NaNO2-mediated transformation of aliphatic secondary nitroalkanes into ketones or oximes under neutral, aqueous conditions: How the nitro derivative catalyzes its own transformation

Article abstract of DOI:10.1021/jo0489824

The nitrosation of secondary nitro derivatives into ketones or oximes depending on the nitro substituents has been reinvestigated. The reaction efficiently takes place under neutral conditions, thus allowing acid-sensitive substrates to be converted in very good yields. The generation of nitrosating species under such mild conditions is unprecedented. Mechanistic investigations strongly suggest that they result from the nucleophilic attack of the nitrite anion on the aci-nitro(nate) form of the secondary nitroalkane. The latter acts in turn as an autocatalyst for its own transformation by means of the nitrosating species generated in situ from it.

Full text of DOI:10.1021/jo0489824

NaNO2-Mediated Transformation of Aliphatic Secondary
Nitroalkanes into Ketones or Oximes under Neutral, Aqueous
Conditions: How the Nitro Derivative Catalyzes Its Own
Transformation
Arnaud Gissot,† Silvere N’Gouela, Christophe Matt, Alain Wagner,* and Charles Mioskowski*
Laboratoire de Synthe`se bioorganique, Universite´ Louis Pasteur de Strasbourg, Unite´ associe´e au CNRS,
UMR 7514, Faculte´ de Pharmacie, 74 route du Rhin-BP 24-F-67401 Illkirch-Graffenstaden, France
alwag@bioorga.u-strasbg.fr; mioskowsi@bioorga.u-strasbg.fr
Received June 17, 2004
The nitrosation of secondary nitro derivatives into ketones or oximes depending on the nitro
substituents has been reinvestigated. The reaction efficiently takes place under neutral conditions,
thus allowing acid-sensitive substrates to be converted in very good yields. The generation of
nitrosating species under such mild conditions is unprecedented. Mechanistic investigations strongly
suggest that they result from the nucleophilic attack of the nitrite anion on the aci-nitro(nate)
form of the secondary nitroalkane. The latter acts in turn as an autocatalyst for its own
transformation by means of the nitrosating species generated in situ from it.
The chemistry of aliphatic nitro derivatives relies
largely on the electron-withdrawing character of the nitro
group.1-3 Stabilized anions of nitroalkanes have, for
instance, been extensively used in the Michael,4 Henry,5
and Knœvenagel reactions.6 Starting from primary ni-
troalkanes, these reactions afford valuable secondary
nitro derivatives which can eventually be converted into
ketones. Several methods have indeed been reported to
transform secondary nitro derivatives into ketones.7 As
of yet, none of them have proven general owing to
oxidative and/or acidic conditions or broad functional
group incompatibility.8
Kornblum first reported that secondary aliphatic ni-
troalkanes react with ethyl nitrite to give the correspond-
ing ketones.9,10 This transformation involves the nitro-
sation11,12 of the aci-nitronatesgenerated from the
nitroalkane and NaNO2 which acts as a baseswith ethyl
nitrite. Similarly, we reported the efficient nitrosation
of primary nitroalkanes into acids.13 In that case, the
nitrosating species are generated in situ under weakly
acidic conditions from the readily available sodium nitrite
and acetic acid. We then sought to expand this strategy
to secondary nitro derivatives and found that in marked
contrast to primary nitroalkanes13 secondary derivatives
do not require any acid catalysis. Depending on the
substituents of the nitroalkane, the corresponding ke-
tones or oximes are obtained in good yields under neutral,
aqueous conditions (Scheme 1).
Mechanistic investigations allowed us to propose a
general mechanism for this transformation and to shed
light on the striking reactivity observed in the absence
of acid and on the important substituent dependence of
this reaction.
Results
The commercially available nitrocyclohexane was first
reacted under our previously reported conditions used
with primary nitroalkanes, i.e., 2 equiv of sodium nitrite
and 10 equiv of acetic acid in hot DMSO.13 The cyclohex-
anone is obtained in 86% yield under these conditions
(Table 1, entry 1).
The optimum temperature is in the range of 40-65 °C.
At lower temperature, cyclohexanone is obtained in low
yield (result not shown) and the amount of cyclohexanone
oxime increases with increasing temperatures (entry 2).
No significant loss of reactivity is observed with water
as a cosolvent (entry 3) or in an alcoholic solvent (entry
4). More interestingly, the transformation turned out to
be feasible under neutral conditions, i.e., with H2O as
the only H+ supply (entry 5). Yet, the reaction is clearly
† Present address: The Scripps Research Institute, MB 210, 10550
North Torrey Pines Rd, La Jolla, CA 92037.
(1) Adams, J. P.; Paterson, J. R. J. Chem. Soc., Perkin Trans. 1 2000,
3695-3705.
(2) Ono, N. The nitro group in organic synthesis; John Wiley: New
York, 2001.
(3) Adams, J. P. J. Chem. Soc., Perkin Trans. 1 2002, 2586-2597.
(4) Krawczyk, H.; Wolf, W. M.; Sliwinski, M. J. Chem. Soc., Perkin
Trans. 1 2002, 2794-2798.
(5) Trost, B. M.; Yeh, V. S. C.; Ito, H.; Bremeyer, N. Org. Lett. 2002,
4, 2621-2623.
(6) Carey, F. A.; Sundberg, R. J. In Advanced organic chemistry part
B, 4th ed.; Plenum: New York, 2001; pp 100-101.
(7) Ballini, R.; Petrini, M. Tetrahedron 2004, 60, 1017-1047.
(8) A very mild transformation of secondary nitro derivatives into
ketones using DBU in acetonitrile has been published in the course of
the redaction of this article. See: Ballini, R.; Bosica, G.; Fiorini, D.;
Petrini, M. Tetrahedron Lett. 2002, 43, 5233-5235.
(9) Kornblum, N. J. Am. Chem. Soc. 1956, 78, 1501-1504.
(10) Kornblum, N.; Wade, P. A. J. Org. Chem. 1973, 38, 1418-1420.
(11) Williams, D. L. H. In Nitrosation; Cambridge University
Press: Cambridge, 1986; pp 36-57.
(13) Matt, C.; Wagner, A.; Mioskowski, C. J. Org. Chem. 1997, 62,
234-235.
(12) Williams, D. L. H. Nitric Oxide 1997, 1, 522-527.
10.1021/jo0489824 CCC: $27.50 © 2004 American Chemical Society
Published on Web 11/20/2004
J. Org. Chem. 2004, 69, 8997-9001
8997

Gissot et al.
SCHEME 1. General Transformation of Secondary Nitro Derivatives into Ketones or Oximesa
a Conditions: NaNO2 (2 equiv), H2O/DMSO 1/7 (v/v), 65 °C unless otherwise stated.
TABLE 1. Nitrosation of Nitrocyclohexane into
Cyclohexanone
TABLE 3. Influence of the Temperature and Acid
Strength in the Synthesis of 2g
yield (%)
yielda (%)
2a 3a
86 (35)b <2
entry
cosolvent
T (°C)
time (h)
2g
3g
entry H+ donor (equiv) T (°C)
solvent
1
2
3
H2O
CH3COOH
H2O
71
70
20
72
14
148
65
35
15a
0
45a
1
2
3
4
5
CH3COOH (1.2)
CH3COOH (1.2)
CH3COOH (10)
CH3COOH (5)
H2O (excess)
65
95
65
70
69
DMSO
DMSO
100
85
10
<2
0
DMSO50% 82
a The oxime partially undergoes a Beckman rearrangement
under these conditions (yield ca. 15%).
EtOH65%
DMSO
78
85 (12)
<2
a Yields based on GC analysis of the reaction mixture with
naphthalene as an internal standard. b Yields in parentheses refer
to the yields obtained after 2 h.
sodium nitrite (pKa ) 3.3).11,12 Furthermore, both the
striking substituent effect that governs the oxime/ketone
product distribution of the reaction and the critical
influence of the temperature on the formation of 2g need
to be explained. Therefore, we explored in detail the
mechanism responsible for the formation of cyclohex-
anone from nitrocyclohexane under our standard condi-
tions; our results are presented in the following section.
Mechanistic Investigations. We propose the mech-
anism depicted in Scheme 2 for the conversion of second-
ary nitro derivatives into ketones and/or oximes when
treated with 2 equiv of NaNO2 in aqueous DMSO at 65
°C.
H+ catalyzed as shown by the yields obtained after 2 h
(lines 1 and 5, yields in parentheses).
These conditionssNaNO2 (2 equiv), H2O/DMSO 1/7
(v/v), 65 °Csproved quite general (Table 2). On one hand,
electronically rich nitro 1b-d are converted to the
ketones 2b-d in good yields (Table 2, entries 1-3).
Interestingly, no protecting group is required for alcohol
1b and ketone 1c (entries 1 and 2), and the silyl ether of
1d is not cleaved under these conditions so that ketone
2d is obtained in very good yield (entry 3).14
We believe three different paths account for the
conversion of secondary nitro derivatives into ketones
under our neutral conditions (paths A-C, Scheme 2). In
path A, the sodium nitrite acts as an O-nucleophile and
adds to the aci-nitro eventually giving the ketone in a
straightforward way. Similar mechanisms were actually
postulated for the hydration and the addition of oxone
to aci-nitro derivatives.17,18 As pointed out by one re-
viewer, homolytic cleavage of intermediate 5 to give the
ketone and two molecules of nitrogen monoxide is also
likely. Alternatively, the N-nitration of the aci-nitro
yields the pseudonitrole 4 which further evolves to the
oxime or the ketone depending on the nitro substituents
(path B). As evidenced by our mechanism, nitrosating
species such as N2O4 and N2O3, or others,16 are formed
in the course of the reaction from the pseudonitrole 4 and
intermediate 5 (see reactions II and III in Scheme 2).
Alternatively, the aci-nitro(nate) can be directly nitro-
In contrast, electronically poor R-nitroesters 1e and
1f yield the oxime quantitatively (entries 4 and 5).15
1-Phenylnitrohexane 1g exhibits an intermediate reac-
tivity and invariably yields a 35:65 mixture of oxime and
ketone at 65 °C (entry 6). Neither the use of an excess of
NaNO2 nor the use of acetic acid instead of water (Table
3, entry 2) increased the yield of ketone 2g. In the latter
case, the oxime partially undergoes a Beckman rear-
rangement as a consequence of the more acidic medium.
Nevertheless, we found that 2g can be obtained quanti-
tatively if the reaction is carried out at room temperature
(Table 3, entry 3).
At this point, several observations are worth noting.
First, one can reasonably question the involvement of
nitrosating species under neutral conditions. Indeed, in
contrast to acetic acid (pKa ) 4.8), water alone is not
acidic enough to generate such NO+-like species from
(14) This result is noteworthy since the silyl ether bond is cleaved
under the conditions used to convert primary nitro derivatives into
acids, i.e., in the presence of acetic acid instead of water.
(15) Kornblum, N.; Eicher, J. H. J. Am. Chem. Soc. 1956, 78, 1494-
1497.
(16) Williams, D. L. H. In Nitrosation; Cambridge University
Press: Cambridge, 1986; Vol. Chapter 1, pp 1-35.
(17) White, E. H.; Considine, W. J. J. Am. Chem. Soc. 1958, 80, 626-
630.
(18) Cundall, R. B.; Locke, A. W. J. Chem. Soc. B 1968, 98-103.
8998 J. Org. Chem., Vol. 69, No. 26, 2004

NaNO2-Mediated Transformation of Aliphatic Secondary Nitroalkanes
TABLE 2. Reaction of Various Secondary Nitroalkanes under Standard Conditionsa
a Conditions: NaNO2 (2 equiv), H2O/DMSO 1/7 (v/v), 65 °C. b Isolated yields. c Not detected.
SCHEME 2. Proposed General Mechanism for the Conversion of Secondary Nitro Derivatives into
Ketones or Oximesa
a The original Kornblum mechanism is shown in blue.
J. Org. Chem, Vol. 69, No. 26, 2004 8999

Gissot et al.
SCHEME 3. Nitrosated Species Are Needed To
Convert Primary Nitro Derivatives into Acids
sated by these nitrosating species (path C) as already
evidenced by Kornblum, thus overtaking path B.10 The
final ketone/oxime ratio obtained at the end of the
reaction largely depends on the propensity of the oxime
to react with such species (path D). While electronically
rich oximes are easily nitrosated to the corresponding
ketones, electronically poor ones are not and are obtained
as the sole product.
FIGURE 1. Nitrosation of 1a in the presence of N,N-
dimethylaniline. Conditions: NaNO2 (4 equiv), N,N-dimethy-
laniline (2 equiv), DMSO/H2O 1.4/0.2, 70 °C.
Cyclohexanone is indeed formed in that case. Conse-
quently, the nitro derivative is not only transformed into
ketone but is also responsible for the generation of
nitrosating species from NaNO2 under neutral, aqueous
conditions. Hence, the nitro derivative can be considered
as a kind of a catalyst for its own transformation as the
nitrosating species formed catalyze the transformation
(path C, Scheme 2). Yet, one could argue the nitro
derivative might simply be acidic enough to promote the
generation of nitrosating species from NaNO2 through
the simple acid-base reaction between those two species
(see the aci-nitro-aci-nitronate equilibrium I in Scheme
2). In that case, path C alone (the original Kornblum’s
mechanism) could account for the transformation of
secondary nitro derivatives into ketones. Based on this
hypothesis alone, no reaction should take place in the
absence of nitrosating species. Yet, the reaction does take
place in the presence of N,N-dimethylanilinesa potent
NO+ species scavengers21,22 even though excess NaNO2
is needed (Figure 1). Under these conditions, both
transformations involving nitrosated species (see red
arrows in Scheme 2) are shut down. The only way for
the substrate to undergo the transformation is through
paths A and B. Since the oxime and ketone are formed
under these conditions, this strongly supports the hy-
pothesis that NaNO2 can act as a nucleophile toward
the aci-nitro(nate). To the best of our knowledge, this is
the first time the nitrite ion has been shown to be able
to react as a nucleophile toward a nitroalkane. The
aptitude of nitrite ion to act as a nucleophile has been
precluded so far by the acidic conditions usually employed
to perform such transformations (the nitrite ion is
protonated at pH < 3.3). The 7:3 oxime/ketone ratio
obtained may in turn reflect the N/O-nitration addition
ratio of NaNO2 to the aci-nitro (paths B and A, respec-
tively).23 This experiment also suggests that nitrosat-
ing species are indeed good catalysts for this transforma-
tion, the reaction time being much longer in their
absence.24
Discussion
While under acidic conditions the protonation of NaNO2
is responsible for the formation of NO+-like species11,12
and in turn the reactivity observed with primary nitroal-
kanes,13 the anionic character of the nitrite remains
unaltered under our neutral conditions. Thus, it is likely
to act as a powerful nucleophile toward the aci-nitro, and
both the O- and N-nitrations of the latter can be
anticipated by virtue of the ambident character of the
nitrite ion. Several experimental observations support
this hypothesis and prove that nitrosating species are
actually formed in the course of the reaction under
neutral, aqueous conditions.
First, primary derivatives such as 2-phenylnitroethane
are not reactive and do not give the corresponding acid
unless acidic conditions are employed (Scheme 3).
Thus, if primary nitroalkanes do require the formation
of nitrosating species from NaNO2 and acetic acid to
afford the corresponding acid, secondary derivatives do
not. This result can be explained on the basis of the
nitro-aci-nitro equilibrium unfavorable to the latter with
primary derivatives;19 the amount of the aci-nitro form
in solution is then too low to observe the nucleophilic
attack of the nitrite (paths A and B). The same observa-
tion goes for the intermediately formed cyclohexanone
oxime that is not transformed into cyclohexanone under
our standard conditions unless acetic acid is added to the
solution (Scheme 4).20
This result is in agreement with our mechanism, as
the oxime-ketone transformation requires nitrosating
species previously formed from the intermediates 4 and
5 (see path D, Scheme 2). Therefore, those species must
somehow be formed from the nitro derivative itself. To
further evidence the ability of the nitro derivative to act
as the actual NO+ supply, we carried out the same test
reaction in the presence of an external secondary nitro
derivative, namely 2-nitropropane (Scheme 5).
(21) Liddell, H. F.; Saville, B. Chem. Ind. 1957, 493-494.
(22) Loeppky, R. N.; Singh, S. K.; Elomari, S.; Hastings, R.; Theiss,
T. E. J. Am. Chem. Soc. 1998, 120, 5193-5202.
(23) While the cyclohexanone 2a is formed quantitatively in the
absence of N,N-dimethylaniline with a strong nitrosating reagent such
as the nitrosyl tetrafluoroborate, it is not detected in the presence of
2 equiv of N,N-dimethylaniline. As a consequence, the cyclohexanone
formed in this test is likely to result from the O-nitration of the aci-
nitro (path A, Scheme 2).
(19) Bordwell, F. G.; Boyler, W. J., Jr.; Yee, K. C. J. Am. Chem. Soc.
1970, 92, 5926-5932.
(20) Since sodium nitrate was formed during the course of the
reaction, the reactions were also conducted in the presence of this salt.
9000 J. Org. Chem., Vol. 69, No. 26, 2004

NaNO2-Mediated Transformation of Aliphatic Secondary Nitroalkanes
SCHEME 4 Conversion of Cyclohexanone Oxime into Cyclohexanone Requires Nitrosating Species
SCHEME 5. Nitrosating Species Are Formed from
the Secondary Nitro Derivative and NaNO2 under
Neutral Conditions
(path D). This is especially true in the case of a weakly
reactive oxime such as 3g. While nitrosating species are
predominantly decomposed at high temperature leading
to substantial amounts of the oxime (Table 2, entry 6),
the ketone 2g is formed as the sole product at room
temperature where nitrosating species are stable (Table
3, entry 3).
At first glance, the results obtained with R-nitroesters
(Table 2, entries 4 and 5) would appear incompatible with
our proposed mechanism as no ketone is formed. Even
though path D is blocked with this substrate, some
ketone would at least result from the O-nitration of the
derived aci-nitro (path A, Scheme 2). Nevertheless, as
noted by Kornblum,15 the acidity of these compounds is
much greater, thus favoring path C over paths A and B.
Furthermore, the addition of NaNO2 to the aci-nitro
(paths A and B) are all the more unlikely because the
double bond of the corresponding aci-nitro is in conjuga-
tion with the ester group.
SCHEME 6. Influence of the Substituents for the
Nitrosation of Oximesa
In conclusion, an efficient method to transform second-
ary nitro compounds into ketones or oximessdepending
on the nature of their substituentssunder mild condi-
tions was developed. Unlike Kornblum’s nitrosation
method,10 small amounts of ketones or oximes result from
the direct nitrosation of the aci-nitro(nates) in our case.
A detailed analysis of the mechanism allowed us to
conclude that the nitrite ion acts as a potent nucleophile
toward the aci-nitro(nate). Not only does the neutral pH
employed in our case is important for the nitrite to act
as a nucleophile, it also allows the conversion of acid-
sensitive substrates such as 1d and 1g to take place in
high yields. We have also shown that nitrosated species
are generated in the course of the reaction from NaNO2
and the secondary nitro derivative. These species are
necessary to convert oximes into ketones, and their
generation under neutral aqueous conditions is remark-
able and unprecedented.
a A transient blue color from the pseudonitrole is transiently
seen in the course of the reaction.
The reaction is strongly substituent-dependent (Table
2). While electronically poor nitro derivatives such as
R-nitroesters 1e and 1f yield the oxime quantitatively,
cyclohexanone 1g is formed from the electronically rich
nitrocyclohexane. These results emphasize the ease with
which the respective oxime intermediates can be nitro-
sated (Scheme 6).
The more electronically rich the substituents of the
oxime, the more nucleophile the oxime (3a > 3g . 3f)
and the easier the nitrosation to the ketone (path D,
Scheme 2). Besides, most of the nitrosated species formed
in the course of the reaction are known to be thermally
unstable.12,16,25 Hence, the thermal decomposition of the
different nitrosated species (see reaction IV in Scheme
2) competes with the nitrosation of the oxime into ketone
Acknowledgment. We thank Byron Purse for re-
viewing this manuscript and the Ministe`re de la re-
cherche et de l’enseignement supe´rieur for financial
support through an MRE grant to A.G.
Supporting Information Available: Spectroscopic data
for compounds 1b-d,g, 2b,d, and 3e,f. General procedure for
the nitrosation of secondary nitroalkanes. This material is
available free of charge via the Internet at http://pubs.acs.org.
(24) Iglesias, E.; Williams, D. L. H. J. Chem. Soc., Perkin Trans. 2
1988, 1035-1040.
(25) Hugues, E. D.; Ingold, C. K.; Ridd, J. H. J. Chem. Soc. 1958,
88-98.
(26) Seebach, D.; Lehr, F. Helv. Chim. Acta 1979, 62, 2239-2257.
JO0489824
J. Org. Chem, Vol. 69, No. 26, 2004 9001