SODIUM NITRITE 1
Cycloalkylamines (ring sizes C4 and C6 C8) can undergo ring
Sodium Nitrite1
contraction on diazotization (eq 2); conversely, cycloalkylmethy-
lamines (ring sizes C3 C8) undergo ring expansion under similar
NaNO2
conditions (Demjanov rearrangement) (eq 3).6 Ring expansions
of certain alkanolamines (ring sizes C4 C8) also occur on diazoti-
[7632-00-0] NNaO2 (MW 69.00)
zation, affording cyclic ketones (Tiffeneau Demjanov rearrange-
InChI = 1/HNO2.Na/c2-1-3;/h(H,2,3);/q;+1/p-1/fNO2.Na/q-1;m ment) (eq 4).7 Product yields from the latter reaction are generally
InChIKey = LPXPTNMVRIOKMN-BUTCQXEJCY superior to those from the corresponding simple Demjanov rear-
rangements.
(diazotization of primary aliphatic and aromatic amines;1 N- and
C-nitrosating agent;2,3 reacts with alkyl halides to form aliphatic
R
 H+
+
nitro compounds4)
H
R R  N2
+ R
ć% ć%
Physical Data: mp 271 C; dec. above 320 C; d 2.17 g cm-3.
(1)
NH2 N N
ć%
Solubility: very sol water (0.815 g mL-1, 15 C); sol DMSO, R
R R + 
N N
DMF; slightly sol Et2O, MeOH, EtOH.
(1)
R
Form Supplied in: white crystalline, hygroscopic solid; reagent
grade 97 %+; widely available.
Handling, Storage, and Precautions: should be kept dry in tightly
NaNO2, HCl
closed containers. Nitrites undergo slow oxidation to the nitrate
n
NH2 n 1 CH2OH (2)
in air. Aqueous solutions of NaNO2, which are alkaline (ca.
H2O
pH 9), are unstable on prolonged storage and should be made
up fresh prior to use. NaNO2 decomposes in the presence of
weak acids with the evolution of brown fumes of N2O3. Since
NaNO2 is classified as toxic, oral ingestion should be avoided.
nn+1 OH (3)
CH2NH2
O
NH2
Original Commentary
OH
(4)
Kevin J. McCullough
40 42%
Heriot-Watt University, Edinburgh, UK
Introduction. In many synthetic applications, NaNO2 is used Diazotization of amino acids using NaNO2 in HCl affords the
as a convenient precursor of the unstable nitrous acid HONO corresponding Ä…-chloro carboxylic acids in moderate yield and
which is generated in situ on treatment with a variety of mineral with almost complete retention of configuration (95 98% ee)
and carboxylic acids. Reactions involving HONO are complex (eq 5).8 Analogous deamination/halogenation transformations
because, in solution, it exists in equilibrium with a variety of other have also been effected on 6²-aminopenicillanic acid (2) with
reactive species, including N2O3, nitrosyl halides, and the nitroso- inversion of configuration.9 In the presence of Bromine, the cor-
nium ion ON+. Although LiNO2 and KNO2 will also react in a responding geminal dibromide (ca. 30%) is obtained;10 yields can
similar fashion to the sodium salt, the latter is preferred on the be increased to 80% if a two-phase solvent system is used (eq 6).11
basis of price and availability. Diazotization and nitrosation reac- The S,S-dioxide derivative of (2) affords the corresponding gemi-
tions can also be carried out using a variety of reagents including nal dibromide in good yield and high purity with methanol, rather
Nitrosyl Chloride and alkyl nitrites. than water, as solvent.12
NaNO2, HCl
Reactions with Amines and Related Compounds. In such NH2 Cl
H2O
reactions, a solution or suspension of the amine in dilute hydro-
(5)
R CO2H 60 65% R CO2H
chloric acid (2.5 molar equiv per mole of amine) is treated with
ć%
a molar equiv of NaNO2 solution at 0 10 C. Reactions are nor-
H
X
mally rapid and in many cases quantitative.1 The reaction out-
S
NaNO2, HX, H2O
come depends markedly on the nature of the amine. With primary
N
0 °C
aliphatic amines, the reaction (usually described as diazotization)
O
produces the corresponding diazonium ion (1) as the first sig-
CO2H
H
H2N
nificant intermediate. This can subsequently eliminate either a
S
X = Cl, Br
molecule of nitrogen to generate a carbocation, or H+ to give a
(6)
N
diazoalkane (eq 1).5 In the diazotization of simple primary
Br H
O
S
Br
aliphatic amines with sodium nitrite in dilute mineral acid, the
CO2H NaNO2, dil H2SO4, Br2
former process predominates resulting in rapid evolution of N2,
(2) N
an observation which forms the basis for the characteristic chemi- O
CO2H
cal test for primary aliphatic amines.
Avoid Skin Contact with All Reagents
2 SODIUM NITRITE
When primary aliphatic amines with strongly electron-
NaNO2, dil. H+
withdrawing substituents attached to the amino carbon atom are
N O
diazotized, the corresponding diazoalkanes can be isolated.5,13
H
Diazotization of 2,2,2-trifluoroethylamine affords the correspond- (9)
ing diazoalkane in 70% yield.14 Treatment of glycine ethyl ester
N NH2 NaNO2, conc. HX, "
hydrochloride with sodium nitrite in dilute sulfuric acid affords
the important synthetic intermediate Ethyl Diazoacetate (eq 7).15 N X
The benzyl ester of acid (2) has also been transformed into the
corresponding Ä…-diazo derivative using sodium nitrite in aqueous
Treatment of secondary dialkyl-, diaryl-, and alkylarylamines
acetone.16 Attempted diazotization of 2-aminocyclohexanone re-
with sodium nitrite in mineral acid with gentle heating usually
sults in deamination and rearrangement to cyclopentanecarboxylic
results in the formation of the corresponding N-nitrosamines
acid (57%).17
which, being unable to lose a proton, are comparatively stable to
further reaction (eq 10).2,26 Secondary amides will also undergo
N-nitrosation.27
NaNO2, H2O
EtO2C NH2 EtO2C
N2 (7)
H2SO4, CH2Cl2
R2
NaNO2
R2
(10)
N H N N O
HX
R
R
Primary aromatic amines readily undergo diazotization to give
Although erroneously considered to be inert towards nitro-
the corresponding diazonium salts, which are generally stable in
ć%
solution at temperatures below 0 C.1 These are important inter- sation,28 tertiary amines do undergo nitrosative dealkylation when
ć%
treated with NaNO2 in aqueous acetic acid at 90 C to give mix-
mediates in electrophilic aromatic substitution reactions, e.g. the
tures of products including dialkyl-N-nitrosamines, carbonyl com-
formation of azo dyes, and a variety of coupling/displacement
reactions including the Sandmeyer, Balz Schiemann, and Gom- pounds, and nitrous oxide (eq 11).29 A diterpenylalkanolamine
was found to lose a terpenyl substituent selectively on nitrosation
berg reactions. Amines with strongly acidic groups are best
with NaNO2 in acetic acid.30
diazotized by the slow addition of a solution of the amine and
NaNO2 in dilute alkali to the acid with vigorous stirring.1a To
avoid hydrolysis of the diazonium salt, amines with strongly
R2 R1 R2 R1
NaNO2, H2O
electron-withdrawing groups should be diazotized in concentrated
+
N N N O O + N2O (11)
AcOH, 90 °C
acid.1a,18 The transformation of aromatic 1,2-diamines to bis-
R R2 R R2
diazonium salts should also be carried out in concentrated acid.
In dilute or weak acid, the mono-diazonium ions derived from
Nitrosation of hydrazine derivatives using NaNO2 in acid
1,2-phenylenediamines cyclize to give 1,2,3-benzotriazoles
solution provides a convenient method of preparing the corres-
(eq 8).1a,b,19 By analogy, diazotization of p-nitro-o-toluidine
ponding azide derivatives.31 For example, phenyl azide can be
affords 5-nitroindazole under similar conditions.20
prepared by treating a suspension of phenylhydrazine hydrochlo-
ć%
ride in dilute HCl with NaNO2 at 0 C in a two-phase water/ether
N
NaNO2, AcOH, H2O
system (eq 12).32 Highly substituted hydrazines undergo nitro-
N
70 °C
sative dealkylation in an analogous fashion to give tertiary ami-
N
NH2
H
nes.33 Hydrazinium salts, derived from N,N-dimethylhydrazine
(8)
and an alkyl halide, are deaminated on treatment with NaNO2
N2+ X-
NH2 NaNO2, conc. HX
in HCl (4 M) to yield tertiary amines (eq 13).34 Like simple
hydrazines, hydrazides can be converted into the corresponding
N2+ X-
acyl azides by reaction with NaNO2 in dilute HCl at low
temperature.31,35
Ph
NaNO2, HCl
Ph
Treatment of diazonium salts, preferably the tetrafluoroborates,
+ 
N NH2 (12)
N N N
with NaNO2 in the presence of a CuI catalyst at pH > 7 results
H2O, Et2O
H
in the formation of the corresponding aromatic nitro compounds
Me
(cf. the Sandmeyer reaction).21 For analogous reactions involving
Me
NaNO2
+
(13)
amines with strongly electron-withdrawing groups, a CuI catalyst R N NH2 N R
HCl (4 M)
is not required.22 Me
Me
Heteroaromatic amines also undergo diazotization on treatment
with sodium nitrite in acid; for example, 3-aminopyridines give
isolable diazonium salts whereas the 2- and 4-derivatives afford C-Nitrosation Reactions. Aliphatic carbon centers in alkanes
either the corresponding pyridones in dilute acid23 or halopy- do not readily undergo C-nitrosation with nitrous acid unless acti-
ridines in concentrated HCl or HBr (eq 9).24 Diazotization of vated by an electron-withdrawing substituent such as acyl, aroyl,
2-aminopyrimidine in concentrated HCl produces 2-chloropyri- carbonyl, carboxyl, nitro, cyano, imino, or aryl.3 The usual prod-
midine.25 ucts are C-nitrosamines or oximes, depending on the degree of
A list of General Abbreviations appears on the front Endpapers
SODIUM NITRITE 3
O
OH OH
substitution at the carbon center in question (eq 14). Detailed
procedures have been reported for the preparation of the oximes
derived from the active methylene compounds Ethyl Acetoacetate
(18)
and Diethyl Malonate.36,37 The unstable ²-chloro- and bromo-
pyruvaldoximes have been obtained by treatment of the appro-
NOH
NO
priate Å‚-haloacetoacetyl chlorides with NaNO2 in ether water via
a reaction sequence which involves hydrolysis and nitrosation of
Although anisole and diphenyl ether are readily nitrosated, they
the resulting ²-keto acid followed by decarboxylation.38
both give rise to 4-nitrosophenol.47 4-Nitrosoanisole is, however,
obtained in 57% yield from anisole if the nitrosation reaction is
NO
R `" H
ć%
carried out in CH2Cl2/CF3CO2H under argon at 0 C.48 Nitration
R Y
H of simple aromatic compounds is reported to be readily achieved
X
ć%
(14) by reaction with NaNO2 in Trifluoroacetic Acid at 25 C;
R Y
NOH
isomer ratios are similar to those expected from electrophilic aro-
X
R = H
matic substitution reactions.49 Hydroquinones are conveniently
X Y
oxidized to quinones by excess NaNO2 in acetic acid.50 Reaction
of 2,3,5-trisubstituted pyrroles and 3,5-disubstituted pyrazoles
Although gaseous NOCl is generally the reagent of choice for
with buffered nitrous acid gives rise to diazo compounds.51
the direct nitrosation of alkenes, the simultaneous addition of con-
centrated solutions of NaNO2 and hydrochloric acid to limonene
Oxidation Reactions. NaNO2 in various acidic media,
ć%
in isopropanol (t <10 C) affords the corresponding chloro oxime
including dilute HCl, acetic acid, and CF3CO2H, oxida-
in good yield (eq 15).39 The rate of nitrosation of alkenes using
tively cleaves C=N bonds in oximes,52 semicarbazones,53 and
NaNO2 and aqueous hydrochloric acid can be accelerated to a
hydrazones,54,55 thereby regenerating the carbonyl group under
significant extent by bromide and chloride ions.40 Tetracyclone
mild reaction conditions (eq 19). 2,4-Dinitrophenylhydrazones,
undergoes cis-dihydroxylation on treatment with NaNO2 in acetic
acid; the reaction is thought to proceed via a cycloaddition of N2O3 which are normally resistant to hydrolysis, are transformed to
carbonyl compounds in ca. 80% yield.55 Reaction of secondary
to one of the double bonds (eq 16).41a Under similar conditions,
or tertiary thioamides with NaNO2 in HCl (4 M) affords the cor-
methyl methacrylate and tricyclone are nitrated at unsubstituted
responding amides in good yield (70 90%).56
sp2 carbon centers, and 2,5-disubstituted furans ring open to unsat-
urated diketones.41b Isopropylidene and terpene alkenes undergo
dehydromethylation to give alkynes in moderate to good yield on X
O
N (19)
reaction with NaNO2 in acetic acid; the reaction is complex and
the Me group is lost as CO2 (eq 17).42 Mucobromic acid in ethanol
is transformed to the sodium salt of nitromalonaldehyde, a useful
X = OH, NHCONH2, NHNHR
building block for the synthesis of pyrimidines, by the action of
Ä…-Nitro esters57 and sulfones58 are readily converted into their
aqueous NaNO2.43
respective Ä…-oximino derivatives on reaction with NaNO2 in
aqueous ethanol and DMF, respectively. Reactions between secon-
Cl
dary aliphatic nitro compounds and mixtures of NaNO2 and alkyl
NOH
nitrites give ketones in good yield;59 with primary aliphatic
NaNO2
(15)
nitro compounds, carboxylic acids are obtained in low yield.60
conc. HCl
Carboxylic acids can undergo oxidative decarboxylation with
concomitant formation of cyano compounds (50 70%) on treat-
ment with a mixture of NaNO2 and Trifluoroacetic Anhydride
Ph
Ph Ph Ph (1:3) in CF3CO2H.61 Benzylic alcohols can be oxidized to
OH
aldehydes with NaNO2 in aqueous CF3CO2H.62 Diazotization
NaNO2
OH
ć%
(16)
of benzylamine with NaNO2/CF3CO2H in dry DMSO at 100 C
Ph
Ph
Ph
MeCO2H
Ph
results in the formation of benzaldehyde (60 80%); poorer yields
O
O
are obtained from the analogous isoamyl nitrite reaction.63
NaNO2
Nitroalkanes and Nitrite Esters. Since the nitrite ion is
R (17)
MeCO2H
bidentate, nucleophilic displacement reactions with alkyl halides
R
can take place through either nitrogen or oxygen to give nitro
compounds or nitrite esters respectively (eq 20). NaNO2 in either
Nitrosation of phenols using NaNO2 in hydrochloric acid
DMF or DMSO reacts readily with primary and secondary alkyl
generally results in formation of the corresponding nitroso
bromides or iodides to yield the corresponding nitro compounds;
compound.44 Thus, for example, phenol yields 4-nitrosophenol,
together with a small quantity of the 2-isomer (ca. 10 %) (eq 18),44 Silver(I) Nitrite gives better yields with primary alkyl halides.64
It is important that significant quantities of both the nitrite and
and 2-naphthol produces 1-nitroso-2-naphthol.45 Treatment of
the halide are in solution or the reaction does not take place.
phenols with  buffered nitrous acid (NaNO2 in large excess
Secondary nitrosation reactions can be minimized by the addi-
compared to HCl) in aqueous acetone results in the formation
tion of a nitrite scavenger such as phloroglucinol.
of diazonium salts.46
Avoid Skin Contact with All Reagents
4 SODIUM NITRITE
O
readily available lower homologs.74 Tin and silicon have also been
+
R N
shown to have a directing effect in the Tiffeneau-Demjanov reac-
O O
tion, although moderate (eq 22).75
(20)
N O + R X
O
O O
R O N
HO CH2NH2
NaNO2
(22)
+
AcOH
MMe3
Simple alkyl nitrites can be prepared by direct esterification of
MMe3
the appropriate alcohol with aqueous NaNO2 in sulfuric acid at
MMe3
ć%
0 C. The preparations of methyl,65 ethyl,66 and butyl nitrites67
M = Si, 72% 27%
have been described in detail. Isopentyl Nitrite is obtained in high
M = Sn, 87% 13%
yield by treatment of a mixture of the alcohol and NaNO2 with
aluminum sulfate.68 Propargyl bromides have been transformed
into 3-nitroisoxazoles (20 60%) using NaNO2 in DMF (eq 21).69 Aminopurine nucleosides can be converted to halopurine
nucleosides, which are valuable synthetic intermediates. When
6-aminochloropurine is treated in a non aqueous media with
NO2
NaNO2 in the presence of antimony trichloride (or tribromide), the
NaNO2
Br
corresponding 2,6-dichloropurine (or 6-bromo-2-chloropurine) is
(21)
R
N
DMF
R obtained in good yield (eq 23).76 The same reaction has been
O
applied to adenosine derivatives. Similarly, aminofurazans can be
converted to their iodo analogs, albeit in moderate yields, by reac-
tion with sodium nitrite and iodine in CH3CN/CH2Cl2 (eq 24).77
Fremy s Salt. Potassium Nitrosodisulfonate, a useful reagent
Cl
Cl
for the selective oxidation of phenols and aromatic amines to
BnEt3NX, SbX3, NaNO2
quinones (Teuber reaction), has been prepared by the reaction N
N
N
N
(23)
of NaNO2 with NaHSO3 and SO3 followed by electrolysis using CH2X2 , CHCl2CO2H
N
N
a stainless steel anode in alkaline solution.70 Fremy s salt has also H2N N
X N
AcO X = Cl, 80%
AcO
been generated in situ as a marker in ESR spectroscopy by bub-
O
O
X = Br, 60%
bling O2 through an equimolar mixture of NaNO2 and NaHSO3
AcO OAc
in alkaline solution (pH 9).71 AcO OAc
R NH2 R I
NaNO2, I2
(24)
N N N N
First Update
O O
When secondary amines are reacted with sodium nitrite in
Bernard Bessieres
the presence of an acid, the corresponding N-nitrosoamines are
Université Joseph Fourier, Grenoble, France
obtained. The reaction can be run in homogeneous solution, or
the acid can be a solid78 or immobilized on a solid support,
Reactions with Amines and Related Compounds. Deami-
facilitating the isolation of the product (eq 25). In the case of
nation of arylamines is an important reaction that is used pri-
silica chloride79 and silica sulfuric acid,80 HCl and H2SO4,
marily for the removal of amines after they have been used for
respectively, are generated in situ. This method is very mild, high
directing electrophilic aromatic substitutions. The transformation
yields are obtained, and no C-nitrosation is observed even when
is generally achieved in a two-step process involving diazotization
an aromatic moiety is connected directly to the nitrogen.
followed by reduction. The drawbacks of these procedures are that
they require the preparation of unstable aryldiazonium salts and
R1
R1
CH2Cl2, wet SiO2
that the following reduction is not efficient with electron donat-
N H + NaNO2 silica chloride N N O (25)
R2
ing groups in the para position as well as with any substituent in R2
or silica sulfuric acid
the meta position. These problems can be overcome with a pro- or Nafion-H
cess involving acetic acid, sodium nitrite and sodium bisulfite as
the reductant. The reaction is performed by dissolving the ani- When thiols are treated under the same mild heterogeneous
ć%
lines in a mixture of ethanol, acetic acid and water at 24 C, and reaction conditions, thionitrites are formed. These unstable thioni-
by adding an aqueous solution of sodium nitrite followed imme- trites further react by loss of NO to give a thiyl radical that couple
diately by aqueous sodium bisulfite.72 Ethyl acetate has been used to give the disulfide in good yields.81
as a pro reducing agent in a one-pot deamination of nitroanilines, When N-aromatic amides in a solution of acetic anhydride
with acetic acid and ethanol being generated under the reaction and acetic acid are treated with solid sodium nitrite, the corres-
conditions.73 ponding O-aromatic esters are obtained in good yield (eq 26).82
Diazotization of cyclic alkanolamines gives the one-carbon ring Oxime carbamates, readily available from the oximes and sodium
expanded cycloalkanone (Tiffeneau-Demjanov rearrangement). cyanate, can be reacted with sodium nitrite/sulfuric acid to give
Thus odd numbered cycloketones can be obtained from their more the amides.83 This environmentally friendly Beckman rearrange-
A list of General Abbreviations appears on the front Endpapers
:
:
SODIUM NITRITE 5
ment uses mild conditions, and the by-products are CO2 and N2 displacement of a triflate. The axial nitrite was hydrolyzed under
(eq 27). the reaction conditions.92 Epoxides are opened regioselectively
with sodium nitrite/methanol/magnesium sulfate93 or sodium
H
nitrite/acetic acid (eq 32).94 The ONO- nucleophile has a very
O R
NaNO2
N R
Ar
Ar
(26) strong preference for the less hindered carbon of the epoxide, but
Ac2O, AcOH
O
O in the case of styrene oxide the attack takes place exclusively at
the benzylic position. The 1,2-nitrite alcohols thus obtained are
H
OH
readily hydrolyzed to 1,2-diols.
1. NaNO2, H2SO4
N N R2
(27)
R1
2. NH4OH
OH
NaNO2, AcOH
O
R1 R2 O
(32)
ONO
water
R
R
N-Carbamylamino alcohols can be subjected to a nitrosation-
deamination reaction to yield oxazolidinones (eq 28).84 Ä…-
It was claimed erroneously95 that aliphatic nitro compounds
Hydroxy hydrazides are also converted to oxazolidinones by
could be obtained simply by the reaction of sodium nitrite on
treatment with sodium nitrite/sulfuric acid under an inert atmo-
alcohols in the presence of acetic acid/HCl mixture. It was demon-
sphere. The ring formation proceeds via a concerted mechanism
strated soon after that, under those reaction conditions, alkyl
and full retention of stereochemistry is observed (eq 29).85
nitrites were obtained, not nitroalkanes.96
Aromatic substrates can also be nitrated in various acidic
O
O media. Naphthalenes yield 1-alkoxy-4-nitronaphthalene as the
NH
HN NH2 NaNO2, HCl
major product (50%) when treated with CAN/NaNO2/H2SO4.97
(28)
H2O, AcOH Tetraphenylporphyrin can be nitrated in the para-position with
O
OH
sodium nitrite/TFA. The selective nitration of one, two, or three
of the phenyl rings can be controlled by varying the amount of
sodium nitrite and the reaction time (eq 33).98
O
OH O
O
NaNO2, H+
NH (29)
R1 NHNH2
R1
R2
R2
Nitro Compounds and Nitrite Esters. Acrylic esters can
NH N
NaNO2
be converted to their ²-nitro acrylic homologs by NaNO2-ceric
TFA
ammonium nitrate. The intermediate nitro alcohol is then fur-
N HN
ther dehydrated (eq 30).86 Alternatively, methyl acrylate has been
treated with HgCl2 and sodium nitrite to give the nitromercu-
rated product. Subsequent bromination/elimination of HBr leads
to trans-nitroacrylate.87 When performed on simple alkenes, the
reaction leads to a nitroacetamidation of the double bond (eq 31).88
OH
NO2
R1 CO2R
R1 CO2R
CAN, NaNO2
(30)
CH3CN
R2 H
R2 H
NO2
NO2
CAN, NaNO2
(31)
NH N
CH3CN
NHCOCH3 (33)
NO2
N HN
Similarly, allylsilane can be nitrated to give Ä…,²-unsaturated
nitro compounds with NaNO2/CAN/AcOH under microwave
irradiation.89
Aromatic substrates have been nitrated by the action of sodium
nitrite combined with Selectfluor in acetonitrile. The strongly elec-
trophilic F+ ion reacts with NO2- to give the NO2+ electrophilic
NO2
agent.90 The yields can be good but reactions times are long (the
nitration of benzene takes 72 h with 100% yield). Allylic oximes
derived from terpenes can be reacted with sodium nitrite and acetic
acid to give the allylic nitro compounds in modest yields.91 Reduction Reactions. The hydrogenation of steroid (3) with
Sodium nitrite can also act as a nucleophile, mostly through the palladium over charcoal provided an inseparable mixture of
oxygen to give the nitrite ester. Sodium nitrite in DMF was used to compounds, whereas in the presence of sodium nitrite, smooth
introduce an axial hydroxyl group on a carbohydrate template by reduction occurred to give the desired compounds in 96% yield
Avoid Skin Contact with All Reagents
6 SODIUM NITRITE
(eq 34).99 Cerium(III) chloride gave a similar result but with Primary nitroalkanes can be efficiently oxidized to the corres-
longer reaction time. ponding carboxylic acids using a mixture of sodium nitrite
ć%
and acetic acid in dimethyl sulfoxide at 35 C (eq 38).105 The
reaction works also with primary alkyl bromides and mesylates
R
although in lower yields. The reaction proceeds via the forma-
tion of a nitrolic acid intermediate that can be isolated by running
ć%
the reaction at 18 C. It further evolved to a nitrile oxide and then
H2, Pd/C
OH
to the carboxylic acid. This method was applied to the enantio-
HO
NaNO2
selective synthesis of Ä…-amino acids from nitroalkenes.106 When
secondary nitroalkanes are treated under the same reaction con-
HO
H
ditions, the product obtained is the Ä…-keto oxime (eq 39).107
O
Under similar, but neutral conditions, with H2O as the only pro-
3
ton source, secondary nitroalkanes are oxidized to the ketone
R
(eq 40).108
NaNO2, AcOH
H OH
HO (34)
R NO2 DMSO, 35 °C RCO2H (38)
H
HO
H
OH
O
N
NO2 NaNO2, AcOH
(39)
DMSO, 35 °C
O
Oxidation Reactions. Primary, benzylic and allylic alcohols
R
R
can be oxidized selectively and rapidly to the corresponding
aldehyde by using sodium nitrite-acetic anhydride under mild and
solvent free conditions.100 The reaction is rapid (less than 1 min),
NO2 NaNO2 (2 equiv) O
and no over-oxidation to the acid is observed. Cyano, TBDMS,
(40)
DMSO/H2O
and THP ether groups are unchanged during the oxidation. In the
Bu Bu
20 °C
presence of trifluoroacetic acid, molecular oxygen, and sodium
nitrite, cycloalkanols can be converted to the Ä…, É-dicarboxylic
acids (eq 35).101 Furthermore, aliphatic primary alcohols are con-
verted to the acid while secondary acyclic alcohols are mainly
Similar to the Curtius rearrangement of amide to amine, acyl
converted to the ketone. An efficient catalytic, transition-metal
free oxidation process using TEMPO/bromine/sodium nitrite102 hydrazides were converted to the primary amines using sodium
ć%
nitrite and TFA at 0 C (eq 41).109 Ä…,²-Unsaturated acyl
(eq 36) or TEMPO/sodium nitrite/1,3-dibromo-5,5-dimethylhy-
hydrazides are transformed to the corresponding azo compounds
dantoin103 convert primary and secondary alcohols to the corres-
with a combination of sodium nitrite and NaHSO4 with wet SiO2
ponding carbonyl derivative in almost quantitative yields.
in acetone,110 and diaryl carbazides are oxidized to carbazones
OH with sodium nitrite-acetic anhydride.111 1,4-Dihydropyridines are
oxidized under mild and heterogeneous conditions to pyridines
NaNO2 in TFA
CO2H
(35) with sodium nitrite, NaHSO4 and wet SiO2 in methylene
O2
CO2H
chloride.112
R1 R1
TEMPO, Br2, NaNO2
CONHNH2 NH2
(36)
OH O
air, CH2Cl2, 80 °C
R2 R2 NaNO2, TFA, H2O
(41)
0 °C then 80 °C
O O
N N
Ketones can be reacted with sodium nitrite and HCl in THF
Bn Bn
to give the 1,2-diketone, thus affording an interesting alternative
to the use of the classical selenium dioxide.104 When 1 equiv of
sodium nitrite is used, the monoxime intermediate can be isolated
Oxathioacetals and dithioacetals can be efficiently deprotected
whereas with 3 equiv, the diketone is the only product (eq 37).
to regenerate the starting carbonyl group using sodium nitrite and
ć%
O acetyl chloride in dichloromethane/water at 0 C.113
O
NaNO2, HCl
Naphthalene radicals have been generated by treatment of
R2 (37)
R2 R1
THF, 0 °C
the aromatic compounds in acetonitrile with sodium nitrite and
R1
X
CF3SO3H (eq 42).114 Most of the substrates give good yields of
X = NOH the binaphthyls, except from naphthalene itself and some bulky
X = O
derivatives.
A list of General Abbreviations appears on the front Endpapers
SODIUM NITRITE 7
Me
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Avoid Skin Contact with All Reagents
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A list of General Abbreviations appears on the front Endpapers