerization of dimethyldioxiranes to methyl acetate. Difluorooxirane is formed as a pale-yellow, normally stable gas when an equimolar mixture of FCO2F and GIF is passed over a CsF catalyst [20].
3.6 Oxaziridine 3.6 Oxaziridine
[A,B] Oxaziridines are structural isomers of oximes and nitrones. Trialkyl oxaziridines are colorless liquids, sparingly soluble in water. The following reactions are typical for oxaziridine. Oxaziridines are structural isomers of oximes and nitrones. Trialkyl oxaziridines are colour- less liquidsIsomerization, sparinglto ynitrones soluble in water. The following reactions are typical for oxaziridine. As a reversal to the photoisomerization of nitrones, oxaziridines can be converted into nitrones by Isomerization tothermolysis nitrones. The required temperature depends on the type of oxaziridine substituents.
As a reversal to thRinge photoisomerizatio-opening by nucleophilesn of nitrone3.6s (see Oxaziridinp 33), oxaziridinee s can be converted3 3into ni- On acid-catalyzed hydrolysis, 2-alkyl-3-phenyloxaziridines yield benzaldehyde and N- trones by thermolysisalkylhydroxylamines. The require, ed.g .:temperature depends on the type of oxaziridine substituents.
w / \ +MH222U0(H® (M ) // Ring-opening by nucleophiles •h-/X --^—L» - P^ HO— N H — C M e 3 I CMe3 H On acid-catalysed hydrolysis, 2-alkyl-3-phenyloxaziridines yield benzaldehyde and A^-alkylhydroxyl- amines, e.g.: Reduction to imines 17 Oxaziridines, particularly 2-(phenylsulfonyl)oxaziridines, are used as reagents in a number of oxidation procedures. The oxidation of sulfides to sulfoxides may serve as an example:
R1 O R1 I Ph / \ I s + rn^/—-N - ^ s_o + Ph—CH=N-S02Ph
The synthesis of oxaziridines can be accomplished from imines, nitrones or carbonyl com- pounds:
(1) Oxidation of imines withperoxy acids:
R1 0 O Kv PhC0H ^ RU/\ R2^/X C=N 3 . N .. + /2 3 2 k 3 R R R' R3 rfl 'R
As in the epoxidation of alkenes, (see p 20), a stereospecific czs-addition is involved. In the case of 2- substituted oxaziridines (AG* = 100-130 kJ mol"1), the activation enthalpy of the pyramidal inversion of the N-atom is so high that the configuration of the N-atom is fixed at room temperature. Thus, the configuration of the starting material is preserved and the racemate of one of the diastereoisomeric oxaziridines is formed. In the case of chiral imines or chiral peroxy acids, the reaction proceeds enanti- oselectively.
(2) Photoisomerization of nitrones:
p
6
(3) Amination of carbonyl compounds: In the presence of a base, hydroxylamine-O-sulfonic acid or chloramine aminate carbonyl compounds nucleophilically (SCHMITZ 1961), e.g.:
+ HSO + H H2N-OS03H - * jn - * \ ' 4 2° 3.6 Oxaziridine 33
w / \ +MH222U0(H® (M ) // - - •h-/X 3.6 -^—L»Oxaziridin e P^ HO— N H — C M e 3 33 I CMe3 H
w Reduction to imines/ \ +MH222U0(H® (M ) // •h-/X --^—L» - P^ HO— N H — C M e 3 Oxaziridines, particularlI y CMe2-(phenylsulfonyl)oxaziridines3 H, are used as reagents in a number of oxidation procedures. The oxidation of sulfides to sulfoxides may serve as an example: Reduction to imines
ReductionOxaziridinesto imines, particularlRy1 2-(phenylsulfonyl)oxaziridinesO , are usedR a1s reagents in a number of oxidation I Ph / \ I procedures. The oxidations o+f sulfide rn^/s— toN sulfoxide s may serv^e as asn_ exampleo + :Ph—CH=N-S02Ph Oxaziridines, particularly 2-(phenylsulfonyl)--oxaziridines, are used as reagents in a number of oxidation procedures. The oxidation of sulfides to sulfoxides may serve as an example:
R1 O R1 I rn^/Ph —/ \ ^I_ Ph—CH=N-S02Ph The synthesis + s of -oxaziridineN- s can be accomplisheso +d from imines, nitrones or carbonyl com- pounds: [C] The synthesis of oxaziridines can be accomplished from imines, nitrones or carbonyl compounds: (1)Th e Oxidation synthesis ooff iminesoxaziridine withperoxys can b e acids:accomplished from imines, nitrones or carbonyl com- (1) Oxidationpoundsof imines: with peroxy acids:
R1 0 O Kv PhC0H ^ RU/\ R2^/X (1) Oxidation of imines withperoxyC=N acids: 3 . N .. + /2 3 2 k 3 R R R' R3 rfl 'R
R1 0 O As in the epoxidation of alkenes,Kv a stereospecificPhC0H ^ cis-additionRU/\is involved R2^/. InXthe case of 2-substituted C=N 3 . N .. + As in the epoxidation of -1alkenes, (see p 20), a stereospecific czs-addition is involved. In the case of 2- oxaziridines (�G*= 100-130 kJ mol/2 ),3the activation enthalpy2 of kthe pyramidal inversion3 of the N-atom is so high thatsubstitutethe configurationd oxaziridineRof sthe (AGRN- atom* = 100-13is fixed0 atkJroom mol"R' temperature1), Rth3e activatiorf.l Thus,n'R enthalpthe configurationy of the pyramidaof the l inversion starting materialof the N-atois preservedm is so higandh thetharacematet the configuratioof one ofnthe of diastereoisomericthe N-atom is fixeoxaziridinesd at room istemperatureformed. . Thus, the In the case of chiral imines or chiral peroxy acids, the reaction proceeds enantioselectively. As iconfiguration the epoxidation onf othf ealkenes startin, g(se materiae p 20),l ai sstereospecifi preservedc anczs-additiod the racematn is involvede of on. eIn othf eth case ediastereoisomeri 18of 2- c 1 substituteoxaziridined oxaziridines is formeds (AG. *I n= th100-13e cas0e koJf mol"chiral) ,imine the activatios or chiran enthalpl peroxyy o acidsf the ,pyramida the reactiol inversion proceedn s enanti- of thoselectivelye N-atom is. so high that the configuration of the N-atom is fixed at room temperature. Thus, the configuration of the starting material is preserved and the racemate of one of the diastereoisomeric oxaziridines is formed. In the case of chiral imines or chiral peroxy acids, the reaction proceeds enanti- (2) Photoisomerization of nitrones: oselectively.
(2) Photoisomerization of nitrones: p
6 p
6 (3) Amination of carbonyl compounds: In the presence of a base, hydroxylamine-O-sulfonic acid or chloramine aminate carbonyl compounds (3) nucleophilicall Amination of carbonyly (SCHMIT compounds:Z 1961), e.g.: In the presence of a base, hydroxylamine-O-sulfonic acid or chloramine aminate carbonyl compounds nucleophilically (SCHMITZ 1961), e.g.:
+ HSO + H H2N-OS03H - * jn - * \ ' 4 2°
+ HSO + H H2N-OS03H - * jn - * \ ' 4 2° 3.6 Oxaziridine 33
w / \ +MH222U0(H® (M ) // •h-/X --^—L» - P^ HO— N H — C M e 3 I CMe3 H
Reduction to imines 3.6 Oxaziridine 33 Oxaziridines, particularly 2-(phenylsulfonyl)oxaziridines, are used as reagents in a number of oxidation
procedures. The oxidation of sulfides to sulfoxidew s may serve as an example: / \ +MH222U0(H® (M ) // •h-/X --^—L» - P^ HO— N H — C M e 3 I CMe3 H
R1 O R1 Reduction toI imines Ph / \ I s + rn^/—N ^ s_o + Ph—CH=N-S02Ph Oxaziridines, particularly 2-(phenylsulfonyl)oxaziridines-- , are used as reagents in a number of oxidation procedures. The oxidation of sulfides to sulfoxides may serve as an example:
The synthesisR 1o f oxaziridineO s can be accomplisheR1 d from imines, nitrones or carbonyl com- I rn^/Ph —/ \ ^I_ Ph—CH=N-S02Ph pounds: s + -N- so +
(1) Oxidation of imines withperoxy acids: The synthesis of oxaziridines can be accomplished from imines, nitrones or carbonyl com- pounds: R1 0 O (1) Oxidation of iminesKv withperoxy acids:PhC0H ^ RU/\ R2^/X C=N 3 . N .. + /2 3 2 k 3 R R R' R3 rfl 'R R1 0 O Kv PhC0H ^ RU/\ R2^/X C=N 3 . N .. + /2 3 2 k 3 As in the epoxidation of alkenesR R, (see p 20), a stereospecifiR' R3 crf l czs-additio'R n is involved. In the case of 2- 1 substituteAsd i noxaziridine the epoxidatiosn (AGof alkenes* = ,100-13 (see p 20)0 ,k aJ stereospecifi mol" ), thc eczs-additio activation ins involvedenthalp. Iyn thofe casthee opyramidaf 2- l inversion of the N-atosubstitutem di soxaziridine so high s tha(AGt *th = e100-13 configuratio0 kJ mol"1n), thoef activatiothe N-aton enthalpm isy fixeof thed pyramidaat rooml inversio temperaturen . Thus, the configuratioof then N-ato of mth ies sstartino high thag tmateria the configuratiol is preserven of the N-atod anmd isth fixee racematd at room etemperature of one . oThusf th,e th ediastereoisomeric oxaziridineconfiguratios is formedn of the. Istartinn theg casmateriae olf ichiras preservel imined ands thoer racematchiral eperox of onye oacidsf the ,diastereoisomeri the reactionc proceeds enanti- oxaziridines is formed. In the case of chiral imines or chiral peroxy acids, the reaction proceeds enanti- oselectivelyoselectively. .
(2) Photoisomerization(2) Photoisomerization o fo fnitrones: nitrones:
p p (2) Photoisomerization of nitrones: 6
6
(3) Amination of carbonyl compounds: (3) AminationIn thofe presenccarbonyle of compoundsa base, hydroxylamine-O-sulfoni: c acid or chloramine aminate carbonyl compounds In the(3) presence Aminationnucleophilicallof a base, of ycarbonyl (SCHMIThydroxylamineZ 1961) compounds:, e.g.-O-:sulfonic acid or chloramine aminate carbonyl compounds nucleophilically (SCHMITZ 196134 ). In this reaction,3the intramolecularThree-Memberenucleophilicd Heterocyclesubstitutions occurs onIann thN-eatom presenc. e of a base, hydroxylamine-O-sulfonic acid or chloramine aminate carbonyl compounds nucleophilically (SCHMITZ 1961), e.g.: In this reaction, the intramolecular nucleophilic substitution occur +s o HSOn an N-atom+ H. H2N-OS03H - * jn - * \ ' 4 2° Oxaziridines are oxidizing agents as well as important synthetic intermediates [21]. F o r in- [E] Oxaziridines are oxidizing agentsstance, as7V-hydroxyaminocarboxyliwell as important syntheticc esters 2 caintermediatesn be prepared fro. mFor a-aminocarboxyliinstance, N-c acid esters hydroxyaminocarboxylic esterswith oxaziridine2 can s be1 as intermediateprepared s fromas follows�-aminocarboxylic: acid esters with + HSO + H oxaziridines 1 as intermediatesH2N-OS0as follows3H : - * jn - * \ ' 4 2° o Ph— °\ H20® P JN *- Ph^f + HO-NH-CH-COOMe / ^CH-COOMe H R H I n R19 R 3.7 3//-Diazirine 3//-Diazirines are structural isomers of diazoalkanes. They are gases or colourless liquids, e.g. 3,3-dimethyldiazirine, bp 21°C. Liquid 3//-diazirines can decompose explosively. Their basicity is very low. U n l i k e diazoalkanes, they react with acids only slowly, with the liberation of ni- trogen. The dediazoniation of 3//-diazirines can be effected thermally or photochemically [22]. In the ab- sence of carbene acceptors, the initially formed carbenes isomerize to give olefins, e.g.: A or hv H3C— C - C H 3 - *- H3C— C H = C H 2 -N2 H3C 3//-Diazirines are prepared by oxidation of 7V-unsubstituted diaziridines with silver oxide or mercury oxide (PAULSEN 1960, SCHMITZ 1961): R + 2 A g + H Ag20 - *• 2° 3-Chloro-3/f-diazirines are formed by oxidation of amidines with sodium hypochlorite: 34 3 Three-Membered Heterocycles In this reaction, the intramolecular nucleophilic substitution occurs on an N-atom. 34 3 Three-Membered Heterocycles Oxaziridines are oxidizing agents as well as important synthetic intermediates [21]. F o r in- stance, 7V-hydroxyaminocarboxylic esters 2 can be prepared from a-aminocarboxylic acid esters In thiwits reactionh oxaziridine, the intramoleculas 1 as intermediater nucleophilis as followsc substitutio: n occurs on an N-atom. 34 3 Three-Membered Heterocycles Oxaziridines are ooxidizing agents as well as important synthetic intermediates [21]. F o r in- stance, 7V-hydroxyaminocarboxyliPh— 3.7 3//-Diazirine °\ H20® P3//-Diazirines are structural isomers of diazoalkanes. They are gases or colourless liquids, J *- Ph^f + HO-NH-CH-COOMe N e.g. 3,3-dimethyldiazirine, bp 21°C. Liquid 3//-diazirines can decompose explosively. Their / ^CH-COOMe H R H I basicitn y is very low. U n lR i k e diazoalkanes, they react with acids only slowly, with the liberation of ni- R trogen. 3//-Diazirines are structural isomers of diazoalkanes. They are gases or colourless liquids, 3.7 3H-DiazirineThe dediazoniation of 3//-diazirines can be effected thermally or photochemically [22]. In the ab- e.g. 3,3-dimethyldiazirine, bp 21°C. Liquid 3//-diazirines can decompose explosively. Their sence of carbene acceptors, the initially formed carbenes isomerize to give olefins, e.g.: [A-D] 3H-Diazirinesbasicitarey is structuralvery lowisomers. U n l i k e diazoalkanesof diazoalkanes, the. yThey reacaret witgasesh acidors onlcolorlessy slowlyliquids,, with eth.ge .liberation of ni- 3,3-dimethyldiazirine,trogen. bp 21 °C. Liquid 3H-diazirines can decompose explosively. Their basicity is very low. Unlike diazoalkanes, they react with acids only slowly, with the liberation of nitrogen. The dediazoniation of 3//-diazirines caA nor bhve effected thermally or photochemically [22]. In the ab- H3C— C - C H 3 - *- H3C— C H = C H 2 The dediazoniationsence ofof 3carbenH-diazirinese acceptorscan ,be theeffected initiallythermally forme-N2 d carbeneor photochemicallys isomerize t.o Ingivthee olefinsabsence, e.g.of: 3.7 3//-Diazirine carbene acceptors, the initially formed carbenesH3C isomerize to give olefins, e.g.: A or hv 3//-Diazirines are prepared by oxidation oHf3 C7V-unsubstitute— C - C H 3 - d diaziridine*- H3C— Cs H wit = C Hh2 silver oxide or mercury -N2 oxide (PAULSENH 31960C , SCHMITZ 1961): 3H-Diazirines are prepared by oxidation of N-unsubstituted diaziridines with silver oxide or mercury oxide (PAULSEN3//-Diazirine1960, SCHMITZs are prepare1961) d by oxidation of 7V-unsubstituted diaziridines with silver oxide or mercury 3//-Diazirines are structural isomers of diazoalkanes. They are gases or colourless liquids, oxide (PAULSEN 1960, SCHMITZ 1961): Ag 0 - *• R + 2 A g + H2° e.g. 3,3-dimethyldiazirine, bp 21°C. Liquid 3//-diazirines can decompos3.8 e explosively2 DiazJridine. Their 35 basicity is very low. U n l i k e diazoalkanes3-,Chloro they- 3reacH-diazirinest with areacidformeds onlbyy oxidationslowly, ofwitamidinesh the withliberatiosodiumn hypochloriteof ni- : R + 2 A g + H trogen. Ag20 - *• 2° 3-Chloro-3/f-diazirineNH s are formed by oxidationN of amidines with sodium hypochlorite: The dediazoniation of 3//-diazirines can be effected thermally o+r photochemicall2NaOCI y> > [22]R^/\., In the+ abNaC-I + NaOH + H2O NH2 / sence of carbene acceptors, the initially formed carbenes isomerize to give olefins, e.g.: 20 3-Chloro-3/f-diazirines are formed by oxidation of amidines with sodium hypochlorite: A or hv 3.H83C — CDiaziridin - C H 3 - e*- H3C— C H = C H 2 -N2 H3C 3//-Diazirines are prepared by oxidation of 7V-unsubstituted diaziridines with silver oxide or mercury oxide (PAULSEN 1960, SCHMITZ 1961): Diaziridines are crystalline, weakly basic compounds. As already explained in connection with oxaziridines (see p 33), the N-atoms are configurationally stable so that stereoisomer- ism is possible. The acid-catalysed hydrolysis of diaziridines yields ketones and hydrazines: R + 2 A g + H Ag20 - *• 2° H H\®/H 1 . 1 N MHoOU® N u ~ R NHx 2 R ' \ 3 _i / \ + H 2O 2 1 , Y_ ® ^ \. »- p^-r-M ^ \=n + H N_NH_RcJ 3-Chloro-3/f-diazirines are formed by oxidation of amidines with sodium hypochlorite: Thus, a synthesis of hydrazines is available starting from imines and hydroxylamine-0-sulfonic acid, or from TV-substituted hydroxylamine-0-sulfonic acids. Diaziridines unsubstituted on the N-atoms can be oxidized to give 3//-diazirines. Diaziridines are prepared by the action of ammonia and chlorine on ketones (PAULSEN, SCHMITZ 1959). Initially, chloramine is formed: 2NH3 + CI2 *• NH2CI + NH4CI H O N 1 R —/ + NH2CI + 2NH3 ** R^Z^NH + NH4CI + H20 R2 IT The action of ammonia or primary amines and hydroxylamine-O-sulfonic acid upon ketones also yields diaziridines. Likewise, the amination of imines (azomethines) with hydroxylamine-O-sulfonic acid yields diaziridines: NH2—OS03H R2 3.8 DiazJridine 35 3.8 DiazJridine 35 NH N NH N + 2NaOCI >> R^/\, + NaCI + NaOH + H2O + 2NaOCI >> R^/\, + NaCI + NaOH + H2O NH2 / NH2 / 3.8 Diaziridin3.8 e Diaziridine 3.8 Diaziridine [A-C] DiaziridinesDiaziridinearescrystalline, are crystallineweakly, weaklybasic basicompoundsc compounds. As .already As alreadexplainedy explainein dconnection in connectiowithn Diaziridineoxaziridiness are crystallinewit, theh oxaziridineN-atoms, weaklyares (seconfigurationally ebasi p 33)c , compoundsthe N-atomstables. soarAethats configurationall alreadstereoisomerismy explainey stabldis epossiblei ns oconnectio that. stereoisomern - with oxaziridineism is possibles (see .p 33), the N-atoms are configurationally stable so that stereoisomer- The acid-catalyzed hydrolysis of diaziridines yields ketones and hydrazines: ism is possible. The acid-catalysed hydrolysis of diaziridines yields ketones and hydrazines: The acid-catalysed hydrolysis of diaziridines yields ketones and hydrazines: H H\®/H 1 . 1 N MHoOU® N u ~ R NHx 2 R ' \ 3 _i / \ + H 2O 2 1 , Y_ ® ^ \. »- p^-r-M ^ \=n + H N_NH_RcJ H H\®/H 1 . 1 N MHoOU® N u ~ R NHx 2 R ' \ 3 _i / \ + H 2O 2 1 , Y_ ® ^ \. »- p^-r-M ^ \=n + H N_NH_RcJ Thus,Thus, aa synthesissynthesis ofof hydrazineshydrazines isis availableavailable startingstarting fromfromimines iminesand andhydroxylamine hydroxylamine-0-sulfoni-O-sulfoniccacid, acid, ororfrom fromN TV-substitute-substituteddhydroxylamine hydroxylamine-0-sulfoni-O-sulfoniccacids acids. . Diaziridines unsubstituted on the N-atoms can be oxidized to give 3//-diazirines. Thus, a synthesis oDiaziridinesf hydrazineunsubstituteds is availablone thestartinN-atomsg frocanm iminebe oxidizeds andto hydroxylamine-0-sulfonigive 3H-diazirines. c acid, or from TV-substituteDiaziridined hydroxylamine-0-sulfonis are prepared by cth e acidsactio.n of ammonia and chlorine on ketones (PAULSEN, SCHMITZ Diaziridines unsubstitute1959). Initiallyd on th, chloramine N-atomes i sca formedn be :oxidized to give 3//-diazirines. 21 2NH + CI *• NHCI + NHCI Diaziridines are prepared by the action of ammoni3 a an2 d chlorine2 on ketone4 s (PAULSEN, SCHMITZ H 1959). Initially, chloramine is formed: O N 1 R —/ + NH2CI + 2NH3 ** R^Z^NH + NH4CI + H20 R2 IT 2NH3 + CI2 *• NH2CI + NH4CI H The actioOn of ammonia or primary amines and hydroxylamine-O-sulfoniNc acid upon ketones also yields 1 diaziridinesR —/ +. LikewiseNH2CI +, 2NHthe aminatio3 n* *o f R^Z^imines N(azomethinesH + NH4CI) +wit Hh 20hydroxylamine-O-sulfonic acid yields diaziridinesR2 : IT The action of ammonia or primary amines and hydroxylamine-O-sulfonic acid upon ketones also yields diaziridines. Likewise, the amination of imineNH2—OS0s (azomethines3H ) with hydroxylamine-O-sulfonic acid R2 yields diaziridines: NH2—OS03H R2 3.8 DiazJridine 35 3.8 DiazJridine 35 NH N NH N + 2NaOCI >> R^/\, + NaCI + NaOH + H2O + 2NaOCI >> R^/\, + NaCI + NaOH + H2O NH2 / NH2 / 3.8 3.Diaziridin8 Diaziridine e DiaziridineDiaziridines are crystallines are crystalline, weakly, basi weaklyc compounds basic compounds. As alread. Ays explainealreadyd explaine in connectiod in nconnection with oxaziridinewith oxaziridines (see ps 33)(se, eth pe 33)N-atom, thes N-atomare configurationalls are configurationally stable syo stablthat estereoisomer so that stereoisomer- - ism is possibleism is possible. . The acid-catalyseThe acid-catalysed hydrolysid hydrolysis of diaziridines of diaziridines yields ketones yieldss anketoned hydraziness and hydrazines: : HH H \®/ HH 1 . H \®/ 1 1 . N MHoOU® N u ~ R NHx 2 R 1 ' \ N 3 MHoO_i U®/ \ N+ H 2O 2u 1~ , R NHx 2 Y_ R® ^ ' \ 3 \. _i / \ »- p^-r-+ H 2OM 2 1 ,^ \=n + HY _N_ NH_RcJ® ^ \. »- p^-r-M ^ \=n + H N_NH_RcJ Thus, a synthesis of hydrazines is available starting from imines and hydroxylamine-0-sulfonic acid, Thus, a synthesis of hydrazines is available starting from imines and hydroxylamine-0-sulfonic acid, or from TV-substituted hydroxylamine-0-sulfonic acids. or from TV-substituted hydroxylamine-0-sulfonic acids. Diaziridines unsubstituted on the N-atoms can be oxidized to give 3//-diazirines. Diaziridines unsubstituted on the N-atoms can be oxidized to give 3//-diazirines. Diaziridines are prepared by the action of ammonia and chlorine on ketones (PAULSEN, SCHMITZ 1959). InitiallyDiaziridine, chloramins are preparee is formedd by: the action of ammonia and chlorine on ketones (PAULSEN, SCHMITZ Diaziridines1959)are. Initiallyprepared, chloraminby the actione is formedof ammonia: and chlorine on ketones (PAULSEN, SCHMITZ 1959). Initially, chloramine is formed: 2NH3 + CI2 *• NH2CI + NH4CI 2NH3 + CI2 *• NH2CI + NH4CI H O N 1 H R —/ + NH2OC I + 2NH3 ** R^Z^NH + NNH4CI + H20 2 1 R R —/ + NH2CI + 2NH3 IT** R^Z^NH + NH4CI + H20 R2 IT The action of ammonia or primary amines and hydroxylamine-O-sulfonic acid upon ketones also yields diaziridinesThe actionThe .actio ofLikewiseammonian of ammoni, thore primaryaminatioa or primaraminesn ofy imineamineand shydroxylamine s (azomethinesand hydroxylamine-O-sulfoni-O) -sulfonicwith hydroxylamine-O-sulfoniacid uponc aciketonesd upon alsoketonec acis dalso yields yieldyieldss diaziridinesdiaziridinesdiaziridines.:.Likewise, Likewisethe, thaminatione aminatioofnimines of imine(azomethines)s (azomethineswith )hydroxylamine with hydroxylamine-O-sulfoni-O-sulfonic c acid acid yieldsyielddiaziridiness diaziridines: : NH2—OS03H R2 NH2—OS03H R2 22 Summary of the general chemistry of three-membered heterocycles • The reactivity of the compounds is determined mainly by the ring strain, but also by the nature of the heteroatom or heteroatoms. • A typical reaction of three-membered heterocycles is nucleophilic ring-opening resulting in the formation of 1,2-disubstituted aliphatic compounds. • A consequence of three-membered heterocycles possessing nonbonding electron pairs is that they behave as BRÖNSTED bases as well as LEWIS bases. Accordingly, they react with BRÖNSTED acids and with electrophiles. • Some systems isomerize to give aliphatic compounds, namely — oxiranes give carbonyl compounds — dioxiranes give esters of carboxylic acids — oxaziridines give nitrones • Appropriate reagents remove the heteroatoms to form alkenes (deoxygenation, desulfonation, deamination, dediazoniation). 23 • The most important synthetic principle is the intramolecular nucleophilic substitution of a �- positioned leaving group — by an O-atom (oxiranes) — by an S-atom (thiiranes) — by an N-atom (aziridines) — by an anionic C-atom (2H-azirines) • Oxygen-containing heterocycles can be synthesized by the action of peroxy compounds on alkenes, ketones or imines. • Amination of carbonyl compounds or imines yield oxaziridines and diaziridines. • Azides and alkenes furnish N-heterocycles (aziridines, 2H-azirines) • Only oxiranes are important in preparative chemistry. In some cases, however, other three- membered heterocycles are useful synthetic intermediates or reagents (2H-azirines, dioxiranes, oxaziridines, diaziridines). 24