One-pot diastereoselective synthesis of 2-acyl-4-nitrocyclohexanol derivatives in aqueous medium

Article abstract of DOI:10.1016/S0040-4020(00)00324-0

The reaction of primary nitroalkanes with conjugated enones, in water and in the presence of K₂CO₃ as base, allows the synthesis of 2-acyl-4- nitrocyclohexanol derivatives in which the diastereoisomer (±)- (1S*,2R*,5R) is highly pred

Full text of DOI:10.1016/S0040-4020(00)00324-0

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 4095±4099
One-Pot Diastereoselective Synthesis of
2-Acyl-4-nitrocyclohexanol Derivatives in Aqueous Medium
a
a
b
a
Roberto Ballini,a, Luciano Barboni, Giovanna Bosica, Paolino Filippone and Sabina Peretti
*
a
Á
Dipartimento di Scienze Chimiche dell'Universita, Via S. Agostino n. 1, 62032 Camerino, Italy
Á
Istituto di Chimica Organica della Facolta di Scienze, Piazza della Repubblica n. 13, 61029 Urbino, Italy
b
Dedicated to Prof. Goffredo Rosini on the occasion of his 60th birthday
Received 23 February 2000; revised 27 March 2000; accepted 13 April 2000
AbstractÐThe reaction of primary nitroalkanes with conjugated enones, in water and in the presence of K2CO3 as base, allows the synthesis
of 2-acyl-4-nitrocyclohexanol derivatives in which the diastereoisomer (^)-(1Sp,2Rp,5R) is highly predominant. The reaction proceeds by
double Michael addition of the nitroalkane to the enone, followed by intramolecular aldol reaction. q 2000 Elsevier Science Ltd. All rights
reserved.
Introduction
ketones 2, in the presence of potassium carbonate as
base, provides after 24 h at the appropriate temperature
(see Table 1), the `one-pot' formation of the nitrocyclo-
hexanol derivatives 4±7 in excellent chemical and stereo-
chemical yields (Table 1).
2-Acyl-4-nitrocyclohexanol derivatives are an interesting
class of polyfunctionalized molecules bearing three stereo-
genic centers. These compounds have already been obtained
by Michael addition of nitroalkanes with 2 equiv. of a,b-
unsaturated carbonyl compounds, followed by intra-
molecular aldol reaction of the formed adduct.123 However,
the ®rst two methods reported1,2 were performed under basic
conditions, in an organic solvent, apparently without any
diastereoselectivity. Later, ruthenium dihydride, in aceto-
nitrile, was employed for this reaction and a 2:1:1:1 mixture
of diastereoisomers was obtained,3 although the assignment
of the relative stereochemistry was not described.
In recent years there has been increasing recognition that
organic reactions carried out in aqueous media offer advan-
tages over those occurring in organic solvents. In fact, the
aqueous medium is less expensive, less dangerous, environ-
ment-friendly and allows a precise control of the pH. In
addition, the reactivity and selectivity of the reaction can
be dramatically in¯uenced when carried out in water.4
Recently we discovered that nitroalkanes exhibit a remark-
able reactivity in water,5 in particular in the formation of
C±C bonds via their conjugate addition to electron de®cient
alkenes.5a,c Following these previous results, now we have
found that the reaction in water (Scheme 1) of a primary
nitroalkane 1 with two equivalents of a,b-unsaturated
Keywords: diastereoselection; nitro compounds; cyclisation; reaction in
water.
* Corresponding author. Tel.: 139-0737-402270; fax: 139-0737-637345;
e-mail: ballini@camserv.unicam.it
Scheme 1. Diastereoselective synthesis of 2-acyl-4-nitrocyclohexanol
derivatives 4±7.
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00324-0

4096
R. Ballini et al. / Tetrahedron 56 (2000) 4095±4099
Table 1. Synthesis of nitrocyclohexanol derivatives 4±7
R1
R2
Overall yield (%) of 4±7
Ratio of
diastereomeric
mixture,
determined by GCa
a
b
c
d
e
e
g
h
i
Me
Et
Me
Me
Me
Me
Me
Me
Me
Et
90b
85b
93b
95c
95c
75c
70c
77c
75c
80c
5.4:1:1
12.8:3:1
9:2.2:1
12:5.2:1
9:2:1
17:1
16.5:1:1
18.5:4:2:1
27:5:2:1
17:3.5:1.5:1
Figure 2. NOE correlations of 5a.
n-Pr
n-Bu
n-C5H11
i-Pr
Ph
Me
Et
Me
arrangement7 (see bold bonds in Fig. 1) that is made pos-
sible by the hydrogen bond between the hydroxyl and the
acetyl groups. As previously reported,3 it reveals that the
hydroxyl and the acetyl group are cis and the assignation of
other coupled protons becomes quite easy. The relative
stereochemistry of C-1 and C-2 substituents was con®rmed
by the ROESY spectrum, which revealed the spatial
proximity between C-2 methyl and H-1, and between C-2
hydroxyl proton and equatorial H-3. Moreover, the C-5
methyl showed NOE correlation with axial H-6 and axial
H-4, con®rming its b orientation.
Et
n-Pr
j
a The ®rst number refers to the diastereomer 4.
b Reaction performed at room temperature.
c Reaction performed at 608C.
Results and Discussion
Analogous considerations permitted the proton signal
assignment of compounds 5a (COSY spectrum) and 6a
(selective decoupling). In both compounds the coupling
constants of the H-1 signal (5a: Jˆ13.1 and 3.5 Hz. 6a:
Jˆ13.4 and 3.2 Hz) indicate its axial orientation.
The ®rst step of the reaction is the double Michael addition
of the nitroalkane to the enone, followed by, in situ, intra-
molecular aldol reaction of the adduct 3. The cyclohexanols
4± 7 are obtained in 70±95% yield and the diastereomer 4 is
largely predominant (Table 1). As a model reaction, we take
the reaction of nitroethane with methyl vinyl ketone (R1 and
R2ˆMe), the GC±MS analysis of the crude mixture showed
that all the four diastereoisomers are formed, but one of
them (7a) is present in a very small amount.
The ROESY spectrum of compound 5a revealed the b
orientation of C-2 and C-5 methyls, both showing noe
correlation with axial H-6 and axial H-4.
Moreover, irradiation of H-1 enhanced the intensity of the
OH, equatorial H-6 and axial H-3 signals, con®rming the
relative stereochemistry of C-1 and C-2 (Fig. 2).
The chromatographic puri®cation gave 4a and a mixture of
5a and 6a which were separated by fractional crystallization
(EtOAc±hexane), while 7a could not be isolated. The three
diastereoisomers isolated were in a 5:1.5:1 ratio, very
similar to that obtained by GC, showing a signi®cant
improvement of the diastereoselectivity of the reaction in
water with respect to the previously reported methods. The
structures of the three isolated diastereomers, which had
hitherto not been assigned, were elucidated on the basis of
their NMR spectra.
The 1H NMR spectrum of compound 6a showed a coupling
between OH and axial H-3, revealing the cis stereo-
chemistry of the C-2 hydroxyl and acetyl group, which
was con®rmed by the noe correlation of the C-2 methyl to
H-1 and axial H-3 (Fig. 3).
Finally, irradiation of the C-5 methyl enhanced the H-1,
equatorial H-6, equatorial H-4 and axial H-3 signals,
revealing its a orientation.
The COSY spectrum of compound 4a, the major stereo-
isomer, showed two isolated spin systems: H-1/H-6 and
H-3/H-4 respectively.6
It is worth noting that the structure of the major diastereo-
mer is in agreement with the substituent conformational
energies,8 the methyl group having the larger conforma-
tional energy value.
The relative position of the two geminal H-6 protons were
determined on the basis of their coupling to H-1; the signal
at 2.52 ppm, which shows an axial±equatorial coupling
constant (3.1 Hz) to H-1, was attributed to equatorial H-6,
whereas the signal at 1.91 ppm shows a trans diaxial
coupling constant (13.2 Hz) and was attributed to axial
H-6. The coupling of hydroxyl proton signal (3.86 ppm,
Jˆ3.0 Hz) to axial H-3 is due to their sterically ®xed `W'
The reaction was then extended to different primary
nitroalkanes and alkyl vinyl ketones and in each ®nal
product the diastereomer 4, which can be easily obtained
by chromatographic puri®cation, is highly predominant
Figure 1. NOE correlations of 4a.
Figure 3. NOE correlations of 6a.

R. Ballini et al. / Tetrahedron 56 (2000) 4095±4099
4097
(Table 1). Since in the 1H NMR spectra of compounds 4b±j
the OH proton is a doublet (J,2.5±3.0 Hz), we assumed
that in each case the OH and the acyl group are cis.3 More-
over, as the C-5 alkyl substituents in the compounds 4b±j
have a greater conformational energy than the methyl group,
they were assumed to be equatorial and, as a consequence,
the compounds 4b±j were considered to have the same
relative stereochemistry as 4a. It is worth noting that in
the examples reported the diastereoselectivity is much
higher if compared to the previously reported synthesis.3
32.48, 36.00, 55.32, 67.22, 88.11, 210.41; 13C NMR
(50 MHz, CDCl3)(d 28.86, 29.31, 31.09, 31.85, 34.05,
35.28, 53.18, 68.99, 88.48, 215.04; MS (EI) m/z 200
[M2CH3]1, 168 [M2HNO2]1, 153 [M2HNO2±CH3]1,
111, 109, 107, 93, 71, 67, 55, 43 (100). Anal. Calcd for
C10H17NO4: C, 55.80; H, 7.96; N, 6.51. Found: C, 55.69;
H, 7.88; N, 6.62.
(^)-1-[(1Sp,2Sp,5Rp)-2-Hydroxy-2,5-dimethyl-5-nitro-
cyclohexyl]-1-ethanone (5a). White crystals (EtOAc±
hexane); mp 127±1298C; IR (nujol) nmax 3565, 1710,
1
1520, 1365, 850 cm21; H NMR (300 MHz, DMSO-d6) d
Conclusions
0.96 (s, 3H), 1.42 (ddd, Jˆ13.8, 13.5, 3.6 Hz, 1H), 1.52 (s,
3H), 1.56 (ddd, Jˆ13.5, 4.1, 3.3 Hz, 1H), 1.70 (ddd, Jˆ14.6,
13.8, 4.1 Hz, 1H), 1.86 (dd, Jˆ15.5, 13.1 Hz, 1H), 2.20 (s,
3H), 2.24 (dt, Jˆ15.5, 3.5 Hz, 1H), 2.38 (ddd, Jˆ14.6, 3.6,
3.3 Hz, 1H), 2.66 (dd, Jˆ13.1, 3.5 Hz, 1H), 4.90 (s, 1H,
OH); 13C NMR (75.4 MHz, DMSO-d6) d(21.24, 28.30,
32.47, 33.13, 34.00, 38.61, 55.42, 70.12, 88.55, 211.20;
MS (EI) m/z 200 [M2CH3]1, 168 [M2HNO2]1, 153
[M2HNO2±CH3]1, 111, 109, 107, 93, 71, 67, 55, 43
(100). Anal. Calcd for C10H17NO4: C, 55.80; H, 7.96; N,
6.51. Found: C, 55.69; H, 7.88; N, 6.62.
In conclusion, we have found that our procedure for the
preparation of nitro-substituted cyclohexanol derivatives
can be carried out in water and, in addition to the obvious
economical and ecological advantages, proceeds with
higher diastereoselectivity with respect to the reported
methods.
Experimental
1
(^)-1-[(1Sp,2Rp,5Sp)-2-Hydroxy-2,5-dimethyl-5-nitro-
cyclohexyl]-1-ethanone (6a). White crystals (EtOAc±
hexane); mp 112±1148C; IR (nujol) nmax 3570, 1710,
All H NMR spectra were collected on a 300 MHz NMR
spectrometer in CDCl3 or DMSO-d6. 13C NMR were
recorded at 75.4 or 50 MHz with CDCl3 or DMSO-d6 as
reference. All mass spectra were determined on a HP5890
Series II capillary GC operating in split mode with helium
carrier gas and ®tted with a mass selective detector (MDS).
1530, 1375, 855 cm21 1H NMR (300 MHz, CDCl3) d
;
1.21 (s, 3H), 1.38 (dddd, Jˆ14.4, 13.3, 4.1, 2.5 Hz, 1H),
1.64 (s, 3H), 1.79 (ddd, Jˆ14.4, 4.4, 3.1 Hz, 1H), 1.89 (m,
1H), 2.03 (dt, Jˆ12.6, 2.8 Hz, 1H), 2.24 (s, 3H), 2.42 (dd,
Jˆ13.4, 12.6 Hz, 1H), 2.45 (ddd, Jˆ13.5, 13.3, 4.4 Hz, 1H),
2.58 (dd, Jˆ13.4, 3.2 Hz, 1H), 3.82 (d, Jˆ2.5 Hz, 1H, OH);
13C NMR (75.4 MHz, CDCl3) d 22.97, 28.65, 31.10, 31.56,
34.13, 36.06, 54.03, 69.06, 87.33, 213.69; MS (EI) m/z 200
[M2CH3]1, 168 [M2HNO2]1, 153 [M2HNO2-CH3]1,
111, 109, 107, 93, 71, 67, 55, 43 (100). Anal. Calcd for
C10H17NO4: C, 55.80; H, 7.96; N, 6.51. Found: C, 55.69;
H, 7.88; N, 6.62.
The column used was
a
HP5 capillary column
30 m£0.25 mm, with 0.25 mm ®lm thickness of 5% phenyl-
methylsilicone gum. The temperature of 658C was main-
tained for 3 min and then ramped at 158C min21 to 3008C.
The products were puri®ed by ¯ash chromatography on
Merck silica gel (0.040±0.063 mm). The enones 2 were
commercially available; the nitroalkanes 1 (R1ˆMe, Et,
n-Pr, n-Bu, n-C5H11) were commercially available or
prepared9,10 (R1ˆi-Pr, Ph) by standard procedures.
(^)-1-[(1Sp,2Rp,5Rp)-5-Ethyl-2-hydroxy-2-methyl-5-nitro-
cyclohexyl]-1-ethanone (4b). White solid (EtOAc±
hexane); mp 87±898C; IR (nujol) nmax 3550, 1720, 1560,
General procedure for the preparation of nitrocyclo-
hexanol derivatives (4±7)
1
1365, 860 cm21; H NMR (300 MHz, CDCl3) d 0.87 (t,
Nitroalkane 1 (2 mmol) and K2CO3 (0.138 g, 1 mmol) were
dissolved in water (10 ml). The solution was cooled with an
ice bath, then conjugated enone 2 (0.42 g, 5 mmol) was
added. After stirring at the appropriate temperature (room
temperature or 608C, Table 1) for 24 h, the aqueous medium
was extracted with Et2O (3£15 ml). The organic phase was
dried (MgSO4), and the crude product 4±7 was puri®ed by
¯ash chromatography and/or by crystallization (see text).
Jˆ7.5 Hz, 3H), 1.15 (s, 3H), 1.23 (m, 1H), 1.64 (ddd,
Jˆ14.5, 4.2, 2.8 Hz, 1H), 1.75±2.05 (m, 4H), 2.26 (s,
3H), 2.38 (m,1H), 2.51 (dt, Jˆ14.1, 3.0 Hz, 1H), 2.60 (dd,
Jˆ13.0, 3.4 Hz, 1H), 3.85 (d, Jˆ2.7 Hz, 1H, OH); 13C NMR
(75.4 MHz, CDCl3) d 7.78, 28.41, 28.86, 31.42, 31.68,
34.72, 34.90, 52.60, 68.81, 91.60, 214.70; MS (EI) m/z
214 [M2CH3]1, 182 [M2HNO2]1, 167 [M2HNO2-
CH3]1, 139, 123, 109, 93, 71, 55, 43 (100); Anal. Calcd
for C11H19NO4: C, 57.63; H, 8.35; N, 6.11. Found: C,
57.70; H, 8.48; N, 5.98.
(^)-1-[(1Sp,2Rp,5Rp)-2-Hydroxy-2,5-dimethyl-5-nitro-
cyclohexyl]-1-ethanone (4a). White solid (EtOAc±
hexane); mp 108±1108C; IR (nujol) nmax 3560, 1700,
(^)-1-[(1Sp,2Rp,5Rp)-2-Hydroxy-2-methyl-5-nitro-5-pro-
pylcyclohexyl]-1-ethanone (4c). White solid (EtOAc±
hexane); mp 98±1008C; IR (nujol) nmax 3650, 1690, 1535,
1520, 1370, 860 cm21 1H NMR (300 MHz, CDCl3) d
;
1.14 (s, 3H), 1.22 (dddd, Jˆ14.5, 13.8, 4.0, 3.0 Hz, 1H),
1.55 (s, 3H), 1.63 (ddd, Jˆ14.5, 4.3, 2.7 Hz, 1H), 1.91
(dd, Jˆ14.2, 13.2 Hz, 1H), 2.00 (ddd, Jˆ14.6, 13.8,
4.3 Hz, 1H), 2.25 (s, 3H), 2.39 (ddd, Jˆ14.7, 4.0, 2.7 Hz,
1H), 2.52 (dt, Jˆ14.2, 3.2 Hz, 1H), 2.61 (dd, Jˆ13.2,
3.2 Hz, 1H), 3.86 (d, Jˆ3.0 Hz, 1H); 13C NMR
(75.4 MHz, DMSO-d6) d 28.16, 28.45, 29.91, 29.94,
1
1375, 855 cm21; H NMR (300 MHz, CDCl3) d 0.88 (t,
Jˆ7.3 Hz, 3H), 1.15 (s, 3H), 1.26 (m, 3H), 1.63 (ddd,
Jˆ14.6, 4.3, 2.8 Hz, 1H), 1.77 (m, 2H), 1.88 (dd, Jˆ14.1,
13.0 Hz, 1H), 1.99 (ddd, Jˆ14.6, 13.8, 4.3 Hz, 1H), 2.25 (s,
3H), 2.38 (m,1H), 2.52 (dt, Jˆ14.1, 3.0 Hz, 1H), 2.59 (dd,

4098
R. Ballini et al. / Tetrahedron 56 (2000) 4095±4099
Jˆ13.0, 3.2 Hz, 1H), 3.85 (d, Jˆ2.6 Hz, 1H, OH); 13C NMR
(50 MHz, CDCl3) d 14.23, 17.07, 28.81, 29.63, 31.76,
32.42, 35.18, 44.38, 53.03, 69.17, 91.65, 214.95; MS (EI)
m/z 228 [M2CH3]1, 196 [M2HNO2]1, 181 [M2CH3-
HNO2]1, 153, 137, 109, 93, 71, 55, 43 (100); Anal. Calcd
for C12H21NO4: C, 59.24; H, 8.70; N, 5.76. Found: C, 59.15;
H, 8.80; N, 5.80.
3.1 Hz, 1H), 3.92 (d, Jˆ2.7 Hz, 1H, OH), 7.38 (m,5H);
13C NMR (75.4 MHz, CDCl3) d 28.34, 29.75, 31.45,
33.43, 35.21, 53.09, 68.36, 92.94, 124.73 (£2), 128.97,
129.26 (£2), 139.07, 214.28; MS (EI) m/z 231
[M2HNO2]1, 213 [M2(H2O1HNO2)]1, 169, 155, 129,
115, 105, 91, 77, 55, 43 (100); Anal. Calcd for
C15H19NO4: C, 64.97; H, 6.91; N, 5.05. Found: C, 64.90;
H, 6.95; N, 5.11.
(^)-1-[(1Sp,2Rp,5Rp)-5-Butyl-2-hydroxy-2-methyl-5-nitro-
cyclohexyl]-1-ethanone (4d). White solid (EtOAc±
hexane); mp 66±688C; IR (nujol) nmax 3510, 1690, 1545,
(^)-1-[(1Sp,2Rp,5Rp)-2-Ethyl-2-hydroxy-5-methyl-5-
nitrocyclohexyl]-1-propanone (4h). Yellow oil; IR (nujol)
1
1370, 855 cm21; H NMR (300 MHz, CDCl3) d 0.86 (t,
nmax 3505, 1690, 1540, 1375, 845 cm21 1H NMR
;
Jˆ6.9 Hz, 3H), 1.15 (s, 3H), 1.23 (m, 5H), 1.63 (ddd,
Jˆ14.7, 4.2, 2.7 Hz, 1H), 1.77 (m, 2H), 1.88 (dd, Jˆ14.0,
13.1 Hz, 1H), 2.00 (ddd, Jˆ14.6, 13.8, 4.3 Hz, 1H), 2.25 (s,
3H), 2.38 (m,1H), 2.52 (dt, Jˆ14.1, 3.0 Hz, 1H), 2.60 (dd,
Jˆ13.0, 3.3 Hz, 1H), 3.85 (d, Jˆ2.7 Hz, 1H, OH); 13C NMR
(75.4 MHz, CDCl3) d 13.74, 22.44, 25.34, 28.42, 29.28,
31.42, 32.02, 34.73, 41.64, 52.62, 68.81, 91.30, 214.73;
MS (EI) m/z 195 [M2CH3±HNO2]1, 151, 135, 125, 109,
93, 71, 55, 43 (100); Anal. Calcd for C13H23NO4: C, 60.68;
H, 9.01; N, 5.44. Found: C, 60.76; H, 8.92; N, 5.57.
(300 MHz, CDCl3) d 0.81 (t, Jˆ7.5 Hz, 3H), 1.05 (t,
Jˆ7.2 Hz, 3H), 1.17 (m,1H), 1.30 (dd, Jˆ13.9, 7.5 Hz,
1H), 1.45 (dd, Jˆ13.9, 7.6 Hz, 1H), 1.54 (s, 3H), 1.66
(ddd, Jˆ14.4, 4.1, 2.8 Hz, 1H), 1.96 (dd, Jˆ14.1, 13.0 Hz
1H), 2.00 (ddd, Jˆ14.6, 13.5, 4.1 Hz 1H); 2.34±2.56
(m,5H), 3.82 (d, Jˆ2.7 Hz, 1H, OH); 13C NMR
(75.4 MHz, CDCl3, DEPT) d(7.71q, 8.23q, 29.28q, 30.86t,
31.01t, 34.19t, 34.45t, 38.15t, 51.05d, 71.58s, 88.48s,
218.06s; MS (EI) m/z 214 [M2C2H5]1, 197 [M2HNO2]1,
167 [M2(C2H51HNO2)]1, 149, 139, 121, 111, 93, 81, 69,
57 (100), 43; Anal. Calcd for C12H21NO4: C, 59.24; H, 8.70;
N, 5.76. Found: C, 59.05; H, 8.75; N, 5.85.
(^)-1-[(1Sp,2Rp,5Rp)-2-Hydroxy-2-methyl-5-nitro-5-
pentylcyclohexyl]-1-ethanone (4e). Yellow oil; IR (nujol)
nmax 3500, 1700, 1540, 1380, 844 cm21
;
1H NMR
(^)-1-[(1Sp,2Rp,5Rp)-2,5-Diethyl-2-hydroxy-5-nitrocyclo-
hexyl]-1-propanone (4i). Yellow oil; IR (nujol) nmax 3495,
1700, 1540, 1375, 845 cm21; 1H NMR (300 MHz, CDCl3) d
0.82 (t, Jˆ7.5 Hz, 3H), 0.86 (t, Jˆ7.5 Hz, 3H), 1.05 (t,
Jˆ7.3 Hz, 3H),1.13 (m, 1H), 1.32 (m, 1H), 1.43 (m, 1H),
1.67 (m, 1H), 1.88 (m, 4H), 2.43 (m, 3H), 2.65 (m, 2H), 3.81
(d, Jˆ2.7 Hz, 1H, OH); 13C NMR (75.4 MHz, CDCl3,
DEPT) d(7.23q, 7.71q, 7.77q, 28.63t, 30.46t, 32.08t,
33.77t, 34.89t, 37.72t, 50.47d, 71.43s, 89.44s, 217.75s;
MS (EI) m/z 228 [M2C2H5]1, 210 [M2HNO2]1, 181
[M2(C2H51HNO2)]1, 163, 135, 121, 107, 95, 79, 67, 57
(100), 43; Anal. Calcd for C13H23NO4: C, 60.68; H, 9.01; N,
5.44. Found: C, 60.60; H, 8.95; N, 5.58.
(300 MHz, CDCl3) d 0.85 (t, Jˆ6.9 Hz, 3H), 1.15 (s, 3H),
1.24 (m, 7H), 1.64 (ddd, Jˆ14.6, 4.3, 2.8 Hz, 1H), 1.78 (m,
2H), 1.88 (dd, Jˆ13.9, 13.0 Hz, 1H), 2.00 (ddd, Jˆ14.6,
13.7, 4.3 Hz, 1H), 2.26 (s, 3H), 2.38 (m,1H), 2.52 (dt,
Jˆ14.1, 3.0 Hz, 1H), 2.60 (dd, Jˆ12.9, 3.3 Hz, 1H), 3.86
(d, Jˆ2.6 Hz, 1H, OH); 13C NMR (75.4 MHz, CDCl3)
d(13.87, 22.29 (x2), 22.88, 28.41, 29.27, 31.42, 32.00,
34.72, 41.86, 52.60, 68.79, 91.30, 214.74; MS (EI) m/z
256 [M2CH3]1, 124 [M2HNO2]1, 209 [M2CH3±
HNO2]1, 165, 149, 123, 109, 95, 71, 55, 43 (100); Anal.
Calcd for C14H25NO4: C, 61.97; H, 9.29; N, 5.16. Found: C,
62.10; H, 9.22; N, 5.11.
(^)-1-[(1Sp,2Rp,5Rp)-2-Hydroxy-5-isopropyl-2-methyl-
5-nitrocyclohexyl]-1-ethanone (4f). White solid (EtOAc±
hexane); mp 72±748C; IR (nujol) nmax 3500, 1695, 1540,
(^)-1-[(1Sp,2Rp,5Rp)-2-Hydroxy-5-methyl-5-nitro-2-pro-
pylcyclohexyl]-1-butanone (4j). White solid (EtOAc±
hexane); mp 50±528C; IR (nujol) nmax 3505, 1695, 1545,
1
1
1375, 840 cm21; H NMR (300 MHz, CDCl3) d 0.91(d,
1370, 850 cm21; H NMR (300 MHz, CDCl3) d 0.83 (t,
Jˆ2.5 Hz, 3H), 0.94(d, Jˆ2.6 Hz, 3H), 1.14 (s, 3H), 1.21
(m, 1H), 1.65 (ddd, Jˆ14.6, 4.3, 2.9 Hz, 1H), 1.92 (dd,
Jˆ14.0, 13.0 Hz, 1H), 2.07 (m, 2H), 2.25 (s, 3H), 2.29
(m, 1H), 2.41 (dt, Jˆ14.0, 3.0 Hz, 1H), 2.56 (dd, Jˆ13.0,
3.2 Hz, 1H), 3.84 (d, Jˆ2.6 Hz, 1H, OH); 13C NMR
(75.4 MHz, CDCl3) d(17.28, 17.37, 26.22, 28.39, 29.16,
31.47, 34.83, 37.57, 52.64, 68.69, 95.21, 214.91;( MS
(EI) m/z 228 [M2CH3]1, 196 [M2HNO2]1, 181
[M2(HNO21CH3)]1, 159, 137, 121, 109, 95, 81, 71, 55,
43 (100); Anal. Calcd for C12H21NO4: C, 59.24; H, 8.70; N,
5.76. Found: C, 59.20; H, 8.77; N, 5.86.
Jˆ6.9 Hz, 3H), 0.92 (t, Jˆ7.5 Hz, 3H), 1.10±1.40 (m,
4H), 1.54 (s, 3H), 1.59 (q, Jˆ7.3 Hz, 2H), 1.66 (ddd,
Jˆ14.4, 4.3, 2.7 Hz 1H), 1.94 (dd, Jˆ14.3, 13.4 Hz 1H),
1.99 (ddd, Jˆ14.5, 13.7, 4.3 Hz 1H), 2.42 (m, 3H); 2.54
(t, Jˆ7.5 Hz, 1H), 2.60 (t, Jˆ7.4 Hz, 1H), 2.63 (dd,
Jˆ13.0, 3.2 Hz 1H), 3.86 (d, Jˆ2.5 Hz, 1H, OH); 13C
NMR (75.4 MHz, CDCl3, DEPT) d(13.60q, 14.55q,
16.54t, 16.71t, 28.83q, 30.44t, 31.21t, 33.80t, 43.65t,
46.30t, 50.99d, 71.01s, 88.02s, 217.186s; MS (EI) m/z 228
[M2C3H7]1, 224 [M2HNO2]1, 206 [M2(H2O1HNO2)]1,
181 [M2(C3H71HNO2)]1, 163, 137, 110, 93, 71 (100), 55,
43; Anal. Calcd for C14H25NO4: C, 61.97; H, 9.29; N, 5.16.
Found: C, 62.05; H, 9.32; N, 5.02.
(^)-1-[(1Sp,2Rp,5Rp)-2-Hydroxy-2-methyl-5-nitro-5-
phenylcyclohexyl]-1-ethanone (4g). White solid (EtOAc±
hexane); mp 119±1218C; IR (nujol) nmax 3505, 1690, 1545,
1
1385, 850 cm21; H NMR (300 MHz, CDCl3) d 1.20 (s,
Acknowledgements
3H), 1.36 (m, 1H), 1.80 (ddd, Jˆ14.6, 4.2, 2.9 Hz, 1H),
2.28 (dd, Jˆ14.1, 13.0 Hz, 1H), 2.30 (s, 3H), 2.47 (ddd,
Jˆ14.6, 13.5, 4.2 Hz, 1H), 2.73 (dd, Jˆ13.0, 3.1 Hz, 1H),
2.83 (ddd, Jˆ14.6, 6.3, 3.2 Hz, 1H), 2.95 (dt, Jˆ14.1,
This work was carried out in the framework of the National
Project `Stereoselezione in Sintesi Organica: Metodologie
Á
ed Applicazioni' supported by the Ministero dell`Universita

R. Ballini et al. / Tetrahedron 56 (2000) 4095±4099
4099
5. (a) Ballini, R.; Bosica, G. Tetrahedron Lett. 1996, 37, 8027±
8030. (b) Ballini, R.; Bosica, G. J. Org. Chem. 1997, 62, 425±427.
(c) Ballini, R.; Bosica, G. Eur. J. Org. Chem. 1998, 355±357.
(d) Ballini, R.; Papa, F.; Abate, C. Eur. J. Org. Chem. 1999, 87±90.
6. The numeric assignation of the atoms in the discussion of struc-
ture determination has been made considering the compounds 4±7
as substituted cyclohexanols.
e della Ricerca Scienti®ca e Tecnologica, Rome, and by the
University of Camerino.
References
1. Feuer, H.; Harmetz, R. J. Org. Chem. 1961, 26, 1061±1072.
2. Patterson, J. M.; Barnes, M. W. Bull. Chem. Soc. Jpn 1967, 40,
2715±2716.
7. Friebolin, H. In Basic One- and Two-Dimensional NMR
Spectroscopy (2nd enlarged ed.); VCH: Weinheim, 1993; p 94.
8. Eliel, E. L., Wilen H. S. In Stereochemistry of Organic
Compounds; Wiley: New York, 1994; pp. 696±697
3. Gomez-Bengoa, E.; Cuerva, J. M.; Mateo, C.; Echavarren,
A. M. J. Am. Chem. Soc. 1996, 118, 8553±8565.
4. (a) Li, C. J. Chem. Rev. 1993, 93, 2023±2035. (b) Lubineau, A.
Chem. Ind. 1996, 123±126. (c) Fringuelli, F.; Piermatti, O.; Pizzo,
F. In Target in Heterocyclic Systems, Chemistry and Properties;
Attanasi, O., Spinelli, D., Eds.; Italian Society of Chemistry:
Rome, 1997; Vol. 1, pp 57±73.
9. Ballini, R.; Bosica, G. J. Chem. Res. (Synop.) 1993, 371.
10. Kornblum, N.; Larson, H. O.; Blackwood, R. K.; Mooberry, D.
D.; Oliveto, E. P.; Graham, G. E. J. Am. Chem. Soc. 1956, 78,
1497±1501.