Encyclopedia of Reagents for Organic Synthesis || Hydroxylamine- O ...

HYDROXYLAMINE-O-SULFONIC ACID 1

Hydroxylamine-O-sulfonic Acid

H2NOSO2OH

[2950-43-8] H3NO4S (MW 113.11)InChI = 1S/H3NO4S/c1-5-6(2,3)4/h1H2,(H,2,3,4)InChIKey = DQPBABKTKYNPMH-UHFFFAOYSA-N

(amination; hydroxymethylation; reduction; conversion ofalkenes to primary amines1–3)

Alternate Name: HOSA.Physical Data: mp 210 ◦C (dec); single crystal X-ray diffraction

analysis.51

Solubility: sol cold water, methanol; slightly sol ethanol; insolether, CHCl3.

Form Supplied in: white solid; widely available.Analysis of Reagent Purity: quantitative analysis of HOSA can

be made by iodometric titration.4,5

Preparative Methods: by reacting hydroxylamine sulfate with30% fuming H2SO4

4 or 60% oleum6 at rt, or by heating amixture of hydroxylamine sulfate and chlorosulfonic acid at100 ◦C for several hours.5

Handling, Storage, and Precautions: hygroscopic; should bestored in tightly sealed bottles in a refrigerator. Aqueous so-lutions are unstable, decomposing rapidly above 25 ◦C. It isthus important to use freshly prepared solutions in reactions.Use in a fume hood.

Original Commentary

Ender ErdikAnkara University, Ankara, Turkey

Introduction. The use of HOSA in organic synthesis resultsfrom its ability to act both as a nucleophile and as an electrophile(eq 1), as well as being able to provide an in situ route to otherchemical entities, such as diimide.

NH2NuE

HN

SO2OH

Nu E(1)H2NOSO2OH

neutral or acidicconditions

basic conditions

Amination at Nitrogen. Monosubstituted and 1,1-disubstituted hydrazines can be prepared in fair to goodyields by reacting HOSA with primary or secondary amines,respectively, in basic aqueous solution (eq 2).7,8 Tertiary aminesgive 1,1,1-hydrazinium salts when they are treated with HOSAunder basic conditions in aqueous or alcoholic solution (eq 3).7–9

(2)

HOSA, KOH, H2O75 ºC, 10–40 min

PhNH2 PhNHNH288%

(3)

1. HOSA, KOH, H2O, heat2. HI

Me3N–NH2 I–+

Me3N85%

Many nitrogen heterocycles, including pyridine,7,8

quinoline,7,8 pyrimidine,9 azetidine,10 pyridazine,11 tetrazole,12

indole (eq 4),13,14 benzimidazole,14,15 triazine,16 benzoxazole,17

and purine14,18 ring systems, can also be aminated on nitrogenusing HOSA.

(4)NH

N

NH2

HOSA, KOH, H2ODMF, rt, 1 h

96%

Amination at Carbon. One of the two published reports oncarbanion aminations with HOSA19 concerns its reaction withsome β-diketo compounds to furnish symmetrically substitutedpyrroles (eq 5).

O O O O

NH2

O OHOSA, K2CO3, H2O

NH

MeOC

COMe

(5)

28%

The other attempted amination with HOSA20 yielded a traceamount of an amino acid from an α-lithiated carboxylic acid.Triphenylborane, prepared from phenylmagnesium bromide andboron trifluoride, reacts with HOSA to give aniline in 35% yield.21

Two different methods have been reported for the direct ami-nation of an aromatic ring in low yields using HOSA. The firstemploys Aluminum Chloride as a catalyst (eq 6);22,23 the sec-ond is an homolytic amination procedure in which a protonatedamino radical is generated using iron(II) ion together with HOSA(eq 7).24

(6)

HOSA, AlCl3100 ºC, 30 min

NH2

50%

(7)

NH2

MeO MeO

HOSA, FeSO4, MeOHrt, 15 min

34%

Certain heterocycles react with HOSA to give C-substitutedamino derivatives (eq 8).25

N

N

O

Me

O

MeN

N

Me

O

MeHOSA, pH 237 ºC, 40 h NH2

(8)

O

~100%

Amination at Sulfur. Organosulfur compounds, includingthiols,26 thioacids (eq 9),27 thioamides,27,28 dithioacids,27 andthioethers (eq 10),29 undergo amination with HOSA in goodyields.

2 HYDROXYLAMINE-O-SULFONIC ACID

(9)O

O

SNa

O

O

SNH2HOSA, NaOH, H2O20 ºC

70%

(10)

HOSA, MeONa, MeOHrt, 4 h

Et2S (Et2SNH2)2SO459%

Hydroxymethylation. Quinolines can be hydroxymethylatedin the 2-and/or 4-position using HOSA in methanol (eq 11).30

N

R1

R2N

R1

R2

N

R1

R2

OH

(11)+

R1 = R2 = HR1 = Me, R2 = Cl

55%–

OH

25%95%

HOSA

MeOH

Reduction. HOSA, alone31 or together with hydroxylaminesulfate,32 provides under basic conditions a source of Diimide,HN=NH, which will reduce multiple bonds (eqs 12 and 13).Yields obtained by using HOSA alone seem to be lower comparedwith those obtained with HOSA–hydroxylamine sulfate.

(12)

HOSA, MeONa, MeOHrt, 16 h

40%

(13)HO2C CO2H HO2CCO2H

HOSA, (NH3OH)2SO4NaOH, H2O20 ºC, 3 h

77%

Conversion of Alkenes into Primary Amines. Methods forthe conversion of alkenes into primary amines via the corre-sponding organoboranes using HOSA have been developed.33–36

Organoboranes are prepared in situ by the addition of Diborane tothe alkene in THF (eq 14)33 or by the addition of Boron Trifluo-ride Etherate to the alkene and Sodium Borohydride in diglyme,in which HOSA is soluble (eq 15).35

(14)

Ph HOSA

Ph

B2H6, THF

NH2

58%

(PhMeCHCH2)3Brt, 1 h reflux, 3 h

(15)

NH2

1. NaBH4, BF3, diglyme rt, 3 h2. HOSA, 100 ºC, 3 h

3. H2O

58%

The limitation to quantitative utilization of the alkyl groups hasbeen overcome by preparing a mixed organoborane, R1R2

2B, inwhich R1 shows a significantly greater migratory aptitude than R2.For this purpose, organodimethylboranes, prepared by hydrobo-ration of alkenes with dimethylborane, were treated with HOSAto afford the corresponding primary amines stereospecifically inalmost quantitative yields (eq 16).37

(16)

NH2

TMSCl, ether0 ºC to rt, 4 h

+ Me2BH80%

α-Chiral primary amines of high optical purity can be obtainedfrom the chiral boronic esters through the intermediate formationof alkyl methyl borinic esters and their stereospecific reaction withHOSA in very good yields (eq 17).38,39 Synthesis of chiral α-methylorganyl primary amines, which are difficult to prepare viadirect asymmetric hydroboration, can be accomplished by treatingborinate esters with HOSA (eq 18).40

B

O

O

Me

O

O

B

O

NH2

1. MeLi, –78 °C, 3 h

(17)

1. HOSA, THF

rt, 8 h

76%, 99% ee

2. H2O

2. MeCOLi, –78 °C to rt

(18)

1. HOSA, THF, rt, 8 h2. H2O

99% ee

Ph BOMe

MePh NH2 70%

Conversion of Carboxylic Acids to Primary Amines. Heat-ing a carboxylic acid or its anhydride with HOSA in mineral oilat 160–180 ◦C41 or in polyphosphoric acid at 115–125 ◦C42 givesa primary amine in a low yield (eq 19).

(19)

HOSA, polyphosphoric acid115–125 ºC, 1 h

MeO CO2H

MeO NH2

35%


Conversion of Primary Amines to Hydrocarbons (Reduc-tive Deamination). In an indirect route, a primary amine is con-verted into its sulfonamide which is isolated, dissolved in aqueousbase, and then treated with HOSA to give the hydrocarbon in ahigh yield (eq 20).43 In a direct route, a primary amine is allowedto react with 2–3 equiv of base to give the hydrocarbon in a mod-erate yield (eq 21).44

(20)TsCl, py HOSA, NaOH

90%

C6H13NH2 C6H13NHTs C6H14H2O100 ºC, 30 min

(21)HOSA, NaOH, H2O

CO2H

NH2

CO2H72%

Conversion of Carbonyl Compounds to Oxime Sulfonates.Aldehydes and ketones react with HOSA in aqueous solution togive oxime-O-sulfonic acids and salts in good yields (eq 22).45,46

(22)

HOSA, K2CO30 ºC, 1 min

Bu

O

Bu

NOSO2K

55%

Conversion of Aldehydes to Nitriles. With aldehydes, pro-longed treatment with HOSA, at rt or above, generates nitriles(eq 23).46,47

(23)

HOSA, H2O20–40 ºC, 20 min

C6H13CHO C6H13CN87%

Conversion of Ketones to Oximes. Reaction of aliphatic ke-tones with HOSA at 100 ◦C gives oximes in high yields (eq 24).48

The method has the advantage over the standard oxime prepara-tion procedure employing hydroxylamine hydrochloride in thatno adjustment in pH of the reaction medium is required to facili-tate reaction and a solvent is not necessary, the ketone and HOSAsimply being mixed together.

(24)O NOHHOSA

100 ºC

90%

Conversion of Ketones to Amides. Under the conditions de-scribed above, alkyl aryl ketones yield N-aryl aliphatic amides,again in high yields (eq 25).48 Alicyclic ketones have been con-verted to lactams using HOSA (eq 26).49

(25)Ph

O

NH

O

Ph

HOSA100 ºC

90%

(26)O NH

OHOSA, HCO2Hreflux, 3 h

83%

Conversion of Oximes to Diazo Compounds. Oximes reactwith HOSA in aqueous base to give diazo compounds (eq 27).50

(27)

HOSA, NaOH, H2O4 ºC, 2 h

NOH N2

60%

First Update

Jarosław SaczewskiMedical University of Gdansk, Gdansk, Poland

Introduction. Hydroxylamine-O-sulfonic acid (HOSA), sim-ilarly to other electronegatively substituted amines such as O-alkyl, O-acyl and O-sulfonylhydroxylamines, behaves as either anucleophile (NH2

− synthon) or an electrophile (NH2+ synthon)

depending on substrates used and reaction conditions. Over thepast two decades, considerable progress has been made in theapplication of HOSA, particularly in the area of organic func-tional group transformations and heterocyclic chemistry. Oftenthe construction of a nitrogen-containing heterocyclic ring sys-tem is based on a multistep procedure, which takes advantage ofboth the nucleophilic and electrophilic properties of this versatilereagent.

Conversion of Alkenes into Primary Amines. The challeng-ing direct enantioselective addition of ammonia to alkenes hasbeen achieved by catalytic asymmetric hydroboration/aminationreaction using electrophilic HOSA as an aminating reagent.52

Styrene or other vinylarene undergoes catalytic asymmetric hy-droboration with catecholborane in the presence of rhodiumcomplexes of 1,1′ -(2-diarylphosphino-1-naphthyl)isoquinoline togive catecholboronate ester. Since reactivity of the borane ester inelectrophilic substitution is rather low, in the next step, a more ac-tive trialkylborane is obtained by the displacement of the catecholmoiety with nucleophilic alkylating agent, such as MeMgCl orEt2Zn. Finally, upon treatment with HOSA, electrophilic amina-tion takes place with complete retention of configuration, leadingto a range of primary α-arylalkylamines in up to 97% enantiomericexcess (eq 28).52

Me

BMe Me

Me

NH2

HOSA

diglyme, THF

1. catecholborane

Rh catalyst

2. MeMgCl

54%

(28)

THF, 20 ºC


Hydroboration of fluoro-substituted styrenes with catecholbo-rane yields the Markovnikov product, while 4-fluorostyrene and4-trifluoromethylstyrene treated with BH2I·SMe2 (prepared viathe iodination of BH3·SMe2 in CS2) furnishes the formation of β-fluoroarylethyl boranes as major products. Later compounds maybe further converted to the corresponding primary β-phenethylamines upon treatment with HOSA (eq 29).53

BI

H

NH2

HOSA, MeOH0 ºC to rtCS2, rt

F

F

F

(29)Me

F

93:3, 72%

NH2

+

Me

F

BH I

+

major product

minor product

BH2I·SMe2

Conversion of Carboxylic Acids into Primary Amines.Treatment of aroyl and heteroaroyl chlorides with HOSA in drytoluene, under reflux, provides the corresponding primary aryl-(heteroaryl)amines in good yields (eq 30).54 This method has ad-vantages over classical Hofmann, Lossen, and Curtis proceduresin that it can be carried out in a one-pot manner and avoids the useof hazardous azides.

O

Cl

toluene, ΔHOSA

67%

(30)

O

N O

SO3H

O

N OSO3H

HH

H

NC

O

H

Δ

NH2

–H+

H2O–CO2

–H2SO4

H+

Sulfamoylation at Heteroaromatic and Benzylic CarbonAtom. Sulfamoylation reaction at C2 of furane and thiophenederivatives was achieved by a sequence employing n-butyllithium,sulfur dioxide and HOSA (eq 31).55 A similar method was ap-plied for preparation of carbonic anhydrase inhibitors containingprimary sulfonamide function at benzylic carbon atom (eq 32).56

O O SO2NH2

n-BuLi, SO2, AcONaHOSA, THF, –78 ºC

59%(31)

Me Me

N

S

N

N

S

N

CH2SO2NH2

n-BuLiSO2, HOSATHF, –78 ºC

25%N

Me

Me

N

Me

Me

Me

(32)

Conversion of Methyl Sulfones to Sulfonamides. An alter-native method for the preparation of aromatic sulfonamides con-sists in the application of methylsulfones as starting materials.Here, the reaction of phenyl methyl sulfone with either the Grig-nard reagent or LDA causes deprotonation of the methyl groupwith the formation of corresponding carbanion. Treatment withtrialkylborane leads to the formation of the “ate” complex, which,at elevated temperature, rearranges to a sulfinic acid salt. Thisreacts with HOSA to give the desired sulfonamide (eq 33).57

It has been suggested that, by taking advantage of this proce-dure, a methylsulfone may be used as a protected aryl sulfonamideto be carried out through multistep synthesis. As anticipated, ben-zyl methyl sulfone gives only methylsulfonamide, because depro-tonation and “ate” complex formation occurs exclusively at themore acidic methylene group.

Ph S

O

O

Me

1. MeMgCl or LDA

THF, 0 ºC to rt2. BEt3, 0 ºC to Δ

HOSA, 0 °C

Ph S

O

O

NH2(33)

Ph S

O

O B Et

Et EtM

Ph S

O

O

M

50%–Et2PrB

“ate” complex

–

–

NaOAc

Conversion of Alkyl and Aryl Halides into Sulfonamides.Aryl (eq 34) and alkyl (eq 35) sulfonamides can also be syn-thesized from the corresponding halides with use of sodium3-methoxy-3-oxopropane-1-sulfinate (SMOPS) and HOSA un-der alkaline conditions. Again, the electrophilic amination withHOSA involves sulfinic acid salts formed from the intermediatesulfones by the treatment with NaOMe in DMSO solution.58


3. NaOMe, DMSO

4. HOSA (5 equiv)

NaOAc/H2O

S OO

NH2

1. SMOPS (3 equiv)

2. CuI (3 equiv)

DMSO, 110 ºC

92%

(34)

SMOPS = sodium 3-methoxy-3-oxopropane-1-sulfinate

S

CO2Me

O

O

SOO Na

rt, 15 min62%

rt, 16 h

I

OMe OMe

OMe OMe

NaOS

CO2Me

O

CH2Cl85%

H3CO

CH2SO2NH2H3CO (35)

1. SMOPS (1.2 equiv), DMSO, rt

2. NaOMe, DMSO, rt, 15 min

3. HOSA (5 equiv), NaOAc, H2O, rt

Conversion of Carbonyl Compounds and Imines toDiaziridines. The general reaction of ketones and HOSA in thepresence of ammonia gives diaziridines (eq 36), which, upon oxi-dation with silver oxide, provide diazirines, some popular carbeneprecursors.59–61

O

or NH4OH·H2O

HOSA, 0 ºC, 2 hNHHN

(36)

71%

Ag2O, Et2O

75%

NNNH3/MeOHrt, 1 h

The reaction is functional even for sterically hindered ketones62

(eq 37) and imines63 (eq 38) though careful consideration of pHand temperature is needed. Optimal results are obtained when2 equiv of ammonia are used to neutralize the liberated sulfate,and the reaction is carried out for several weeks at −20 ◦C.62 Thepretreatment of the imine with excess of ammonia initiates anexchange reaction and the formation of unsubstituted diaziridine(eq 38).63

The N-substituted diaziridine is formed when the excess of pri-mary amine used for the in situ imine synthesis, and the diaziridi-nation reaction is run in the presence of triethylamine (eq 39),64 orin the presence of 2 equiv of ammonia required for neutralizationof the eliminated sulfate dianion (eq 40).65

O NH

HN

NH3 (2 equiv)

–H2SO4NH2

(37)

HNNH

–H2O –20 ºC

HOSA

HO3SO

NN

I2/Et3N

N

Me

N

Me

Me2HC

CHMe2

HOSAMeOH, –70 ºC

47%

MeMe

HN NH

NHHN

(38)

NH3 (excess)

Ag2O (excess)

29% MeMe

N N

NN

N

Me

Me MeNH2

HOSA

Me

NHNMe

MeOH/H2O–10 ºC

60%

(39)

NHOSA, MeOH

38%

N

NH

(40)NH3

Alkyl and aryl aldehydes can be converted into diazirines byreaction with LiHMDS and HOSA in the presence of a base andsubsequent oxidation of the initially formed aziridine with tert-butyl hypochlorite. The intermediate diaziridine is stabilized bythe substitution of one of the reactive hydrogens with a trimethylsi-lyl group (eq 41).66

OH

Ph

H

Ph

NH

NSi(Me)3

t-BuOCl1. LiHMDS, THF, –30 ºC

2. HOSA

H

Ph

N

N

12%

(41)

Conversion of Carbonyl Compounds to Oxaziridines. Thereaction of benzaldehyde with HOSA in the presence of NaOHprovides 3-phenyl oxaziridine.67 Direct in situ acylation withbenzyl chloroformate gives stable oxaziridine derivative suitablefor electrophilic N-amination reactions. In this manner, chiralα-hydrazino acids, including l-hydrazino-serine, were obtained(eq 42).68


PhO

H

HOSA, NaOH BnOCOCl, Et2O

PhO

NCOOBn

12%

(42)

PhO

NH

NH2

COO

CH2Cl2, rt

HN

COOH

NHCOOBn– PhCHO

55%

BnO

BnO

–

NMe4

The title compound was also used for the preparation of tri-phenylphosphineimide sulfate, which in turn served in the prepa-ration of N-Boc hydrazines via diethyl ketomalonate-derivedN-Boc-oxaziridines (eq 43).69

Ph3P

HOSA

MeOH, rtPh3P NH · H2SO4

(43)

76%

O

EtO2C CO2Et

NBocN

H

NHBoc

BnNH2

toluene

Bnrt, 72 h

75%

Synthesis of Heterocyclic Compounds via N-, O- and S-Amination. Hydroxylamine-O-sulfonic acid is applied for thesynthesis of a wide range of five-membered heterocyclic ring sys-tems employing a tandem nucleophilic addition (or substitution)–electrophilic amination approach. Substrates for these procedurescan be depicted as tautomeric structures A, B, and C (eq 44).

2-Hydroxybenzaldehyde70 and 2-hydroxyacetophenone71 canbe efficiently transformed into benzo[d]isoxazole and 3-methylbenzo[d]isoxazole, respectively, through the intramolecu-lar O-amination reaction of the transiently formed oxime hydrogensulfate (eq 45).

Similar reactions of 1,3-diketones provide isoxazoles (eq 46)and 5,6-dihydro-4H-cyclopenta[c]isoxazoles as well as 4,5,6,7-tetrahydrobenzo[c]isoxazoles and 4,5,6,7-tetrahydrobenzo[d]-isoxazoles.71

X

ZR1 R2

Y

XH

ZR1 R2

Y

X

ZR1 R2

YHX = N–R, O, SY = O, S, N(Me)2

Z = CH2, CHR, NH

A

B

C

N

ZR1 R2

NH-OSO3

X

ZR1 R2

N-OSO3HOSA

base – SO42–

– HSO4–

NX

Z R2R1

NX

Z R2R1

X = N

X = O, S

RR

––

–

(44)

HOSA

base

O

H

OH

ON

HOSA, H2O

NaHCO3

95%

(45)

N-OSO3

H

O– SO4

2–

–

–

O

Me Ph

O N O

PhMe

HOSA, H2O

NaHCO3

40%(46)

The reaction of enaminones with HOSA gives isoxazoles inhigh yields (eq 47).72 Here, the starting material represents a gen-eral tautomeric structure C in which the dimethylamino moietybehaves as a good leaving group that can be easily displaced withHOSA.

ON(Me)2

1. HOSA, MeOH

2. NaHCO3, H2O

82%

NO

Me

Me (47)

ON-OSO3Me

ONH-OSO3HMe

base–SO4

2–

––


Thioenaminones (eq 48)72 and amidines (eq 49)73 react in ananalogous fashion, and in the presence of pyridine give rise to theformation of isothiazoles and 1,2,4-thiadiazoles, respectively, ingood to excellent yields.

PhS

N(Me)2

HOSA, MeOH

pyridine

62%Ph

NS(48)

PhN

SN(Me)2

HOSA, MeOH

pyridine

90%Ph

N

NS(49)

Finally, the pyridine or isoquinoline formimidates and for-mamidines react with HOSA in a methanol solution in the pres-ence of pyridine to give the corresponding [1,2,4]triazolo[1,5-a]pyridine (eq 50) or [1,2,4]triazolo[5,1-a]isoquinoline.74

N

N

N(Me)2

HOSA, MeOH

pyridine

84%

N

N

N

Me Me

(50)

A mechanistically similar reaction sequence has been appliedfor the synthesis of 4-unsubstituted isothiazoles. Initially, the re-quired substrate with tautomeric structure of type B is generatedin a one-pot procedure using α-acetylenic aldehydes or ketones,HOSA, and NaSH. Subsequent intramolecular electrophilic am-ination reaction proceeds easily in a buffered aqueous solution(eq 51).75

MeMe

O1. HOSA, NaHCO3

2. NaSH, H2O

45%

Me

NS

Me(51)

N-OSO3

Me

SMe

– SO42–

––

Diselenide treated with NaBH4 and acetylenic ketone gives thecorresponding carbamate, which, in the presence of HOSA, pro-vides isoselenazole and its N-oxide (eq 52).76 The actual pathwayleading to the formation of N-oxide remains unclear.

An analogous reaction of tellurocarbamate with HOSA leads tothe 12-membered macrocyclic compound featuring the periodic–O–Te–N– sequence (eq 53).77

Nucleophilic Substitution of Activated HeterocyclicHalides. The nucleophilic properties of HOSA are particularlyuseful for its reactions with activated heterocyclic halides. Thus,2-chloro-4,5-dihydroimidazole reacts with a slight excess ofHOSA in aqueous solution at room temperature, giving riseto the formation of 2-hydroxylamino-4,5-dihydroimidazolium-O-sulfonate (eq 54).78 Betaine 1 can be converted into thecorresponding sulfonate salt upon treatment with either aqueousNaOH or triethylamine in DMF solution and further used for

various tandem nucleophilic addition–electrophilic aminationreactions, as depicted in eq 55.

N-OSO3

Me

Se

Ph

O

SeMe2N Se NMe2

O

1. NaBH4, MeoH, MeCN2. PhC COCH3

3. HOSA 6 equiv, rt

SeN

Ph

MeSe

N

Ph

Me

O

(52)

29% 5%

–

–

O

TeMe2N

t-Bu Me

O

O

TeN O

N

TeN

O

TeNOTe

Met-Bu

Me

t-Bu

Me t-Bu

Me

t-Bu

HOSA 4.4 equiv

MeOH, Δ

(53)

60%

NH

HN

Cl

NH

HN

N

HSO469%

OSO3

H

(54)

1

–

NH

HN

NOSO3

NaOH/H2O or Et3N/DMF

– –

HOSA (1.25 equiv)

H2O, NaOH (1 equiv)

rt, 12 h

Thus, the compound 1 reacts with aromatic aldehydes aswell as cyclic ketones to give 6,7-dihydro-imidazo[2,1-c][1,2,4]-oxadiazoles, while the use of carbon disulfide or aryl isoth-iocyanates allows for the preparation of corresponding 6,7-dihydroimidazo[2,1-c][1,2,4]thiadiazoles.78 The reactions of 1with arylisocyanates, arylsulfonyl isocyanates, or their stablenonhazardous substitutes 4-dimethylaminopyridinium N-(arylsulfonyl)carbamoylides, lead to the formation of 6,7-dihydro-2H-imidazo[2,1-c][1,2,4]triazoles.79 Finally, treatmentof 1 with Eschenmoser’s salt or benzotriazole aminals results inthe formation of 6,7-dihydroimidazo[2,1-c][1,2,4]triazol-2-iumsalts.80


1

O

HPh

N

HN

NOSO3

HO

Ph

–NaOH, H2O N

HN

N

O

PhH–SO4

2–

CS2

N

HN

NOSO3

S –N

HN

N

S–SO42–

SS

Et3N, DMF

Et3N, DMFTol-NCS

N

HN

NOSO3

S –N

HN

N

S–SO4

2–

NN

Tol Tol

Et3N, DMFTol-NCO

N

HN

NOSO3

N–N

HN

N

N–SO42–

OO

TolTol

TolSO2NCOor

N

HN

NOSO3

N–N

HN

N

N–SO4

2–

O OS

STol

TolO

O

O

O(–DMAP)

(55)

Et3N, DMF

1,

N

HN

NOSO3

N

N

HN

N

N

–SO42–

MeMe

Me

Me

N

Me

Me

NH

HN

NOSO3

–

–

–

–

–

–

–

74%

50%

18%

71%

66 or 62%

64%

I–

N N

OS

NMe

Me

Tol

O

O

Similarly, hydroxylamine-O-sulfonic acid can be used as anefficient nucleophilic aminating reagent for 2-chloropyrimidines(eq 56), 2-chloroquinolines, and 1-chloroisoquinoline.81 The het-eroaromatic hydroxylamine-O-sulfonates 2 thus obtained and sub-jected to the reaction with acetyl, benzoyl (eq 57), or ethoxy-carbonyl isothiocyanates undergo tandem nucleophilic addition–electrophilic 5-endo-trig cyclizations with formation of 1,2,4-thiadiazolo[2,3-a]pyrimidine derivatives.

Finally, 6-chloropurine, when subjected to the reactionwith a four-fold excess of HOSA, provides (Z)-1H-purin-6-

ylideneaminooxysulfonic acid, a probable secondary metaboliteof adenine (eq 58).82

N

N

NOSO3

H HN

N

Cl

HOSA

H2O, rt, 12 h

67%(56)–

2


N

N

N

OSO3

NHS

PhCO-N=C=S

Et3N, DMF, rt

nucleophilic

addition

Et3N

– Et3NH

N

N

N

PhO

Ph

O

N

N

NH

Ph

O

S

N

S

N

N

N

N

H

OSO3

N

–

5-endo-trig

cyclization

– SO42–

(57)

2

–

53%

Et3NH

N

N NH

N

Cl

HN

N NH

HN

NO3SO

HOSA (4 equiv)

DMF, rt, 12 h

76%(58)

–

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