HYDROXYLAMINE

Hydroxylamine1
HONH2

(HONH2 ) (MW 33.04) [7803-49-8] H3 NO InChI = 1/H3NO/c1-2/h2H,1H2 InChIKey = AVXURJPOCDRRFD-UHFFFAOYAD (HONH2 HCl) (MW 69.50) [5470-11-1] ClH4 NO InChI = 1/ClH.H3NO/c;1-2/h1H;2H,1H2 InChIKey = WTDHULULXKLSOZ-UHFFFAOYAT ((HONH2 )3 H3 PO4 ) (MW 197.12) [20845-01-6] H12 N3 O7 P InChI = 1/3H3NO.H3O4P/c3*1-2;1-5(2,3)4/h3*2H,1H2;(H3,1, 2,3,4)/f/h;;;1-3H InChIKey = XBUFCZMOAHHGMX-CWCSVAMXCQ ((HONH2 )2 H2 SO4 ) (MW 164.17) [10039-54-0] H8 N2 O6 S InChI = 1/2H3NO.H2O4S/c2*1-2;1-5(2,3)4/h2*2H,1H2;(H2,1, 2,3,4)/f/h;;1-2H InChIKey = VRXOQUOGDYKXFA-IPLSSONACA (nucleophile in aromatic substitution,63 oxime-,36 hydroxamic acid-,30 pyridine-61 and isoxazole-forming56 reactions; reducing agent;66 in combination with dehydrating agents, used for the conversion of aldehydes to nitriles43 ) Physical Data: HONH2 : hydroscopic white needles or akes; decomposes rapidly at rt; mp 32.05 C; bp 56.5 C/22 mmHg, 70 C/60 mmHg, 110 C/760 mmHg. HONH2 HCl: white crystals; mp 151 C; d 1.67 g cm3 ; pKa1 5.97; pKa2 13.7.10 (HONH2 )3 H3 PO4 : mp 169171 C. (HONH2 )2 H2 SO4 : mp 170 C (dec). Solubility: HONH2 : decomposes in hot water; sol cold water, methanol; sparingly sol ether, benzene, chloroform, carbon disulde.2 HONH2 HCl: 83 g/100 mL in cold water; very sol hot water; 4.43 g/100 mL in EtOH; 16.4 g/100 mL in MeOH; insol ether. Form Supplied in: hydroxylamine hydrochloride is widely available and is the most commonly used hydroxylamine salt. Each of the other salts listed above is also commercially available, as are HONH2 HCl-d4 and HONH2 HCl-15 N.6 Preparative Methods: hydroxylamine base has been prepared by the action of sodium butoxide on the hydrochloride in butanol.3 The free base can be isolated as a white solid at 30 C and is stable to storage for several days at 20 C.4 It can be prepared just prior to use or, more typically, in situ from one of the salts by treatment with hydroxide, alkoxide, carbonate, or amine base (see below). The preparation of hydroxylamine via the electrochemical reduction of nitric acid has been reported.5 Handling, Storage, and Precautions: all of the salts of hydroxylamine are corrosive and hygroscopic. Specic precautions in the literature indicate that the free base is a much more hazardous substance to work with than are the salts.7 HONH2 : a moderately toxic, corrosive irritant to the eye, skin, and mucous membranes. Explodes at 130 C. Explodes in air when heated above 70 C. May ignite spontaneously in air, or in contact with PCl3 or PCl5 . Calcium reacts to give the heat-sensitive

explosive bis(hydroxylamide). In the event of a spill, cover with sodium bisulte and sprinkle with water. HONH2 HCl: harmful if inhaled or swallowed (oral LD50 400420 mg kg1 ; mouse). Not compatible with oxidizing agents. May explode if heated above 115 C; do not store above 65 C. A comprehensive review of the biological activity of hydroxylamine and its salts has appeared.2

Original Commentary
Michael A. Walters & Andrew B. Hoem Dartmouth College, Hanover, NH, USA Introduction. Hydroxylamine, usually as one of its more stable salts, has been used as a nucleophile in a wide variety of reactions and only the most common uses of this versatile reagent are described here. The name hydroxylamine is used throughout this review as a interchangable designator for either the free base or one of its salts. Where appropriate, the specic derivative will be named. General Reactivity with Simple Electrophiles. Hydroxylamine and its derivatives undergo reaction with many simple electrophiles such as alkylating, acylating, phosphinylating, and silylating agents, aldehydes and ketones, and Michael acceptors. The potent nucleophilic reactivity of hydroxylamine evident in these transformations is thought to arise as a consequence of what has been labeled the -effect, an effect observed in a variety of nucleophiles which possess a heteroatom in the position to the attacking nucleophilic atom.8 Hydroxylamine reacts with simple electrophiles typically at both nitrogen and oxygen, with multiple reactions often giving rise to undesired sideproducts. Many derivatives of hydroxylamine have been prepared in an effort to circumvent this potential problem of ambident reactivity (see below).9 Reactions with Alkylating Agents: N vs. O Selectivity. The products obtained in the reaction of simple alkylating agents with hydroxylamine are exemplary of the ambident reactivity discussed above. In a study directed toward the preparation of O-alkylated hydroxylamines, it was found that several benzylic and one alkyl halide react preferentially at oxygen in t-butoxide/t-butanol solution (eq 1).10 Results similar to those obtained with benzyl bromide were found for ve other benzylic halides.
RX + NH2O RX PhCH2Br 1-Bromo-2-ethylhexane RONH2 + RNHOH + R2NOH (1) Yield (%) Product distribution 52 30 66:22:12 79:21:

Selective N-alkylation has been accomplished in a wide variety of cases using the hydroxylamine derivative t-butyl N-benzyloxycarbamate.11 The preparation of N-octylhydroxylamineHCl is illustrative of this process (eq 2). Ethyl 3-methylhydroxy-4-isoxazolecarboxylate12 is another versatile reagent which has been developed for this purpose. O-Trimethylsilyl- and O-(t-butyldiphenylsilyl)hydroxylamine13 have also seen use in the preparation
Avoid Skin Contact with All Reagents

HYDROXYLAMINE

of N-alkylhydroxylamine derivatives, although these reagents have not been shown to be as generally useful in this regard as the previously mentioned two. N-Allylation has recently been accomplished via the Pd0 -mediated reaction of N,O-bis(Boc)hydroxylamine with allylic carbonates, chlorides, and acetates.14 A similar study showed that the use of HONH2 HCl in the same reaction leads to N,N-diallylated products.15 N,O-DimethylhydroxylamineHCl has been prepared on a large scale by dimethylation (Dimethyl Sulfate) of ethyl hydroxycarbamate at pH 1112 followed by acidolysis.16
t-BuO O H N
1. NaH, DMF 2. RX

duction of the hydroxyamine is effected with a second equiv of HONH2 HCl (eq 5).27 In a more comprehensive investigation of this reaction, it was found that catalytic reduction of the intermediate hydroxylamine leads to better yields (70% in the case shown in eq 5) of the amino acid.28
NH2OHHCl NaOEt H2O, EtOH 34%

NH2 Ph CO2H (5)

Ph

CO2H

OBn

t-BuO O

R N

1. hydrogenolysis

6199%

OBn 2. acidolysis RNHOHHCl (2)

Tandem Michael additions are also known, the reaction of phorone with hydroxylamine giving a highly congested, cyclic hydroxylamine derivative (eq 6).29
O O
'NH2OH'

R = octyl, 80%

(6) N OH

Reactions with Silylating Agents. O-Mono-, N,O-bis-,17 and N,N,O-tris(trimethylsilylated)18 derivatives of hydroxylamine have been prepared. One distinct advantage of these silylated hydroxylamine reagents is their solubility in nonpolar solvents in which hydroxylamine and its salts show poor solubility. N,OBis(trimethylsilyl)hydroxylamine undergoes facile O,N-silyl transfer upon treatment with Butyllithium in ether, allowing the generation the lithium salt of N,N-bis(trimethylsilyl)hydroxylamine in situ.19 This species plays an important role in the preparation of O-arenesulfonyl- and O-arenecarbonylhydroxylamines.20 Reactions with -Halo or -Hydroxy Esters: Preparation of N-Hydroxy- -amino Acids. Hydroxylamine and its derivatives have been reacted with both -halo and -hydroxy esters as a method to prepare N-hydroxy--amino acid derivatives.21 While hydroxylamine has seen some utility along these lines with t-butyl esters (eqs 3 and 4),22,23 the use of derivatives such as N-[(trichloroethoxy)carbonyl]-O-benzylhydroxylamine24 and O-Benzylhydroxylamine Hydrochloride25 appear to offer some advantages. The latter reagent has been used in the displacement of the triates of (R)- or (S)--hydroxy esters, leading to Nhydroxy--amino methyl esters with both excellent chemical yield and optical purity.26
R Br CO2-t-Bu
NH2OH MeOH, reflux

Reaction with Acid Derivatives: Preparation of Hydroxamic Acids. Hydroxylamine and its derivatives have been reacted with esters and acid halides to prepare hydroxamic acids. The reaction of HONH2 HCl with esters is particularly useful along these lines because overacylation is not a problem (eq 7).30,31
O Ph OEt
NH2OHHCl KOH MeOH

O Ph NHO
K+

AcOH or dry HCl (g)

O Ph NHOH (7)

Reaction of hydroxylamine with acid halides can result in the formation of di- and triacylated products in addition to the desired hydroxamic acid. As is the case with alkylation, several hydroxylamine derivatives have been developed to address this problem. O-benzyl-,32 N,N,O-tris(trimethylsilyl)- (eq 8),33 NBoc-O-TBDMS-, and N-Boc-O-THP-hydroxylamine (eq 9)34 have all proven to be useful for the synthesis of protected hydroxamic acids.
TMS N O TMS
rt, hexane hydrolysis

CO2-t-Bu NHOH

(3)

TMS

RCOCl

air

O R NHOH (8)

R = H, 98%; Me, 97%; Et, 97% Br O SMe O-t-Bu

NH2OH MeOH, reflux

R = Me, 85%; Et, 92%; Ph, 95% O R Cl

+ Boc N OTHP
H

Et3N, DMAP MeCN, 0 C

Boc O

OTHP R O

TFA CH2Cl2

HO

H N O

SMe

MeS

NHOH (4) R O-t-Bu 11%

+
O-t-Bu 50% O

NHOH 5060%

(9)

Reactions with Michael Acceptors. The reaction of hydroxylamine hydrochloride with Michael acceptors offers a convenient synthesis of -amino acids and esters. The preparation of ()-aminophenylpropionic acid has been reported wherein the reA list of General Abbreviations appears on the front Endpapers

The reaction of succinic anhydride with hydroxylamine (prepared from NaOMe and H2 NOHHCl in MeOH) leads to Nhydroxysuccinimide.35 Reaction with Aldehydes and Ketones: Oxime Formation. Reaction of hydroxylamine with an aldehyde or ketone under

HYDROXYLAMINE

basic or acidic conditions leads to the formation of the corresponding oxime. For example, the (E) and (Z) isomers of 4acetylpyridine oxime have been prepared via the reaction of 4acetylpyridine with HONH2 HCl (eq 10).36
O N
8188% NH2OHHCl aq. NaOH

NOH N

HO N

+ N
5:1

(10)

Two hydroxylamine-derived reagents, O-(2-aminobenzoyl)hydroxylamine46 and Hydroxylamine-O-sulfonic Acid,47 have also been used to effect this transformation, although in a more limited number of cases. Several methods exist which do not rely on hydroxylamine, including NH4 Cl/Cu0 /py/O2 ,48 EtNO2 /NaOAc/AcOH,49 and N,N-dimethylhydrazine/MeOH/MMPP 6H2 O50 (MMPP = magnesium monoperoxyphthalate). Reaction with Phosphinylating Agents. Both N- and Ophosphinylated hydroxylamine are available via reaction of the appropriate hydroxylamine derivative with diphenylphosphinyl chloride. Use of hydroxylamine base results in the formation of O-(Diphenylphosphinyl)hydroxylamine,4 while employment of TMSONH2 followed by hydrolysis gives N-diphenylphosphinylhydroxylamine (eq 16).51
O Ph P ONH2 Ph
NH2OH

Other examples of this reaction include the preparation of the oxime of methyl glyoxylate (eq 11)23 and the oximes of some diuoromethylene-containing chiral aldehydes (eq 12).37
O H F F R OBn O CO2Me
NH2OHHCl NaHCO3, H2O 83% NH2OH, AcOH EtOH 4 sieves

HON

CO2Me

(11)

F F R OBn R = Ph, 72%; Me, 77% NOH (12)

O Ph P Cl Ph

1. NH2OTMS 2. MeOH

O Ph P NHOH Ph (16)

Both hydrazones (eq 13)38 and enol esters (eq 14)39 are efcient carbonyl surrogates in this transformation.
TMS Br + Me N Me N TMS NOH (13) OAc AcO O OAc OAc
NH2OHHCl, py 25 C 74% 1. THF, 0 C 2. NH2OHHCl, py 20 C 64%

Reaction with Miscellaneous Electrophiles. Hydroxylamine reacts with nitriles to yield amide oximes (eq 17).52,53 The reaction of hydroxylamine with uracil and cytosine has been applied in the Chemical Cleavage of Mismatch (CCM) technique for identifying DNA mutants.54
EtO2C Ph N H O CN
NH2OHHCl

EtO2C Ph N H

NH2 NOH (17)

OAc AcO O OAc NOH (14)

Preparation of Isoxazoles and Isoxazolines. Isoxazoles are conveniently prepared via the reaction of HONH2 HCl with 1,3dicarbonyl compounds or their equivalents.55 In some cases, the regiochemistry of the reaction can be controlled. For example, the regiochemistry of the reaction of hydroxylamine with acylketene dithioacetals depends on reaction conditions (eqs 18 and 19).56
O R1 SR2 SR2
NH2OHHCl NaOMe, MeOH reflux, 1015 h 5878%

A solid-phase reagent which binds carbonyl compounds as their corresponding oximes has been developed and employed in the isolation of steroidal ketones.40 -Halo ketones produce hydroxylamino oximes on treatment with hydroxylamine.41 The mechanism of this nucleophilic additiondehydration process has been studied by a number of groups.42 Reaction with Aldehydes: Nitrile Formation. Nitriles can be effectively prepared directly from aldehydes by a wide variety of methods involving hydroxylamine. Two convenient methods employ HONH2 HCl and either reuxing formic acid43 or pyridine with azeotropic removal of water with reuxing toluene (eq 15).44 The former reaction has been used to convert a 4-formyl -lactam into its corresponding nitrile derivative.45
NH2OHHCl HCO2H reflux, 30 min

N O R1 SR2 (18)

O R1

SR2 SR2

NH2OHHCl, AcOH NaOAc, EtOH, PhH reflux, 810 h 5168%

N O R2S R1 (19)

In like fashion, reaction conditions are important in the preparation of 3-amino-5-t-butylisoxazole from 4,4-dimethyl-3-oxopentanenitrile (eqs 20 and 21).57
O t-Bu CN
2. 36% HCl (aq) 100 C, 1 h 86% NH2OH1/2H2SO4 NaOH (aq) 100 C, 2.5 h 1. NH2OH1/2H2SO4 NaOH (aq) 100 C, 30 min

NH2 t-Bu O N (20)

CHO

99% 1. HONH2HCl pyridine 2. PhMe, reflux 68%

CN

(15) O t-Bu CN

t-Bu H2N N (21)

98%

Avoid Skin Contact with All Reagents

HYDROXYLAMINE
NH2OH, EtOAc, DMF 90100 C, 1 h

Functionalized 4,5-dihydroisoxazoles58 have been prepared by the reaction of ,-epoxy ketones with HONH2 HCl (eq 22)59 and also by the cycloaddition reaction between styrene and aryl nitrile oxides prepared in situ from trichloromethylarenes and hydroxylamine.60
R1 O O R1 = R2
NH2OHHCl py, EtOH reflux, 5 h

OH

96%

OH (27)

OH R1 O N R2 = Ph; 5584% R2 (22)

Ph, cyclopropane derivs.;

Use in Peptide Chemistry. Hydroxylamine has been used as a reagent to cleave the acetoacetyl amino acid protecting group69 and has also been employed to cleave the asparaginylglycyl peptide bond.70

Preparation of Substituted Pyridines. Two novel approaches to the synthesis of substituted pyridines have appeared. Treatment of dihydropyran acetals61 with HONH2 HCl (eq 23) or bicyclic acetals62 with HONH2 HCl and Aluminum Chloride (eq 24) leads to good yields of pyridines. The rst process appears to be the more general of the two, though it is limited somewhat by the availability of starting materials.
R1 O OR4 R3
NH2OHHCl EtOH reflux, 10 h

First Update
Masakatsu Shibasaki & Noriyuki Yamagiwa The University of Tokyo, Tokyo, Japan Reactivity with Alkylating Agents. Hydroxylamine, which has ambident reactivity, can react with nucleophiles to afford Nand/or O-substituted products. The chemoselectivity seems to be dependent on the pKa of the reaction media according to a calculation study.10 The HOMO population of NH2 OH is mainly located on the N atom, whereas that of anionic NH2 O is located on the O atom.10 Free hydroxylamine usually attacks alkyl halides and methanesulfonates at the N atom. The reaction is often used for the construction of N-fused rings such as aziridines,71 pyrrolydines,72 and azepines.73 Reaction with Michael Acceptors. Substituted hydroxylamines such as N-substituted,74 O-substituted,7577 and N,O-disubstituted78 hydroxylamines are widely used for reaction with Michael acceptors. Lewis acid-catalyzed asymmetric conjugate additions of O-alkoxylamine,77 enabling the resulting -alkoxylaminoketones to be transformed into chiral aziridines by basic treatment.77d,e Conjugate additions of N-protected hydroxylamines with ,-unsaturated esters afford isoxazolidin-5-ones with high diastereoselectivity.74 The mechanism for the conjugate addition of N-methylhydroxylamine is considered to proceed via ve-membered ring transition state (eq 28).79
H Me N O H H Ph H Ph O OEt
NH2OMe

R1

R3 (23)

R2 R1 R4 = Me, Et Ph Ph 2-furyl
NH2OHHCl AlCl3, AcOH

R2 R2 Ph Cy Ph R3 H H H Yield 81% 40% 95%

, 20 h

(24)

R =Me, 83%; Et, 99%; Pr, 84%

Aromatic Substitution Reactions. In certain cases, hydroxylamine can act as a nucleophile in aromatic substitution reactions. This has shown to be the case in the reactions with 6-nitroquinoxalines (eq 25)63 and N,N-dimethyl-2,4-bis(triuoroacetyl)1-naphthylamine (eq 26).64 Other examples are known.65
X O2N N N X = Br, Cl NMe2 COCF3
NH2OHHCl Et3N, MeCN reflux, 5 h 94% NH2OH, KOH EtOH 50%

X O2N NH2 N O

N (25) N
MeNHOH

Ph MeHN+ O

O OEt

CO2Et

CF3 (26) COCF3

(28) Ph No reaction MeN O O

COCF3

Use as a Reducing Agent. The combination of hydroxylamine and ethyl acetate in DMF represents a useful in situ preparation of Diimide and this procedure has been reported to reduce a variety of unsaturated compounds (eq 27).66,67 Diimide formation from hydroxylamine has been used to explain the reductive cyclization of some o-nitroazobenzenes.68
A list of General Abbreviations appears on the front Endpapers

Reaction with Acid Derivatives: Preparation of Hydroxamic Acids. Reaction of hydroxylamine with esters or acid halides generally affords N-acylhydroxylamines (hydroxamic acids) rather than O-acylhydroxylamines.80 Recent examples of N-acylating reagents for hydroxylamine include acid

HYDROXYLAMINE

anhydrides,81 N-acyloxazolidinones in the presence of Lewis acids,82 and acylbenzotriazoles.83 Alternatively, hydroxylamine directly reacts with carboxylic acids to generate hydroxamic acids in the presence of an activating agent such as 2,4,6-trichloro[1,3,5]triazine.84 Reaction with Aldehydes and Ketones: Oxime Formation. Selective synthesis of either E- or Z-aldoximes is possible with aromatic aldehydes. Hydroxylamine hydrochloride in the presence of K2 CO3 or CuSO4 affords E- or Z-aldoximes, respectively, in high chemoselectivity and high chemical yield (eq 29).85 Aromatic E-ketoximes are prepared from aromatic ketones using K2 CO3 catalyst in high selectivity (eq 30). In contrast, application of CuSO4 catalyst for ketoxime synthesis is unsuccessful. Ketoximes are also prepared in ionic liquid.86
HO
K2CO3 90 C, 60 min

hydes and ketones are converted to the corresponding amides. Although aldehydes can afford either nitriles or amides, optimization enables selective formation of either functionality. For example, benzaldehyde and hydroxylamine hydrochloride with dry-Al2 O3 /CH3 SO2 Cl affords benzonitrile in high yield; alternatively, the wet catalyst affords benzamide in high yield (eq 31).99 Zinc oxide,100 titanium oxide,101 or oxalic acid102 is also effective at transforming aldehydes to amides in high chemical yield. Ketoximes are converted to amides in the presence of sodium hydrogen sulfate/silica gel,94 HY-zeolite,96 silica chloride,97 zinc oxide,100 titanium oxide,101 Al2 O3 /CH3 SO3 H,103 and P2 O5 /SiO2 ,104 For ketones, the regioselectivity of rearrangement is often problematic. In general, oximination of unsymmetrical ketones affords E- and Z-oximes with low regioselectivity, thereby ultimately affording a mixture of two different amides.
dry-Al2O3 MeSO2Cl NH2OHHCl

N H

CN

100 C, 25 min

CHO

Z 90% N
CuSO4 90 C, 60 min

90% (29) OH H
wet-Al2O3 MeSO2Cl NH2OHHCl 100 C, 90 min

CHO (31) O NH2 90%

E 90% HO
K2CO3

N Me

O Me N

90 C, 60 min

N Z 85% (30)

Reaction with Miscellaneous Electrophiles. N-BOC-protected hydroxylamine is easily oxidized to generate a t-butyl nitrosoformate, which reacts with olens and dienes to give the allylamines (ene-reaction) (eq 32)105 and 1H,4H-dihydro-1,2oxazines (hetero-Diels-Alder reaction) (eq 33),106 respectively.
O
aq H2O2, CuCl cat ClCH2CH2Cl/CH3CN

CuSO4 90 C, 360 min

No Reaction

HN + HO

OH N O 70%

Reaction with Aldehydes: Nitrile Formation. One-pot syntheses of aliphatic and aromatic nitriles from the oximes of aldehydes include dehydration by reuxing in N-methylpyrrolidone,87 triethylamine/phthalic anhydride,88 triphosgene,89 sodium iodide,90 and graphite/methanesulfonyl chloride.91 Microwave-assisted one-pot syntheses of nitriles are also plentiful. Nitrile formation in the presence of peroxymonosulfate/alumina,92 N-methylpyrrolidone,93 sodium hydrogen sulfate/silica gel,94 ammonium acetate,95 HY-zeolite,96 or silica chloride97 is accelerated by microwave irradiation. Transition metal catalyst, [RuCl2 (p-cymene)]2 ,98 smoothly catalyzes the nitrile formation from aldoximes, which are readily prepared form aldehydes and hydroxylamine hydrochloride.

(32)

O + HN HO O

aq H2O2, CuCl cat ClCH2CH2Cl/CH3CN

O N O O quant. (33)

Reaction with Aldehydes and Ketones: Beckmann Rearrangement for Amide Synthesis. Various conditions have been reported for the one-pot Beckmann rearrangement, where alde-

Preparation of Isoxazoles and Isoxazolines. Hydroxylamine hydrochloride reacts with the internal and terminal alkynes to afford isoxazoles in moderate yield.107 Regioselective synthesis of isoxazoles using -bromo enones is possible.108
Avoid Skin Contact with All Reagents

HYDROXYLAMINE
OMe O2N NO2 NHOH O2N 91% NO2 (37)
NH2OHHCl Na, MeOH, 0 C then, rt 19 h

Preparation of Substituted Pyridines. Substituted pyridines are prepared from hydroxylamine and 1,5-dioxopentane derivatives including dihydropyran acetals.109 Substituted pyridines are obtained by reuxing dihydropyran acetals with hydroxylamine hydrochloride in acetonitrile.110 Unsymmetrical 1,5-dioxopentanes, prepared by the ozonolysis of cyclopentene derivatives, are converted to the substituted pyridines by reaction with hydroxylamine hydrochloride at reux.111 A wide variety of unsaturated carbonyl compounds serve as useful precursors of fused pyridine rings, including substituted 2,4-pentanal (eq 34),112 2-substituted indole (eq 35),113 and 3-substituted indole (eq 36).114

1.

H O TBDMSO CO2Et N TBDMSO CO2Et 53%

6. 7.
NH2OHHCl then, AcCl/pyridine

(34)

2. 3. 4. 5.

1. LDA, THF, N,N-dimethylacetamide

MeO

N Et

2. NH2OHHCl, AcONa o-dichlorobenzene

(35) MeO N Et 60% N Me

8. 9. 10. 11. 12. 13.

H O N
1. NH2OHHCl KOAc, MeOH 2. toluene, 110 C

N N

(36)

14. 15. 16. 17.

60%

Nucleophilic Aromatic Substitution. As expected, aromatic substitution with hydroxylamine is limited to electron-decient aromatic rings. Treatment of 2,4-dinitromethoxybenzene with hydroxylamine hydrochloride, provides N-(2,4-dinitrophenyl)hydroxylamine in 91% yield (eq 37).115
A list of General Abbreviations appears on the front Endpapers

18. 19. 20. 21.

22.

Several excellent reviews have appeared covering the preparation and reactivity of hydroxylamine and its derivatives. (a) Andree, R.; Neuth, J. F.; Wroblowsky, Hs.-J., Methoden Org. Chem. (Houben-Weyl) 1990, E16a, 1. (b) Askani, R.; Taber, D. F., Comprehensive Organic Synthesis 1991, 6, 103. (c) Roberts, J. S. In Comprehensive Organic Chemistry; Barton, D. H. R., Ed.; Pergamon: Oxford, 1979; Vol. 2, p 185. Several references to the use of hydroxylamine are presented in Fieser & Fieser: 1, 478, 565, 903, 939; 2, 217; 5, 206; 6, 400, 533, 538; 7, 176, 225; 9, 245, 409; 10, 206; 11, 257; 12, 67, 251; 15, 170. Gross, P., CRC Crit. Rev. Toxicol. 1985, 14, 87. Hurd, C., Inorg. Synth., 1939, 1, 87. Klotzer, W.; Stadlwieser, J.; Raneburger, J., Org. Synth., Coll. Vol., 1990, 7, 8. Fioshin, M. Ya.; Avrutskaya, I. A.; Surov, I. I.; Novikov, V. T., Collect. Czech. Chem. Commun. 1987, 52, 182. Chem Sources 1993; Chemical Sources International; Fernandina Beach, FL, 1993. Information in this section was compiled from several sources: (a) Sittig, M. Handbook of Toxic and Hazardous Chemicals and Carcinogens; Noyes: Park Ridge, NJ, 1991; p 918. (b) The Merck Index, 11th ed.; Merck & Co.: Rahway, NJ, 1991. (c) Bretherick, L. Brethericks Handbook of Reactive Chemical Hazards, 4th ed.; Butterworths: Boston, 1990; p 1233. (d) Toxic and Hazardous Industrial Chemicals Safety Manual; The International Technical Information Institute; Japan, 1985; p 281. (e) Lewis, R. J. Saxs Dangerous Properties of Industrial Materials, 8th ed.; Van Nostrand Reinhold: New York, 1992; p 1936. March, J. Advanced Organic Chemistry; Wiley: New York, 1992. Lee, B. H.; Miller, M. J., J. Org. Chem. 1983, 48, 24. Kashima, C.; Yoshiwara, N.; Omote, Y., Tetrahedron Lett. 1982, 23, 2955. Sulsky, R.; Demers, J. P., Tetrahedron Lett. 1989, 30, 31. Doleschall, G., Tetrahedron Lett. 1987, 28, 2993. (a) Stewart, A. O.; Martin, J. G., J. Org. Chem. 1989, 54, 1221. (b) For a similar reaction with HONH2 HCl see: Lamanec, T. R.; Bender, D. R.; DeMarco, A. M.; Karady, S.; Reamer, R. A.; Weinstock, L. M., J. Org. Chem. 1988, 53, 1768. Genet, J.-P.; Thorimbert, S.; Touzin, A. M., Tetrahedron Lett. 1993, 34, 1159. Murahashi, S.-I.; Imada, Y.; Taniguchi, Y.; Kodera, Y., Tetrahedron Lett. 1988, 29, 2973. Goel, O. P.; Krolls, U., Org. Prep. Proced. Int. 1987, 19, 75. Bottaro, J. C.; Bedford, C. D.; Dodge, A., Synth. Commun. 1985, 15, 1333. Other bis-silylated hydroxylamines are also known: West, R.; Boudjouk, P., J. Am. Chem. Soc. 1973, 95, 3983. Ando, W.; Tsumaki, H., Synth. Commun. 1983, 13, 1053. West, R.; Boudjouk, P., J. Am. Chem. Soc. 1973, 95, 3987. King, F. D.; Walton, D. R. M., Synthesis 1975, 788. For an excellent review of the preparation and reactions of these compounds, see: Ottenheijm, H. C. J.; Herscheid, J. D. M., Chem. Rev. 1986, 86, 697. Shin, C.-g.; Nanjo, K.; Ando, E.; Yoshimura, J., Bull. Chem. Soc. Jpn. 1974, 47, 3109.

HYDROXYLAMINE
23. Huang, N. Z.; Miller, M. J.; Fowler, F. W., Heterocycles 1988, 27, 1821. 24. Kolasa, T.; Miller, M. J., J. Org. Chem. 1987, 52, 4978. 25. Akiyama, M.; Iesaki, K.; Katoh, A.; Shimizu, K., J. Chem. Soc., Perkin Trans. 1 1986, 851. 26. Feenstra, R. W.; Stokkingreef, E. H. M.; Nivard, R. J. F.; Ottenheijm, H. C. J., Tetrahedron 1988, 44, 5583. 27. Steiger, R. E., Org. Synth., Coll. Vol. 1963, 3, 91. 28. Basheeruddin, K.; Siddiqui, A. A.; Khan, N. H.; Saleha, S., Synth. Commun. 1979, 9, 705. 29. Rozantzev, E. G.; Neiman, M. B., Tetrahedron 1964, 20, 131. 30. Hauser, C. R.; Renfrow, W. B. Jr., Org. Synth., Coll. Vol. 1943, 2, 67. 31. Brown, D.; Ismail, S., lnorg. Chim. Acta 1990, 171, 41. 32. Lee, B. H.; Miller, M. J., J. Org. Chem. 1983, 48, 24. 33. Ando, W.; Tsumaki, H., Synth. Commun. 1983, 13, 1053. 34. Altenburger, J. M.; Mioskowski, C.; dOrchymont, H.; Schirlin, D.; Schalk, C.; Tarnus, C., Tetrahedron Lett. 1992, 33, 5055. 35. Wang, K.-T.; Brattesani, D. N.; Weinstein, B., J. Heterocycl. Chem. 1966, 3, 98. 36. LaMattina, J. L.; Suleske, R. T., Org. Synth., Coll. Vol. 1990, 7, 149. 37. Bravo, P.; Pregnolato, M.; Resnati, G., J. Org. Chem. 1992, 57, 2726. 38. Fox, M. E.; Holmes, A. B.; Forbes, I. T.; Thompson, M.; Ziller, J. W., Tetrahedron Lett. 1992, 33, 7425. 39. Lichtenthaler, F. W.; Jarglis, P., Tetrahedron Lett. 1980, 21, 1425. 40. Prasad, V. V. K.; Warne, P. A.; Lieberman, S., J. Steroid Biochem. 1983, 18, 257. 41. Volodarsky, L. B.; Tikhonov, A. Ya., Synthesis 1986, 704. 42. Brighente, I. M. C.; Vottero, L. R.; Terezani, A. J.; Yunes, R. A., J. Phys. Org. Chem. 1991, 4, 107. Lamaty, G.; Roque, J. P.; Natat, A.; Silou, T., Tetrahedron 1986, 42, 2667. Agami, C.; Rizk, T.; Durand, R.; Geneste, P., Can. J. Chem. 1982, 60, 2355. 43. Olah, G.; Keumi, T., Synthesis 1979, 112. 44. Saednya, A., Synthesis 1982, 190. 45. Alcaide, B.; Gomez, A.; Plumet, J.; Rodriguez-Lopez, J., Tetrahedron 1989, 45, 2751. 46. Reddy, P. S. N.; Reddy, P. P., Synth. Commun. 1988, 18, 2179. 47. Streith, J.; Fizet, C.; Fritz, H., Helv. Chim. Acta 1976, 59, 2786. 48. Capdevielle, P.; Lavigne, A.; Maumy, M., Synthesis 1989, 451. 49. Karmarkar, S. N.; Kelkar, S. L.; Wadia, M. S., Synthesis 1985, 510. 50. Fernandez, R.; Gasch, C.; Lassaletta, J.-M.; Llera, J.-M.; Vazquez, J., Tetrahedron Lett. 1993, 34, 141. 51. (a) Harger, M. J. P., J. Chem. Soc., Perkin Trans. 1 1983, 2699. (b) Harger, M. J. P., J. Chem. Soc., Perkin Trans. 1 1981, 3284. 52. Piskunova, I. P.; Eremeev, A. V.; Mishnev, A. F.; Vosekalna, I. A., Tetrahedron 1993, 49, 4671. 53. Showell, G. A.; Gibbons, T. L.; Kneen, C. O.; MacLeod, A. M.; Merchant, K.; Saunders, J.; Freedman, S. B.; Patel, S.; Baker, R., J. Med. Chem. 1991, 34, 1086. 54. Smooker, P. M.; Cotton, R. G. H., Mutat. Res. 1993, 288, 65. 55. For other isoxazole syntheses see:(a) Tronchet, J. M. J.; Massoud, M. A. M., Mansour J. Pharm. Sci. 1988, 2, 99. (b) Cherton, J.-C.; Lanson, M.; Ladjama, D.; Guichon, Y.; Basselier, J.-J., Can. J. Chem. 1990, 68, 1271. 56. Purkayastha, M. L.; Ila, H.; Junjappa, H., Synthesis 1989, 20. 57. Takase, A.; Murabayashi, A.; Sumimoto, S.; Ueda, S.; Makisumi, Y., Heterocycles 1991, 32, 1153. 58. For other syntheses of 4,5-dihydroisoxazoles, see:(a) Colla, A.; Martins, M. A. P.; Clar, G.; Krimmer, S.; Fischer, P., Synthesis 1991, 483. (b) Curzu, M. M.; Pinna, G. A.; Cignarella, G.; Barlocco, D.; Demontis, M. P., Collect. Czech. Chem. Commun. 1991, 56, 2494. 59. Ito, S.; Sato, M., Bull. Chem. Soc. Jpn. 1990, 63, 2739.

60. Brokhovetskii, D. B.; Belenkii, L. I.; Krayushkin, M. M., Izv. Akad. Nauk SSSR, Ser. Khim. 1990, 1692 (Chem. Abstr. 1991, 115, 279 557). 61. Ciufolini, M. A.; Byrne, N. E., J. Chem. Soc., Chem. Commun. 1988, 1230. 62. Jun, J.-G.; Shin, H. S.; Kim, S. H., J. Chem. Soc., Perkin Trans. 1 1993, 1815. 63. Nasielski-Hinkens, R.; Kotel, J.; Lecloux, T.; Nasielski, J., Synth. Commun. 1989, 19, 511. 64. Hojo, M.; Masuda, R.; Okada, E., Synthesis 1990, 481. 65. Reaction with (a) halobenzonitriles: Wrubel, J.; Mayer, R., Z. Chem. 1984, 24, 254 (Chem. Abstr. 1985, 102, 45 820h). (b) Nitroimidazoles: Suwinski, J.; Swierczek, K.; Glowiak, T., Tetrahedron 1993, 49, 5339. 66. Wade, P. A.; Amin, N. V., Synth. Commun. 1982, 12, 287. 67. Gangadhar, A.; Rao, T. C.; Subbarao, R.; Lakshminarayana, G., J. Am. Oil Chem. Soc. 1989, 66, 1507 (Chem. Abstr. 1990, 112, 22 677j). 68. Wilshire, J. F. K., Aust. J. Chem. 1988, 41, 617. 69. Di Bello, C.; Filira, F.; Giormani, V.; DAngeli, F., J. Chem. Soc. (C) 1969, 350. 70. Bornstein, P.; Balian, G., Methods Enzymol. 1977, 47, 132. 71. Boukhris, S.; Souizi, A., Tetrahedron Lett. 2003, 44, 3259. 72. (a) Yu, J.; DePue, J.; Kronenthal, D., Tetrahedron Lett. 2004, 45, 7247. (b) Merino, P.; Revuelta, J.; Tejero, T.; Cicchi, S.; Goti, A., Eur. J. Org. Chem. 2004, 776. 73. Scafato, P.; Cunsolo, G.; Labano, S.; Rosini, C., Tetrahedron 2004, 60, 8801. 74. Sibi, M. P.; Prabagaran, N.; Ghorpade, S. G.; Jasperse, C. P., J. Am. Chem. Soc. 2003, 125, 11796. 75. (a) Tong, X.-H.; Hong, A., Tetrahedron Lett. 2000, 41, 8857. (b) Seko, S.; Tani, N., Tetrahedron Lett. 1998, 39, 8117. 76. Bongini, A.; Cardillo, G.; Gentilucci, L.; Tomasini, C., J. Org. Chem. 1997, 62, 9148. 77. (a) Jrgensen, K. A.; Falborg, L., J. Chem. Soc. Perkin Trans. 1 1996, 2823. (b) Sibi, M. P.; Shay, J. J.; Liu, M.; Jasperse, C. P., J. Am. Chem. Soc. 1998, 120, 6615. (c) Cardillo, G.; Gentilucci, L.; Gianotti, M.; Kim, H.; Perciaccante, R.; Tolomelli, A., Tetrahedron: Asymmetry 2001, 12, 2395. (d) Jin, X. L.; Sugihara, H.; Daikai, K.; Takeishi, H.; Jin, Y. Z.; Furuno, H.; Inanaga, J., Tetrahedron 2002, 58, 8321. (e) Yamagiwa, N.; Matsunaga, S.; Shibasaki, M., J. Am. Chem. Soc. 2003, 125, 16178. 78. Keen, S. P.; Weinreb, S. M., Tetrahedron Lett. 2000, 41, 4307. 79. Niu, D.; Zhao, K., J. Am. Chem. Soc. 1999, 121, 2456. 80. Geffken, D., Chem. Ber. 1986, 119, 744. 81. Reddy, A. S.; Kumar, M. S.; Reddy, G. R., Tetrahedron Lett. 2000, 41, 6285 82. Sibi, M. P.; Hasegawa, H.; Ghorpade, S. R., Org. Lett. 2002, 4, 3343. 83. Katritzky, A. R.; Kirichenko, N.; Rogovoy, B. V., Synthesis 2003, 2777. 84. Giacomelli, G.; Porcheddu, A.; Salaris, M., Org. Lett. 2003, 5, 2715. 85. Sharghi, H.; Hosseini Sarvari, M., Synlett 2001, 99. 86. Ren, R. X.; Ou, W., Tetrahedron Lett. 2001, 42, 8445. 87. Sampath Kumar, H. M.; Subba Reddy, B. V.; Tirupathi Reddy, P.; Yadav, J. S., Synthesis 1999, 586. 88. Wang, E.-C.; Lin, G.-J., Tetrahedron Lett. 1998, 39, 4047. 89. Bose, D. S.; Goud, P. R., Synth. Commun. 2002, 32, 3621. 90. Ballini, R.; Fiorini, D.; Palmieri, A., Synlett 2003, 1841. 91. Sharghi, H.; Hosseini Sarvari, M., Synthesis 2003, 243. 92. Bose, D. S.; Narsaiah, A. V., Tetrahedron Lett. 1998, 39, 6533. 93. Chakraborti, A. K.; Kaur, G., Tetrahedron 1999, 55, 13265. 94. Das, B.; Madhusudhan, P.; Venkataiah, B., Synlett 1999, 1569. 95. Das, B.; Ramesh, C.; Madhusudhan, P., Synlett 2000, 1599. 96. Srinivas, K. V. N. S.; Reddy, E. B.; Das, B., Synlett 2002, 625. 97. Srinivas, K. V. N. S.; Mahender, I.; Das, B., Chem. Lett. 2003, 32, 738. 98. Yang, S. H.; Chang, S., Org. Lett. 2001, 3, 4209. Avoid Skin Contact with All Reagents

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99. 100. 101. 102.

HYDROXYLAMINE
Sharghi, H.; Hosseini Sarvari, M., Tetrahedron 2002, 58, 10323. Sharghi, H.; Hosseini Sarvari, M., Synthesis 2002, 1057. Sharghi, H.; Hosseini Sarvari, M., J. Chem. Res. (S) 2003, 176. Chandrasekhar, S.; Gopalaiah, K., Tetrahedron Lett. 2003, 44, 7437. 109. Chumakov, Y.; Sherstyuk, V. P., Tetrahedron Lett. 1965, 129. 110. (a) Bennabi, S.; Narkunan, K.; Rousset, L.; Bouchu, D.; Ciufolini, M. A., Tetrahedron Lett. 2000, 41, 8873. (b) Cordaro, J. G.; McCusker, J. K.; Bergman, R. G., Chem. Commun. 2002, 1496. 111. Nakagawa, H.; Sugahara, T.; Ogasawara, K., Tetrahedron Lett. 2001, 42, 4523. 112. Tanaka, K.; Mori, H.; Yamamoto, M.; Katsumura, S., J. Org. Chem. 2001, 66, 3099. 113. Kusurkar, R. S.; Goswami, S. K., Tetrahedron 2004, 60, 5315. 114. Gilchrist, T. L.; Kemmitt, P. D., Tetrahedron 1997, 53, 4447. 115. Singh, S.; Nicholas, K. M., Synth. Commun. 2001, 31, 3087.

103. Sharghi, H.; Hosseini Sarvari, M., J. Chem. Res. (S) 2001, 446. 104. Eshghi, H.; Gordi, Z., Synth. Commun. 2003, 33, 2971. 105. Fakhruddin, A.; Iwasa, S.; Nishiyama, H.; Tsutsumi, K., Tetrahedron Lett. 2004, 45, 9323. 106. Kalita, B.; Nicholas, K. M., Tetrahedron Lett. 2005, 46, 1451. 107. Guan, H.-P.; Tang, X.-Q.; Luo, B.-H.; Hu, C.-M., Synthesis 1997, 1489. 108. Katritzky, A. R.; Wang, M.; Zhang, S.; Voronkov, M. V., J. Org. Chem. 2001, 66, 6787.

A list of General Abbreviations appears on the front Endpapers