HYDROXYLAMINE

1

Hydroxylamine

1

HONH

2

(HONH

2

)

[7803-49-8]

H

3

NO

(MW 33.04)

InChI = 1/H3NO/c1-2/h2H,1H2
InChIKey = AVXURJPOCDRRFD-UHFFFAOYAD
(HONH

2

·HCl)

[5470-11-1]

ClH

4

NO

(MW 69.50)

InChI = 1/ClH.H3NO/c;1-2/h1H;2H,1H2
InChIKey = WTDHULULXKLSOZ-UHFFFAOYAT
((HONH

2

)

3

·H

3

PO

4

)

[20845-01-6]

H

12

N

3

O

7

P

(MW 197.12)

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
((HONH

2

)

2

·H

2

SO

4

)

[10039-54-0]

H

8

N

2

O

6

S

(MW 164.17)

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-forming

56

reactions; reducing

agent;

66

in combination with dehydrating agents, used for the

conversion of aldehydes to nitriles

43

)

Physical Data:

HONH

2

: hydroscopic white needles or flakes;

decomposes rapidly at rt; mp 32.05

◦

C; bp 56.5

◦

C/22 mmHg,

70

◦

C/60 mmHg, 110

◦

C/760 mmHg. HONH

2

·HCl: white

crystals; mp 151

◦

C; d 1.67 g cm

−3

; pK

a1

5.97; pK

a2

13.7.

10

(HONH

2

)

3

·H

3

PO

4

: mp 169–171

◦

C. (HONH

2

)

2

·H

2

SO

4

: mp

170

◦

C (dec).

Solubility:

HONH

2

: decomposes in hot water; sol cold water,

methanol; sparingly sol ether, benzene, chloroform, carbon
disulfide.

2

HONH

2

·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 HONH

2

·HCl-d

4

and HONH

2

·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 hydrox-

ylamine are corrosive and hygroscopic. Specific precautions
in the literature indicate that the free base is a much more
hazardous substance to work with than are the salts.

7

HONH

2

:

a moderately toxic, corrosive irritant to the eye, skin, and mu-
cous membranes. Explodes at 130

◦

C. Explodes in air when

heated above 70

◦

C

. May ignite spontaneously in air, or in con-

tact with PCl

3

or PCl

5

. Calcium reacts to give the heat-sensitive

explosive bis(hydroxylamide). In the event of a spill, cover with
sodium bisulfite and sprinkle with water. HONH

2

·HCl: harmful

if inhaled or swallowed (oral LD

50

400–420 mg kg

−1

; 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 sta-

ble 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 specific derivative will
be named.

General Reactivity with Simple Electrophiles.

Hydroxyl-

amine 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 α-effect, an effect observed in a vari-
ety of nucleophiles which possess a heteroatom in the position
α

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 side-
products. 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 solu-
tion (eq 1).

10

Results similar to those obtained with benzyl bro-

mide were found for five other benzylic halides.

(1)

R–ONH

2

+

R–NHOH

+

R

2

NOH

R–X

+

NH

2

O

–

Product distribution

66:22:12

79:21: –

RX

PhCH

2

Br

1-Bromo-2-ethylhexane

Yield (%)

52

30

Selective N-alkylation has been accomplished in a wide variety

of cases using the hydroxylamine derivative t-butyl N-benzyloxy-
carbamate.

11

The preparation of N-octylhydroxylamine·HCl is

illustrative of this process (eq 2). Ethyl 3-methylhydroxy-4-isoxa-
zolecarboxylate

12

is another versatile reagent which has been

developed for this purpose. O-Trimethylsilyl- and O-(t-butyldi-
phenylsilyl)hydroxylamine

13

have also seen use in the preparation

Avoid Skin Contact with All Reagents

2

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 accom-
plished via the Pd

0

-mediated reaction of N,O-bis(Boc)hydroxyl-

amine with allylic carbonates, chlorides, and acetates.

14

A similar

study showed that the use of HONH

2

·HCl in the same reac-

tion leads to N,N-diallylated products.

15

N,O-Dimethylhydroxyl-

amine·HCl has been prepared on a large scale by dimethyla-
tion (Dimethyl Sulfate) of ethyl hydroxycarbamate at pH 11–12
followed by acidolysis.

16

t

-BuO

H
N

OBn

O

t

-BuO

N

OBn

O

R

(2)

R = octyl, 80%

1. hydrogenolysis

1. NaH, DMF
2. RX

61–99%

RNHOH•HCl

2. acidolysis

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 hy-
droxylamine reagents is their solubility in nonpolar solvents in
which hydroxylamine and its salts show poor solubility. N,O-
Bis(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)hydroxyl-
amine in situ.

19

This species plays an important role in the prepara-

tion of O-arenesulfonyl- and O-arenecarbonylhydroxylamines.

20

Reactions with α

α

α

-Halo or α

α

α

-Hydroxy Esters: Preparation

of N-Hydroxy-α

α

α

-amino Acids.

Hydroxylamine and its deriva-

tives have been reacted with both α-halo and α-hydroxy esters
as a method to prepare N-hydroxy-α-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-benzylhydroxylamine

24

and

O-Benzylhydroxylamine Hydrochloride

25

appear to offer some

advantages. The latter reagent has been used in the displacement
of the triflates of (R)- or (S)-α-hydroxy esters, leading to N-
hydroxy-α-amino methyl esters with both excellent chemical yield
and optical purity.

26

(3)

R

CO

2

-t-Bu

Br

R

CO

2

-t-Bu

NHOH

NH

2

OH

MeOH, reflux

R = H, 98%; Me, 97%; Et, 97%

NH

2

OH

MeOH, reflux

O-t-Bu

O

Br

SMe

O-t-Bu

O

H
N

SMe

O-t-Bu

O

(4)

MeS

NHOH

HO

11%

+

50%

Reactions with Michael Acceptors.

The reaction of hydroxy-

lamine hydrochloride with Michael acceptors offers a convenient
synthesis of β-amino acids and esters. The preparation of (±)-
β

-aminophenylpropionic acid has been reported wherein the re-

duction of the hydroxyamine is effected with a second equiv of
HONH

2

·HCl (eq 5).

27

In a more comprehensive investigation of

this reaction, it was found that catalytic reduction of the interme-
diate hydroxylamine leads to better yields (70% in the case shown
in eq 5) of the amino acid.

28

(5)

CO

2

H

Ph

CO

2

H

Ph

NH

2

NH

2

OH•HCl

NaOEt

H

2

O, EtOH

34%

Tandem Michael additions are also known, the reaction of

phorone with hydroxylamine giving a highly congested, cyclic
hydroxylamine derivative (eq 6).

29

'NH

2

OH'

(6)

O

N

O

OH

Reaction with Acid Derivatives: Preparation of Hydrox-

amic Acids.

Hydroxylamine and its derivatives have been re-

acted with esters and acid halides to prepare hydroxamic acids.
The reaction of HONH

2

·HCl with esters is particularly use-

ful along these lines because overacylation is not a problem
(eq 7).

30,31

(7)

Ph

OEt

O

Ph

NHO

–

K

+

O

Ph

NHOH

O

NH

2

OH•HCl

KOH

MeOH

AcOH

or dry HCl (g)

Reaction of hydroxylamine with acid halides can result in the

formation of di- and triacylated products in addition to the de-
sired 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

N

-

Boc-O-TBDMS-, and N-Boc-O-THP-hydroxylamine (eq 9)

34

have all proven to be useful for the synthesis of protected hy-
droxamic acids.

(8)

N O

R

NHOH

O

RCOCl

rt, hexane

air

hydrolysis

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

TMS

TMS

TMS

R

Cl

O

Boc

N

OTHP

O

R

(9)

Et

3

N, DMAP

Boc

N
H

OTHP

50–60%

+

R

NHOH

O

TFA

CH

2

Cl

2

MeCN, 0 °C

The reaction of succinic anhydride with hydroxylamine (pre-

pared from NaOMe and H

2

NOH·HCl in MeOH) leads to N-

hydroxysuccinimide.

35

Reaction with Aldehydes and Ketones: Oxime Formation.

Reaction of hydroxylamine with an aldehyde or ketone under

A list of General Abbreviations appears on the front Endpapers

HYDROXYLAMINE

3

basic or acidic conditions leads to the formation of the corres-
ponding oxime. For example, the (E) and (Z) isomers of 4-
acetylpyridine oxime have been prepared via the reaction of 4-
acetylpyridine with HONH

2

·HCl (eq 10).

36

(10)

N

O

N

NOH

N

N

HO

+

NH

2

OH•HCl

aq. NaOH

81–88%

5:1

Other examples of this reaction include the preparation of the

oxime of methyl glyoxylate (eq 11)

23

and the oximes of some

difluoromethylene-containing chiral aldehydes (eq 12).

37

NH

2

OH•HCl

NaHCO

3

, H

2

O

O

CO

2

Me

H

HON

CO

2

Me

(11)

83%

NH

2

OH, AcOH

EtOH

R

O

OBn

R

NOH

OBn

R = Ph, 72%; Me, 77%

F

F

F

F

(12)

4Å sieves

Both hydrazones (eq 13)

38

and enol esters (eq 14)

39

are efficient

carbonyl surrogates in this transformation.

TMS

Br

N

N

Me

Me

TMS

NOH (13)

+

1. THF, 0 °C
2. NH

2

OH•HCl, py

20 °C

64%

–

O

NH

2

OH•HCl, py

25 °C

AcO

OAc

OAc

OAc

O

AcO

OAc

NOH

OAc

(14)

74%

A solid-phase reagent which binds carbonyl compounds as

their corresponding oximes has been developed and employed
in the isolation of steroidal ketones.

40

α

-Halo ketones produce α-

hydroxylamino oximes on treatment with hydroxylamine.

41

The

mechanism of this nucleophilic addition–dehydration 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 em-
ploy HONH

2

·HCl and either refluxing formic acid

43

or pyridine

with azeotropic removal of water with refluxing toluene (eq 15).

44

The former reaction has been used to convert a 4-formyl β-lactam
into its corresponding nitrile derivative.

45

1. HONH

2

•HCl

pyridine
2. PhMe, reflux

68%

NH

2

OH•HCl

HCO

2

H

reflux, 30 min

99%

CHO

CN

(15)

Two hydroxylamine-derived reagents, O-(2-aminobenzoyl)-

hydroxylamine

46

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 NH

4

Cl/Cu

0

/py/O

2

,

48

EtNO

2

/-

NaOAc/AcOH,

49

and N,N-dimethylhydrazine/MeOH/MMPP·

6H

2

O

50

(MMPP = magnesium monoperoxyphthalate).

Reaction with Phosphinylating Agents.

Both N- and O-

phosphinylated 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

TMSONH

2

followed by hydrolysis gives N-diphenylphosphinyl-

hydroxylamine (eq 16).

51

O

P

Ph

Ph

Cl

(16)

O

P

Ph

Ph

NHOH

O

P

Ph

Ph

ONH

2

1. NH

2

OTMS

2. MeOH

NH

2

OH

Reaction with Miscellaneous Electrophiles.

Hydroxylamine

reacts with nitriles to yield amide oximes (eq 17).

52,53

The reac-

tion of hydroxylamine with uracil and cytosine has been applied
in the Chemical Cleavage of Mismatch (CCM) technique for
identifying DNA mutants.

54

(17)

Ph

N
H

EtO

2

C

O

CN

Ph

N
H

EtO

2

C

O

NOH

NH

2

NH

2

OH•HCl

Preparation of Isoxazoles and Isoxazolines.

Isoxazoles are

conveniently prepared via the reaction of HONH

2

·HCl with 1,3-

dicarbonyl 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

SR

2

SR

2

R

1

N O

R

1

SR

2

NH

2

OH•HCl

NaOMe, MeOH

reflux, 10–15 h

58–78%

(18)

O

SR

2

SR

2

R

1

N O

R

2

S

R

1

(19)

NH

2

OH•HCl, AcOH

NaOAc, EtOH, PhH

reflux, 8–10 h

51–68%

In like fashion, reaction conditions are important in the prepa-

ration of 3-amino-5-t-butylisoxazole from 4,4-dimethyl-3-oxo-
pentanenitrile (eqs 20 and 21).

57

O

CN

t

-Bu

N

O

t

-Bu

NH

2

(20)

1. NH

2

OH•1/2H

2

SO

4

NaOH (aq)
100 °C, 30 min

2. 36% HCl (aq)
100 °C, 1 h
86%

O

CN

t

-Bu

N

O

H

2

N

(21)

NH

2

OH•1/2H

2

SO

4

NaOH (aq)

100 °C, 2.5 h

t

-Bu

98%

Avoid Skin Contact with All Reagents

4

HYDROXYLAMINE

Functionalized 4,5-dihydroisoxazoles

58

have been prepared by

the reaction of α,β-epoxy ketones with HONH

2

·HCl (eq 22)

59

and also by the cycloaddition reaction between styrene and aryl
nitrile oxides prepared in situ from trichloromethylarenes and
hydroxylamine.

60

R

1

R

2

O

O

O N

OH

R

2

R

1

R

1

= Ph, cyclopropane derivs.; R

2

= Ph; 55–84%

NH

2

OH•HCl

py, EtOH

(22)

reflux, 5 h

Preparation of Substituted Pyridines.

Two novel approaches

to the synthesis of substituted pyridines have appeared. Treatment
of dihydropyran acetals

61

with HONH

2

·HCl (eq 23) or bicyclic

acetals

62

with HONH

2

·HCl and Aluminum Chloride (eq 24) leads

to good yields of pyridines. The first process appears to be the
more general of the two, though it is limited somewhat by the
availability of starting materials.

R

1

Ph
Ph
2-furyl

R

3

H
H
H

Yield

81%
40%
95%

NH

2

OH•HCl

EtOH

O

R

2

R

1

N

R

1

R

3

R

2

R

4

= Me, Et

R

3

OR

4

(23)

R

2

Ph

Cy

Ph

reflux, 10 h

O

O

N

R

NH

2

OH•HCl

AlCl

3

, AcOH

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

R

(24)

∆, 20 h

Aromatic Substitution Reactions.

In certain cases, hydroxyl-

amine can act as a nucleophile in aromatic substitution reactions.
This has shown to be the case in the reactions with 6-nitro-
quinoxalines (eq 25)

63

and N,N-dimethyl-2,4-bis(trifluoroacetyl)-

1-naphthylamine (eq 26).

64

Other examples are known.

65

N

N

X

O

2

N

N

N

X

O

2

N

NH

2

(25)

NH

2

OH, KOH
EtOH

X = Br, Cl

50%

NMe

2

COCF

3

COCF

3

COCF

3

(26)

O

N

CF

3

NH

2

OH•HCl

Et

3

N, MeCN

reflux, 5 h

94%

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

(27)

OH

OH

NH

2

OH, EtOAc, DMF

90–100 °C, 1 h

96%

Use in Peptide Chemistry.

Hydroxylamine has been used as

a reagent to cleave the acetoacetyl amino acid protecting group

69

and has also been employed to cleave the asparaginyl–glycyl
peptide bond.

70

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 N-
and/or O-substituted products. The chemoselectivity seems to be
dependent on the pK

a

of the reaction media according to a calcu-

lation study.

10

The HOMO population of “NH

2

OH” is mainly

located on the N atom, whereas that of anionic “NH

2

O

−

” is

located on the O atom.

10

Free hydroxylamine usually attacks alkyl halides and methane-

sulfonates at the N atom. The reaction is often used for the cons-
truction of N-fused rings such as aziridines,

71

pyrrolydines,

72

and

azepines.

73

Reaction with Michael Acceptors.

Substituted hydroxyl-

amines such as N-substituted,

74

O

-substituted,

75

–

77

and N,O-di-

substituted

78

hydroxylamines are widely used for reaction with

Michael acceptors. Lewis acid-catalyzed asymmetric conjugate
additions of O-alkoxylamine,

77

enabling the resulting β-alkoxyl-

aminoketones to be transformed into chiral aziridines by ba-
sic treatment.

77d,e

Conjugate additions of N-protected hydroxyl-

amines with α,β-unsaturated esters afford isoxazolidin-5-ones
with high diastereoselectivity.

74

The mechanism for the conjugate

addition of N-methylhydroxylamine is considered to proceed via
five-membered ring transition state (eq 28).

79

Ph

O

OEt

MeNHOH

Ph

O

O

MeN

NH

2

OMe

H

O

N

H

Ph

CO

2

Et

H

Me

H

Ph

O

OEt

MeHN

+

O

No

reaction

(28)

−

Reaction with Acid Derivatives: Preparation of Hydrox-

amic Acids.

Reaction of hydroxylamine with esters or acid

halides generally affords N-acylhydroxylamines (hydroxamic
acids) rather than O-acylhydroxylamines.

80

Recent exam-

ples of N-acylating reagents for hydroxylamine include acid

A list of General Abbreviations appears on the front Endpapers

HYDROXYLAMINE

5

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 pres-
ence of K

2

CO

3

or CuSO

4

affords E- or Z-aldoximes, respec-

tively, in high chemoselectivity and high chemical yield (eq 29).

85

Aromatic E-ketoximes are prepared from aromatic ketones us-
ing K

2

CO

3

catalyst in high selectivity (eq 30). In contrast,

application of CuSO

4

catalyst for ketoxime synthesis is unsuc-

cessful. Ketoximes are also prepared in ionic liquid.

86

CHO

E

90%

N

HO

H

Z

H

N

OH

90%

90

°C, 60 min

90

°C, 60 min

(29)

K

2

CO

3

CuSO

4

K

2

CO

3

N

Me

O

85%

No Reaction

N

N

HO

Me

Z

(30)

90

°C, 60 min

90

°C, 360 min

CuSO

4

Reaction with Aldehydes: Nitrile Formation.

One-pot

syntheses of aliphatic and aromatic nitriles from the oximes
of aldehydes include dehydration by refluxing in N-methyl-
pyrrolidone,

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 peroxymono-
sulfate/alumina,

92

N

-methylpyrrolidone,

93

sodium hydrogen sul-

fate/silica gel,

94

ammonium acetate,

95

HY-zeolite,

96

or silica

chloride

97

is accelerated by microwave irradiation. Transition

metal catalyst, [RuCl

2

(p-cymene)]

2

,

98

smoothly catalyzes the ni-

trile formation from aldoximes, which are readily prepared form
aldehydes and hydroxylamine hydrochloride.

Reaction with Aldehydes and Ketones: Beckmann Rear-

rangement for Amide Synthesis.

Various conditions have been

reported for the one-pot Beckmann rearrangement, where alde-

hydes and ketones are converted to the corresponding amides.
Although aldehydes can afford either nitriles or amides, opti-
mization enables selective formation of either functionality. For
example, benzaldehyde and hydroxylamine hydrochloride with
dry-Al

2

O

3

/CH

3

SO

2

Cl affords benzonitrile in high yield; alterna-

tively, the wet catalyst affords benzamide in high yield (eq 31).

99

Zinc oxide,

100

titanium oxide,

101

or oxalic acid

102

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

Al

2

O

3

/CH

3

SO

3

H,

103

and P

2

O

5

/-

SiO

2

,

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.

CHO

CN

NH

2

O

90%

90%

dry-Al

2

O

3

MeSO

2

Cl

NH

2

OH·HCl

wet-Al

2

O

3

MeSO

2

Cl

NH

2

OH·HCl

(31)

100

°C, 25 min

100

°C, 90 min

Reaction with Miscellaneous Electrophiles.

N

-BOC-pro-

tected hydroxylamine is easily oxidized to generate a t-butyl
nitrosoformate, which reacts with olefins and dienes to give the
allylamines (ene-reaction) (eq 32)

105

and 1H,4H-dihydro-1,2-

oxazines (hetero-Diels-Alder reaction) (eq 33),

106

respectively.

HN

HO

O

O

aq H

2

O

2

, CuCl cat

ClCH

2

CH

2

Cl/CH

3

CN

N

OH

O

O

70%

+

(32)

HN

HO

O

O

aq H

2

O

2

, CuCl cat

ClCH

2

CH

2

Cl/CH

3

CN

O

N

O

O

quant.

+

(33)

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 α-bromo enones is possible.

108

Avoid Skin Contact with All Reagents

6

HYDROXYLAMINE

Preparation of Substituted Pyridines.

Substituted pyridines

are prepared from hydroxylamine and 1,5-dioxopentane deriva-
tives including dihydropyran acetals.

109

Substituted pyridines are

obtained by refluxing dihydropyran acetals with hydroxylamine
hydrochloride in acetonitrile.

110

Unsymmetrical 1,5-dioxopen-

tanes, prepared by the ozonolysis of cyclopentene derivatives, are
converted to the substituted pyridines by reaction with hydroxyl-
amine hydrochloride at reflux.

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

TBDMSO

CO

2

Et

O

H

NH

2

OH·HCl

TBDMSO

CO

2

Et

N

53%

then, AcCl/pyridine

(34)

N

Et

MeO

1. LDA, THF,
N

,N-dimethylacetamide

2. NH

2

OH·HCl, AcONa

o

-dichlorobenzene

N

N

Me

MeO

Et

60%

(35)

N

O

H

1. NH

2

OH·HCl

KOAc, MeOH

2. toluene, 110

°C

N

N

60%

(36)

Nucleophilic Aromatic Substitution.

As expected, aromatic

substitution with hydroxylamine is limited to electron-deficient
aromatic rings. Treatment of 2,4-dinitromethoxybenzene with
hydroxylamine hydrochloride, provides N-(2,4-dinitrophenyl)-
hydroxylamine in 91% yield (eq 37).

115

OMe

NO

2

O

2

N

NHOH

NO

2

O

2

N

NH

2

OH·HCl

Na, MeOH, 0

°C

then, rt 19 h

91%

(37)

1.

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.

2.

Gross, P., CRC Crit. Rev. Toxicol. 1985, 14, 87.

3.

Hurd, C., Inorg. Synth., 1939, 1, 87.

4.

Klotzer, W.; Stadlwieser, J.; Raneburger, J., Org. Synth., Coll. Vol.,
1990

, 7, 8.

5.

Fioshin, M. Ya.; Avrutskaya, I. A.; Surov, I. I.; Novikov, V. T., Collect.
Czech. Chem. Commun. 1987

, 52, 182.

6.

Chem Sources 1993

; Chemical Sources International; Fernandina

Beach, FL, 1993.

7.

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. Bretherick’s 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. Sax’s Dangerous
Properties of Industrial Materials

, 8th ed.; Van Nostrand Reinhold:

New York, 1992; p 1936.

8.

March, J. Advanced Organic Chemistry; Wiley: New York, 1992.

9.

Lee, B. H.; Miller, M. J., J. Org. Chem. 1983, 48, 24.

10.

Kashima, C.; Yoshiwara, N.; Omote, Y., Tetrahedron Lett. 1982, 23,
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11.

Sulsky, R.; Demers, J. P., Tetrahedron Lett. 1989, 30, 31.

12.

Doleschall, G., Tetrahedron Lett. 1987, 28, 2993.

13.

(a) Stewart, A. O.; Martin, J. G., J. Org. Chem. 1989, 54, 1221. (b) For
a similar reaction with HONH

2

·HCl see: Lamanec, T. R.; Bender, D.

R.; DeMarco, A. M.; Karady, S.; Reamer, R. A.; Weinstock, L. M., J.
Org. Chem. 1988

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14.

Genet, J.-P.; Thorimbert, S.; Touzin, A. M., Tetrahedron Lett. 1993, 34,
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15.

Murahashi, S.-I.; Imada, Y.; Taniguchi, Y.; Kodera, Y., Tetrahedron
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16.

Goel, O. P.; Krolls, U., Org. Prep. Proced. Int. 1987, 19, 75.

17.

Bottaro, J. C.; Bedford, C. D.; Dodge, A., Synth. Commun. 1985, 15,
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18.

Ando, W.; Tsumaki, H., Synth. Commun. 1983, 13, 1053.

19.

West, R.; Boudjouk, P., J. Am. Chem. Soc. 1973, 95, 3987.

20.

King, F. D.; Walton, D. R. M., Synthesis 1975, 788.

21.

For an excellent review of the preparation and reactions of these
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1986

, 86, 697.

22.

Shin, C.-g.; Nanjo, K.; Ando, E.; Yoshimura, J., Bull. Chem. Soc. Jpn.
1974

, 47, 3109.

A list of General Abbreviations appears on the front Endpapers

HYDROXYLAMINE

7

23.

Huang, N. Z.; Miller, M. J.; Fowler, F. W., Heterocycles 1988, 27,
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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
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26.

Feenstra, R. W.; Stokkingreef, E. H. M.; Nivard, R. J. F.; Ottenheijm,
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27.

Steiger, R. E., Org. Synth., Coll. Vol. 1963, 3, 91.

28.

Basheeruddin, K.; Siddiqui, A. A.; Khan, N. H.; Saleha, S., Synth.
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29.

Rozantzev, E. G.; Neiman, M. B., Tetrahedron 1964, 20, 131.

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31.

Brown, D.; Ismail, S., lnorg. Chim. Acta 1990, 171, 41.

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Lee, B. H.; Miller, M. J., J. Org. Chem. 1983, 48, 24.

33.

Ando, W.; Tsumaki, H., Synth. Commun. 1983, 13, 1053.

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Altenburger, J. M.; Mioskowski, C.; d’Orchymont, H.; Schirlin, D.;
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Wang, K.-T.; Brattesani, D. N.; Weinstein, B., J. Heterocycl. Chem.
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36.

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38.

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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

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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.
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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.,
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51.

(a) Harger, M. J. P., J. Chem. Soc., Perkin Trans. 1 1983, 2699.
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52.

Piskunova, I. P.; Eremeev, A. V.; Mishnev, A. F.; Vosekalna, I. A.,
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, 49, 4671.

53.

Showell, G. A.; Gibbons, T. L.; Kneen, C. O.; MacLeod, A. M.;
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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.
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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.;
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483. (b) Curzu, M. M.; Pinna, G. A.; Cignarella, G.; Barlocco, D.;
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59.

Ito, S.; Sato, M., Bull. Chem. Soc. Jpn. 1990, 63, 2739.

60.

Brokhovetskii, D. B.; Belen’kii, L. I.; Krayushkin, M. M., Izv. Akad.
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61.

Ciufolini, M. A.; Byrne, N. E., J. Chem. Soc., Chem. Commun. 1988,
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62.

Jun, J.-G.; Shin, H. S.; Kim, S. H., J. Chem. Soc., Perkin Trans. 1 1993,
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63.

Nasielski-Hinkens, R.; Kotel, J.; Lecloux, T.; Nasielski, J., Synth.
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, 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.; D’Angeli, F., J. Chem. Soc. (C)
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70.

Bornstein, P.; Balian, G., Methods Enzymol. 1977, 47, 132.

71.

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72.

(a) Yu, J.; DePue, J.; Kronenthal, D., Tetrahedron Lett. 2004, 45, 7247.
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73.

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74.

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75.

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76.

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79.

Niu, D.; Zhao, K., J. Am. Chem. Soc. 1999, 121, 2456.

80.

Geffken, D., Chem. Ber. 1986, 119, 744.

81.

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82.

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Sharghi, H.; Hosseini Sarvari, M., Synlett 2001, 99.

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87.

Sampath Kumar, H. M.; Subba Reddy, B. V.; Tirupathi Reddy, P.; Yadav,
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89.

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90.

Ballini, R.; Fiorini, D.; Palmieri, A., Synlett 2003, 1841.

91.

Sharghi, H.; Hosseini Sarvari, M., Synthesis 2003, 243.

92.

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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.

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97.

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98.

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Avoid Skin Contact with All Reagents

8

HYDROXYLAMINE

99.

Sharghi, H.; Hosseini Sarvari, M., Tetrahedron 2002, 58, 10323.

100.

Sharghi, H.; Hosseini Sarvari, M., Synthesis 2002, 1057.

101.

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102.

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106.

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107.

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109.

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110.

(a) Bennabi, S.; Narkunan, K.; Rousset, L.; Bouchu, D.; Ciufolini, M.
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111.

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112.

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113.

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114.

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115.

Singh, S.; Nicholas, K. M., Synth. Commun. 2001, 31, 3087.

A list of General Abbreviations appears on the front Endpapers