Alkylnitrogen Compounds: Compounds with NHalogen, NO, NS, NSe and NTe Functional Groups

2.06 Alkylnitrogen Compounds: Compounds with N0Halogen, N0O, N0S, N0Se and N0Te Functional Groups W. RUSSELL BOWMAN and ROBERT J. MARMON Loughborough University of Technology, UK 1[95[0 N!HALOGENOALKYLAMINES^ RNHHal\ R0R1NHal\ RNHal1\ AND SALTS THEREOF 1[95[0[0 N!Fluoroalkylamines^ RNHF\ R1NF\ RNF1\ R2N ¦F 1[95[0[0[0 Primary and secondary N!~uoroalkylamines^ RNHF\ R1NF 1[95[0[0[1 N\N!Di~uoroalkylamines^ RNF1 1[95[0[0[2 N!Fluoro quaternary salts^ R2N ¦F 1[95[0[1 N!Chloroalkylamines^ RNHCl\ R1NCl\ RNCl1\ R2N ¦Cl 1[95[0[1[0 Primary and secondary N!chloroalkylamines^ RNHCl\ R1NCl 1[95[0[1[1 N\N!Dichloroalkylamines^ RNCl1 1[95[0[1[2 N!Chloro quaternary salts^ R2N ¦Cl 1[95[0[1[3 N!Perchlorylamines^ R1NClO2 1[95[0[2 N!Bromoalkylamines^ RNHBr\ R1NBr\ RNBr1\ R2N ¦Br 1[95[0[3 N!Iodoalkylamines^ RNHI\ R1NI\ RNI1 1[95[1 HYDROXYLAMINES AND RELATED FUNCTIONS 1[95[1[0 N!Alkylhydroxylamines^ RNHOH\ R0R1NOH\ and Salts Thereof 1[95[1[0[0 N!Alkylhydroxylamines^ RNHOH 1[95[1[0[1 N\N!Dialkylhydroxylamines^ R1NOH 1[95[1[0[2 Alkylhydroxylamine salts^ RN ¦H1OH\ R1N ¦HOH 1[95[1[1 N!Oxides^ R2NO and Salts Thereof 1[95[1[1[0 N!Oxides^ R2NO 1[95[1[1[1 Salts of N!oxides^ R2N ¦OH\ R02N ¦OR1 1[95[1[2 O!Substituted N!Alkylhydroxylamines] R0NHOR1\ R0N"OR1#1 1[95[1[2[0 N!Alkoxy primary amines] R0NHOR1 1[95[1[2[1 N!Alkoxy secondary amines^ R01NOR1 1[95[1[2[2 N\N!Dialkoxyamines] RN"OR0#1 1[95[1[2[3 Salts of O!substituted N!alkylhydroxylamines^ R0N ¦H1OR1\ R0N ¦H"OR1#1 1[95[1[2[4 N!Chloro!N!alkoxylamines^ R0N"Cl#OR1 1[95[1[3 N!Sulfonyloxyamines R01NOSO1R1 and Related Compounds 1[95[1[4 N!Phosphinyloxyamines^ RNH0O0P"1O#R1\ R1N0O0P"1O#R1 1[95[2 THIOHYDROXYLAMINES AND RELATED FUNCTIONS 1[95[2[0 Thiohydroxylamines^ R1NSH 1[95[2[1 Sulfenamides^ R0NHSR1\ R01NSR1 1[95[2[1[0 Primary sulfenamides^ R0NHSR1 1[95[2[1[1 Secondary sulfenamides^ R01NSR1 1[95[2[1[2 Sulfenamide salts^ R02N ¦SR1\ R01N0S ¦R11 1[95[2[2 Derivatives of Thiohydroxylamines^ RN"X#SY 1[95[2[2[0 RNH0SY and R1N0SY\ with Yhalo`en

222

223 223 223 224 225 226 226 227 227 228 228 228 239 239 239 232 236 236 236 249 249 249 242 244 245 246 246 246 246 246 247 248 248 259 259 259

223

N!Halo`en\ N0O\ N0S\ N0Se and N0Te Functional Groups

1[95[2[2[1 RNH0SY\ R1N0SY 1[95[2[2[2 Disulfenamides] R0N"SR1#1 1[95[2[3 Dialkylaminosulfur Tri~uorides^ R1NSF2 1[95[2[4 Sul_namides^ R0NHS"O#R1\ R01NS"O#R1\ and Derivatives Thereof 1[95[2[4[0 Redox methods 1[95[2[4[1 From substitution at sulfur"IV# 1[95[2[4[2 Other `eneral methods 1[95[2[4[3 Derivatives of sul_namides 1[95[2[5 Sulfonamides^ R0NHSO1R1\ R01NSO1R1 1[95[2[5[0 From reaction at sulfur"VI# 1[95[2[5[1 Other `eneral methods 1[95[2[6 Sulfonamide Salts^ R0SO1N ¦R12 1[95[2[7 N!Substituted Sulfonamides^ R0N"X#SO1R1 1[95[2[8 Sulfamic Acids and Derivatives Thereof^ R0NHSO2R1\ R01NSO2R1 1[95[2[8[0 Sulfamic Acids^ R1NSO2H 1[95[2[8[1 Sulfamate esters^ R0NHSO2R1\ R01NSO2R1 1[95[2[8[2 N\N?!Bisalkyl sulfamides^ R0NHSO1NHR1\ R01NSO1NR11 1[95[2[8[3 Sulfamoyl halides^ R0R1NSO1X 1[95[2[8[4 Other derivatives of sulfamic acids 1[95[3 SELENIUM AND TELLURIUM ANALOGS OF THIOHYDROXYLAMINES AND THEIR DERIVATIVES 1[95[3[0 Selenenamides^ R01NSeR1 1[95[3[1 Amino Selenium"IV# Derivatives] R1NSe"IV# 1[95[3[2 Seleninamides and Derivatives^ R01NSe"O#R1 1[95[3[3 Selenonamides and Derivatives^ R01NSeO1R1 1[95[3[4 Tellurenamides and Derivatives^ R01NTeR1

250 250 251 251 251 251 252 252 253 253 254 254 254 255 255 255 256 257 257 257 257 258 258 269 269

1[95[0 N!HALOGENOALKYLAMINES^ RNHHal\ R0R1NHal\ RNHal1\ AND SALTS THEREOF Halogenation of amines can be regarded as an oxidation reaction[ Most syntheses of N!halo! genoalkylamines involve the reaction between the amine and a positive source of the halogen[ The most obvious source of positive halogen is from the respective dihalogens X1\ but a range of other common halogen sources are used and are referred to in the following sections[ Reaction between primary and secondary amines and dihalogens X1 in suitably bu}ered solutions yield the respective N!halogenoalkylamines\ whereas reaction between tertiary amines and halogens yield N!halogeno quaternary halides R2N¦X X−[ The latter normally give elimination of HX to yield iminium salts\ which readily hydrolyze to aldehydes and secondary amines[ No reports of mixed N\N?!dihalogenoalkylamines "e[g[\ RNXX? "XF\ X?Cl\ Br\ I^ XCl\ X?Br\ I## were located in Chemical Abstracts[ Syntheses should be feasible from primary N!~uoro! or N!chloroalkylamines\ RNHF or RNHCl[ 1[95[0[0 N!Fluoroalkylamines^ RNHF\ R1NF\ RNF1\ R2N¦F Methods of synthesis of N!~uoroalkylamines have been reviewed as parts of larger reviews[ The synthesis of N!~uoroamines has been covered in a review on nitrogen ~uorides ð56CRV554Ł\ and in reviews on N!halogenoalkylamines ð51HOU"4#685\ 80COS"6#624Ł[ Fluorinating agents have been reviewed ð75CRV886\ B!78MI 195!90Ł\ and most should react with amines\ although many have not been reported in the literature[ However\ certain reagents "e[g[\ caesium ~uoroxysulfate Ce¦ −OSO1F# have been shown not to yield N!~uoroamines\ even though they work well with amides ð80T6336Ł[ 1[95[0[0[0 Primary and secondary N!~uoroalkylamines^ RNHF\ R1NF Per~uorination is a common problem with ~uorinations of amines using ~uorine\ and per~uoro! amines are readily N!~uorinated ð56CRV554Ł[ For instance\ per~uoro!N!~uoropiperidine is used as a ~uorinating agent ð80JFC"41#278Ł[ However\ tri~uoroamine oxide NF2O has been reported to ~uorinate secondary amines successfully\ to yield the corresponding N!~uoroamines R1NF "Equa! tion "0## ð89JA1272Ł[ The reactions also yield the corresponding N!nitrosoamines which is a dis! advantage because of their toxicity[ The method allows selective ~uorination of the amino group\ and per~uorinated dialkylamines are not required[ A range of dialkylamines "R1NH\ RMe\ Et\

N!Haloalkylamines

224

Prn\ Pri\ cyclohexyl and other cycloalkylamines# give good yields of N!~uoroamines[ The addition of ~uorine to imines to yield secondary N!~uoroamines has been reported ð56JOC305Ł[ 4 R2NH + NF3O

≤0 °C

(1)

R2NF + R2N–NO + 2 R2NH•HF

No useful syntheses of N!~uoro primary amines RNHF are located in the literature\ and ~uo! rination of primary amines yields N\N!di~uoroalkylamines[

1[95[0[0[1 N\N!Di~uoroalkylamines^ RNF1 In contrast to mono~uoroamines\ a number of methods for synthesizing N\N!di~uoroalkylamines have been reported\ and the earlier methods have been reviewed ð56CRV554\ B!57MI 195!90Ł[ Primary alkylamines have been ~uorinated successfully in bicarbonate bu}ered aqueous solutions "HCO2−\ H1O\ CCl2F# using ~uorine to give N\N!di~uoroalkylamines "e[g[\ Rcyclohexyl\ But\ Bun# ð57JOC0997Ł[ Fluorine gas in nitrogen gas was bubbled through the solutions at 9>C[ The ~uorination of amides is also known\ and provides several methods for synthesizing N\N!di~uoroamines ð58JA0568\ 69JOC0434Ł[ Fluorination of secondary amides with ~uorine yields intermediate N!~uoroamides which react further with displacement of acylium ions to yield N\N!di~uoroamines[ Sulfamides\ urethanes\ and ureas give similar results[ The use of ~uoroxy! tri~uoromethane CF2OF\ developed as a ~uorinating reagent by Barton et al[ ð63JCS"P0#621Ł\ gives high yields of N\N!di~uoroamines for a wide range of substrates[ N!Fluoroamides are initially formed and undergo further ~uorination with cleavage of the amide bond "Scheme 0#[ The use of CF2OF is compared to bis"~uoroxy#di~uoromethane CF1"OF#1\ and ~uoroxysulfur penta~uoride SF4OF\ for example the yields of 0!"N\N!di~uoroamino#adamantane from 0!acetamidoadamantane are 64) "CF2OF#\ 66) "SF4OF# and 85) "CF1"OF#1#[ CF2OF reacts faster with electron!rich arenes\ such as phenols\ than with amides which limits its use[ A second procedure using CF2OF also gives high yields of N\N!di~uoroamines from primary amines\ "e[g[\ N\N!di~uoroaminoadamantane "69)# and 3!"N\N!di~uoroamino#butyric acid "53)## ð64CC86Ł[ In this protocol\ reaction between the primary amine and benzaldehyde yields the respective imine\ which is treated with CF2OF in MeOH "Scheme 1#[ The method was also used for the di~uorination of aminomonosaccharides ð64CC86Ł[ R2

+ H+ + CF3O–

R1CO N

R1CONHR2 + F–OCF3

F CF3OF

R1CO

R2 N F F

CF3O–

+

or F–

R1COF + R1CO2CF3 + R2NF

Scheme 1

R RNH2 + PhCHO

CF3OF

R

N

Ph

CF3OF

N Ph

MeOH

F

OMe

MeOH

F + R N F

OMe Ph OMe

OMe RNF2

+ Ph OMe Scheme 2

Nitrogen ~uorides ð78MI 195!91Ł have been used for several synthetic procedures[ The acidic properties of the hydrogen in di~uoroamine have been exploited to react with alkenes\ bromides\ and alcohols\ but the conditions are not very practical ð56JA605Ł[ Tetra~uorohydrazine has been extensively used for addition to alkenes ð56CRV554\ 56JOC3923\ B!58MI 195!90Ł[ A wide range of alkenes

225

N!Halo`en\ N0O\ N0S\ N0Se and N0Te Functional Groups

"e[g[\ Equation "1## have been converted to vicinal bis"N\N!di~uoroamino# compounds\ including cycloalkenes\ arylalkenes and ole_nic steroids[ Evidence indicates a radical mechanism as shown in Scheme 2 ð56JOC3923Ł[ But

100 °C, 3 h

But

NF2

+ N2F4 pressure tube

2 F2N•

N2F4

+ F2N•

F2N

•

(2)

NF2

•

F2N

+ N2F4

F2N

NF2 + F2N•

Scheme 3

1[95[0[0[2 N!Fluoro quaternary salts^ R2N ¦F The reaction between tertiary amines and ~uorine yields quaternary ~uorides R2N¦F[ The latter normally give elimination of HF to yield iminium salts\ which readily hydrolyze to aldehydes and secondary amines[ Some important exceptions are reported\ for example the preparation of the ~uorinating reagent N!~uoroquinuclidinium ~uoride "NFQNF# "0# "Equation "2##\ an extremely hygroscopic white solid ð77JCS"P0#1794Ł[ Treatment of quinuclidine in trichloro~uoromethane with ~uorine at low pressure\ in a specially designed glass vacuum system\ gives good yields of the ~uorinating agent "Equation "2##[ A range of 0!alkyl!3!~uoro!0\3!diazabicycloð1[1[1Łoctane salts "1# have been prepared by ~uorination of the 0!alkyl!0\3!diazabicycloð1[1[1Łoctane salt with ~uorine[ These compounds are used as reactive ~uorinating reagents^ 0!chloromethyl!3!~uoro! 0\3!diazabicycloð1[1[1Łoctane bis"tetra~uoroborate# is available commercially "Select~uor# ð81USP4972067Ł[ F2

N

(3)

CF3Cl

N+

F–

F (1) R N N

+

+

F (2) selectfluor R = CH2Cl

N!Fluoroammonium salts\ for example "2#\ have been synthesized using perchloryl ~uoride\ FClO2\ from the corresponding tertiary amine ð72JOU0192Ł[ N!Fluoro secondary ammonium salts\ R1NH¦F ClO2− "3#\ have been reported to be formed in the reaction between the 1\1\5\5!tetra! methylpiperidin!3!one and perchloryl ~uoride\ and further reaction with excess amine gives the corresponding secondary N!~uoro!amine ð56JOC0004Ł[ The gas FClO2 is explosive and must be used in dilute solutions[

N!Haloalkylamines

226 O

+

+

N R

F

N

ClO3–

H

(3) R = Me, Et, Bu

F

ClO3–

(4)

1[95[0[1 N!Chloroalkylamines^ RNHCl\ R1NCl\ RNCl1\ R2N¦Cl The syntheses and reactions of N!chloroamines have been reviewed ð51HOU"4#685\ B!57MI 195!90\ Most sources of positive chlorine have been reported for the chlorination of primary\ secondary and tertiary amines\ for example chlorine\ hypochlorous acid\ hypochlorite ion\ N!chlorophthalimide\ N!chlorosuccinimide "NCS#\ N!chloroacetamide\ N!chloro! and N\N! dichlorourea\ N\N\N!trichloroisocyanuric acid\ N!chlorosaccharin\ N!chloro! and N\N!dichloro!p! toluenesulfonamide and chloroamine[ 69CRV528\ 80COS"6#624Ł[

1[95[0[1[0 Primary and secondary N!chloroalkylamines^ RNHCl\ R1NCl Monochlorination of primary amines has not been commonly reported but the use of one equivalent of chlorinating agent "e[g[\ NCS or t!butylhypochlorite# allows the synthesis of primary N!chloroamines ð80COS"6#624Ł[ Volatile primary N!chloroamines have been synthesized in high yields "×84)# using solid NCS under high vacuum "9[0 tor "mm Hg## at room temperature ð74S0020Ł[ Chloroamine NH1Cl acts as a source of positive chlorine and has been used to chlorinate a range of amines including a!amino acids\ to yield primary N!chloroamines\ but the reaction is in equilibrium and not satisfactory for synthesis ð71IC1434Ł[ Secondary N!chloroamines are common synthetic targets "e[g[\ as precursors for forming aminyl radicals ð72AG"E#226Ł# and are readily prepared using various sources of positive chlorine[ This latter review provides references to the syntheses of a wide range of secondary N!chloroamines[ Chlorination of amines using sodium hypochlorite has been known for over 099 years\ but has been supplanted largely by more convenient modern reagents such as NCS[ Practical details of the use of sodium hypochlorite are given in Houben!Weyl ð51HOU"4#685Ł[ Alkenyl secondary amines can be chlorinated selectively to yield chloroamines without reaction of the alkene ð70TL50Ł[ The synthesis of chloroamines by addition of amine salts to strongly alkaline sodium hypochlorite "09Ð03)# is high yielding "Equation "3## ð61CJC0056Ł[ The use of hypochlorous acid in Et1O allows the chlorine equivalents to be measured accurately[ NaOCl +

N H H

Cl–

NaOH (aq.) >90%

(4)

N Cl

In the 0889s\ the most common method for synthesizing secondary N!chloroamines is the use of NCS[ Many N!chloroamines do not possess long!term stability\ and are often made in situ and then reacted immediately ð83JCS"P0#666Ł[ N!Chloroamines formed by selective chlorination of alkenyl secondary amines have been used in synthesis\ for example the indolizidine gephyrotoxin!112AB "Equation "4## ð75JOC4934\ 77JOC1033Ł[ NCS, Et2O

N H

0 °C, 1 h 86%

(5) N Cl

N!Chlorination of homochiral 1!substituted aziridines using NCS or t!butyl hypochlorite "ButOCl# in the presence of various chiral tri~uoromethylcarbinols "e[g[\ "S#!"¦#!PhCH"OH#CF2# gave mixtures of "E# and "Z# diastereoisomers with little stereoselectivity ð72JOC1539Ł[ The nitrogen inversion barrier in N!chloroaziridines is ca[ 004 kJ mol−0 and therefore\ the invertomers "0R\1S and 0S\1S# formed by NaOCl chlorination of 1"S#!methylaziridine can be separated easily by GLC and characterized ð77JA0608Ł[

227

N!Halo`en\ N0O\ N0S\ N0Se and N0Te Functional Groups

Ethyl hypochlorite\ and more commonly ButOCl\ have been used as chlorinating reagents[ t!Butyl hypochlorite is not available commercially although the preparation is reported ð62OSC"4#073Ł[ N!Chloroamines of N!BOC!protected a!amino acid esters are synthesized using ButOCl and sodium methoxide in methanol\ but prolonged exposure to sodium methoxide leads to elimination of HCl\ to yield a\b!unsaturated amino acids ð64CB1806\ 65AG"E#183Ł[ Chlorination of 1\5!diphenylpiperidine "with labile benzylic hydrogens# using ButOCl\ yields the N!chloro derivative without elimination of HCl[ However\ several other amines with a!benzylic hydrogens readily undergo loss of HCl during chlorination ð72CB2820Ł[ The sodium salts of dichloroisocyanuric acid ð77SC1024Ł and trichloroisocyanuric acid ð80CJC0371Ł have been reported to be better chlorinating reagents than NCS or NaOCl[ Both reagents are stable and commercially available[ Hindered chloroamines have also been synthesized by direct reaction between the sodium salt of dichloroisocyanuric acid and the amine in water or benzene[ Secondary trimethylsilylamines R1N!TMS react with chlorine to yield secondary N!chloroalkylamines ð69CRV528Ł[

1[95[0[1[1 N\N!Dichloroalkylamines^ RNCl1 Most of the methods used for monochlorination of secondary amines have also been used for dichlorination of primary amines to yield N\N!dichloroalkylamines\ for example sodium hypo! chlorite\ NCS\ ButOCl[ Two equivalents or an excess of chlorinating reagent with suitable bu}ering are required ð80COS"6#624Ł[ Trichloroamine NCl2 can be used to add across alkenes to yield 0!"N\N!dichloro!amino#!1! chloroalkanes ð17JA1628Ł[ NCl2 must be prepared in solution because of its very explosive properties[ The use of NCl2:AlCl2 as an aminating system gives synthetically useful yields of N\N!dichloroamines from tertiary alkanes "e[g[\ adamantane and methylcyclohexane# via the tertiary cation of the alkane and the anion NCl1− ð57OS"37#3\ 69CRV528Ł[ Skeletal rearrangements expected of intermediate cations take place prior to dichloroamination[ This aminating system has also been used with tertiary chloroalkanes to yield N\N!dichloroamines formed via the intermediate cation\ but the results are variable with several by!products ð58JOC800Ł[

1[95[0[1[2 N!Chloro quaternary salts^ R2N ¦Cl Stable N\N!dichloroalkylamines "e[g[\ with electron!withdrawing a!substitutents# can be isolated as their hydrochloride salts R1C"CN#NCl1 = HCl ð78RCR149Ł[ N!Chloroammonium salts are normally unstable\ and their formation from the tertiary amine and hypochlorite is reversible[ In general\ elimination of HCl takes place to yield intermediate iminium salts\ which rapidly undergo hydrolysis to the corresponding aldehydes and secondary amines "Scheme 3#[ N!Chloro!0!azobicycloð1[1[1Łoctane does not undergo oxidative elimination and is stable even in aqueous acid at 14>C ð58JCS"C#515Ł[ N!Chlorotrimethylammonium chloride Me2N¦Cl Cl− is stable for several days\ but Et2N¦Cl Cl− is unstable and cannot be isolated ð43JCS0649Ł[ N!Chlorotrialkylammonium chlorides "N!chloro derivatives of 0!azobicycloð1[1[1Ł octane\ N!methylmorpholine\ N!methylpiperidine\ and N!methyl!1\1\5\5!tetramethylpiperidine# have been stabilized by conversion to the corresponding perchlorate "Scheme 4# ð70JCS"P1#434Ł[

Cl R1

NR22 + HOCl

R1

+

–HCl

NR22

R1

+

NR22

R1CHO + R22NH

base

Scheme 4

R3N + Cl2

+

R3N–Cl Cl– Scheme 5

AgClO4

+

R3N–Cl ClO4–

N!Haloalkylamines

228

1[95[0[1[3 N!Perchlorylamines^ R1NClO2 N!Perchlorylamines are explosive and need to be handled with care[ Primary and secondary amines have been reacted with dichlorine heptoxide Cl1O6 in CCl3 solution to yield N!per! chlorylamines "Scheme 5# ð63JA2126\ 76ZAAC"436#122Ł[ Examples include N!perchlorylamines from aziridine\ adamantane\ azetidine\ piperidine "62)#\ 1!ethylaziridine "72)# and isopropylamine "59)#[ Salts can be formed from primary N!perchlorylamines[ Treatment of 0!"N!perchloryl! amino#adamantane with HgCl1 gives the mercury"II# salt "Scheme 5#\ which is explosive when heated\ and treatment with hydroxides ZOH also yields the respective salt RNClO2−Z¦ "ZAg\ Na\ Ba\ K\ Et3N#[ Primary N!perchlorylamines have been chlorinated with NaOCl to give N!chloro!N!perchlorylamines "Scheme 6# ð63JA2126Ł[ N\N?!Disubstituted diamines react with Cl1O6 to give the respective N\N?!diperchlorylamines ð74ZAAC"415#075Ł[ Tertiary amines give unstable perchloryl derivatives\ for example the reaction between triethylamine and perchloryl ~uoride in dilute solution gave N!perchloryltriethylamine ~uoride which\ with excess amine\ eliminated HClO2\ to yield the corresponding iminium salt ð56JOC0004Ł[ R 2 RNH2 + Cl2O7

RNH3•ClO4 +

O N Cl O

H

O

R = 1-adamantyl R

O N Cl O

H

+ HgCl2

(RN–ClO3)2Hg

O Scheme 6

H

Cl

NaOCl

R N

R N ClO3

84–87%

ClO3

R = n-hexyl, n-butyl Scheme 7

1[95[0[2 N!Bromoalkylamines^ RNHBr\ R1NBr\ RNBr1\ R2N¦Br Alkylamines are brominated by a range of brominating agents such as bromine\ aqueous sodium hypobromite\ NBS\ N!bromophthalimide\ etc[ ðB!57MI 195!90\ 69CRV528\ 80COS"6#624Ł[ There has been some discussion on the mechanism of NBS bromination\ about whether the brominating agent is a low dilution of Br1\ as for allylic bromination with NBS[ Reactions between NBS and alkenyl secondary amines show that amines are brominated much faster than alkenes\ but that the bromine is slowly transferred from the amine to the alkene\ probably via a six!membered ring transition state ð83UPŁ[ Therefore\ the selective synthesis of alkenyl N!bromoamines is di.cult[ Trimethyl! silylamines are also readily brominated as with chlorination[ Tertiary amines are brominated with Br1 in CCl3 to yield tertiary ammonium bromides\ which readily revert to the amine and Br1 ð40CB069\ 70JCS"P1#434Ł[ Even the N!bromoammonium salt of 0! azabicycloð1[1[1Łoctane\ unlike the stable N!chloro analogue\ reverted to amine and Br1[

1[95[0[3 N!Iodoalkylamines^ RNHI\ R1NI\ RNI1 There is little mention in the literature of N!iodoamines[ N!Iododimethylamine Me1NI and N\N!diiodoethylamine and !methylamine are known ð80COS"6#624Ł[ N!Iodobistri~uoromethylamine "CF2#1NI has been prepared by treatment of di"bistri~uoromethylamino#mercury with iodine in CCl3 ð57JCS"C#685Ł[ Iodination of tertiary amines\ as for chlorination and bromination\ yields N! iodoammonium salts\ which give elimination of HI to yield iminium salts\ which undergo hydrolysis[

239

N!Halo`en\ N0O\ N0S\ N0Se and N0Te Functional Groups

1[95[1 HYDROXYLAMINES AND RELATED FUNCTIONS The synthesis and chemistry of hydroxylamines and related functions have been extensively reviewed and readers are referred to these reviews for further detailed information and older references ðB!57MI 195!90\ 60HOU"09:0#0980\ B!63MI 195!90\ 68COC"1#074\ B!78MI 195!92\ 89HOU"E05#0Ł[ Attempts have been made here to survey methodology in general and not to repeat previous reviews[ More recent examples of synthetic methods have been cited where possible[

1[95[1[0 N!Alkylhydroxylamines^ RNHOH\ R0R1NOH\ and Salts Thereof Hydroxylamines have been reviewed ð80COS"5#092Ł\ and while not part of this chapter\ reviews on N!hydroxy!a!amino acids ð75CRV586Ł and a!hydroxylamino oximes ð75S693Ł detail further synthetic methods[

1[95[1[0[0 N!Alkylhydroxylamines^ RNHOH "i# Oxidative methods The oxidation of primary amines with aqueous hydrogen peroxide yields N!substituted hydroxyl! amines RNHOH but further oxidation to nitroso and nitro compounds is a problem[ 1\1!Dimethyl! dioxirane smoothly oxidizes a variety of primary amines to hydroxylamines in high yield ð89JOC0870Ł[ The methodology has been applied to amino mono! and disaccharides in particular "Equation "5##[ Some amines did not react or were oxidized further to yield oximes[ O O

OAc AcO AcO

OMe NH2

acetone –40 °C to RT 76%

OAc (6)

AcO AcO

OMe N H HO

Reaction between primary and secondary amines and dibenzyl peroxide involves nucleophilic displacement on the peroxide bond to yield O!benzyloxyamines\ which can be subjected to hydro! genolysis to yield N!alkylhydroxylamines ð72S426\ 73S106Ł[ N!Benzoyloxyamines RNHOCOPh prepared by treatment of primary amines with dibenzoyl peroxide\ are readily hydrolyzed to N!alkylhydroxylamines "Scheme 7# ð72S426Ł[ Because of the dangers of explosion\ the procedure should only be carried out on small scale[ Oxidation of primary amines with diphenylphosphinyl! peroxide "Ph1PO1#1 yields diphenylphosphinyloxyamines "Scheme 8# ð75T1692Ł which\ after two rearrangements facilitated by further heating of the reaction and treatment with methoxide\ yield N!substituted hydroxylamines RNHOH[ R

R

(BzO)2

N H

N OBz

H

R

NaOH

N OH

H

H Scheme 8

Ph RNH2 +

Ph

O P

O

O

P O

CHCl3, –40 °C

Ph

P O

Ph Ph

NaOMe, MeOH

O N O P

3 h, 61–86%

Ph

OH R N

H

H

O N O P

R

R

Ph

Ph

Ph

Ph

R = Et, Prn, Bun, But Scheme 9

Ph

CHCl3, ∆

Ph

5 h, 71–82%

O P OMe

+ RNHOH

230

Hydroxylamines "ii# Reductive methods

The most common and satisfactory protocol for the synthesis of N!substituted hydroxylamines RNHOH is by reduction of a nitrogen precursor which is at a higher oxidation state\ for example nitro and nitroso compounds and oximes[ Various nitro compounds are reduced by diborane to N!substituted hydroxylamines ð80COS"7#262Ł[ The reduction of nitro alkanes with four equivalents of samarium diiodide provides a facile and mild method with good yields "Equation "6## ð80TL0588Ł[ The reduction is compatible with acetals\ arenes\ esters and silyl protected alcohols[ The use of di! "benzenesulfenyl#tin "PhS#1Sn for the reduction of tertiary nitro compounds\ which have no a!hydrogens\ gives excellent yields of N!alkylhydroxylamines "Scheme 09# ð89T476Ł[ The reagent is best made in situ from benzenethiol\ SnCl1\ and triethylamine[ Secondary nitro compounds can also be reduced to N!alkylhydroxylamines if the intermediate nitroso compound does not tautomerize rapidly to the corresponding oxime\ and a polar solvent is used[ 4 SmI2 THF, MeOH, RT

O NO2

O

RNO2

O Sn(SPh)3

–Sn(SPh) 3

O

58%

R N

O –(PhS)3SnO–

(7)

NHOH

–Sn(SPh) 3

RNO

O– O Sn(SPh)3 R N–

O Sn(SPh)3

Et3NH+ –Et3N

RNHOH

R N H

Sn(SPh)2 (2.5 equiv.), PhSH, Et3N in PhH, RT, 10 min Scheme 10

Primary and secondary nitronate anions R0R1C1NO1−"R0 alkyl\ R1 H or alkyl# are reduced by diborane to N!substituted hydroxylamines R0R1CHNHOH ð54JOC1779Ł[ Sodium borohydride\ which is commonly used to reduce nitroalkenes to nitronate anions\ which are subsequently pro! tonated to yield nitroalkanes\ can be used in catalytic amounts with borane complexes to produce N!substituted hydroxylamines "Scheme 00# ð74JOC022Ł[ A recent example uses BH2 = THF with catalytic NaBH3 to reduce 2!nitrochromenes to 2!hydroxylamino!1H!0!benzopyrans in high yield ð76JHC656Ł[ NO2

NO2–

NaBH4 (cat.)

NHOH

i, BH3•THF ii, hydrolysis

Scheme 11

The reduction of oximes to N!substituted hydroxylamines RNHOH is more reliable and is fully reviewed\ and tables of examples are given ð80COS"7#59Ł[ Aldoximes and ketoximes are reduced to N!substituted hydroxylamines by a wide range of reagents including LiBH3\ NaBH3 in basic or acidic media\ NaBH2CN in acidic medium ð64T1484\ 75TL3850Ł\ BH2:THF and BH2 = pyridine:HCl\ for example in the synthesis of hydroxylamino nucleotides "Equation "7## ð89TL420Ł[ HO O

OH

HO

Ur i, BH3• pyridine complex

N OH

ii, MeOH, HCl pH 0–2

O

Ur (8)

OH

NHOH

Ur = uracil

"iii# From alkylation\ C0N bond formation Monoalkylation of hydroxylamine is not normally a good procedure\ owing to problems of further alkylation\ and because the products are di.cult to predict ðB!78MI 195!92\ 80COS"5#092Ł[

231

N!Halo`en\ N0O\ N0S\ N0Se and N0Te Functional Groups

SN0 Substitution has been reported for the reaction between NH1OH and "p!chlorophenyl# diphenylmethyl chloride to yield N!ð"p!chlorophenyl#diphenylmethylŁ!hydroxylamine ðB!78MI 195! 92Ł[ Acid!catalyzed SN0 substitution of benzylic hydroxyl groups by hydroxylamine has been reported ð77JOC0657Ł[ Development of speci_c alkylating agents allows selective formation of the N!alkyl! hydroxylamines[ Reaction between O!benzyloxylamine BnONH1 and alkyl halides yield N!alkylated products[ The benzyl group is removed by hydrogenolysis to yield the N!alkyl!hydroxylamine "Scheme 01#[ The N!alkylation of the isoxazole "4# with alkyl halides provides an excellent method for the synthesis of N!alkylhydroxylamines RNHOH "Scheme 02# ð76TL1882Ł[ alkylation

hydrogenation

BnONH2

RNHOBn

RNHOH

RX

Scheme 12

CO2Et

CO2Et

CO2Et

CO2Et

N

N

OH

O

H2O, HCl

RX, DMF

base

O

–N

O–

O

63–73% 110–120 °C

O

R

N O

O

54–96%

(5) R

+

NH2 Cl– + 2 CO2 + Me2CO + EtOH HO R = Et, 73%; Bn, 63%; CO2Me, 70%; (CH2)7Me, 63%; (CH2)4OH, 54% Scheme 13

Other less common alkylating reagents have been reported but not extensively investigated\ for example the reaction between oxiranes and NH1OH or N!alkylhydroxylamines ðB!78MI 195!92Ł[ Hydroxylamine isodisulfonate HO2S0NH0OSO2H can be alkylated in strongly basic media to yield an intermediate\ RN"SO2−#OSO2−\ which on acid hydrolysis gives N!alkylhydroxylamines ðB!78MI 195!92\ 68COC"1#493Ł[

"iv# From hydrolysis of nitrones The hydrolysis of nitrones to yield N!alkylhydroxylamines and aldehydes or ketones has been used for some 099 years "Scheme 03# ðB!71MI 195!90\ B!78MI 195!92\ 89HOU"E05#0Ł[ Alkylation of the respective oximes provides the most facile route to the required nitrones[ Nitrones may also be cleaved by hydroxylamine or hydrazine to yield N!alkylhydroxylamines and oximes or hydrazones\ respectively[ R1

alkylation

R1

NOH R2

+

R3

hydrolysis

N

R3X

R2

O–

H2O, H+

R1 O + R3NHOH R2

Scheme 14

The use of oxaziridines\ including Davis reagents\ provides a protocol for the conversion of amines to the corresponding N!substituted hydroxylamine ð63TL1342\ 78T4692Ł[ The methodology is particularly important because it has been used as the main method for converting homochiral amines to the corresponding homochiral N!substituted hydroxylamines ð64T1484\ 74T2344\ 80TL3320Ł[ An example using "S#"−#!1!phenylethylamine is shown in Scheme 04 ð74T2344Ł[ The amine is converted to an imine using an aromatic aldehyde[ The imine is peroxidized to the corresponding

232

Hydroxylamines

oxaziridine which is ring opened with acid to yield the nitrone[ The nitrone may be hydrolyzed by various reagents\ but the use of hydroxylamine hydrochloride works well\ giving the N!substituted hydroxylamine and the oxime of the aldehyde[ O NH2 Ph

N

ArCHO

H

Ph

mcpba

Ar

H

N

CH2Cl2, 17 °C

Ph

H

H2NOH•HCl

Ar

O– N+ Ph

Ar

H2NOH•HCl

NHOH

H

Ph

+

Ar NOH

H

Scheme 15

"v# From addition of alkyllithium rea`ents to oximes and nitrones Alkyllithium reagents add to oximes to yield sterically hindered N!alkylhydroxylamines "Scheme 05# ð65TL122Ł[ Higher yields can be obtained using O!benzyl oxime ethers followed by removal of the benzyl group ð77TL2344Ł[ Heteroarene lithium reagents are added to N!THP protected nitrones in THF to yield N!THP protected hydroxylamines which are hydrolyzed with acid to yield N! alkylhydroxylamines in moderate yield ð80TL2672Ł[ R1 NOH R2

R3Li

R1 R2

R2

N R3

R1

OLi Li

NHOH R3

Scheme 16

"vi# From addition of hydroxylamine to alkenes Hydroxylamine undergoes Michael reactions and adds to electron!de_cient alkenes "a\b!unsatu! rated ketones\ esters\ amides and sulfones\ and nitroalkenes#[ The addition to a\b!unsaturated ketones is used in the synthesis of 0\1!oxazoles[ When two equivalents of the electron!de_cient alkenes are used\ secondary N\N!dialkylhydroxylamines result ð60HOU"09:0#0980\ B!78MI 195!92Ł[

"vii# From nitroxides The disproportionation of nitroxides\ R1NO = \ yields N!alkylhydroxylamines RNHOH and nitroso compounds RNO\ but useful synthetic methods have not been located ðB!71MI 195!91Ł[

1[95[1[0[1 N\N!Dialkylhydroxylamines^ R1NOH "i# Oxidative methods The oxidation of secondary amines with peroxide to yield N\N!disubstituted hydroxylamines R1NOH is more useful than the equivalent reaction for synthesizing N!substituted hydroxylamines RNHOH from primary amines\ but can also lead to further oxidation products[ Oxidation of secondary amines with hydrogen peroxide normally gives nitrones but in the presence of selenium dioxide\ the solanum steroid alkaloids\ spirosolane and tomatidine\ it gives low yields of the cor! responding N\N!disubstituted hydroxylamines ð81LA0980Ł[ 1\1!Dimethyldioxirane oxidation of sec! ondary amines provides the _rst general method for oxidizing secondary amines to the corresponding hydroxylamines in high yield "Scheme 06# ð78SC2498Ł[ The method allows oxidation of amines selectively over alcohols and of sterically hindered amines[ The method is facile\ and at the end of

233

N!Halo`en\ N0O\ N0S\ N0Se and N0Te Functional Groups

the reaction the solvent is removed leaving crystalline hydroxylamines[ Secondary amines with an a!benzylic hydrogen are oxidized further to the corresponding nitrone if two equivalents of 1\1! dimethyldioxirane are used ð89JOC1843Ł[ OH R2NH

O O RT, acetone 80–100%

Ph

e.g., But2NOH

R2NOH

N OH 99%

97%

N

But

OH 100%

Scheme 17

N!Acyloxyamines R1NOCOPh\ prepared by treatment of secondary amines with dibenzoyl peroxide\ are readily hydrolyzed to N\N!dialkylhydroxylamines as shown for primary amines in Scheme 7 ð72S426\ 89JOC2353\ 89JOC2364Ł[ This was the standard method of preparing hydroxylamines from secondary amines until the dioxirane route was developed\ although the yields were low "14Ð 24)#[ The procedure requires the use of two equivalents of amine\ one for neutralizing the benzoic acid that is formed[ The use of added base "Na1HPO3 or polyvinylpyridine# to prevent reversibility increases the yield two! to three!fold[ The use of potassium methoxide in anhydrous methanol instead of sodium hydroxide in water also improves the yields[ Because of the dangers of explosion\ the procedure should only be carried out on a small scale[ The use of 1!chlorobenzoyl peroxide in place of benzoyl peroxide gave improved yields ð89JOC2353\ 89JOC2364Ł[ The reaction between secondary amines and diphenylphosphinylperoxide "Ph1PO1#1 yields diphenylphosphinyloxyamines\ which are hydrolyzed to yield N\N!disubstituted hydroxylamines ð74S796Ł[ The use of Davis reagents\ 1!"phenylsulfonyl#!2!aryloxaziridines\ to oxidize secondary amines to hydroxylamines gives variable yields\ and often mixtures which contain nitrone impurities ð78T4692Ł[ In the synthesis of novel polyamines from the venom of A`elnopsis aperta spiders\ the use of Davis reagent gave better yields of the required N\N!disubstituted hydroxylamines than the use of mcpba or 1\1!dimethyldioxirane ð89JA5585Ł[

"ii# Reductive methods Nitrones are reduced to N\N!disubstituted hydroxylamines with LAH\ NaBH3\ or NaBH2CN in acid ð60HOU"09:0#0980\ 68COC"1#074\ 80COS"7#59Ł[ A 0889 example illustrated the use of LAH "Equation 8# ð89JOC2996Ł[ More unusual reducing agents\ such as trichlorosilane\ also give good yields of hydroxylamines from nitrones ð67JOC1178Ł[ R1

+

R3

N

R2

O–

LiAlH4 Et2O or THF

R3

R1

(9)

N R2

OH

N!Substituted hydroxylamines RNHOH can be reacted with aldehydes to give intermediate nitrones which can be further reduced with NaBH3 to yield N\N!disubstituted hydroxylamines ð80COS"7#59\ 89TL420Ł[

"iii# From alkylation^ C0N bond formation Monoalkylation of hydroxylamine is troublesome\ but dialkylation has been commonly used[ Stepwise alkylation takes place\ and the alkylation of the oxygen takes place last[ A large number of examples and procedures for the monoalkylation of N!alkylhydroxylamines RNHOH into N\N! dialkylhydroxylamines R1NOH are reviewed ðB!57MI 195!90\ 60HOU"09:0#0980\ 67CL0946\ B!78MI 195!92Ł[ Palladium"9#!catalyzed reactions between hydroxylamines and allylic acetates yield the cor! responding N!alkyl!N!allylic hydroxylamines\ "Equation "09## ð77TL1862Ł[ A new and more rigorous procedure uses benzyloxy primary amines to form benzyloxy secondary amines ð80TL1600Ł[ The

234

Hydroxylamines

benzyl protecting group is selectively removed by standard methods to yield N\N!dial! kylhydroxylamines in high yield^ an example is shown in Scheme 07[ NHOH

AcO

+

i, Pd(PPh3)4, THF, RT, 2 h ii, Et3N, 3 h

(10)

iii, 2 M HCl, Et2O iv, base 92%

NC

NC

N OH

OBn MeO2C

BnONHMe

Br

MeO2C

THF, reflux 87%

NPhth

N

OH HCl, HOAc

Me

MeO2C

reflux 75%

NPhth

N

Me

NPhth

Scheme 18

"iv# From nucleophilic addition to nitrones The addition of organometallic reagents to aldonitrones has been reviewed ð68COC"1#493\ B!77MI Acyclic ketonitrones are resistant to addition by organometallic reagents[ The addition of Grignard reagents yields N\N!dialkylhydroxylamines[ The addition of Grignard reagents to cyclic aldonitrones has been used in several natural product syntheses\ for example the Grignard "5# was added to cyclic nitrone "6# in the synthesis of "2#!porantheridine "Equation "00## ð79TL1118Ł[ 195!90\ 80COS"0#244Ł[

+

+

OSiMe2But

OSiMe2But

ClMg

N

(11)

N

O– (7)

OH (6)

Diastereoselectivity is observed in the addition of Grignard reagents to nitrones with a chiral a! centre to yield N\N!dialkylhydroxylamines in high yield "Scheme 08# ð77CC0492Ł[ Attack by the Grignard reagent takes place preferentially on the least hindered side of the nitrone to yield "7# over "8# "ca[ 1 ] 0# as predicted by the FelkinÐAnh modi_cation of Cram|s rule "Scheme 08#[ The diastereoselectivity in the formation of hydroxylamines can be improved dramatically by using nitrones bearing stereogenic N!substituents "e[g[\ b!methoxyalkyl\ b!"silyloxy#alkyl\ a!arylethyl ð89JOC2353\ 89JOC2364Ł#[ The high facial diastereoselectivity observed with the b!methoxyalkyl sub! stituents has been explained by a simple chelation transition state model "09# "Scheme 19#[ The diastereoselectivity has been fully investigated with a variety of examples and is discussed fully[ This methodology has been applied to the enantioselective synthesis of amines ð89JOC2364\ 81TL0578Ł[ O– Ph

N+

OH

R2MgCl

R1

Et2O, 0 °C

N

Ph

OH

R1

+

R2 (8) Ph

O–

R1

R2 (9) Ph

N+

N

Ph

OH N H

Me– Scheme 19

The addition of allylamines to nitrones yields N\N!disubstituted hydroxylamines ð82CC058Ł[ The hydroxylamines rapidly undergo retro!Cope rearrangements to tertiary amine N!oxides\ and _nally yield 0\1\4!oxadiazinanes[

235

N!Halo`en\ N0O\ N0S\ N0Se and N0Te Functional Groups R–

O– RMgX

N+

R1

OMe

H

major route

Ph

Ph

Me O

O

R Mg

R1

L

H

L

O

L

H

OMe

Mg

N :

H

H

R1

Ph

L

(10) Scheme 20

"v# From or`anometallic addition to nitro and nitroso compounds Methyl and propyl Grignard reagents have been added to alkylnitro compounds in the presence of anhydrous CeCl2 in THF at −69>C to give N\N!dialkylhydroxylamines in good yield ð89JCS"P0#1022\ 82CC0262Ł[ Grignard reagents also add to N1O double bond of alkylnitroso compounds to yield N\N!dialkylhydroxylamines ð60HOU"09:0#0980\ 68COC"1#074Ł[

"vi# From addition of N!alkylhydroxylamines to alkenes N!Substituted hydroxylamines are readily added to a\b!unsaturated esters ð73T3252Ł and to the double bond of 4\5!dihydroquinolines in acid!catalyzed reactions "Equation "01## ð80TL5678Ł[ RNHOH•HCl MeOH, RT, 1 h

N

N

R

N

R = PhCHMe, 56% R = Me, 65% R = Pr, 49%

(12)

OH

Retro!Cope reactions involving cyclization of N!alkylhydroxylamines onto alkenes in N!3!alk! enylhydroxylamines give cyclic N\N!disubstituted hydroxylamines "Scheme 10# ð67AJC1206\ 68TL3280\ 77JOC0657\ 82CC058\ 83JA2028Ł[ Evidence indicates that the cyclizations are thermal\ and proceed stereospeci_cally in a suprafacial manner as exempli_ed in Scheme 10 ð83JA2028Ł[ The "E#!dia! stereoisomer "00# cyclizes suprafacially to yield "01#\ and the "Z#!diastereoisomer cyclizes to yield the opposite diastereoisomer[ The methodology has been applied to the synthesis of "2#!a!lycorane ð83JA2028Ł[ Ph

Ph 80 °C, 18 h

HO

H N

81%

H (11)

Ph

Ph H H+

H –O

O N H

N+ H

transfer

H N HO (12)

Scheme 21

"vii# From nitroxides Nitroxides have been used as oxidizing agents and are reduced to hydroxylamines R1NOH in the process ðB!71MI 195!91Ł[

"viii# From rearran`ements The Cope rearrangement of tertiary amine N!oxides provides a useful synthetic method with yields up to 89) with few side products "Equation "02##[ The methodology and mechanism are reviewed and procedures reported ð59CRV337\ 59OR"00#206\ B!78MI 195!92\ 82S152Ł[ The rearrangements are carried out by pyrolysis under vacuum or by heating in solution in solvents such as DMSO\ THF\ or DIGLYME[ The tertiary amine N!oxide is commonly generated from the amine and aqueous hydrogen peroxide\ and reacted without full puri_cation[ The nature of the b!hydrogen is

236

Hydroxylamines

crucial to the rate and yield\ for R01R1NO^ R1 PhCH1CH1 ŁBut ×1!methylpropyl× Pri ½Bun ×Et×Prn[ The b!hydrogen must be lined up such that a planar _ve!membered transition state for syn elimination is permitted[ The regiochemistry of elimination is explained by steric reasons[ ∆

+ R2NOH

+

H

(13)

NR2 –O

Hydroxylamines have been synthesized from the rearrangement of hydrazone N!oxides ð82TL030Ł[

"ix# From hydrolysis of O!substituted N\N!disubstituted hydroxylamines Hydrolysis of N!acyloxyamines ð72S426\ 89JOC2353\ 89JOC2364Ł\ R1NOCOPh "Section 1[95[1[0[1["i# and Scheme 7#\ and diphenylphosphinyloxyamines ð74S796Ł R1NOP"O#Ph1 yield N\N!dialkyl! hydroxylamines "Section 1[95[1[0[1"i##[ Hydrolysis of the N!aroyl derivatives of 0\1\4!oxadiazinanes yields b!aroylamino N\N!disubstituted hydroxylamines ð82CC058Ł[

1[95[1[0[2 Alkylhydroxylamine salts^ RN ¦H1OH\ R1N ¦HOH Hydroxylamines are protonated in acid and have acid:base properties similar to amines and hydrazines[ However\ there are reports of di.culty in forming stable salts ð77CC0492Ł[ The salts of hydroxylamines are stable at ambient temperatures\ and are normally neutralized without any decomposition to yield the corresponding hydroxylamine "Equation "03##[ Reports suggest that the salts should be treated with care\ as explosions are possible at elevated temperatures ðB!78MI 195!92Ł[ The salts of hydroxylamines are initially formed in a number of synthetic reactions\ for instance salts of N!alkylhydroxylamines result from the synthetic method using isoxazoles "Scheme 02#[ The salts are also used for puri_cation and storage if the hydroxylamines are unstable\ for example homochiral N!substituted hydroxylamines are converted to oxalate salts ð74T2344Ł[

R2

R1 + N OH X– + B:

R1 N OH + BH+

H

R2

(14)

1[95[1[1 N!Oxides^ R2NO and Salts Thereof The synthesis and synthetic applications of tertiary amine N!oxides have been reviewed ð47HOU"00#089\ 80COS"6#624\ 89HOU"E05:0#393\ 82S152Ł[ Only a few common methods of synthesis are used\ most involve an oxidizing agent\ and are facile with good yields[

1[95[1[1[0 N!Oxides^ R2NO "i# From oxidation of tertiary amines with hydro`en peroxide Oxidation of tertiary alkylamines to tertiary amine N!oxides using aqueous hydrogen peroxide is the oldest method and works well in most cases\ commonly in ×89) yields "Scheme 11# ð47HOU"00#089\ 60JCS"B#0229Ł[ Methanol and ethanol are used as co!solvents with the water to improve the solubility of the tertiary alkylamines[ A standard procedure is reported in Or`anic Synthesis ð52OSC"3#501Ł[ A number of more modern hydrogen peroxide reagents\ which are either safer or

237

N!Halo`en\ N0O\ N0S\ N0Se and N0Te Functional Groups

more e.cient\ are now available and have been thoroughly researched[ Urea!hydrogen peroxide "UHP# is the safest and most applicable of these reagents and has been reviewed ð82MI 195!90Ł[ This review contains an up!to!date survey and comparison of modern peroxidizing reagents[ NMe2

+

+

NMe2 OH–

30% H2O2

OH

MeOH, H2O

NMe2

fast

O–

–H2O

Scheme 22

"ii# From oxidation of tertiary amines with alkyl peroxides The use of alkyl peroxides provides one of the common and successful methods of oxidizing tertiary amines to amine N!oxides\ and good yields are obtained[ However\ yields can be improved by using metal catalysis\ such as vanadium and molybdenum salts ð55CB2273\ 69OS"49#45\ B!78MI 195!93Ł[ The Sharpless peroxide methodology using t!butyl peroxide allows stereoselective oxidation and kinetic resolution of one isomer of a racemic mixture of b!hydroxy tertiary amines "Equation "04## ð72JOC2597\ 89CL436Ł[ The "¦# or "−# isomers of diisopropyl tartrate can be used to give the respective enantiomers of the N!oxide[ Trituration is used to separate the amine N!oxide and chromatography is not required[ ButOOH, Ti(OPri)4

OH Ph

N

(+)-diisopropyl tartrate 60%

HO

OH Ph

N

+

+

(15)

N Ph

O–

"iii# From oxidation of tertiary amines with peroxy acids A variety of organic and inorganic peroxy acids readily convert tertiary amines into amine N! oxides even at low dilution ð38CRV23\ B!57MI 195!90Ł[ The mechanism is considered to be nucleophilic attack by the amine on the electrophilic oxygen in a reaction which is _rst order in each reagent[ The resulting salt is neutralized by the carboxylate anion in a fast reaction "Scheme 12#[ m!Chloroperoxybenzoic acid is most commonly used ð80TL3370Ł[ R3N:

O

R

O H

slow

R3N+

OH + R1CO2–

R3N+

O– + H+

O

R3N+

OH

fast

Scheme 23

"iv# From oxidation of tertiary amines with ozone and oxy`en The oxidation of tertiary amines with ozone has been reviewed ð47CRV814\ 47HOU"00#089Ł\ but reports suggest that mixtures of products are formed\ and the reactions are not synthetically useful ð67JOC1551Ł[ Yields are reasonable if protic solvents and tertiary amines with no b!hydrogens are used[ Autoxidation of tertiary amines occurs under high oxygen pressures "up to 049 atm# and tem! perature "099>C# in polar solvents such as MeOH or water via single electron transfer to yield tertiary amine N!oxides as the major product ð72AJC608\ 74JOC0452\ 77JOC0584\ 89JOC2122Ł[ The mechanism is uncertain but the initial single electron transfer between the amine and oxygen to yield the radical cation R2N=¦ and superoxide O1=− is rate determining[ The latest study suggests that hydrogen peroxide\ which is eventually formed in the reaction\ further oxidizes the tertiary amine to the

238

Hydroxylamines

N!oxide ð89JOC2122Ł[ Only one atom of the O1 molecule is incorporated into the N!oxide[ This surprising reaction has not yet been applied synthetically but has important implications for redox reactions carried out with O1 in the presence of tertiary amines[

"v# Use of Davis rea`ents Oxidation of a range of tertiary amines with Davis reagents\ 1!"phenylsulfonyl#!2!aryloxaziridines\ gives ×84) yields of pure amine N!oxides ð77JOC4745Ł[ The reaction is facile\ and the N!oxide precipitates out of the chloroform solution of the reaction and is _ltered[ The use of Davis reagents in synthesis have been reviewed ð78T4692Ł[

"vi# From alkylation of hydroxylamines The alkylation of hydroxylamine with three equivalents of alkyl halide to yield amine N!oxides has been known for nearly 099 years[ However\ treatment of N\N!dialkylhydroxylamines with alkyl halides to yield the corresponding tertiary amine N!oxides is a more satisfactory reaction "Scheme 13# ðB!78MI 195!92Ł[ R1 N OH + R3X

R2

R2

R1 + N OH X–

B: –BH+X–

R3

R1 + N O–

R2

R3

Scheme 24

"vii# From retro!Cope rearran`ements Retro!Cope rearrangements of v!alkenyl N\N!disubstituted hydroxylamines\ for example "02#\ proceed rapidly at ambient temperatures to yield cyclic tertiary amine N!oxides "Scheme 14# ð68TL3280\ 89JOC2996Ł[ The retro!Cope rearrangements proceed thermally and stereospeci_cally in a suprafacial manner\ for example "03# to "04# ð89JOC2996Ł[ The Cope rearrangement of the cyclic tertiary amine N!oxides back to the alkenyl N\N!disubstituted hydroxylamines is often possible at high temperature[ Retro!Cope rearrangements of intermediate N\N!disubstituted hydroxylamines\ formed from the addition of allylamines to nitrones\ yield tertiary amine N!oxides ð82CC058Ł[

+ +

25 °C

N

OH distillation

N Me

Me

N Me

O H

(13) R2

R3

Ph

R1

Ph

OH

R2 25 °C

Ph Ph

N

R3 R1 + – N O Me

Me (14)

(15) Scheme 25

O–

249

N!Halo`en\ N0O\ N0S\ N0Se and N0Te Functional Groups

1[95[1[1[1 Salts of N!oxides^ R2N ¦OH\ R02N ¦OR1 Amine N!oxides are weak bases and when treated with acid form stable salts\ R2N¦OH X−\ which can be isolated and in most cases are crystalline ð80COS"6#624\ 82S152Ł[ The pKBH¦ of the salts range between pH 3 and 4[ The salts R2N¦OH X− are readily neutralized by base to yield the corresponding tertiary amine N!oxides without problem[ The salts are also formed initially in many synthetic procedures[ The salts can also be formed by direct oxidation of tertiary amines by the anion of peroxysulfuric acid HO0OSO2− to give high yields of the N!oxide sulfate "R2N¦OH#1 SO31− ð65MI 195!90Ł[ N!Alkoxy!N\N\N!trialkylamine salts R02N¦OR1 can be formed by alkylation of either N!alkoxy secondary amines R01NOR1 ð48JA4799\ 68JA6003\ 72JHC0196Ł\ or N\N\N!trialkylamine N!oxides R2N¦O− ð78MI 195!92Ł[ Intramolecular alkylation of an intermediate N!alkoxy secondary amine has been used in the synthesis of "2#!epilupinine ð65TL3926Ł[

1[95[1[2 O!Substituted N!Alkylhydroxylamines] R0NHOR1\ R0N"OR1#1 The Chemical Abstracts rules of nomenclature are used\ R0NHOR1 and R01NOR1 are named N! alkoxyamines and not N\O!dialkylhydroxylamines and R0N"OR1#1 are named N\N!dialkoxyamines[ The related hydroxylamine derivatives\ N!silyloxyamines\ R01NOSiR12 and R0N"OSiR12#1\ and N! acyloxyamines\ R01NOCOR1 and R0N"OCOR1#1\ are reported in later chapters[ The synthesis and chemistry of O!substituted N!alkylhydroxylamines have been reviewed ð60HOU"09:0#0980\ B!78MI 195! 92\ 89HOU"E05#0Ł[

1[95[1[2[0 N!Alkoxy primary amines] R0NHOR1 "i# Reductive methods Similar reagents which are used to reduce oximes to N!substituted hydroxylamines RNHOH can be successfully applied to the reduction of O!alkyl!\ and O!aryloximes to N!alkoxy! and N! aryloxyamines\ for example LiBH3\ NaBH3 in basic or acidic media\ NaBH2CN in acid ð64T1484Ł\ BH2:THF and BH2 = pyridine:HCl ð81JOC1615Ł[ The methods are fully reviewed ð80COS"7#59Ł[ Most of the reagents are used under mild conditions\ and selectively reduce the O!substituted oximes in the presence of groups such as nitriles\ acetals\ amides\ and esters[ Diastereoselective reduction of a!hydroxyoximo benzyl ethers using tetramethylammonium triacetoxyborohydride "TABH# to acyclic 0\1!syn!N!benzyloxyamino alcohols "e[g[\ "05## has been rationalized via a Felkin model for external hydride delivery "e[g[\ "06## "Scheme 15# ð82TL2160Ł[

OH

OH

Ph

TBAH

N

Ph

MeCN/HOAc (1:1) 100%

OBn

HN

OAc OAc –B O H

OH BnONH

N BnO Ph

Me

Ph

H

H H

H– (16)

(17) Scheme 26

OBn

240

Hydroxylamines "ii# By C0N bond formation

Dialkylation of N!hydroxyurethanes and !ureas followed by hydrolysis has been a common procedure for the synthesis of N\O!dialkylamines since the turn of the century ðB!78MI 195!92Ł[ A more modern procedure uses N!benzyloxyamine BnONH1 which is converted to the corresponding N!benzyloxyamine RNHOBn via alkylation of an intermediate urethane "Scheme 16# ð78TL20Ł[ The anion of the urethane formed from the reaction between O!benzylhydroxylamine and di!t!butyl dicarbonate was alkylated by primary and secondary mesylates and iodides[ The resulting urethanes are hydrolyzed to yield the corresponding N!benzyloxyamine[ O!Benzylhydroxylamine has also been alkylated using allyl esters with palladium"9# catalysis "Equation "05## ð77TL1862Ł[ The reaction is particularly useful because of the high regioselectivity[ SN0 Substitution of 0!aryl!0!alkyl! ethylalcohols with N!benzyloxyamine BnONH1 in TFA gives good yields of benzyloxy!"0!aryl!0! alkylethyl#amine ð78JOC0110Ł[

BnONH2

H

(ButO)2CO

But

O

N

R

i, NaH, DMF

OBn

But

ii, RX

O

O

N

H H+

OBn

R

N

OBn

O Scheme 27

CO2Me

CO2Me

CO2Me Pd(PPh3)4 BnONH2 93%

OPO2Et2

+ HN

(16) HN

OBn

OBn 80% de

"iii# From N0O bond formation Reaction between primary and secondary amines and dibenzyl peroxide involves nucleophilic displacement on the peroxide bond to yield O!benzyloxylamine "see Section 1[95[1[0[0["i## "Scheme 7#[

"iv# From addition of or`anometallic rea`ents to oxime ethers Reasonable yields are obtained when a range of unstabilized aryllithium reagents are added to methyl and benzyl oxime ethers in the presence of BF2 = Et1O^ an example is shown in Equation "06# ð77TL2344Ł[

S

Li

+

N

OMe

BF3•Et2O THF, –78 °C 41%

(17)

S NHOMe

"v# From radical addition to oxime ethers Radical cyclization on to oxime ethers is more favored than cyclization on to aldehydes\ and yields cyclic exo!N!alkoxyamines[ The radicals have been generated from a range of precursors using a variety of reagents used in radical chemistry[ Early studies used alkyl radicals\ generated from ketones using zinc and TMS0Cl ð72TL1710Ł\ and from alcohols via their phenyl thionocarbonate derivatives PhOC"1S#OR\ using tributyltin hydride ð77JA0522Ł[ Radicals generated from vinyl bromides using tributyltin hydride undergo 5!exo!cyclization "Scheme 17# ð80CC0137Ł[ b!Allenic O! methyl oximes undergo radical hydrostannylation to yield cyclopentene N!methoxyamines "Equa! tion "07## ð81TL0946Ł[ Aryl radicals resulting from enediyne cyclization have been trapped using oxime ethers in tandem radical cyclizations ð82JOC5448Ł[ Intermediate ketyl radicals\ generated using

241

N!Halo`en\ N0O\ N0S\ N0Se and N0Te Functional Groups

samarium diiodide ð80TL1444Ł and electroreduction ð80TL414Ł\ have been added to oxime ethers to yield acyclic b!hydroxy!N!alkoxyamines[ Oxime ethers connected by a tether to aldehydes or ketones undergo Bu2SnH!mediated radical cyclization to yield cyclic amino alcohols "Scheme 18# ð83TL1194Ł[ ButON

ButON

Br

Bu3SnH

O

H

• ButON

•

ButON

O

O

O

Scheme 28

Bu3Sn R1 R3 R2

Bu3SnH, AIBN

R4 NOMe

•

PhH, reflux

R

O

NOMe Bu3SnH, AIBN

m( )

N

( )n

PhH, reflux

CO2Bn

• ( ) m

O

N

OH NHOMe

OH NHOMe

R

NOMe

m(

( )n

R )

N

( )n

+

CO2Bn

CO2Bn

R = H, Me m = 1, 2, 3 n = 1, 2

(18)

R4 NHOMe

R2

SnBu3 R

R3

R1

m(

)

N

( )n

CO2Bn

Scheme 29

"vi# From 0\2!dipolar addition of nitrones to alkenes 0\1!Prototopy in aliphatic oximes generates a small equilibrium concentration of the cor! responding NH!nitrones which act as 0\2!dipoles and undergo cyclization to yield cyclic N!alkoxy! amines\ isoxazolidines "Scheme 29# ðB!77MI 195!91\ 80T3996\ 81T5818Ł[ The factors which favor and disfavor the prototropic generation of NH!nitrones are discussed in the publication[ O H N

+

X

O–

X

N

O N H

H R

R

X

X

R X +

N O–

N OH R = Ph, H X = O, S, CH2

H O N H H

H Scheme 30

"vii# From cycloaddition of alkylnitroso compounds and alkenes Chiral acylnitroso compounds have been developed as chiral auxiliaries in cycloaddition reactions with alkenes "Scheme 20# ð81TL2472Ł[ The acylnitroso compound stereoselectively undergoes DielsÐ

242

Hydroxylamines

Alder addition with dienes to yield a cyclic acyl alkoxyamine[ The chiral auxiliary "07# is crucial for the selectivity of the cycloaddition reaction[ The acyl group is removed by hydrolysis or reduction to yield cyclic N\O!dialkylamines with good enantiomeric excesses[ a!Chloronitro compounds undergo cycloaddition followed by elimination to yield cyclic N\O!dialkylamines "Equation "08## ð65AG"E#659Ł[ CO2Et

EtO2C

O

+

N

X*

N

X*

CO2Et

O

O

O

i, Na/Hg, MeOH (aq.), NaH2PO4 ii, NaOH, EtOH (aq.)

NH2

iii, HCl (aq.)

O

+

Cl–

HO ButO

(18) X*OH =

Scheme 31 R1

R1 CN

NO O + NH

MeOH

Cl

+

Cl–

(19)

2

R2

R2

1[95[1[2[1 N!Alkoxy secondary amines^ R01NOR1 "i# From O!alkylation of N\N!dialkylhydroxylamines Selective methylation of the hydroxylamine function over b!alcohols in N\N!dialkylhydroxyl! amines "e[g[\ "08## with BuLi followed by alkylation with methyl iodide yields the corresponding N!methoxyamine without racemization of chiral a!centres "Equation "19## ð89JOC2353Ł[ The oxygen anions of dialkylhydroxylamines can be added to electron!de_cient alkenes^ a 0877 example is shown in Equation "10# ð77JOC4665Ł[ OH Ph

OH

OMe OH BuLi

N

Ph

N

(20)

MeI

(19) O R1 N OH +

N R2

R1 O

O ButOK (cat.)

R1

THF

N

R1

N R2

(21)

O O

R1 = Bn, Et R2 = H, Ph, alkyl

"ii# From C0N bond formation N!Alkoxyamines R01NOR1 can be synthesized by N!alkylation of N!alkoxyamines\ RONH1 and R0NHOR1\ by a variety of methods\ for example with dimethylsulfate\ oxiranes and Mannich reactions ð60HOU"09:0#0980\ 89HOU"E05#0Ł[ Electrophilic nitrogen atom cyclization of alkenyl

243

N!Halo`en\ N0O\ N0S\ N0Se and N0Te Functional Groups

N!alkoxyamines using electrophiles such as HgCl1 or iodine provides a useful protocol for the synthesis of trans!1\2 and 2\4!disubstituted pyrrolidino iodides which is analogous to the better known cyclization using amines\ commonly called the Giese reaction ð80COS"3#252Ł[ An example of the protocol is shown in Equation "11# ð78TL0216Ł[

H

I2, 0 °C MeCN solid NaHCO3

NH O

O

N O

(22)

I H

O

"iii# From 0\2!dipolar addition of nitrones to alkenes The 0\2!dipolar cycloaddition of nitrones on to alkenes has been widely investigated and provides a major synthetic method for carbonÐcarbon bond formation[ The general protocol is shown in Equation "12#[ The isoxazolidines which are formed in the cycloaddition reactions are regarded as synthetic relays\ and are reductively cleaved to yield a range of hydroxylated and aminated inter! mediates in synthesis[ The methodology has been used in a large number of natural products syntheses\ and has been extensively reviewed ð57OSC"5#569\ 64S194\ 65AG"E#012\ 66AG"E#09\ B!73MI 195!90\ B!76MI 195!90\ B!77MI 195!92Ł[ For example\ d?!pyrroline!N!oxides have been used for the synthesis of pyrrolizidines and indolizidines ð82TL2828Ł[ The nitrones may be preformed or made in situ\ which is particularly useful for intramolecular cycloadditions "Scheme 21#[ The cycloadditions are con! certed cis!additions "suprafacial#[ The factors in~uencing the stereoisomeric ratios in 0\2!dipolar cycloadditions vary widely and are yet to be clearly elucidated ð80TL3320Ł[ Evidence indicates that secondary orbital interactions are not important ð89JOC2316Ł[ Further stereoselectivity can be induced by the use of chiral nitrones\ for example the use of chiral nitrones derived from 4!alkenylaldehydes and chiral hydroxylamines in the cycloadditions shows diastereoselectivity ranging between 0[6 ] 0 and 05 ] 0 "Scheme 21# ð80TL3320Ł[ R1

R2

R1

R2

R2

+ –O

N+

N

R3

O

R3

(23) N

R1

O

R3

R1 = Ar, OR, CN, CO2R, CH2OH, NO2, OCOR, SO2Ar, alkyl R2 = Ar, H, electron withdrawing group (EWG) R3 = Me, But

R3

R2

R3

R2 R1

R*NHOH

R1 CHO

R1

HOHN H Ph

R2 O

O–

+

N R*

R*NHOH =

R3

R1

+

R1 = R3 = H; R2 = CO2Et R1 = R2 = H; R3 = Me R1 = Ph; R2 = H; R3 = CO2Et

R2 O

N H

R3

N H

R*

R*

10:1 4.4:1 5.3:1

Scheme 32

"iv# Cycloaddition of alkylnitroso compounds to alkenes The cycloaddition of alkylnitroso compounds to dienes to form six!membered ring N!alkoxy! amines\ tetrahydro!0\1!oxazines\ has been reviewed ð60HOU"09:0#0980\ 66CSR0\ 76MI 195!90Ł[

244

Hydroxylamines "v# From rearran`ements of amine N!oxides

Thermal rearrangement of amine N!oxides in which one alkyl group is allylic or benzylic yields N!alkoxyamines R01NOR1 ð60HOU"09:0#0980\ B!78MI 195!92\ 89HOU"E05#0\ 82S152Ł[ The rearrangements have been reviewed ð82S152Ł\ and only representative examples are shown[ The benzylic rearrange! ment\ called the Meisenheimer rearrangement\ is considered to proceed by a homolysis to benzylic radicals and nitroxides and recombination to yield the N!benzyloxyamine "Scheme 22# ð62JOC0702\ 82S152Ł[ Extensive racemization is observed in this protocol as would be expected for the radical mechanism\ and the more stable the intermediate benzylic radical the faster the rearrangement[ Synthetically\ the most useful application is for ring expansion reactions in which aryl and allyl substituted cyclic amine N!oxides undergo expansion to 0\1!oxazaheterocycles[ However\ most allylic compounds proceed by a concerted ð1\2Ł sigmatropic shift with 0\2!transfer of chirality ð65JOC299Ł[ An example is shown in Scheme 23 ð80TL3370Ł[ An interesting example demonstrates the competition between the two mechanisms^ the allyl substituent directs a sigmatropic rearrangement\ whereas in the absence of an allyl group the radical 0\1!rearrangement takes place "Scheme 24#[ O–

homolysis

Me2N +

+•

Me2N

Ph

O–

Me2N

•

recombination

O

Me2N

cage

O

Ph

•CH2Ph Scheme 33

Bn2N

CO2Et

mcpba

+ Bn2N

R

O– CO2Et

R

CO2Et ONBn2

R Scheme 34

O–

N O

+N

R1 = vinyl

N H Me

80%

N H Me

CO2R2 [2,3]-sigmatropic shift

R1

N O

R1 = Et 60%

CO2R2

N Me

H Et CO2R2

H H

'benzylic' rearrangement Scheme 35

"vi# From nitroxides The trapping of alkyl radicals R1 = by nitroxides R01NO = yields N!alkoxyamines R01NOR1\ but no useful synthetic strategies have been located ðB!71MI 195!91Ł[ Dimerization of nitroxides to hydroxylamine peroxides R01NO0ONR01 is energetically unfavorable ðB!71MI 195!91Ł[

1[95[1[2[2 N\N!Dialkoxyamines] RN"OR0#1 The synthesis and reactions of N\N!dialkoxyamines R0N"OR1#1 have been reviewed ð82CRV614Ł and therefore the synthetic methods are only brie~y discussed[ N\N!Dialkoxyamines are also called nitrosoacetals[

"i# From cycloaddition of nitronic esters and alkenes The 0\2!dipolar ð2¦1Ł!cycloaddition of nitronic esters R1R2C1NO1R3 on to alkenes provides the main protocol for synthesis of cyclic N\N!dialkoxyamines "19# "i[e[\ N!alkoxyisoxazolidines

245

N!Halo`en\ N0O\ N0S\ N0Se and N0Te Functional Groups

"Scheme 25## ðB!77MI 195!93\ 82CRV614Ł[ Five! and six!membered ring cyclic alkyl nitronates "isox! azoline N!oxides# can also be used to add to alkenes to form bicyclic N\N!dialkoxyamines "10# and "11# "Scheme 25#[ The cycloadditions proceed fastest when the alkene or alkyl nitronate substituents "R1\ R2\ and R3 in Scheme 25# are electron!withdrawing groups such as nitro or ester groups[ Silyl esters of nitronic acids R01C1NO1SiR12 also make suitable substrates for ð2¦1Ł!cycloadditions and yield the more stable N!silyloxyisoxazolidines\ but the reactions are slower ðB!77MI 195!93\ 82CRV614Ł[ A number of variations allow intermediate formation of isoxazoline N!oxides which react in situ with further alkene[ An example which has been exploited synthetically is the inter! and intra!ð3¦1Ł!heterodiene cycloaddition of nitroalkenes to alkenes to yield unstable isoxazoline N! oxides\ which rapidly react by ð2¦1Ł cycloadditions to yield bicyclic N\N!dialkoxyamines ð74HCA208\ 75JA0295\ 89JA200\ 89T3746\ 80TL1406Ł[ Another example is shown for the stereoselective intermolecular ð3¦1Ł!cycloaddition followed by a ð2¦1Ł 0\2!dipolar cycloaddition to yield the tricyclic N\N! dialkoxyamine "12# "Scheme 26# ð80JOC5627Ł[ In this example\ chiral auxiliaries have been used with the best de "×87)# resulting from the use of trans!1!phenylcyclohexanol[ R2

R2

+

N

R3 N O

O

O–

R2

R2

O–

N+ R3

OR4

O N O

R1

(21)

R1

OR4

R2

(20) R2 O

N

+

O–

N O O (22)

R1

Scheme 36

*GO

MeO2C

O

+

N

O–

–O

Ti(OPri)2Cl2

+

N

O

OG* MeO2C

OG*

O N O

MeO2C

CH2Cl2, –78 °C

H

H

(23)

G*OH = trans-2-phenylcyclohexanol Scheme 37

"ii# From substitution in N!substituted!N!alkoxylamines^ R0N"X#OR1 N!Chloro!N!alkoxyamines R0N"Cl#OMe readily undergo substitution of chlorine by alkoxides\ or by alcohols in Et2N\ under mild conditions to yield N\N!dialkoxyamines R0N"OR1#1 in 10Ð77) yield ð68ZV813\ 70T3134\ 80IZV0958Ł[ N!Chloro!N!alkoxyamines with tertiary alkyl substituents are suitable\ but those with primary or secondary alkylamines lose hydrogen chloride by elimination[ Acid!catalysed trans!esteri_cation of the alkoxy groups in N\N!dialkoxyamines by alcohols has been reported ð82CRV614Ł[

1[95[1[2[3 Salts of O!substituted N!alkylhydroxylamines^ R0N ¦H1OR1\ R0N ¦H"OR1#1 O!Substituted N!alkylhydroxylamines are protonated in acid\ and have properties similar to amines and hydrazines ð60HOU"09:0#0980\ B!78MI 195!92\ 89HOU"E05#0Ł[ The salts of O!substituted N! alkylhydroxylamines are formed in a number of synthetic reactions\ and are neutralized by standard procedures or used for puri_cation[ N!Alkyl salts R02N¦OR1 are regarded as salts of N\N\N! trialkylamine N!oxides R2N¦O− "Section 1[95[1[1[1#[

246

Thiohydroxylamines 1[95[1[2[4 N!Chloro!N!alkoxylamines^ R0N"Cl#OR1

N!Chloro!N!alkoxyamines R0N"Cl#OR1 have been formed in moderate yields by chlorination of the corresponding N!alkoxyamines R0NHOR1 with sodium hypochlorite or t!butylhypochlorite at temperatures between −19>C and 9>C ð68ZV813\ 70T3134\ 80IZV0958Ł[ Good yields are obtained only when no a!hydrogens are present\ otherwise hydrogen chloride is eliminated to yield oxime ethers[ The methoxy group in acylic or monocyclic N!alkoxy!N!methoxyamines R0N"OR1#OMe can be substituted by chlorine using MeCOCl\ TMS!Cl\ SOCl1 or HCl to yield N!chloro!N!alkoxyamines ð82CRV614Ł[

1[95[1[3 N!Sulfonyloxyamines R01NOSO1R1 and Related Compounds Primary and secondary amines react with diarylsulfonyl peroxides "ArSO2#1 at low temperature to yield N!"arenesulfonyloxy#amines "Equation "13## ð62JOC0128\ 65JA5691\ 66S0\ 72S23\ 73S106\ 74JA3620\ 80T0098Ł[ These compounds are of synthetic interest as sources of {positive amines|[ N!Sul! _nyloxyamines R01NO0SOR1 have been prepared from the corresponding hydroxylamines R01NOH with R0 Me\ Et\ and Bn\ and sul_nyl chlorides R1SOCl with R1 Me and Ph\ in dichloromethane at −67>C with Et2N as the base ð75JCS"P1#040Ł[ Sul_toamines R2N¦OSO1− are prepared by addition of SO1 to tertiary amine N!oxides[ In particular\ bridgehead amine N!oxides "e[g[\ strychnine and quinuclidine# give the most stable derivatives in anhydrous solvents ð68JOC2756\ ¦ 89OR74Ł[ Sul_toamines rearrange on standing to aminesulfamates R2N SO2−[ Most sul_toamines are unstable and rapidly undergo Polonovski reactions in acid solution ð89OR"28#74Ł[ Certain sul_toamines are able to transfer SO2 to further amine N!oxide to yield sulfatoamines\ for example Et2N¦OSO1− changing to Et2N¦OSO2−[ R2NH

Et2O

+ (ArSO3)2

R2N

–78 °C, 2–4 h

O

SO2Ar

+

+ RNH ArSO3–

(24)

1[95[1[4 N!Phosphinyloxyamines^ RNH0O0P"1O#R1\ R1N0O0P"1O#R1 The reaction between primary and secondary amines and diphenylphosphinylperoxide "Ph1PO1#1 yields N!"diphenylphosphinyloxy#amines "Scheme 8# ð75T1692\ 74S796Ł[ Treatment of N\N!dialkyl! hydroxylamines with BuLi:"EtO#1POCl gave reasonable yields of the corresponding phosphate derivatives "Equation "14## ð89JOC2353Ł[ OH Ph

N

O

BuLi

Ph

Ph

N

PO3Et2 Ph

(25)

(EtO)2POCl 57–64%

1[95[2 THIOHYDROXYLAMINES AND RELATED FUNCTIONS Certain reviews have dealt comprehensively with the chemistry and preparation of S!alkyl and S!aryl derivatives of thiohydroxylamines "sulfenamides#\ and therefore a brief survey is detailed ð35CRV158\ 62IJS60\ B!62MI 195!90\ 68OPP22\ 74HOU"E00#57\ 78CRV578\ 89RCR721\ B!89MI 195!90Ł[

1[95[2[0 Thiohydroxylamines^ R1NSH The reduction of disul_des R01NSSR1 gives thiohydroxylamines R01NSH ð64CC744Ł[ These thiohy! droxylamines are unstable above −39>C and decompose to give the secondary amine and sulfur[ Thiohydroxylamines have been postulated as reactive intermediates but have not been previously isolated[

247

N!Halo`en\ N0O\ N0S\ N0Se and N0Te Functional Groups

1[95[2[1 Sulfenamides^ R0NHSR1\ R01NSR1 The best known method of preparing sulfenamides is by the reaction between a sulfenyl halide and an amine "Equation "15## ðB!89MI 195!90Ł[ One study ð69JOC2901Ł of this reaction found that amines of lower basicity and higher substitution pattern gave better results in both synthesis and puri_cation[ Excess amine or another base "e[g[\ triethylamine# must be present to react with acid generated during the reaction as sulfenamides are unstable to even traces of acid[ Sulfenamides can be puri_ed by distillation\ crystallization\ or alumina chromatography[ Alkylsulfenyl chlorides often give complex mixtures of products ð50CB523\ 60JCS"C#1739Ł[ Arenesulfenyl chlorides normally give good yields of sulfenamides^ however\ it should be noted that sulfenyl halides can react with hydroxyls\ active methylene compounds and alkenes ð78CRV578Ł[ Sulfenamides containing reactive double bonds have\ however\ been prepared by this method "Equation "15## ð83T0164\ 83T0184Ł[ The reaction between amino acids and o!nitrobenzenesulfenyl chloride to yield the corresponding sulfenamides is used as a method of protecting the amino group ð53JA2559Ł[ R1 NH + PhSCl

R1 N SPh

Et3N (5 equiv.) dry Et2O

R2

+

+ Et3NH Cl–

(26)

R2

R1 = p-methylbenzyl, R2 = cyclopropyl, 96% R1 = butyl, R2 = 4-pentenyl, 95%

Reaction between amines and N!sulfenyl substituted phthalimides gives sulfenamides "Equation "16## ð69TL3872\ 60TL3842\ 83T0164Ł[ The conditions are mild\ and the highly insoluble phthalimide byproduct is precipitated from solution[ Work!up is simply by _ltration of the reaction mixture and evaporation of the solvent[ Yields are normally above 79) after puri_cation[ This method is e}ective for both alkane! and arenesulfenylphthalimides\ but does not work with bulky alkyl groups such as isopropyl\ t!butyl or cyclohexyl[ Reaction with sterically hindered amines is very slow even after re~uxing in toluene for long periods[ O R1 NH +

N SPh

R2

O R1 N SPh

+

NH

(27)

R2 O

O

R1 = Me, R2 = cyclohexyl, 93%, FCH2Cl2, RT, 30 min R1 = allyl, R2 = 4-pentenyl, 86%, benzene, reflux, 3 h

A number of sulfenamide syntheses involve the oxidation of a thiol or its metal salt in the presence of an amine[ The oxidation of thiazolyl thiolate salts by iodine in potassium iodide solution\ chlorine or sodium hypochlorite and reaction with an amine has been described ð38JOC810Ł[ Thiols have been condensed oxidatively with amines in the presence of K1S1O7 ð68ZOB730Ł[ 1!Mercapto! benzothiazole has been cross!coupled electrolytically in the presence of tetraethylammonium per! chlorate with primary and secondary amines[ The yields of cross!coupled products are generally above 89)\ except for sterically hindered amines such as diisopropylamine[ The thiol must also contain electron!withdrawing groups for the reaction to work[ Disul_des have been utilized in a number of syntheses of sulfenamides[ The reaction of alkyl or aryl disul_des with primary or secondary amines in the presence of a metal activator such as silver nitrate\ silver acetate or mercuric chloride has been reported ð66JOC856\ 83T0164Ł[ Reasonable yields are obtained under mild conditions\ and the method is tolerant of many functional groups but the method requires at least two equivalents of amine[ In a variant of this method\ lithium salts of primary or secondary amines are reacted with alkyldisul_des to give the corresponding sulfenamides in excellent yield "Equation "17## ð72S605Ł[ Several research groups ð60JCS"C#2756\ 61JOM"33#26Ł have described the use of arenesul_nic esters in the preparation of sulfenamides[ The reaction between arenesulfenates ArSOMe and either primary or secondary amines gives high yields of sulfenamides\ as did reaction with N\N!dialkylamino silanes or aminoboranes R0R1N0BR2R3[ Thiolsulfonates ArSO10SR have also been reacted with primary and secondary amines "Equation "18## ð55JOC731\ 58ZOR0977\ 69JOC168Ł[ It was found that\ as the electronegative character of the thiol component increased\ formation of the sulfenamide became easier[

248

Thiohydroxylamines R1 N Li

+

R1 N SR2

THF

R2SSR2

69–96%

R1

(28)

+ LiSR2

R1

R1 = Pr, R2 = Et, Pr, Bui

Ts

SMe

+ HN

O

MeS N

O

+

+ Ts– H2N

O

(29)

excess

Alkylthionitroso compounds RN1S undergo DielsÐAlder addition to dienes and addition to alkenes to yield sulfenamides "Scheme 27# ð81AHC"44#0Ł[ R1NHS

N

S

R2

R1

R2

N

R1

S

Scheme 38

1[95[2[1[0 Primary sulfenamides^ R0NHSR1 Tritylsulfenimines can be reduced with sodium cyanoborohydride at pH 2Ð5 giving the cor! responding triphenylmethanesulfenamides "Equation "29## ð72JOC2420Ł[ The addition of Grignard or organolithium reagents to sulfenylimines has been reported to give primary sulfenamides in good yields ð70TL4962\ 83JOC803Ł[ An example which involves complete diastereoselectivity is shown in Equation "20# ð83JOC803Ł[ When an azide is treated with a thiol in the presence of copper"I# salts\ primary sulfenamides are isolated in good yield ð69JOC1868Ł[ The reaction is limited to nonaromatic thiols[ Ph3CS

Ph3CS

N

NaBH3CN

R2

R1

CF3CO2H, THF pH 3–6

(30) R2

R1

Ph

Ph

N

HN

S OR1

NH

R2MgBr THF, –10 °C

H R2

S (31) OR1

R1 = H, Bn, neopentyl; R2 = Me, Bun, But, Pri, allyl

1[95[2[1[1 Secondary sulfenamides^ R01NSR1 The reaction of aminosulfenyl chlorides with organometallic reagents has been reported to give sulfenamides in good yields "Scheme 28# ð76BSF070\ 76T770Ł[ Dimethylaminosulfenyl chloride will react with an alkene at low temperatures to give a b!chlorosulfenamide\ which reverts to starting materials when distillation is attempted at 79>C ð57JOC1000Ł[ N!Sulfenyl substituted lactams and hydantoins can be used in trans!amination reactions to give the corresponding sulfenamides in good yield ð68S117\ 71LA010Ł[ The trans!amination reactions of 1!benzothiazole sulfenamide have also been described^ the reaction is slowed as the amine becomes more basic\ or if water or other basic amines are added[ Acids increase the rate of this reaction ð70ZOB598Ł[ Thiols or disul_des react with amines in the presence of an oxidizing agent to give the corresponding sulfenamides ð67JOC2112\ 68JOC0443Ł[ Chloroamines react with thiols to provide sulfenamides in reasonable yields "Equation

259

N!Halo`en\ N0O\ N0S\ N0Se and N0Te Functional Groups

"21## ð80JOC5691Ł[ A disadvantage is that a further equivalent of the amine precursor is required as a base\ but the advantage is that the method can be used for synthesizing sulfenamides when the corresponding sulfenyl chloride cannot be used[ Certain disul_des have also been reported to react with chloroamines in the presence of excess amine\ which acts as a base ð79EUP09366Ł[ Secondary sulfenamides have been prepared by adding sulfenyl thiocyanates RS0SCN to cold ethereal solu! tions containing two equivalents of the respective secondary amines ð45JA5070Ł[ a!Halomethyl sulfoxides react with four equivalents of various secondary amines to give the corresponding sulfenamides in nearly quantitative yields ð60IJS104Ł[ MgBr

R1

R1

SNR2

Li

R2NSCl

R2N

S

Scheme 39

O

N Cl +

ButSH

excess morpholine

O

N SPh +

+

O

NH2 Cl–

(32)

CHCl3

1[95[2[1[2 Sulfenamide salts^ R02N ¦SR1\ R01N0S ¦R11 Unstable salts R2N¦SAr X− are formed from reaction between tertiary amines and arenesulfenyl chlorides or thiosulfonates\ and react rapidly with nucleophiles ð64CC302Ł[ Azasulfonium salts "13# can be prepared by the reaction between secondary amines\ dimethyl sul_de and ButOCl ð73JCS"P0#0390Ł[ S!Amination of sulfenamides by reaction with N!chloro! succinimide in nonhydrolytic conditions gives the corresponding azasulfonium salts "14#\ which are stable enough to be isolated as their chlorides or tetra~uoroborates ð65S297\ 67JOC541Ł[ The reaction of N!alkyl!N!sul_nylalkaminium salts with sulfoxides and subsequent extrusion of SO1 furnishes the analogous azasulfonium salts "Scheme 39# ð71TL0132Ł[ The reaction of sul_namides with strong methylating agents such as CF2SO1CH2 converts them to the corresponding methoxyazasulfonium salts "15# ð64CL880Ł[ O R2 N

+

Cl–

+

SMe2

R3

N S

Cl–

R12N

+

OMe CF3SO3–

S R2

NR1R2 O (24)

(25)

R1 + N SO– BF4– +

R2 S O

R1

R2

(26) O O S R2

–SO2 +

S N R1 1 R2 R

R1 R2 + BF4– N S 2 R R1

Scheme 40

1[95[2[2 Derivatives of Thiohydroxylamines^ RN"X#SY 1[95[2[2[0 RNH0SY and R1N0SY\ with Yhalogen Amino sulfenyl chlorides R1NSCl have been prepared by treatment of thiobisamines R1NSNR1 with chlorine\ hydrogen chloride or sulfur dichloride\ or by reaction between dithiobisamines R1NSSNR1 and sulfuryl chloride ð60CC0302Ł\ SO1Cl1\ or chlorine ð47CB1417\ 66ZN"B#610Ł[ Secondary alkyl amines react with sulfur dichloride in the presence of a hydrogen chloride acceptor to produce aminosulfenyl chlorides ð53JCS4781\ 63ZN"B#166Ł[

250

Thiohydroxylamines 1[95[2[2[1 RNH0SY\ R1N0SY

Aminosulfenyl chlorides react with nucleophiles such as ethoxide at sulfur\ displacing chloride ð58CB0378\ 77TL2140Ł[ The formation of amino disul_des R01NSSR1 occurs when aminosulfenyl chlorides react with silylated sul_des ð60CC0302Ł[ Amino disul_des R1NSSCF2 are formed when dialkylaminosulfenyl chlorides react with mercury"II# tri~uoromethanethiolate ð64CB0254Ł[ The reaction between secondary amines and sulfur dichloride and S1Cl1 in chlorinated solvents at low temperature gives N\N!thiobisamines R1NSNR1 and N\N!dithiobisamines R1NSSNR1\ respectively ð52CB0020Ł[ t!Butylamine reacts with sulfur dichloride to give the corresponding thio! bisamine "ButNH#1S ð65JOC0222\ 66ZAAC"321#062Ł[ Unsymmetrical N\N?!thiobisamines have been made by the reaction of aminosulfenyl chlorides with secondary amines in the presence of added base ð45GEP837229Ł[ Without added base this reaction gives exclusively the symmetrical thiobisamine because hydrogen chloride is generated in the reaction and causes disproportionation ð59JCS4968Ł[ Aminosulfenyl chlorides react with various diamines to give the corresponding cyclic thiobisamines "Equation "22## ð73JCS"P0#1480Ł[ Thiobisamines have also been prepared from the reaction of amines with N!sulfenyl substituted hydantoins ð71LA010Ł[ Aminobistrimethylsilanes react with amino! sulfenyl chlorides to give aminobisthioamines "Equation "23## ð60CC0302\ 67TL3992Ł[

N SCl

NH2

H H N

NH2

N H H

+

TMS R1

N

(33)

S

SNR2 R1

+ 2 R2N SCl

+ 2 TMS-Cl

N

(34)

SNR2

TMS

The entire series of compounds S6NR to S3"NR#3 are known for RMe[ All of these compounds have puckered eight!membered rings like S7 ð62CJC1493Ł[ The chemistry of N\N!polythiobisamines R1NSnNR1 has been reviewed ð69QRS134Ł[ Primary amines react with S1Cl1 to give cyclic tetra! thiobisamines in reasonable yield ð48CB0038\ 50CR"141#3996Ł[ Sulfenamides phosphorylated on sulfur can be prepared from the reaction between bis"dialkoxyphosphoryl# disul_des and primary or secondary amines in good yields "Equation "24## ð64ZOB0994Ł[ The synthesis of a benzenesulfonyl substituted sulfenamide R1NSSO1Ph has been reported ð71SUL22Ł[ O (R1O)2P

O

+

S

(R1O)2P

R2NH2

O S

NHR2

+

(R1O)

2P

SH

(35)

2

R1 = Et, Pri; R2 = Me, Et, Pri

1[95[2[2[2 Disulfenamides] R0N"SR1#1 Disulfenamides R0N"SR1#1 are synthesized by several routes[ The most common method is the reaction between a primary amine and two equivalents of a sulfenyl chloride in diethyl ether at low temperature with triethylamine as a base "Equation "25## ð73JOC1613\ 78CRV578\ 83UPŁ[ Di! sulfenamides are also formed from the reaction between primary amines and arenesul_nic esters\ unless the amine is in excess ð60JCS"C#2756Ł[ The reaction of acetic anhydride with sulfenamides is reported to give disulfenamides and other products ð59ZOB0320Ł[ Another method of making disulfenamides utilizes the disulfenamide of ammonia "PhS#1NH "Scheme 30# ð69TL2300\ 83UPŁ[ The anion "PhS#1NLi is made using butyllithium and is then reacted with bromides or tosylates to give the analogous disulfenamides in moderate yields[ RNH2 +

2 PhSCl

Et3N dry Et2O

+

RN(SPh)2 + 2 Et3NH Cl–

(36)

251

N!Halo`en\ N0O\ N0S\ N0Se and N0Te Functional Groups PhS

BuLi

N H PhS

PhS

RBr or

PhS

ROTs

PhS

N Li PhS

N R

Scheme 41

1[95[2[3 Dialkylaminosulfur Tri~uorides^ R1NSF2 The syntheses and synthetic applications of a range of NSFx ~uorinating agents have been reviewed ð77OR402Ł[ Dialkylaminosulfur tri~uorides R1NSF2 of which diethylaminosulfur tri~uoride "DAST# is the most common\ bis"dialkylamino#sulfur di~uorides "R1N#1SF1 and tris"dialkyl! amino#sulfonium di~uorotrimethylsilicates "R1N#2S¦Me1−SiF1 are easily handled ~uorinating agents and can be used under very mild conditions ð77OR402Ł[ Reaction between dialkylamino! trimethylsilanes and sulfur tetra~uoride is used to synthesize these compounds "Scheme 31# ð77OR402\ 77OSC"5#339Ł[ Et2N-TMS + SF4

CCl3F

Et2NSF3 + TMS-F

–65 °C to RT 84%

Et2NSF3 + Et2N-TMS

92%

(Et2N)2SF2 + TMS-F

Scheme 42

1[95[2[4 Sul_namides^ R0NHS"O#R1\ R01NS"O#R1\ and Derivatives Thereof Methods for the preparation of sul_namides have been reviewed ðB!89MI

195!91\ B!89MI 195!92\

B!89MI 195!93Ł[

1[95[2[4[0 Redox methods Sulfenamides can be oxidized to sul_namides using a number of reagents including mono! percamphonic acid ð56CC874Ł which gives low stereoselectivity\ Ti"OiPr#3:DET:H1O:ButOOH which gives low ee ð75NJC650Ł\ "Bu2Sn#1O:Br1 ð66TL1302Ł\ and mcpba ð66S687\ 80JCS"P0#1058Ł[ Optically active primary sul_namides have been made by the reduction with retention of con_guration of optically active sulfoximines R0R1S"O#1NMe\ with aluminum amalgam ð60JA4294\ 75JOC70Ł[ Sul_namides of primary amines have been prepared by reduction of N!sul_nylimines R0R1C1N0S"O#R2 with a range of reductants including LAH ð66CC612Ł and dibal ð80JOC3\ 82TA1048Ł[ Reduction of these imines substituted on nitrogen by a chiral sulfoxide group gives substantial chiral induction at the resulting amino carbon of the primary sul_namide "Equation "26## ð82TA1048Ł[

+

S –O

N

Ph

:

ButCONH

dibal, THF

+

S –40 °C, 4 h 98%

–O

H N

H

:

Ph

(37)

ButCONH 86% ee

1[95[2[4[1 From substitution at sulfur"IV# The reaction between alkylsul_nyl chlorides RS"O#Cl and secondary amines has been reported to give low yields of the corresponding sul_namides ð58JOC1286Ł[ The anion of an optically active amine has been added to a sulfoxyl chloride RS"O#Cl to give a sul_namide ð57JA2758Ł[ An excellent general method for preparing sul_namides uses mcpba oxidation of N!"alkane! and arene!

252

Thiohydroxylamines

sulfenyl#phthalimides to yield the corresponding sul_nylphthalimides\ which on reaction with pri! mary or secondary amines give the corresponding sul_namides and phthalimide as a precipitate "Scheme 32# ð61TL4202\ 62JOC3217\ 80JCS"P0#1058Ł[ Succinimides have also been used under these conditions ð66TL852Ł[ The yields of sul_namides prepared by this method are generally above 79)[ Reaction between sul_nic acids and amines in the presence of activating agents have been reported but with moderate yields ð58JOC1286\ 65S228\ 71CPB0535Ł[ The use of 1!chloropyridinium iodide as a coupling agent gives reasonable yields of primary sul_namides "Scheme 33# ð65S228Ł[ O

R2 N H

O O

mcpba

N SR1

N SR1 0 °C, CHCl3 89–100%

O

O R2 O N SR1

R3

+

N H

R3 O

O

R = Me, Ph, But Scheme 43

RSO2H +

Et3N +

N

+

Cl

N

Me

O

S

O

BnNH2

O

R

R

S

Me

+ NHBn

N

O

Me

R = p-Tol, 49%; R = C12H25, 39% Scheme 44

Sul_namides can be synthesized by reaction between organometallic reagents "e[g[\ R1NMgBr# and suitable sul_nyl compounds RS"O#X\ for example sul_nates\ R0S"O#OR1 and N!acyl! sul_namides R0S"O#N"R1#COR2[ The reaction between chiral nonracemic N!sul_nyloxazolidinones "16# and metallated amides R1NMgBr has been applied to the asymmetric synthesis of sul_namides "Equation "27## ð81JA4866Ł[ The reaction proceeds with inversion at sulfur in high yield and enantio! selectivities[ O

O S p-Tol

O

Et2NMgBr

N

O –78 °C 91%

Bn (27)

p-Tol

S

NEt2

(38)

ee > 98%

1[95[2[4[2 Other general methods S!Alkoxysulfenamides\ prepared from reaction between allylic alcohols and amino sulfenyl chlorides\ undergo a ð1\2Ł!sigmatropic rearrangement to give the corresponding allylic sul_namide "Scheme 34# ð77TL2140\ 80T5544Ł[ Some of these rearrangements proceed with complete dias! tereoselectivity ð80T5544Ł[ N!Alkylation of lithium salts of primary sul_namides gives the analogous secondary sul_namides ð69JPR018Ł[ The addition of Grignard reagents to sul_nylimines R0CH1NS"O#R1 has been reported to give primary sul_namides with complete diastereoselectivity and good yields\ using the chiral auxiliary shown in Equation "20# ð83JOC803Ł[ Grignard reagents add to the nitrogen of N!sul_nylamines\ RN1S1O\ to yield sul_namides ð48CB0809Ł[

1[95[2[4[3 Derivatives of sul_namides Amino oxosulfoxonium tetra~uoroborate salts have been synthesized by alkylation of sul! foximines "Scheme 35# ð62ACR230\ 83JA1289Ł[ Sulfoxonium methylides derived from these salts are used synthetically for cyclopropanation[ N!Alkoxysul_namides R0N"OR1#S"O#R2 are prepared from reaction between alkanesul_nyl

253

N!Halo`en\ N0O\ N0S\ N0Se and N0Te Functional Groups R3

R4

R1 R2

OH

+

O

N SCl

R2

–HCl

R1

R4

R1

R3

R4

S

R2 O S

N

N

O

O

R5

O

R5

R3

R5

Scheme 45

Ar H

S Me N

BF4–

O

O Me3O+

–

BF4

Ar Me

+

S Me N

OH–

Ar

H

Me

BF4–

O

O Me3

S Me

O+

–

BF4

N

Ar Me

+

S Me N

H

Scheme 46

chlorides R2S"O#Cl and N!alkoxyamines R0NHOR1 ð61TL070\ 68PS"6#214\ B!89MI 195!92Ł[ The equi! valent arene N!alkoxysul_namides can be prepared using arenesul_nyl chlorides ð62JA4720Ł[ Synthesis of aminosul_tes R01N0S"O#OR1 has been reported\ for example\ a!hydroxyaziridines react with thionyl chloride in the presence of sodium hydride to yield cyclic aminosul_tes ð65TL0982Ł[

1[95[2[5 Sulfonamides^ R0NHSO1R1\ R01NSO1R1 No references were located for aminosul_nic acids R1NSO1H but certain amines form crystalline 0 ] 0 charge transfer complexes with sulfur dioxide^ one of the most stable complexes is formed by trimethylamine ð65JA6506Ł[ The synthesis of sulfonamides is well known\ and only a brief survey is detailed[ Further detail of synthesis can be obtained from the review ðB!89MI 195!94Ł[

1[95[2[5[0 From reaction at sulfur"VI# In general\ activated sulfonyl compounds\ RSO1X with Xleaving group\ can be reacted with amines to yield sulfonamides[ The most common and facile route to sulfonamides is the reaction between sulfonyl chlorides and amines "Equation "28## ð76PS"20#134Ł[ The reaction stoichiometry should be carefully controlled when primary amines are used\ to prevent the formation of di! sulfonamides[ Other activated sulfonyl compounds RSO1X include sulfonyl ~uorides ð77JHC0746Ł\ sulfonic anhydrides ð46JCS1463Ł\ sulfonate esters ð17RTC831Ł\ and a!disulfones RSO1SO1R at elev! ated temperatures ð40RTC143Ł[ Sulfonamides can exchange their nitrogen substituents with amine hydrochlorides in a transamination reaction ð42LA"470#071Ł[ A very mild method for sensitive substrates uses the reaction between 1!pyridylthiolsulfonates and amines in which the sulfonyl halide is generated in situ "Equation "39## ð75TL0042Ł[ R1 N H + R3SO2Cl

base

R2

N

R1 N SO2R3

(39)

R2

S

SO2R1

i, ii or iii

R2 N SO2R1

(40)

R3

i, SO2Cl2; ii, R2R3NH; iii, R2R3NH, DMF, 1,2-dibromo-1,1,2,2-tetrachloroethane

Several methods have been developed for the reaction of primary amines with sulfonic acids to give the corresponding sulfonamides "e[g[\ the use of POCl2# in which case the reaction probably

254

Thiohydroxylamines

proceeds via a sulfonyl chloride ð51LA"546#75Ł[ Reaction of alkyl substituted arenes with sulfamoyl chlorides R1NSO1Cl in the presence of a Lewis acid leads to the formation of arenesulfonamides ð66S28Ł[ Sulfonimidoyl chlorides R0N1S"O#"Cl#R1 react rapidly with alcohols in the presence of base to give sulfonamides ð69JA2714Ł[

1[95[2[5[1 Other general methods Sulfenamides R01NSR1 can be oxidized by mcpba to sulfonamides R01NSO1R1 ð63JA4999Ł[ Unsub! stituted and monosubstituted sulfonamides are acidic and readily deprotonated to yield anions\ which can be alkylated by a range of electrophiles\ such as alkyl halides "Scheme 36# ð64JCS"P0#1334\ B!89MI 195!94Ł[ Intramolecular alkylation to yield _ve! and six!membered ring sultams is facile[ Standard preparative methods are unsuccessful for tertiary alkyl sulfonamides\ although they may be made by reaction of sul_nyl chlorides with hydroxylamines ð61TL070Ł[ R1SO2NHR2 R2

–

N SO2R1

base

R2 N SO2R1

R3X

R2

R3

= alkyl, H Scheme 47

Decomposition of sulfonyl azides to intermediate nitrenes can be used for the synthesis of sulfonamides by insertion into C0H bonds ð64JA565Ł and addition to alkenes to form N!sul! fonylaziridines ðB!89MI 195!94Ł[ N!Alkyl sulfonamides cyclize via radical intermediates to give N! sulfonyl pyrrolidines\ when they are treated with sodium thiosulfate in aqueous copper chloride "Equation "30## ð74T3168Ł[ R

Na2S2O8, CuCl2

NHSO2Me

H2O, 90 °C, 5 h 71–84%

R = H, Me, Et, Pr

R

(41) N SO2Me

1[95[2[6 Sulfonamide Salts^ R0SO1N¦R12 Forced methylation of N\N!disubstituted methanesulfonamides gives salts "e[g[\ CH2SO1N¦"Et#1 Me = FSO2−# which are e}ective methanesulfonating agents towards amines and alcohols under mild conditions ð64JA1455Ł[ N!Methylation of N\N!disubstituted arenesulfonamides with dimethoxy! carbonium hexachloroantimonate gives crystalline sulfonamidium salts ð69CC666Ł[ The synthesis of zwitterions R2N¦SO2− has been reported ð68JOC2756Ł[

1[95[2[7 N!Substituted Sulfonamides^ R0N"X#SO1R1 The synthesis and reactions of N!halogenosulfonamides have been reviewed ð78RCR149Ł[ The anions of sulfonamides are readily halogenated to yield N!chloro! and N!bromosulfonamides[ The preparation of N!~uorosulfonamides has also been described ð73JA341\ 75JA1334Ł[ The method used is to bubble nitrogen!diluted ~uorine through a solution of an alkyl sulfonamide in trichloro! ~uoromethane at low temperature^ yields are generally around 49)[ This method has also been used to prepare N!~uorosultams ð77TL5976\ 78HCA0137Ł[ N!Fluorosulfonamides can also be prepared by ~uorination of sulfonamides with CF2OF ð67IJ59Ł and cesium ~uoroxysulfate in acetonitrile ð80T6336Ł[ The preparation of sulfonamide N!sulfenyl chlorides R0N"SCl#SO1R1 has been described in several patents[ Sulfonamides react with sulfur dichloride in the presence of triethylamine to give the analogous sulfonamide N!sulfenyl chlorides ð50GEP0045392Ł[ Dithiobissulfonamides are also reported to give sulfonamide N!sulfenyl chlorides when they react with gaseous chlorine ð46GEP0090396Ł[ The synthesis of N!sulfonylsulfenamides R0N"SR1#SO1R2 has been reported ð60JA1581Ł[ Com! pounds of this type have also been prepared by ð1\2Ł!sigmatropic rearrangement of allylic sul_limines^

255

N!Halo`en\ N0O\ N0S\ N0Se and N0Te Functional Groups

this still occurs if the allyl group is conjugated to phenyl and rearrangement will lead to deconjugation "Equation "31## ð45JCS0644\ B!89MI 195!91Ł[ p-TolSO2 –

Ph N S+

p-TolSO2

N

SPh (42)

Ph Ph

N!Tosyl cyclic sul_namides\ 2\5!dihydro!1!"p!toluenesulfonyl#!1H!0\1!thiazine!0!oxides\ are pre! pared from hetero DielsÐAlder reactions between dienes and N!sul_nyl!p!toluenesulfonamide TsN1S1O "Equation "32## ð61LA"651#82\ 77ACR202\ B!89MI 195!93Ł[ Disulfonamides can be prepared by treating the anion of a monosubstituted sulfonamide with sulfonyl chlorides or a primary amine with an excess of sulfonyl chloride ð63JOC2414Ł[ Di! sulfonamides can be synthesized by oxidation of N!sulfonyl sulfenamides R0N"SO1R1#SR1 with mcpba ð66S687Ł\ and N!sul_nyl!N!sulfonamides R0N"SO1R1#S"O#R2 with performic acid ð64JA5410Ł[ Stable thallium"I# derivatives of sulfonamides undergo N!substitution to give disulfonamides ð64S28Ł[

S

+

N

O Ts

PhH, reflux

S

73%

N

O (43) Ts

1[95[2[8 Sulfamic Acids and Derivatives Thereof^ R0NHSO2R1\ R01NSO2R1 The synthesis and chemistry of sulfamic acid derivatives has been reviewed ð62IJS358\ 68COC"2#252\ 79CRV040\ B!80MI 195!90Ł[

1[95[2[8[0 Sulfamic Acids^ R1NSO2H The main methods for synthesizing sulfamic acids are by the sulfamation of alkyl amines with sulfur trioxide complexes R2N = SO2 ð47JOC0022Ł\ and by treatment of amines with chlorosulfonic acid ð33JOC78\ B!80MI 195!90Ł[ For example\ the sulfamic acid of 4?!amino!4?!deoxyadenosine was prepared by treatment of 4?!amino!4?!deoxyadenosine with Me2N = SO2 in anhydrous methanol "Equation "33## ð67JMC693Ł[ A number of other preparative methods for sulfamic acids have been reported\ for example the treatment of isocyanates or urethanes with oleum ð65JOC3917Ł\ and the reaction of hydroxylamines or amine N!oxides with sulfur dioxide ð61CJC2491Ł[ Catechol sulfate reacts with amines to give 1!"hydroxyphenyl# sulfamate esters\ which can be hydrolyzed to yield potassium salts of sulfamic acids ð71USP3189864Ł[ A large number of heterocyclic sodium sulfamates\ het!NHSO2−Na¦\ have been prepared for testing as arti_cial sweeteners ðB!80MI 195!90Ł[ Of interest\ although not part of this chapter\ the N!acylsulfamate monobactam antibiotics are b!lactams with a sulfamate moiety on the b!lactam nitrogen\ and are normally prepared using sulfur trioxide complexes[ H 2N

Ad O

HO3SHN Et3N–SO3

Ad O

(44)

anhydrous MeOH

OH OH

OH OH

1[95[2[8[1 Sulfamate esters^ R0NHSO2R1\ R01NSO2R1 The principal methods for synthesizing sulfamate esters are by treatment of sulfamoyl chlorides with alkoxide or phenoxide anions\ but the yields are poor "Equation "34## ð28JA2149\ B!80MI 195!90Ł[ Better yields of sulfamate esters are achieved from reactions between alkyl! and aryl!~uorosulfates\

256

Thiohydroxylamines

ROSO1F\ and amines ð73JA6385Ł[ Much improved yields are also obtained by the use of phase transfer agents for the reactions between sulfamoyl chlorides and alcohols or phenols "Equation "34## ð71JCS"P0#566\ 73PS"19#260Ł[ R1 N SO2Cl

i, R3O– or

R1 N SO2OR3

+

ii, R3OH, BnNMe3Cl–, CH2Cl2, RT, anhydrous Na2CO3

R2

(45)

R2

Sulfamate esters R0NHSO2R1 can be alkylated under phase transfer conditions to give N\N?! disubstituted sulfamate esters R0R2NSO2R1 "Equation "35## ð74S824Ł[ Primary sulfamate esters ROSO1NH1 can also be readily alkylated by this general protocol ð75PS"16#182Ł[ Sulfamate esters are of interest because of their pharmaceutical activity and properties as arti_cial sweeteners\ and a large number of syntheses are reported in patents ðB!80MI 195!90Ł[ R1 N SO3R2 + R3X H

R1 N SO3R2

Na2CO3, 20 °C +

BnNMe3 Cl–

(46)

R3

The synthesis of sulfamate thiolesters R1NSO1SR from alkylsulfamoyl halides has been reported ð58LA"618#39Ł[ 1[95[2[8[2 N\N?!Bisalkyl sulfamides^ R0NHSO1NHR1\ R01NSO1NR11 N\N?!Bisalkyl sulfamides are prepared by several main protocols[ Symmetrical sulfamides are most easily synthesized by treatment of amines with sulfuryl chloride[ Homochiral N\N!bisalkyl sulfamides\ prepared by treatment of chiral amines with sulfuryl chloride\ have been used to make chiral reducing agents "Equation "36## ð73JOC2750Ł[ Unsymmetrical N\N?!bisalkyl sulfamides are commonly prepared by treatment of amines with sulfamoyl chlorides ð56JA1491Ł[ Reaction between silylated amines and sulfuryl chloride yields bisalkyl sulfamides ðB!80MI 195!90Ł[ Reaction between 1!hydroxyphenyl sulfamate esters and amines gives bisalkyl sulfamides in high yields ð79JOC4262Ł[ Transamination reactions of suitable N\N?!bisalkyl sulfamides gives a range of new sulfamides ðB!80MI 195!90Ł[ Sulfamide itself can be used but better leaving groups give higher yields[ For instance\ the use of the cyclic sulfamide "17# gives high yields of symmetrical sulfamides when treated with alkylamines "Scheme 37# ð71JCR"S#73Ł[ Exchange of mono!substituted sulfamides "18# with alkylamines gave unsymmetrical sulfamides at lower temperatures and with equal amounts of amine and sulfamide^ at higher temperatures\ and with two equivalents of amine\ symmetrical sulfamides were obtained "Scheme 38# ð72S081Ł[ The synthesis of bis!N\N?!dichloro!N\N?!bisalkyl sulfamides has also been reported ð53JPR017Ł[ SO2Cl2, 2 Et3N

Ph

CH2Cl2, –78 °C

NH2

O Ph

(R or S)

H N

O

R1R2NH

S O

N H (28)

H N

(47)

N N H H (RR or SS)

Ph

R1 S

N

R2

O O NH2

e.g. BnNH2 c-C6H11NH2

O S

R1R2NH

R2

R1

R1

N

N

NH2

S R2 O O 60–80%

+ NH2

Scheme 48

R2 H

N O

R2 S

N O

R2NH2 (2:1)

H

excess

R1 N SO2NH2 H

R1

R2NH2 (1:1)

H

N O

(29) Scheme 49

R2 S

N O

H

257

N!Halo`en\ N0O\ N0S\ N0Se and N0Te Functional Groups

1[95[2[8[3 Sulfamoyl halides^ R0R1NSO1X The synthesis and uses of sulfamoyl halides has been reviewed ð70AG"E#040Ł[ Amines ðB!80MI 195! amine hydrochlorides ð58LA"618#39Ł and N\N?!bisalkyl sulfamides ðB!80MI 195!90Ł react with sulfuryl chloride to yield sulfamoyl halides "Equation "37##[ These methods are limited to amines not having another reactive functional group[ Sulfuryl chloro~uoride SO1ClF has been used to prepare sulfamoyl chlorides ð54CB1318Ł[ Sulfamoyl chlorides have also been prepared by treatment of sulfamic acids and their salts with phosphorous pentachloride "Equation "37## ð65JOC3917Ł[ Treatment of N!chloroamines with sulfur dioxide yields sulfamoyl chlorides ð52ACS1030Ł[ 90Ł\

R1 N H

R1 N SO2Cl

SO2Cl2 or PCl5

R2

(48)

R2

R1 = alkyl, R2 = alkyl, H

1[95[2[8[4 Other derivatives of sulfamic acids Sulfamoyl azides R1NSO1N2 have been prepared by reaction between sulfamoyl halides and alkali azides in aqueous alcoholic solutions and by treatment of amines with the explosive chlorosulfonyl azide ClSO1N2 ðB!80MI 195!90Ł[ N!Sulfonylsulfamate esters R0N"SO1R1#SO1OR2 can be prepared by reaction between sulfonyl halides and sulfamate esters ð75S0910Ł[ A large number of tertiary amineÐsulfur trioxide complexes have been prepared\ and one example uses the reaction between triethylamine and chlorosulfonic acid to form the complex Et2N0SO2 ð76OPP355Ł[

1[95[3 SELENIUM AND TELLURIUM ANALOGS OF THIOHYDROXYLAMINES AND THEIR DERIVATIVES The chemistry and synthesis of compounds with Se0N and Te0N bonds have been com! prehensively reviewed ðB!76MI 195!91Ł[ The naming of the selenium compounds is as follows] R0R1NSeR2 selenenamide\ R0R1NSe"O#R2 seleninamide\ and R0R1NSeO1R2 selenonamide[ Few references to the corresponding tellurium compounds could be located\ and it appears only tel! lurenamides R0R1NTeR2 are known[ A monograph on the use of selenium reagents and inter! mediates in organic synthesis\ which covers the preparation of some selenenamides\ has been published ðB!75MI 195!90Ł[

1[95[3[0 Selenenamides^ R01NSeR1 Selenenamides can be prepared by the reaction between alkyl amines and benzeneselenenyl chloride ð64JOC2202Ł and arylselenenyl bromides ð82JOC806Ł[ Chiral selenenamides have been pre! pared using areneselenenyl bromides and chiral amines ð74S524Ł[ Benzeneselenenyl chloride reacts rapidly with trimethylsilyl amines to give the corresponding selenenamides in good yield ð74S101Ł[ Selenothiocyanates also react with amines to give selenenamides ðB!76MI 195!91Ł[ A sterically hin! dered selenenate ester and the corresponding acid have been prepared^ these both react with benzylamine to give the corresponding selenenamide in about 84) yield "Equation "38## ð77JOC1278Ł[ Benzeneselenenic acid has been generated via a selenoxide elimination reaction and reacted in situ with an alkyl amine to give a selenenamide ðB!76MI 195!91Ł[

Se

OR

Se But

But

H2N

Ph

H N

Ph But

But

(49) But

R = Me or H

But

258

Selenium and Tellurium Analo`s

Partial decomposition of diaminoseleninamides "R1N#1SeO yields diaminoselenenamides "R1N#1Se ð54ZAAC"227#11Ł[ The preparation of aminotetraselanes and aminotriselanes has been described ð79JCS"D#519Ł[ For example\ piperidine reacts with selenium and Pb2O3 to give an aminotetraselane "R1N#1Se3[ Selanes are compounds with three or more consecutive selenium atoms[ Primary amines can be selenenylated twice when they are reacted with arylselenenyl halides to give diselenenamides RN"SeAr#1 ðB!75MI 195!90Ł[

1[95[3[1 Amino Selenium"IV# Derivatives] R1NSeIV When N!methyl!4H\6H!dibenzoðb\gŁð0\4Łselenazocine "29# is treated with t!butyl hypochlorite followed by KPF5\ a chloroselenurane salt "20# is formed "Equation "49## ð80JA5226Ł[ The same salt is obtained when the selenoxide of "29# is treated with thionyl chloride followed by NH3PF5[ The chloroselenurane salt "20# reacts with either lithium dimethyl cuprate or lithium diphenyl cuprate to give the corresponding Se!methylammonioselenurane and Se!phenyl!ammonioselenurane[ Reac! tion of the selenoxide of "29# with one equivalent of trimethylsilyl tri~ate gives the corresponding hydroxylamino selenurane ð81JCS"P0#1136Ł[ A related cyclic diazaselenurane has also been prepared ð82JA8715Ł[ Cl

i, ButOCl, MeOH

(50)

Se

Se ii, KPF6

N

N+

Me

Me

(30)

(31)

PF6–

Selenium tetra~uoride reacts readily with silylated amines to form aminoselenium tri~uorides\ which are reasonably stable "Equation "40## ð63ZOR1508Ł[ Diaminoselenium di~uorides can be formed either by reaction of aminoselenium tri~uorides with a further equivalent of silylated amine or by reacting selenium tetra~uoride with two equivalents of silylated amine "Scheme 49#[ Diaminoselenium di~uorides are very unstable and decompose vigorously within an hour of their preparation[ When selenenamides are treated with sulfuryl chloride\ dichloroselenenamides R01NSeCl1R1 result ðB!75MI 195!90Ł[ Dichloroselenenamides can also be prepared by the reaction between the corresponding selenenyl halides and chloroamines ðB!75MI 195!90Ł[ SeF4, Et2O, –5 °C

N TMS

(51)

N SeF3 65%

O

N SeF3 +

O

CH2Cl2, 0 °C

N TMS

O

N

2SeF2

80%

SeF4, Et2O, –5 °C

2

N

N TMS 70%

2SeF2

Scheme 50

1[95[3[2 Seleninamides and Derivatives^ R01NSe"O#R1 No reports of simple seleninamides were located\ though it seems likely that the methods used to make seleninamide derivatives of ammonia could be applied to the synthesis of these compounds ðB!76MI 195!90Ł[ "Me1N#1SeO is formed in the reaction between Cl1SeO and Me1NH^ further reaction with Cl1SeO gives Me1NSeOCl\ and reaction with HCl then gives Me1NH1¦SeOCl2− ð54ZAAC"227#11Ł[ Diaminoseleninamides are prepared by reaction between the esters "MeO#1SeO and a primary amine or via a transamination reaction with another diaminoseleninamide ð62ZAAC"390#068Ł[ These

269

N!Halo`en\ N0O\ N0S\ N0Se and N0Te Functional Groups

compounds are reported to be stable only at low temperature[ Trimethylsilyl esters of seleninamides R1NSeO1TMS have been prepared by the reaction of selenium oxide with N!trimethylsilyl amines ð67ZOB0009Ł[

1[95[3[3 Selenonamides and Derivatives^ R01NSeO1R1 Selenonamides have been prepared by the reaction of methyl selenonic esters PhSeO2Me with amines ð66CCC0355Ł[

1[95[3[4 Tellurenamides and Derivatives^ R01NTeR1 Arenetellurenamides R1NTeAr "ArPh\ p!anisyl\ 1!naphthyl^ RMe1CH\ Me1CHCH1# have been prepared by the action of lithium amides on arenetellurenyl iodides ð80OM0984Ł[ These N\N! dialkyl derivatives generally decompose above 9>C[ Tellurium hexa~uoride reacts with silyl amines R1N!TMS "RMe\ Et\ 0"CH1#30# to produce dialkylaminotellurium penta~uorides R1NTeF4 ð60JCS"A#0014Ł[ When the silyl amine is used in excess\ diaminotellurenamide tetra~uorides are formed\ for example "Me1N#1TeF3 is produced in 34) yield[

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#

1995, Elsevier Ltd. All R ights Reserved

Comprehensive Organic Functional Group Transformations