Unprecedented, selective Nef reaction of secondary nitroalkanes promoted by DBU under basic homogeneous conditions

Article abstract of DOI:10.1016/S0040-4039(02)01039-0

Secondary nitrocompounds can be converted into the corresponding ketones under basic conditions using DBU in acetonitrile. Primary nitroalkanes are unaffected by these conditions. Elsevier Science Ltd. All rights reserved.

Full text of DOI:10.1016/S0040-4039(02)01039-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 5233–5235
Unprecedented, selective Nef reaction of secondary nitroalkanes
promoted by DBU under basic homogeneous conditions
Roberto Ballini,* Giovanna Bosica, Dennis Fiorini and Marino Petrini
Dipartimento di Scienze Chimiche, Universita` di Camerino, Via S. Agostino 1, I-62032 Camerino, Italy
Received 31 May 2002; accepted 4 June 2002
Abstract—Secondary nitrocompounds can be converted into the corresponding ketones under basic conditions using DBU in
acetonitrile. Primary nitroalkanes are unaffected by these conditions. © 2002 Elsevier Science Ltd. All rights reserved.
Nitro compounds are very powerful synthetic tools
because they facilitate the carbonꢀcarbon bond-forming
processes and, moreover, they can be easily converted
into many other useful functionalities.1 The conversion
of primary or secondary nitroalkanes into aldehydes or
ketones is normally accomplished by the Nef reaction,
which is one of the most important transformations of
the nitro compounds.
the combined use of tributylphosphine–diphenyl-
disulfide.15 However, the use of the above conditions is
not of general utility since they are often incompatible
with polyfunctional substrates and none of these are
able to convert selectively a secondary nitro group in
the presence of a primary one. In fact, to the best of
our knowledge, although some oxidative methods16
show selectivity towards the transformation of primary
nitro compounds, these procedures are seldom utiliz-
able in synthetic processes since the primary nitro
group is often partially converted into aldehydes,16a
halonitroalkanes,5 or into an intractable mixture of
products.16b Direct cleavage of the nitronate anion
under basic conditions is a rather uncommon process
that has been observed on dry activated silica gel17 or
when proton transfer is facilitated by a neighboring
group participation.18 1,8-Diazabicyclo [5.4.0]undec-7-
ene (DBU), a tertiary amidine base, has been largely
used to promote the addition of nitroalkanes to elec-
trophilic substrates for the formation of both car-
bonꢀcarbon single bonds19 and carbonꢀcarbon double
bonds.20 Now, we have found an unprecedent
behaviour of DBU as a new reagent for the regio- and
chemoselective conversion of secondary nitro com-
pounds into ketones, under homogeneous basic condi-
tions. Thus, treating 1 equiv. of the nitroalkane with 2
equiv. of DBU in CH3CN, and heating at 60°C for 1–5
days, the secondary nitro compounds 1a–k (Eq. (1)) are
converted into the corresponding ketones 2a–k in 54–
80% yields (Table 1), while the primary nitroalkanes
1l–n are unreacted.21
The original Nef reaction involves the formation of an
alkaline nitronate, followed by a quick solvolysis in
aqueous or alcoholic strong acidic solution.2 This pro-
cedure clearly requires rather harsh conditions that are
often incompatible with many acid-sensitive functional
groups that could be present in the molecular frame-
work. For this reason a number of synthetic methods
have been devised in order to perform cleavage of the
carbonꢀnitrogen bond in nitroalkanes under mild and
selective conditions.3 Hydrolysis of the CꢁN bond of
nitronates can be replaced by an oxidative cleavage that
can be carried out with several reagents including
KMnO4,4 mCPBA,5 MoO5–pyridine–HMPA complex,6
ceric ammonium nitrate,7 ozone,8 sodium chlorite,9
sodium nitrite in DMSO10 and dimethyldioxirane
(DMD).11 On the other hand, reduction of the nitro
group to the corresponding oxime or imine followed by
hydrolysis to the parent carbonyl derivative allows an
alternative route for this transformation. The utiliza-
tion of titanium trichloride as reducing agent12 has been
followed by the introduction of other reagents such as
vanadium(II) chloride,13 chromium(II) chloride14 and
O
NO2
R2
1a-k
DBU, CH3CN
60°C, 1-5 days R1
Keywords: nitro compounds; ketones.
R2
R1
(1)
* Corresponding author. Tel.: +39 0737 402270; fax: +39 0737
402297; e-mail: roberto.ballini@unicam.it
2a-k
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01039-0

5234
R. Ballini et al. / Tetrahedron Letters 43 (2002) 5233–5235
Table 1. Conversion of secondary nitroalkanes 1a–k to
ketones 2a–k
nitroalkanes in water or other hydroxylic solvents (pKa
MeNO2=10.2), however, the acidity is considerably
lower when these derivatives are used in other solvents
as acetonitrile, THF or benzene in which proton trans-
fer can be suppressed. Davis and co-workers22 have
demonstrated that DBU in acetonitrile is not able to
efficiently convert nitroethane into the corresponding
nitronate since only a broadening of the a-protons
Entry
Nitrocompound 1
Time (days) Yielda (%)
R1
R2
a
b
Ph(CH2)3
MeOCO(CH2)2 MeOCO(CH2)4
CH3(CH2)2
4
2
60
65
1
signals in H NMR is observed. The situation could be
different when secondary nitroalkanes are used as sub-
strates since they are slightly more acidic than the
primary ones. It is therefore possible that DBU is able
to produce a complex 3, as depicted in Scheme 1, that
behaves similarly to a protonated nitronic acid interme-
diate in the classical Nef reaction. In the absence of a
significant amount of water, it is conceivable that,
similarly to what was observed with nitrones23 that are
structurally related with nitronic acids, an equilibrium
occurs between the complex 3, the oxaziridine 4 and the
hydroxynitroso derivative 5. The last intermediate
would eliminate hyponitrous acid affording the car-
bonyl derivative as the final product.
O
O
c
MeOCO(CH2)2
4
80
CH2
d
e
MeOCO(CH2)4 CH3CO(CH2)2
CH3
5
1
61
58
Me(CH2)2CO-
(CH2)2
C2H5CO(CH2)2
C2H5CO(CH2)2
f
g
CH3
CH3(CH2)3
4
5
55
59
O
h
CH3
5
54
i
j
k
l
m
n
CH3CO(CH2)2 C2H5CO(CH2)2
MeOCO(CH2)2 MeOCO(CH2)2
HOCH2(CH2)4 MeOCO(CH2)2
1
5
2
–
–
–
55
65
56
–
–
–
Table 2. Conversion of nitroalkane 1a to ketone 2a using
different bases
CH3(CH2)4
H
H
H
Entry
Basea
Time (days)
Yieldb % (conversion %)c
MeOCO(CH2)3
CH3(CH2)8
1
2
3
4
5
6
7
DBU
DBN
TBD
TMG
Bu3P
Ph3P
4
3
1
3
3
3
3
60 (100)
50 (80)
55 (96)
25 (33)c
5 (8)c
a Yields of pure, isolated products.
We also tried THF as solvent, but CH3CN gives better
yields in shorter reaction times. We also investigated
the selective conversion of a secondary nitroalkane 1a
in the presence of the primary nitroalkane 1n; after 4
days the GC analysis indicated a complete conversion
of 1a to 2a in 58% yield, while 1n was recovered
unchanged from the reaction mixture in 92% yield.
7 (10)c
8 (12)c
DMAP
a DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene; DBN: 1,5-diazabicyclo-
[4.3.0]non-5-ene; TBD: 1,5,7-triazabicyclo[4.4.0]dec-5-ene; TMG:
tetramethylguanidine; DMAP: 4-dimethylaminopyridine.
b Yields of pure, isolated products.
c Yields evaluated by GC analysis using an internal standard.
Although DBU is the most effective reagent tested for
this conversion, other bases of similar structure are able
to carry out the same transformation to some extent.
Data reported in Table 2 refer to the transformation of
nitroalkane 1a into ketone 2a and show that 1,5-diaza-
bicyclo[4.3.0]non-5-ene (DBN) has an efficiency simi-
lar to that observed with DBU (entry 2). Guanidines
display a variable behaviour depending on their struc-
tural features; N,N,N,N-tetramethylguanidine (TMG)
gives unsatisfactory results (entry 4), while a bicyclic
guanidine such as 1,5,7-triazabicyclo[4.4.0]dec-5-ene
(TBD) possesses a good activity towards the conversion
of 1a into 2a (entry 3). However, the efficiency of TBD
seems to be strongly affected by the nature of
nitroalkane employed, since with other substrates the
yields of the process are lower compared with those
obtained with DBU.
Triphenylphosphine, tributylphosphine as well as 4-
dimethylaminipyridine (DMAP) are unable to react
efficiently with the secondary nitroalkanes tested as
reported in Table 2 (entries 5–7). It is generally under-
stood that a certain acidity level is displayed by
Scheme 1.

R. Ballini et al. / Tetrahedron Letters 43 (2002) 5233–5235
5235
In conclusion a one-step conversion of secondary nitro-
compounds into the corresponding carbonyl derivatives
can be carried out in good yield using DBU in acetoni-
trile. Many functionalities that are difficult to preserve
under acidic (i.e. ketal), oxidative (i.e. hydroxyl), or
reductive (i.e. carbonyl) conditions that are generally
employed for the Nef reaction are unaffected by this
process. Moreover, the efficient chemoselective conver-
sion of a secondary nitro group in the presence of a
primary one is now possible.
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Acknowledgements
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This work was carried out in the framework of the
National Project ‘Stereoselezione in Sintesi Organica.
Metodologie ed Applicazioni’ supported by MIUR
(Ministero dell’Istruzione dell’Universita`
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della
Ricerca), Italy and by the University of Camerino.
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