Microwave solvent-free synthesis of nitrocyclohexanols

Article abstract of DOI:10.1016/j.tetlet.2003.10.148

New nitrocyclohexanols 3a-f are synthesized by a clean and original method from nitromethane 1 and unsaturated ketones 2a-f in the presence of solid potassium fluoride-alumina under solvent-free conditions coupled with microwave irradiation. The reaction involves a double and diastereoselective Michael addition followed by ring closure. Another diastereomer 3′, which differs by the configuration of C-4, is obtained in the presence of piperidine and EtOH at room temperature.

Full text of DOI:10.1016/j.tetlet.2003.10.148

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 391–395
Microwave solvent-free synthesis of nitrocyclohexanols
Olivier Correc,a Karine Guillou,a Jack Hamelin,a Ludovic Paquin,a
b
Francoise Texier-Boulleta, and Loıc Toupet
*
€
ß
aSynthꢀese et Electrosynthꢀese Organiques 3, UMR 6510, CNRS et Universiteꢁ de Rennes I, Campus de Beaulieu, 35042 Rennes, France
bGroupe Matiꢀere Condenseꢁe et Mateꢁriaux, UMR C66-26, Universiteꢁ de Rennes I, Campus de Beaulieu, 35042 Rennes, France
Received 28 May 2003; revised 22 October 2003; accepted 24 October 2003
Abstract—New nitrocyclohexanols 3a–f are synthesized by a clean and original method from nitromethane 1 and unsaturated
ketones 2a–f in the presence of solid potassium fluoride–alumina under solvent-free conditions coupled with microwave irradiation.
The reaction involves a double and diastereoselective Michael addition followed by ring closure. Another diastereomer 30, which
differs by the configuration of C-4, is obtained in the presence of piperidine and EtOH at room temperature.
Ó 2003 Elsevier Ltd. All rights reserved.
1. Introduction
Ph
O2N
Ph
5
4
3
6
1
CH3NO2
The reactivity of primary nitroalkanes especially nitro-
methane1 with electrophilic gem-disubstituted alkenes,
has been largely studied in our laboratory under solvent-
free conditions coupled with microwave irradiation,
with supported reagents on various mineral oxides2–4 in
some cases. As part of our program to develop the
synthesis of carbocycles after Michael additions in this
environmentally benign process, we studied the reaction
of nitromethane 1 with alkenes bearing one electron-
withdrawing group such as unsaturated a,b-enones 2a–f
and we report here our preliminary results.
2 PhCH=CHCOPh
OH
Ph
2
COPh
2a
1
3a
Scheme 1.
Prolabo at 90 °C (monitored temperature5) reached after
5 min and maintained 15 min (Scheme 1). 3a Was iso-
lated after cooling to room temperature, addition of
boiling acetonitrile, elimination of solids by filtration
and acetonitrile evaporation. The reaction is highly
diastereoselective: only one isomer (A) was detected by
1H NMR spectroscopy of the crude product. The rela-
tive configuration of the carbons of isomer A has been
established by X-ray analysis6;7 (Fig. 1).
2. Results and discussion
For example, by mixing nitromethane
1 (0.32 g,
The pure product is obtained after crystallization in the
appropriate solvent (see Table 1). Classical activation of
the reaction in an oil bath with the same temperature
profile, does not allow the formation of cyclohexanol.
Obviously, this is an evidence for a specific microwave
reactivity. If the reaction is realized in EtOH 95%
(anhydrous EtOH or diethyl oxide are inefficient), with
piperidine in excess (1.5 equiv), after 4 days at room
5.2 mmol) and chalcone 2a (1 g, 4.8 mmol) without sol-
vent in the presence of a mixture, in an unusual ratio, of
neutral Alumina 60 Merck (2 g) and a potassium
fluoride (3 g)––the molar ratio of KF and Al2O3 was
carefully optimized––we obtained the new nitrocyclo-
hexanol 3a (60% yield) after 20 min under microwave
irradiation in a monomode reactor Synthewave 402â
1
temperature, the H NMR spectrum of the crude reac-
tion mixture exhibits signals for four products: the well-
known monoadduct 5a (34%),10 the bis-adduct 6a
(24%),8–12 the heteroadduct 4a (15%) (Scheme 2) and
another isomeric cyclohexanol 30a (isomer B: 24%
Keywords: nitrocyclohexanols; a,b-enones; Michael additions; alu-
mina–potassium fluoride; solvent-free reactions; microwave activation.
* Corresponding author. Tel.: +33-2-23-23-57-82; fax: +33-2-23-23-63-
74; e-mail: francoise.texier@univ-rennes1.fr
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.148

392
O. Correc et al. / Tetrahedron Letters 45 (2004) 391–395
Ph
CH2COPh
+
2a
N H
N
4a
Scheme 2.
after prototropy with a second molecule of chalcone to
give either 6a after protonation or cyclohexanol 3a after
intramolecular nucleophilic attack on the carbon of the
benzoyl group and subsequent protonation. The for-
mation of isomers A or B depends on the possibility of
Figure 1. X-ray of 2-benzoyl-4-nitro-1,3,5-triphenyl-cyclohexan-1-ol
3a (isomer A).
obtained after crystallization in acetone). Its structure
was established by X-ray analysis (Fig. 2).6 Isomers A
and B differ by the configuration of carbon-4. Other
bases such as triethylamine or potassium tert-butoxide
were useless.
The Michael reaction is one of the most general methods
for C–C bond formation: the addition of nitroalkanes
has been largely reviewed.13 The formation of cyclic
compounds from chalcones and nitromethane has no
precedent in the literature. We propose the following
mechanism (Scheme 3): nitromethane carbanion reacts
with chalcone and leads to 5a after protonation or reacts
Figure 2. X-ray of 2-benzoyl-4-nitro-1,3,5-triphenyl-cyclohexan-1-ol
30a (isomer B).
Table 1. Preparation of nitrocyclohexanols 3a–f on KF/Al2O3 under microwave irradiation
a,b-Enone 2
3
Molecular formula
3a–f Yield (%)a;b
PhCH@CHCOPh
PhCH@CHCOMe
a
b
C31H27NO4
C21H23NO4
65 (EtOH)
55 (Et2O)
c
Calcd 353.162
Found 353.164
d
p-MeC6H4CH@CHCOPh
p-MeOC6H4CH@CHCOPh
p-ClC6H4CH@CHCOPh
PhCH@CHCOC6H4-p-OMe
c
d
e
f
C33H31NO4
Calcd 505.225
45 (EtOH) after 1 h
20 (EtOH) after 1 h
60 (Et2O)
Found 505.225
e
C33H31NO6
Calcd 537.215
Found 537.213
C31H25Cl2NO4
f
Calcd 515.118
Found 515.116
g
C33H31NO6
Calcd 507.2171
Found 507.2159
30 (EtOH)
a After 30 min at 90 °C under microwave irradiation. No reaction was observed at room temperature.
b Pure crystallized product in appropriate solvent.
c HRMS calcd for Mþꢀ; Anal. Calcd for C21H23NO4: C, 71.37; H, 6.56; N, 3.96. Found: C, 71.15; H, 6.48; N, 4.01.
d HRMS calcd for Mþꢀ
.
e HRMS calcd for Mþꢀ; Anal. Calcd for C33H31NO6: C, 73.73; H, 5.81; N, 2.61. Found: C, 73.36; H, 5.77; N, 2.67.
f HRMS calcd for Mþꢀ)NO; Anal. Calcd for C31H25Cl2NO4: C, 68.14; H, 4.61; N, 2.56. Found: C, 67.98; H, 4.55; N, 2.60.
g HRMS calcd for Mþꢀ)NO.

O. Correc et al. / Tetrahedron Letters 45 (2004) 391–395
393
Ph
5a
O2N
+H+
COPh
-H+
Ph
Ph
+H+
-H+
Ph
CH2NO2
O2N
COPh
Ph
O2N
COPh
COPh
1
st addition
COPh
H
Ph
Ph
COPh
Ph
COPh
R
O
H+
+H+
-H+
OH
Ph
Ph
O2N
O2N
H
Ph
Ph
NO2
Ph
COPh
3a or 3'a
6a
2
nd addition
R = COPh
Ph
Ph
Ph
H
O
R
H
O
Ph
H
Ph
H
O
H
Ph
NO2
N
Ph
O
O
+H+
+H+
HE
HC
HE
HC
OHG
OH
Ph
R
R
O2N
Ph
HD
Ph
HA
Ph
Ph
HA
Ph
Ph
=
O2N
R
HF
HF
Ph
NO2
Ph
OH
HB
HD
HB
3'a
3a
isomer B
isomer A
Scheme 3.
R1
adsorption of polar groups on the solid KF/Al2O3
(Scheme 3).
R1
With the aim to study the influence of the carbonyl
substitution, we have realized the reaction of nitro-
methane with benzalacetone 2b in analogous conditions
(90 °C, 30 min; 2b: 10 mmol; 1: 10.8 mmol; KF/Al2O3:
2.9 g/2 g). The isolated pure product 3b (isomer A: Fig.
3) after crystallization in ether is 55%. In the same way,
+
CH3NO2
O2N
5
2
4
3
6
1
R2
R2
OH
O
R1
O
R2
2a-f
1
3a-f
R1 = H, p-Me, p-OMe, p-Cl
R2 = Ph, p-MeO-C6H4, Me
Scheme 4.
the reaction of 2f leads after 30 min to the corresponding
nitrocyclohexanol 3f (isolated product: 30%). The sub-
stitution of the aromatic ring by an electron-donating
group (Me, OMe) or an electron-withdrawing group
(Cl) has for consequence a decrease of the reactivity with
Me or MeO (3c, 3d, 3f) (Scheme 4). Table 1 gives our
preliminary results. The various chalcones were pre-
pared using our previously reported methods.14
3. Conclusion
In conclusion, we have set up a new diastereoselective
synthetic process for the formation of original nitrocy-
clohexanols by means of tandem Michael additions and
Figure 3. X-ray of 2-acetyl-4-nitro-1-methyl-3,5-diphenyl-cyclohexan-
1-ol 3b (isomer A).

394
O. Correc et al. / Tetrahedron Letters 45 (2004) 391–395
intramolecular cyclization using neat nitromethane
and a,b-enones supported on KF/Al2O3 surface, in
solvent-free conditions coupled with microwave irradi-
ation. Furthermore, in the framework of the 5th RTDP
ÔCompetitive and Sustainable GrowthÕ, we are actually
measuring the dielectric constants e0 and e00 under
407 variables and 5563 observations: R ¼ 0:0425,
RW ¼ 0:0954 and SW ¼ 1:012 (Dq 6 0:22 e Aꢀ3).
ꢂ
Acknowledgements
microwave irradiation with the active collaboration of
15a
ꢀ
Microondes Energie Systemes (MES) in Paris. We are
also studying these reactions in Liverpool15b by means of
a free electron laser, which produces 8.47 GHz micro-
waves. We will fully report later about this.
We thank Dr. Perrocheau J. for helpful discussions
about NMR data. One of us (L.P.) thanks E.C. for
financial support (5th RTDP).
This work is an another example of organic synthesis
in the area of Green Chemistry.16;17
References and Notes
Crystallographic data (excluding structure factors) for
the structures 3a, 30a and 3b reported in this paper have
been deposited with the Cambridge Crystallographic
Data Centre as supplementary publication numbers
CCDC 211264–211266. Copies of the data can be
obtained free of charge on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK [fax: +44(0)-
1223-336033 or e-mail: deposit@ccdc.cam.ac.uk].
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1
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2
3
CDCl3): d 2.25 (dd, 1H, CHa, J ¼ 14 Hz, J ¼ 3:5 Hz),
2
4
2.51 (td, 1H, CHb, J ¼ 14 Hz, J ¼ 2:5 Hz), 4.06 (m,
1H, CHc), 4.13–4.23 (m, 2H, CHd and CHe), 4.49 (d,
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1H, CHf , J ¼ 11:1 Hz), 5.39 (d, 1H, OHg, J ¼ 2:5 Hz),
6.68–7.56 (m, 20H, 4C6H5); 13C NMR (75 MHz,
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0
1
ꢂ
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2
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1H, CHa, J ¼ 14 Hz, J ¼ 4 Hz), 3.34 (td, 1H, CHb,
2J ¼ 14 Hz, J ¼ 2:5 Hz), 4.12–4.20 (m, 2H, CHc and
4
CHe), 5.07 (d, 1H, OHg, 4J ¼ 2:5 Hz), 5.13 (t, 1H, CHd,
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3J ¼ 4 Hz), 5.45 (d, 1H, CHf , J ¼ 12:3 Hz), 7.0–7.65
(m, 20H, C6H5); 13C NMR (75 MHz, CDCl3): d 37.12
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C-2), 75.33 (tm, C-4), 145.37 (s, C-1), 124.9–138.5 (m,
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