Uncatalyzed conversion of linear α-nitro ketones into amides by reaction with primary amines under solventless conditions

Article abstract of DOI:10.1016/S0040-4020(03)00022-X

The reaction of linear α-nitro ketones with primary amines allows the formation of amides through the cleavage of the carbon-carbon bond between the carbonyl group and the carbon-nitro group moiety, promoted by the nucleophilic effect of the amine. The re

Full text of DOI:10.1016/S0040-4020(03)00022-X

Tetrahedron 59 (2003) 1143–1145
Uncatalyzed conversion of linear a-nitro ketones into amides by
reaction with primary amines under solventless conditions
*
Roberto Ballini, Giovanna Bosica and Dennis Fiorini
`
Dipartimento di Scienze Chimiche dell’Universita, Via S. Agostino 1, 62032 Camerino (MC), Italy
Received 31 October 2002; revised 4 December 2002; accepted 2 January 2003
Abstract—The reaction of linear a-nitro ketones with primary amines allows the formation of amides through the cleavage of the carbon–
carbon bond between the carbonyl group and the carbon-nitro group moiety, promoted by the nucleophilic effect of the amine. The reaction is
performed at room temperature, without any catalyst and/or solvent. q 2003 Elsevier Science Ltd. All rights reserved.
The use of a-nitro ketones in organic synthesis is of great
interest.1 – 17 In fact, given the well-known chemical
differences between the carbonyl and carbon-nitro groups,
their juxtaposition on two adjacent positions offers a new
reactivity pattern, peculiar to this class of compounds.
However, cyclic and linear a-nitro ketones have different
reactivities and are utilized differently: (i) 2-nitrocyclo-
Scheme 1.
alkanones are of great importance because a typical
We tried the reaction with different, selected a-nitro ketones
reactivity of these compounds is the cleavage of the
and amines in order to verify the synthetic potential of our
C(1)–C(2) bond by the action of external1,14 or internal2
method. Although this reaction produces, in general, good
nucleophiles under different catalytic conditions (basic,
yields (Table 1) of the compound 3, the reaction times and
acidic, reductive, oxidative, etc.), (ii) linear 2-nitro ketones
the efficiency seem to be dependent upon the bulk of the
being far less prone to carbon–carbon cleavage are mainly
alkyl groups R1 (3i) and R2 (3i,m). Moreover, when the
employed in the synthesis of ketones,3 a-deuterated
amine is an aromatic one (R2¼Ph, 3dh,l,p) the efficacy of
ketones,3 alkanes,5 b-nitroalkanols,15 and many important
the reaction, due to reduced nucleophilicity of the amine,
natural products,3,4,6 by manipulation of the carbonyl or/and
decreases.
the nitro group.
Table 1. Synthesis of amides 3 from linear a-nitro ketones 1
Previously, we treated a-nitro ketones with primary amino
derivatives (NH2–Y; Y¼OH, NHTs) in order to obtain the
R
R1
R2
Reaction time
(h)
Yielda
(%) of 3
corresponding imines,3,5,12,16,17 without observing any
carbon–carbon cleavage of the starting a-nitro ketone.
Now, we wish to report a surprising result obtained by the
reaction of the title nitro ketones with primary aliphatic and
aromatic amines. As reported in Scheme 1, treatment of an
open chain a-nitro ketone 1 with a primary amine 2 (mole
ratio 1/2¼1:5), without any catalyst and solvent, allows,
after an appropriate time and at room temperature, the
cleavage of the carbon–carbon (carbonyl and carbon atom
bearing the nitro group) bond with the formation of the
amide 3.
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
PhCH2CH2 CH3CH2
PhCH2CH2 CH3CH2
PhCH2CH2 CH3CH2
PhCH2CH2 CH3CH2
(CH3)2CH
CH3(CH2)4
PhCH2
15
15
15
168
4
Quant.
Quant.
Quant.
75
Quant.
Quant.
Quant.
20
Ph
Ph
Ph
Ph
Ph
CH3
CH3
CH3
CH3
(CH3)2CH
CH3(CH2)4
PhCH2
5
5
Ph
312
240
15
15
960
140
5
CH3(CH2)3 (CH3)2CH (CH3)2CH
CH3(CH2)3 (CH3)2CH CH3(CH2)4
CH3(CH2)3 (CH3)2CH PhCH2
CH3(CH2)3 (CH3)2CH Ph
42
Quant.
Quant.
31
Ph
Ph
Ph
Ph
H
H
H
H
(CH3)2CH
CH3(CH2)4
PhCH2
10
Quant.
Quant.
6
Keywords: nitro ketones; amides; carbon–carbon bond; cleavage;
solventless.
6
150
Ph
*
Corresponding author. Tel.: þ390737402270; fax: þ390737402297;
a
e-mail: roberto.ballini@unicam.it
Yield of pure isolated product.
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00022-X

1144
R. Ballini et al. / Tetrahedron 59 (2003) 1143–1145
190, 176, 148, 133, 105, 91 (100), 77, 44. Anal. calcd for
C14H21NO: C, 76.67; H, 9.65; N, 6.39. Found: C, 76.75; H,
9.74; N, 6.31.
1.2.3. Compound 3c. Yield¼2.38 g (quant.); light yellow
solid, mp¼82–838C. Spectroscopic data consistent with the
literature.21
Scheme 2.
1.2.4. Compound 3d. Yield¼1.68 g (75%); light yellow
solid, mp¼97–998C. Spectroscopic data consistent with the
literature.22
Our discovery is the first example of the cleavage of linear
a-nitro ketones by an amine and represents a further
extension of the potential of the a-nitro ketones in organic
synthesis and, moreover, since these compounds can be
easily prepared from alkenes1,14,18 A or ketones1,14,19 B, our
methodology can be regarded as a formal way to convert
alkenes or ketones into amides (Scheme 2).
1.2.5. Compound 3e. Yield¼1.62 g (quant.); colourless
solid; mp¼102–1038C. Spectroscopic data consistent with
the literature.23
1.2.6. Compound 3f. Yield¼1.9 g (quant.); colourless
solid; mp¼32–348C. Spectroscopic data consistent with
the literature.24
In conclusion, we report a new reactivity of a-nitro ketones,
under environmentally friendly conditions, with potential
applications in organic synthesis.
1.2.7. Compound 3g. Yield¼2.1 g (quant.); colourless
solid; mp¼128–1308C. Spectroscopic data consistent with
the literature.25
1. Experimental
1.1. General
1.2.8. Compound 3h. Yield¼0.394 g (20%); colourless
solid; mp¼160–1628C. Spectroscopic data consistent with
the literature.26
13C and 1H NMR spectra were recorded in CDCl3 or DMSO
at 50 and 200 MHz, respectively, on a Varian Gemini
instrument; J values are given in Hz. IR spectra were
recorded with a Perkin–Elmer 257 spetrcophotometer.
Mass spectra were determined on a capillary GC/MS
operating in the split mode with helium carrier gas and
fitted with mass-selective detector (MDS). The reactions
were monitored by TLC or GC performed on a Carlo Erba
Fractovap 4160 using a capillary column of Duran Glass,
stationary phase OV1. Microanalyses were performed using
a Fisons model EA 1108. The products were purified by
flash chromatography on Merck silica gel.
1.2.9. Compound 3i. Yield¼0.6 g (42%); colourless waxy
solid. Spectroscopic data consistent with the literature.27
1.2.10. Compound 3j. Yield¼1.7 g (quant.); colourless
waxy solid. IR (film) 3294, 1646 cm21; 1H NMR (CDCl3) d
0.85–0.98 (m, 6H), 1.24–1.70 (m, 10H), 2.16 (t, 2H,
J¼7.5 Hz), 3.24 (q, 2H, J¼6.6 Hz), 5.48 (bs, 1H); 13C NMR
(CDCl3) d 173.0, 39.5, 36.7, 29.4, 29.1, 27.9, 22.4, 22.4,
14.0, 13.8; EI MS 171 (Mþ), 156, 142, 129, 114, 85 (100),
73, 57, 41, 30. Anal. calcd for C10H21NO: C, 67.09; H,
11.96; N, 9.78. Found: C, 66.98; H, 12.04; N, 9.74.
1.2.11. Compound 3k. Yield¼1.9 g (quant.); colourless
solid; mp¼39–418C. IR (film) 3291, 1634 cm21; 1H NMR
(CDCl3) d 0.94 (t, 3H, J¼7.1 Hz), 1.21–1.47 (m, 2H),
1.56–1.75 (m, 2H), 2.23 (t, 2H, J¼7.5 Hz), 4.45 (d, 2H,
J¼5.5 Hz), 5.77 (bs, 1H), 7.23–7.41 (m, 5H); 13C NMR
(CDCl3) d 173.0, 138.4, 128.7, 127.8, 127.5, 43.6, 36.6,
27.8, 22.4, 13.8; EI MS 191 (Mþ), 176, 162, 149, 106, 91
(100), 77. Anal. calcd for C12H17NO: C, 75.35; H, 8.96; N,
7.32. Found: C, 75.44; H, 9.02; N, 7.24.
1.2. General procedure for the conversion of linear
a-nitro ketones 1 into amides 3
The amine 2 (50 mmol) is mixed with the a-nitro ketone 1
(10 mmol) and the mixture is left at room temperature for
the appropriate time (see Table 1). Then, diethyl ether
(100 mL) was added, the organic layer was washed with 2N
HCl (in order to remove the excess of the amine, 3£10 mL),
dried (MgSO4), evaporated and the crude compound 3 is
then purified by flash chromatography (EtOAc/petroleum
ether, 3:7).
1.2.12. Compound 3l. Yield¼0.549 g (31%); colourless
solid; mp¼61–638C. IR (film) 3291, 1634 cm21; 1H NMR
(CDCl3) d 0.95 (t, 3H, J¼7.0 Hz), 1.20–1.48 (m, 2H),
1.56–1.75 (m, 2H), 2.36 (t, 2H, J¼7.0 Hz), 7.03–7.61 (m,
6H), 7.45–7.61 (m, 2H); 13C NMR (CDCl3) d 171.4, 137.8,
128.8, 124.0, 119.7, 37.4, 27.5, 22.2, 13.6; EI MS 177 (Mþ),
148, 135, 120, 93 (100), 77. Anal. calcd for C11H15NO: C,
74.54; H, 8.53; N, 7.90. Found: C, 74.65; H, 8.64; N, 7.81.
1.2.1. Compound 3a. Yield¼1.906 g (quant.); light yellow
solid, mp¼89–908C. Spectroscopic data consistent with the
literature.20
1.2.2. Compound 3b. Yield¼2.183 g (quant.); light yellow
waxy solid. IR (film) 3300, 1638 cm21; 1H NMR (CDCl3) d
0.86 (t, 3H, J¼7.0 Hz), 1.1–1.3 (m, 4H), 1.3–1.4 (m, 2H),
2.44 (t, 2H, J¼7.6 Hz), 2.94 (t, 2H, J¼7.6 Hz), 3.1–3.2 (m,
2H), 5.28 (bs, 1H), 7.1–7.2 (m, 2H), 7.3–7.4 (m, 3H); 13C
NMR (CDCl3) d 171.8, 139.1, 128.7, 127.8, 127.4, 39.4,
36.5, 31.5, 29.3, 27.4, 24.5, 15.3; EI MS 219 (Mþ), 204,
Acknowledgements
This work was carried out in the framework of the National

R. Ballini et al. / Tetrahedron 59 (2003) 1143–1145
1145
14. Ballini, R. Synlett 1999, 1009.
15. Ballini, R.; Bosica, G.; Marcantoni, E.; Vita, P.; Bartoli, G.
J. Org. Chem. 2000, 65, 5854.
Project ‘Stereoselezione in Sintesi Organica. Metodologie e
Applicazioni’ supported by MIUR-Italy, by Fondazione
della Cassa di Risparmio della Provincia di Macerata and by
the University of Camerino.
16. Ballini, R.; Barboni, L.; Filippone, P. Chem. Lett. 1997, 475.
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Pitre, S. V.; Reddy, M. V. R.; Kumareswaran, R.; Vankar,
Y. D. J. Org. Chem. 1999, 64, 4509.
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