HYDROXYLAMINE 1
explosive bis(hydroxylamide). In the event of a spill, cover with
Hydroxylamine1
sodium bisulfite and sprinkle with water. HONH2·HCl: harmful
if inhaled or swallowed (oral LD50 400 420 mg kg-1; mouse).
HONH2
Not compatible with oxidizing agents. May explode if heated
ć% ć%
above 115 C; do not store above 65 C. A comprehensive
(HONH2) review of the biological activity of hydroxylamine and its salts
[7803-49-8] H3NO (MW 33.04) has appeared.2
InChI = 1/H3NO/c1-2/h2H,1H2
InChIKey = AVXURJPOCDRRFD-UHFFFAOYAD
(HONH2·HCl)
Original Commentary
[5470-11-1] ClH4NO (MW 69.50)
InChI = 1/ClH.H3NO/c;1-2/h1H;2H,1H2
Michael A. Walters & Andrew B. Hoem
InChIKey = WTDHULULXKLSOZ-UHFFFAOYAT
Dartmouth College, Hanover, NH, USA
((HONH2)3·H3PO4)
[20845-01-6] H12N3O7P (MW 197.12)
Introduction. Hydroxylamine, usually as one of its more sta-
InChI = 1/3H3NO.H3O4P/c3*1-2;1-5(2,3)4/h3*2H,1H2;(H3,1,
ble salts, has been used as a nucleophile in a wide variety of
2,3,4)/f/h;;;1-3H
reactions and only the most common uses of this versatile reagent
InChIKey = XBUFCZMOAHHGMX-CWCSVAMXCQ
are described here. The name  hydroxylamine is used throughout
((HONH2)2·H2SO4)
this review as a interchangable designator for either the free base
[10039-54-0] H8N2O6S (MW 164.17)
or one of its salts. Where appropriate, the specific derivative will
InChI = 1/2H3NO.H2O4S/c2*1-2;1-5(2,3)4/h2*2H,1H2;(H2,1, be named.
2,3,4)/f/h;;1-2H
InChIKey = VRXOQUOGDYKXFA-IPLSSONACA General Reactivity with Simple Electrophiles. Hydroxyl-
amine and its derivatives undergo reaction with many simple
(nucleophile in aromatic substitution,63 oxime-,36 hydroxamic
electrophiles such as alkylating, acylating, phosphinylating, and
acid-,30 pyridine-61 and isoxazole-forming56 reactions; reducing
silylating agents, aldehydes and ketones, and Michael acceptors.
agent;66 in combination with dehydrating agents, used for the
The potent nucleophilic reactivity of hydroxylamine evident in
conversion of aldehydes to nitriles43)
these transformations is thought to arise as a consequence of
what has been labeled the Ä…-effect, an effect observed in a vari-
Physical Data: HONH2: hydroscopic white needles or flakes;
ć% ć%
ety of nucleophiles which possess a heteroatom in the position
decomposes rapidly at rt; mp 32.05 C; bp 56.5 C/22 mmHg,
ć% ć%
Ä… to the attacking nucleophilic atom.8 Hydroxylamine reacts
70 C/60 mmHg, 110 C/760 mmHg. HONH2·HCl: white
ć%
crystals; mp 151 C; d 1.67 g cm-3; pKa1 5.97; pKa2 13.7.10 with simple electrophiles typically at both nitrogen and oxygen,
ć%
with multiple reactions often giving rise to undesired side-
(HONH2)3·H3PO4: mp 169 171 C. (HONH2)2·H2SO4: mp
ć%
products. Many derivatives of hydroxylamine have been prepared
170 C (dec).
in an effort to circumvent this potential problem of ambident
Solubility: HONH2: decomposes in hot water; sol cold water,
reactivity (see below).9
methanol; sparingly sol ether, benzene, chloroform, carbon
disulfide.2 HONH2·HCl: 83 g/100 mL in cold water; very sol
Reactions with Alkylating Agents: N vs. O Selectivity. The
hot water; 4.43 g/100 mL in EtOH; 16.4 g/100 mL in MeOH;
products obtained in the reaction of simple alkylating agents with
insol ether.
hydroxylamine are exemplary of the ambident reactivity discussed
Form Supplied in: hydroxylamine hydrochloride is widely
above. In a study directed toward the preparation of O-alkylated
available and is the most commonly used hydroxylamine salt.
hydroxylamines, it was found that several benzylic and one alkyl
Each of the other salts listed above is also commercially
halide react preferentially at oxygen in t-butoxide/t-butanol solu-
available, as are HONH2·HCl-d4 and HONH2·HCl-15N.6
tion (eq 1).10 Results similar to those obtained with benzyl bro-
Preparative Methods: hydroxylamine base has been prepared
mide were found for five other benzylic halides.
by the action of sodium butoxide on the hydrochloride in
ć%
butanol.3 The free base can be isolated as a white solid at -30 C
R X + NH2O R ONH2 + R NHOH + R2NOH (1)
ć%
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 RX Yield (%) Product distribution
the salts by treatment with hydroxide, alkoxide, carbonate, or
52 66:22:12
PhCH2Br
amine base (see below). The preparation of hydroxylamine via
30 79:21: 
1-Bromo-2-ethylhexane
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 Selective N-alkylation has been accomplished in a wide variety
in the literature indicate that the free base is a much more of cases using the hydroxylamine derivative t-butyl N-benzyloxy-
hazardous substance to work with than are the salts.7 HONH2: carbamate.11 The preparation of N-octylhydroxylamine·HCl is
a moderately toxic, corrosive irritant to the eye, skin, and mu- illustrative of this process (eq 2). Ethyl 3-methylhydroxy-4-isoxa-
ć%
cous membranes. Explodes at 130 C. Explodes in air when zolecarboxylate12 is another versatile reagent which has been
ć%
heated above 70 C. May ignite spontaneously in air, or in con- developed for this purpose. O-Trimethylsilyl- and O-(t-butyldi-
tact with PCl3 or PCl5. Calcium reacts to give the heat-sensitive phenylsilyl)hydroxylamine13 have also seen use in the preparation
Avoid Skin Contact with All Reagents
2 HYDROXYLAMINE
of N-alkylhydroxylamine derivatives, although these reagents duction of the hydroxyamine is effected with a second equiv of
have not been shown to be as generally useful in this regard as the HONH2·HCl (eq 5).27 In a more comprehensive investigation of
previously mentioned two. N-Allylation has recently been accom- this reaction, it was found that catalytic reduction of the interme-
plished via the Pd0-mediated reaction of N,O-bis(Boc)hydroxyl- diate hydroxylamine leads to better yields (70% in the case shown
amine with allylic carbonates, chlorides, and acetates.14 A similar in eq 5) of the amino acid.28
study showed that the use of HONH2·HCl in the same reac-
NH2OH" HCl
tion leads to N,N-diallylated products.15 N,O-Dimethylhydroxyl-
NaOEt
NH2
amine·HCl has been prepared on a large scale by dimethyla- H2O, EtOH
CO2H
CO2H (5)
Ph
tion (Dimethyl Sulfate) of ethyl hydroxycarbamate at pH 11 12
Ph
34%
followed by acidolysis.16
Tandem Michael additions are also known, the reaction of
1. NaH, DMF
R
H
2. RX
1. hydrogenolysis
phorone with hydroxylamine giving a highly congested, cyclic
t-BuO N t-BuO N
OBn OBn
hydroxylamine derivative (eq 6).29
2. acidolysis
61 99%
O O
O
RNHOH" HCl (2)
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 hy-
Reaction with Acid Derivatives: Preparation of Hydrox-
droxylamine reagents is their solubility in nonpolar solvents in
amic Acids. Hydroxylamine and its derivatives have been re-
which hydroxylamine and its salts show poor solubility. N,O-
acted with esters and acid halides to prepare hydroxamic acids.
Bis(trimethylsilyl)hydroxylamine undergoes facile O,N-silyl
The reaction of HONH2·HCl with esters is particularly use-
transfer upon treatment with Butyllithium in ether, allowing the
ful along these lines because overacylation is not a problem
generation the lithium salt of N,N-bis(trimethylsilyl)hydroxyl-
(eq 7).30,31
amine in situ.19 This species plays an important role in the prepara-
tion of O-arenesulfonyl- and O-arenecarbonylhydroxylamines.20 NH2OH" HCl
O
O
AcOH
KOH
Ph OEt
Ph NHO K+
Ä… Ä…
Reactions withÄ… orÄ… Esters: Preparation
Ä…-Halo Ä…-Hydroxy
or dry HCl (g)
MeOH
Ä…
of N-Hydroxy-Ä… Acids. Hydroxylamine and its deriva-
Ä…-amino
O
tives have been reacted with both Ä…-halo and Ä…-hydroxy esters
(7)
Ph NHOH
as a method to prepare N-hydroxy-Ä…-amino acid derivatives.21
Reaction of hydroxylamine with acid halides can result in the
While hydroxylamine has seen some utility along these lines
formation of di- and triacylated products in addition to the de-
with t-butyl esters (eqs 3 and 4),22,23 the use of derivatives such
sired hydroxamic acid. As is the case with alkylation, several
as N-[(trichloroethoxy)carbonyl]-O-benzylhydroxylamine24 and
hydroxylamine derivatives have been developed to address this
O-Benzylhydroxylamine Hydrochloride25 appear to offer some
problem. O-benzyl-,32 N,N,O-tris(trimethylsilyl)- (eq 8),33 N-
advantages. The latter reagent has been used in the displacement
Boc-O-TBDMS-, and N-Boc-O-THP-hydroxylamine (eq 9)34
of the triflates of (R)- or (S)-Ä…-hydroxy esters, leading to N-
have all proven to be useful for the synthesis of protected hy-
hydroxy-Ä…-amino methyl esters with both excellent chemical yield
droxamic acids.
and optical purity.26
O
NH2OH TMS TMS
air
CO2-t-Bu CO2-t-Bu RCOCl
R R (3)
(8)
N O
MeOH, reflux
R NHOH
hydrolysis
rt, hexane
Br NHOH
TMS
R = Me, 85%; Et, 92%; Ph, 95%
R = H, 98%; Me, 97%; Et, 97%
Br SMe Boc OTHP
O
NH2OH Et3N, DMAP
N TFA
Boc OTHP
+
N
MeOH, reflux MeCN, 0 °C CH2Cl2
R Cl
H
O O-t-Bu O R
H
O
N SMe MeS NHOH
(9)
HO
R NHOH
(4)
+
O O-t-Bu O O-t-Bu 50 60%
50% 11%
The reaction of succinic anhydride with hydroxylamine (pre-
pared from NaOMe and H2NOH·HCl in MeOH) leads to N-
Reactions with Michael Acceptors. The reaction of hydroxy- hydroxysuccinimide.35
lamine hydrochloride with Michael acceptors offers a convenient
synthesis of ²-amino acids and esters. The preparation of (Ä…)- Reaction with Aldehydes and Ketones: Oxime Formation.
²-aminophenylpropionic acid has been reported wherein the re- 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- Two hydroxylamine-derived reagents, O-(2-aminobenzoyl)-
ponding oxime. For example, the (E) and (Z) isomers of 4- hydroxylamine46 and Hydroxylamine-O-sulfonic Acid,47 have
acetylpyridine oxime have been prepared via the reaction of 4- also been used to effect this transformation, although in a more
acetylpyridine with HONH2·HCl (eq 10).36 limited number of cases. Several methods exist which do not
rely on hydroxylamine, including NH4Cl/Cu0/py/O2,48 EtNO2/-
HO
NH2OH" HCl
NaOAc/AcOH,49 and N,N-dimethylhydrazine/MeOH/MMPP·
O NOH N
aq. NaOH
6H2O50 (MMPP = magnesium monoperoxyphthalate).
N N + N (10)
81 88%
5:1
Reaction with Phosphinylating Agents. Both N- and O-
phosphinylated hydroxylamine are available via reaction of the
Other examples of this reaction include the preparation of the
appropriate hydroxylamine derivative with diphenylphosphinyl
oxime of methyl glyoxylate (eq 11)23 and the oximes of some
chloride. Use of hydroxylamine base results in the formation of
difluoromethylene-containing chiral aldehydes (eq 12).37
O-(Diphenylphosphinyl)hydroxylamine,4 while employment of
TMSONH2 followed by hydrolysis gives N-diphenylphosphinyl-
NH2OH" HCl
O
NaHCO3, H2O
hydroxylamine (eq 16).51
HON
CO2Me
(11)
83%
H CO2Me
O O
O
1. NH2OTMS
NH2OH
Ph Ph
Ph
P ONH2 P Cl
P NHOH
NH2OH, AcOH
F F F F Ph Ph
Ph
2. MeOH
(16)
EtOH
(12)
R R
O NOH
4Å sieves
Reaction with Miscellaneous Electrophiles. Hydroxylamine
OBn OBn
reacts with nitriles to yield amide oximes (eq 17).52,53 The reac-
R = Ph, 72%; Me, 77%
tion of hydroxylamine with uracil and cytosine has been applied
in the Chemical Cleavage of Mismatch (CCM) technique for
Both hydrazones (eq 13)38 and enol esters (eq 14)39 are efficient
identifying DNA mutants.54
carbonyl surrogates in this transformation.
EtO2C O EtO2C O NH2
1. THF, 0 °C
NH2OH" HCl
2. NH2OH" HCl, py
CN (17)
Me
TMS
Ph N Ph N NOH
20 °C
+
N
H H
Br
 N Me
64%
TMS
NOH Preparation of Isoxazoles and Isoxazolines. Isoxazoles are
(13)
conveniently prepared via the reaction of HONH2·HCl with 1,3-
OAc OAc
dicarbonyl compounds or their equivalents.55 In some cases, the
NH2OH" HCl, py
regiochemistry of the reaction can be controlled. For example,
AcO AcO
O O
25 °C
OAc OAc
the regiochemistry of the reaction of hydroxylamine with
(14)
74%
acylketene dithioacetals depends on reaction conditions (eqs 18
OAc NOH
and 19).56
NH2OH" HCl
A solid-phase reagent which binds carbonyl compounds as
NaOMe, MeOH
O SR2
N O
their corresponding oximes has been developed and employed
reflux, 10 15 h
in the isolation of steroidal ketones.40 Ä…-Halo ketones produce Ä…-
SR2 (18)
R1
R1 SR2
58 78%
hydroxylamino oximes on treatment with hydroxylamine.41 The
mechanism of this nucleophilic addition dehydration process has
been studied by a number of groups.42
NH2OH" HCl, AcOH
O SR2 NaOAc, EtOH, PhH
N O
reflux, 8 10 h
Reaction with Aldehydes: Nitrile Formation. Nitriles can be
R1 (19)
R2S
R1 SR2
effectively prepared directly from aldehydes by a wide variety of
51 68%
methods involving hydroxylamine. Two convenient methods em-
In like fashion, reaction conditions are important in the prepa-
ploy HONH2·HCl and either refluxing formic acid43 or pyridine
with azeotropic removal of water with refluxing toluene (eq 15).44 ration of 3-amino-5-t-butylisoxazole from 4,4-dimethyl-3-oxo-
pentanenitrile (eqs 20 and 21).57
The former reaction has been used to convert a 4-formyl ²-lactam
into its corresponding nitrile derivative.45
1. NH2OH" 1/2H2SO4
NH2
NaOH (aq)
O
NH2OH" HCl
100 °C, 30 min
HCO2H
(20)
CN N
t-Bu
reflux, 30 min t-Bu
O
2. 36% HCl (aq)
100 °C, 1 h
99%
86%
CHO CN
(15)
1. HONH2" HCl
NH2OH" 1/2H2SO4
t-Bu
pyridine
NaOH (aq)
O
2. PhMe, reflux
100 °C, 2.5 h
(21)
CN N
H2N
98%
t-Bu
68% O
Avoid Skin Contact with All Reagents
4 HYDROXYLAMINE
NH2OH, EtOAc, DMF
Functionalized 4,5-dihydroisoxazoles58 have been prepared by
90 100 °C, 1 h
the reaction of Ä…,²-epoxy ketones with HONH2·HCl (eq 22)59
OH
96%
and also by the cycloaddition reaction between styrene and aryl
nitrile oxides prepared in situ from trichloromethylarenes and
(27)
OH
hydroxylamine.60
OH
NH2OH" HCl
O
Use in Peptide Chemistry. Hydroxylamine has been used as
R1 R2 py, EtOH
R1 R2
(22)
a reagent to cleave the acetoacetyl amino acid protecting group69
reflux, 5 h
O O N
and has also been employed to cleave the asparaginyl glycyl
peptide bond.70
R1 = Ph, cyclopropane derivs.; R2 = Ph; 55 84%
Preparation of Substituted Pyridines. Two novel approaches
to the synthesis of substituted pyridines have appeared. Treatment
First Update
of dihydropyran acetals61 with HONH2·HCl (eq 23) or bicyclic
acetals62 with HONH2·HCl and Aluminum Chloride (eq 24) leads
Masakatsu Shibasaki & Noriyuki Yamagiwa
to good yields of pyridines. The first process appears to be the
The University of Tokyo, Tokyo, Japan
more general of the two, though it is limited somewhat by the
availability of starting materials.
Reactivity with Alkylating Agents. Hydroxylamine, which
has ambident reactivity, can react with nucleophiles to afford N-
OR4 NH2OH" HCl R1 N R3
R1 O and/or O-substituted products. The chemoselectivity seems to be
R3 EtOH
(23) dependent on the pKa of the reaction media according to a calcu-
reflux, 10 h
lation study.10 The HOMO population of  NH2OH is mainly
R2 R2 located on the N atom, whereas that of anionic  NH2O- is
located on the O atom.10
R1 R2 R3 Yield
Free hydroxylamine usually attacks alkyl halides and methane-
R4 = Me, Et Ph Ph H sulfonates at the N atom. The reaction is often used for the cons-
81%
Ph Cy H
40%
truction of N-fused rings such as aziridines,71 pyrrolydines,72 and
2-furyl Ph H
95%
azepines.73
NH2OH" HCl
AlCl3, AcOH
Reaction with Michael Acceptors. Substituted hydroxyl-
R
(24)
O ", 20 h N amines such as N-substituted,74 O-substituted,75 77 and N,O-di-
O R
substituted78 hydroxylamines are widely used for reaction with
R =Me, 83%; Et, 99%; Pr, 84% Michael acceptors. Lewis acid-catalyzed asymmetric conjugate
additions of O-alkoxylamine,77 enabling the resulting ²-alkoxyl-
aminoketones to be transformed into chiral aziridines by ba-
Aromatic Substitution Reactions. In certain cases, hydroxyl- sic treatment.77d,e Conjugate additions of N-protected hydroxyl-
amine can act as a nucleophile in aromatic substitution reactions.
amines with Ä…,²-unsaturated esters afford isoxazolidin-5-ones
This has shown to be the case in the reactions with 6-nitro- with high diastereoselectivity.74 The mechanism for the conjugate
quinoxalines (eq 25)63 and N,N-dimethyl-2,4-bis(trifluoroacetyl)- addition of N-methylhydroxylamine is considered to proceed via
1-naphthylamine (eq 26).64 Other examples are known.65
five-membered ring transition state (eq 28).79
NH2OH, KOH
X N
X N
EtOH
H
(25) Ph O
O
50%
Me
O2N N N H
O2N N
MeNHOH
Ph H
MeHN+ OEt
NH2
O-
X = Br, Cl
H CO2Et
O
NMe2 NH2OH" HCl
N
Ph O
COCF3 Et3N, MeCN
CF3
reflux, 5 h
OEt
(28)
(26)
94%
Ph O
NH2OMe
COCF3 COCF3
No reaction
MeN O
Use as a Reducing Agent. The combination of hydroxylamine
and ethyl acetate in DMF represents a useful in situ preparation of Reaction with Acid Derivatives: Preparation of Hydrox-
Diimide and this procedure has been reported to reduce a variety amic Acids. Reaction of hydroxylamine with esters or acid
of unsaturated compounds (eq 27).66,67 Diimide formation from halides generally affords N-acylhydroxylamines (hydroxamic
hydroxylamine has been used to explain the reductive cyclization acids) rather than O-acylhydroxylamines.80 Recent exam-
of some o-nitroazobenzenes.68 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 hydes and ketones are converted to the corresponding amides.
acids,82 and acylbenzotriazoles.83 Alternatively, hydroxylamine Although aldehydes can afford either nitriles or amides, opti-
directly reacts with carboxylic acids to generate hydroxamic acids mization enables selective formation of either functionality. For
in the presence of an activating agent such as 2,4,6-trichloro- example, benzaldehyde and hydroxylamine hydrochloride with
[1,3,5]triazine.84 dry-Al2O3/CH3SO2Cl affords benzonitrile in high yield; alterna-
tively, the wet catalyst affords benzamide in high yield (eq 31).99
Reaction with Aldehydes and Ketones: Oxime Formation. Zinc oxide,100 titanium oxide,101 or oxalic acid102 is also effective
Selective synthesis of either E- or Z-aldoximes is possible with at transforming aldehydes to amides in high chemical yield.
aromatic aldehydes. Hydroxylamine hydrochloride in the pres- Ketoximes are converted to amides in the presence of sodium
ence of K2CO3 or CuSO4 affords E- or Z-aldoximes, respec- hydrogen sulfate/silica gel,94 HY-zeolite,96 silica chloride,97 zinc
tively, in high chemoselectivity and high chemical yield (eq 29).85 oxide,100 titanium oxide,101 Al2O3/CH3SO3H,103 and P2O5/-
Aromatic E-ketoximes are prepared from aromatic ketones us- SiO2,104 For ketones, the regioselectivity of rearrangement is
ing K2CO3 catalyst in high selectivity (eq 30). In contrast, often problematic. In general, oximination of unsymmetrical
application of CuSO4 catalyst for ketoxime synthesis is unsuc- ketones affords E- and Z-oximes with low regioselectivity, thereby
cessful. Ketoximes are also prepared in ionic liquid.86 ultimately affording a mixture of two different amides.
HO dry-Al2O3
N
MeSO2Cl
CN
NH2OH·HCl
K2CO3
H
100 °C, 25 min
90 °C, 60 min
90%
Z
CHO 90%
CHO
(29)
(31)
OH
N
wet-Al2O3
O
CuSO4
MeSO2Cl
H
NH2OH·HCl
90 °C, 60 min
NH2
100 °C, 90 min
E
90%
90%
HO
N
Reaction with Miscellaneous Electrophiles. N-BOC-pro-
K2CO3
Me
tected hydroxylamine is easily oxidized to generate a t-butyl
90 °C, 60 min
N
nitrosoformate, which reacts with olefins and dienes to give the
O
allylamines (ene-reaction) (eq 32)105 and 1H,4H-dihydro-1,2-
Z
(30)
Me oxazines (hetero-Diels-Alder reaction) (eq 33),106 respectively.
85%
N
O
aq H2O2, CuCl cat
CuSO4
ClCH2CH2Cl/CH3CN
HN O
No Reaction
+
90 °C, 360 min
HO
OH
N O
(32)
Reaction with Aldehydes: Nitrile Formation. One-pot
O
syntheses of aliphatic and aromatic nitriles from the oximes
of aldehydes include dehydration by refluxing in N-methyl-
70%
pyrrolidone,87 triethylamine/phthalic anhydride,88 triphosgene,89
aq H2O2, CuCl cat
sodium iodide,90 and graphite/methanesulfonyl chloride.91 O
ClCH2CH2Cl/CH3CN
Microwave-assisted one-pot syntheses of nitriles are also
+
HN O
plentiful. Nitrile formation in the presence of peroxymono-
HO
O
sulfate/alumina,92 N-methylpyrrolidone,93 sodium hydrogen sul-
fate/silica gel,94 ammonium acetate,95 HY-zeolite,96 or silica
N O
(33)
chloride97 is accelerated by microwave irradiation. Transition
O
metal catalyst, [RuCl2(p-cymene)]2,98 smoothly catalyzes the ni-
quant.
trile formation from aldoximes, which are readily prepared form
aldehydes and hydroxylamine hydrochloride.
Preparation of Isoxazoles and Isoxazolines. Hydroxylamine
Reaction with Aldehydes and Ketones: Beckmann Rear- hydrochloride reacts with the internal and terminal alkynes to
rangement for Amide Synthesis. Various conditions have been afford isoxazoles in moderate yield.107 Regioselective synthesis
reported for the one-pot Beckmann rearrangement, where alde- of isoxazoles using Ä…-bromo enones is possible.108
Avoid Skin Contact with All Reagents
6 HYDROXYLAMINE
NH2OH·HCl
OMe
Preparation of Substituted Pyridines. Substituted pyridines
Na, MeOH, 0 °C
are prepared from hydroxylamine and 1,5-dioxopentane deriva-
then, rt 19 h
tives including dihydropyran acetals.109 Substituted pyridines are
O2N NO2
obtained by refluxing dihydropyran acetals with hydroxylamine
(37)
NHOH
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- O2N NO2
amine hydrochloride at reflux.111 A wide variety of unsaturated
91%
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. 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
H
1991, 6, 103. (c) Roberts, J. S. In Comprehensive Organic Chemistry;
Barton, D. H. R., Ed.; Pergamon: Oxford, 1979; Vol. 2, p 185. Several
NH2OH·HCl
O
references to the use of hydroxylamine are presented in Fieser & Fieser:
then, AcCl/pyridine
TBDMSO 1, 478, 565, 903, 939; 2, 217; 5, 206; 6, 400, 533, 538; 7, 176, 225; 9,
CO2Et
245, 409; 10, 206; 11, 257; 12, 67, 251; 15, 170.
2. Gross, P., CRC Crit. Rev. Toxicol. 1985, 14, 87.
(34)
N
3. Hurd, C., Inorg. Synth., 1939, 1, 87.
TBDMSO
4. Klotzer, W.; Stadlwieser, J.; Raneburger, J., Org. Synth., Coll. Vol.,
CO2Et
1990, 7, 8.
5. Fioshin, M. Ya.; Avrutskaya, I. A.; Surov, I. I.; Novikov, V. T., Collect.
53%
Czech. Chem. Commun. 1987, 52, 182.
6. Chem Sources 1993; Chemical Sources International; Fernandina
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7. Information in this section was compiled from several sources:
1. LDA, THF,
(a) Sittig, M. Handbook of Toxic and Hazardous Chemicals and
N,N-dimethylacetamide
Carcinogens; Noyes: Park Ridge, NJ, 1991; p 918. (b) The Merck
MeO N Index, 11th ed.; Merck & Co.: Rahway, NJ, 1991. (c) Bretherick,
2. NH2OH·HCl, AcONa
o-dichlorobenzene
L. Bretherick s Handbook of Reactive Chemical Hazards, 4th ed.;
Et
Butterworths: Boston, 1990; p 1233. (d) Toxic and Hazardous Industrial
(35)
Chemicals Safety Manual; The International Technical Information
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N
MeO N
Properties of Industrial Materials, 8th ed.; Van Nostrand Reinhold:
Et Me New York, 1992; p 1936.
60% 8. March, J. Advanced Organic Chemistry; Wiley: New York, 1992.
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H
11. Sulsky, R.; Demers, J. P., Tetrahedron Lett. 1989, 30, 31.
1. NH2OH·HCl
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O
KOAc, MeOH
13. (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.
N
2. toluene, 110 °C
R.; DeMarco, A. M.; Karady, S.; Reamer, R. A.; Weinstock, L. M., J.
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(36)
N
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1159.
N
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60%
1333. Other bis-silylated hydroxylamines are also known: West, R.;
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18. Ando, W.; Tsumaki, H., Synth. Commun. 1983, 13, 1053.
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20. King, F. D.; Walton, D. R. M., Synthesis 1975, 788.
Nucleophilic Aromatic Substitution. As expected, aromatic
21. For an excellent review of the preparation and reactions of these
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compounds, see: Ottenheijm, H. C. J.; Herscheid, J. D. M., Chem. Rev.
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1986, 86, 697.
hydroxylamine hydrochloride, provides N-(2,4-dinitrophenyl)-
22. Shin, C.-g.; Nanjo, K.; Ando, E.; Yoshimura, J., Bull. Chem. Soc. Jpn.
hydroxylamine in 91% yield (eq 37).115 1974, 47, 3109.
A list of General Abbreviations appears on the front Endpapers
HYDROXYLAMINE 7
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42. Brighente, I. M. C.; Vottero, L. R.; Terezani, A. J.; Yunes, R. A., J.
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45. Alcaide, B.; Gomez, A.; Plumet, J.; Rodriguez-Lopez, J., Tetrahedron
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48. Capdevielle, P.; Lavigne, A.; Maumy, M., Synthesis 1989, 451.
79. Niu, D.; Zhao, K., J. Am. Chem. Soc. 1999, 121, 2456.
49. Karmarkar, S. N.; Kelkar, S. L.; Wadia, M. S., Synthesis 1985, 510.
80. Geffken, D., Chem. Ber. 1986, 119, 744.
50. Fernandez, R.; Gasch, C.; Lassaletta, J.-M.; Llera, J.-M.; Vazquez, J.,
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87. Sampath Kumar, H. M.; Subba Reddy, B. V.; Tirupathi Reddy, P.; Yadav,
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88. Wang, E.-C.; Lin, G.-J., Tetrahedron Lett. 1998, 39, 4047.
55. For other isoxazole syntheses see:(a) Tronchet, J. M. J.; Massoud, M.
89. Bose, D. S.; Goud, P. R., Synth. Commun. 2002, 32, 3621.
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57. Takase, A.; Murabayashi, A.; Sumimoto, S.; Ueda, S.; Makisumi, Y.,
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Heterocycles 1991, 32, 1153.
94. Das, B.; Madhusudhan, P.; Venkataiah, B., Synlett 1999, 1569.
58. For other syntheses of 4,5-dihydroisoxazoles, see:(a) Colla, A.;
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Martins, M. A. P.; Clar, G.; Krimmer, S.; Fischer, P., Synthesis 1991,
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59. Ito, S.; Sato, M., Bull. Chem. Soc. Jpn. 1990, 63, 2739. 98. Yang, S. H.; Chang, S., Org. Lett. 2001, 3, 4209.
Avoid Skin Contact with All Reagents
8 HYDROXYLAMINE
99. Sharghi, H.; Hosseini Sarvari, M., Tetrahedron 2002, 58, 10323. 109. Chumakov, Y.; Sherstyuk, V. P., Tetrahedron Lett. 1965, 129.
100. Sharghi, H.; Hosseini Sarvari, M., Synthesis 2002, 1057. 110. (a) Bennabi, S.; Narkunan, K.; Rousset, L.; Bouchu, D.; Ciufolini, M.
A., Tetrahedron Lett. 2000, 41, 8873. (b) Cordaro, J. G.; McCusker, J.
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102. Chandrasekhar, S.; Gopalaiah, K., Tetrahedron Lett. 2003, 44, 7437.
111. Nakagawa, H.; Sugahara, T.; Ogasawara, K., Tetrahedron Lett. 2001,
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42, 4523.
104. Eshghi, H.; Gordi, Z., Synth. Commun. 2003, 33, 2971.
112. Tanaka, K.; Mori, H.; Yamamoto, M.; Katsumura, S., J. Org. Chem.
105. Fakhruddin, A.; Iwasa, S.; Nishiyama, H.; Tsutsumi, K., Tetrahedron
2001, 66, 3099.
Lett. 2004, 45, 9323.
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106. Kalita, B.; Nicholas, K. M., Tetrahedron Lett. 2005, 46, 1451.
114. Gilchrist, T. L.; Kemmitt, P. D., Tetrahedron 1997, 53, 4447.
107. Guan, H.-P.; Tang, X.-Q.; Luo, B.-H.; Hu, C.-M., Synthesis 1997, 1489.
115. Singh, S.; Nicholas, K. M., Synth. Commun. 2001, 31, 3087.
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