Michael additions in aqueous media: "on-water" and "in-water" processes from α-nitro ketones and their anions

Article abstract of DOI:10.1002/ejoc.201201431

A variety of α,β-unsaturated aldehydes and ketones gave very high-yielding Michael addition reactions with α-nitrocycloalkanones in water, at room temperature without added catalyst. These can be considered as one of the very few "on-water" Michael reacti

Full text of DOI:10.1002/ejoc.201201431

FULL PAPER
DOI: 10.1002/ejoc.201201431
Michael Additions in Aqueous Media: “On-Water” and “In-Water” Processes
from α-Nitro Ketones and Their Anions
Giorgio Giorgi,[a] Pilar López-Alvarado,[a] Sonia Miranda,[a] Jean Rodriguez,[b] and
J. Carlos Menéndez*[a]
Keywords: Synthetic methods / Michael addition / Solvent effects / Green chemistry / Nitro compounds
A variety of α,β-unsaturated aldehydes and ketones gave
very high-yielding Michael addition reactions with α-nitrocy-
ganic solvents. A related protocol that uses very dilute, aque-
ous solutions of potassium carbonate as the reaction media
cloalkanones in water, at room temperature without added extended the scope of the method to cyclic enones and unsat-
catalyst. These can be considered as one of the very few “on-
water” Michael reactions known in the literature, because
they took place in suspension or emulsion and at increased
speed relative to the same transformations performed in or-
urated esters, nitriles and sulfones and is likely to take place
in the bulk of the aqueous phase, i.e., “in-water”. Both pre-
parative methods constitute environmentally benign and ef-
ficient alternatives to previously known procedures.
water is close to being the ideal green solvent, and prefera-
ble to alternatives such as ionic liquids.[4]
Introduction
For the reasons summarized above, the development of
synthetically-useful reactions, with water as the reaction
medium, has gained considerable interest. To give an exam-
ple, the Michael addition reaction is one of the most impor-
tant methods for creating carbon–carbon bonds[5] and is of
interest to green chemistry because it proceeds with com-
plete atom economy. Nevertheless, Michael reactions in
water have not been explored systematically and the scope
of the method has been quite narrow in terms of the range
of Michael donors and acceptors employed. Some water-
tolerant compounds that catalyse the Michael reaction in-
clude ytterbium(III) triflate on its own[6] or in the presence
of a variety of ligands,[7] scandium tris(dodecylsulfate),[8]
vanadate species in an apatite framework,[9] water-soluble
calixarenes as inverse phase-transfer catalysts,[10] amphi-
philic resin-supported quaternary ammonium hydroxides[11]
and phosphazene bases.[12] For the specific case of the reac-
tion between α-nitro ketones and liquid-conjugated enones,
which also act as the reaction media, a solvent-free protocol
for Michael additions in the presence of silica gel has been
described.[13]
Reactions that involve stirring insoluble reactants in
aqueous emulsions or suspensions without the addition of
organic co-solvents were defined by Sharpless to take place
“on-water”.[14] Although these reactions often exhibit sig-
nificant rate enhancements relative to similar reactions in
organic solvents, they have received relatively little synthetic
attention outside of a few specialized fields. Thus, most
known “on-water” reactions are cycloaddition and other
pericyclic reactions.[15] To the best of our knowledge, there
is only one example of an uncatalysed “on-water” Michael
Organic solvents are the main source of waste from aca-
demic and industrial installations in which synthetic work
is carried out. Therefore, the development of synthetic
methods with decreased use of organic solvents is one of the
priorities of green synthetic chemistry. Water is the reaction
medium used by nature in all biosynthetic routes, and the
chemistry of living organisms depends on its combination
of unusual properties. From the viewpoint of its use as a
reaction medium, water has many favourable properties. It
is non-flammable, non-toxic, stable and has the additional
advantage of being a non-exhaustible resource that is freely
available even in the least developed countries.[1] Water has
a large heat capacity and is therefore a good heat sink, mak-
ing it a safer solvent in which to perform exothermic pro-
cesses, particularly on a large scale. Furthermore, the use
of water as a reaction medium enables new solvation and
molecular assembly processes leading to unique modes of
reactivity.[2] Finally, the use of water as the only supporting
medium for a reaction often provides for ease of product
isolation owing to the low aqueous solubility of most or-
ganic compounds. Therefore, it is generally accepted[3] that
the combination of these desirable properties means that
[a] Departmento de Química Orgánica y Farmacéutica, Facultad
de Farmacia, Universidad Complutense,
28040 Madrid, Spain
Fax: +34-91-3941822
E-mail: josecm@farm.ucm.es
Homepage: http://www.ucm.es
[b] Aix Marseille Université, CNRS, iSm2 UMR 7313
13397 Marseille, France
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201431.
Eur. J. Org. Chem. 2013, 1327–1336
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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J. C. Menéndez et al.
FULL PAPER
reaction, consisting of the dehydrogenative coupling be- ution of the Michael adducts by intramolecular aldoliza-
tween indoles and benzoquinone, a very reactive Michael tion,[24,28] was not detected. The reactions were routinely
acceptor,[16] although some aza-Michael “on-water” reac- performed with tap water at pH = 6.9 but no significant
tions are also known.[17]
differences in reactivity or yield were found when more
In this paper, we present our full report[18] of the “on- acidic de-ionized water was employed. In some cases, the
water” Michael addition reactions of α-nitro ketones. These addition of 10% cetyltrimethylammonium bromide
are a very important class of synthetic intermediates[19] and (CTAB), a surfactant, was found to be beneficial to improve
have been employed as precursors to a wide variety of phar- the dispersion of the substrates. In these examples, the “on-
macologically valuable compounds including ω-nitro- water” effect may co-exist with reactions inside micelles.
alcohols and spiroketals,[20] β-nitroalcohols,[21] bridged Nevertheless, some surfactant-improved reactions carried
macrolactones,[22] bicyclo-[n.3.1]alkanes[23] and their benzo- out in aqueous media have been regarded as “on-water” in
and naphtho-fused derivatives,[24] indanes[25] and macro- the literature.[15c]
carbocycles.[26] Thus, the ready functionalization of α-nitro
ketones is of considerable significance and should allow fur-
ther modes of reactivity and therefore additional synthetic
applications.
Results and Discussion
Scheme 1. “On-water” Michael reactions of cyclic nitro ketones
with acyclic enals or enones.
One of the most widely employed procedures for Michael
reactions of α-alkoxycarbonyl cyclic ketones involves the
use of potassium carbonate in acetone, but we found this
procedure, to be unsuitable for nitro ketones owing to the
precipitation of the corresponding nitronate anion as a po-
Table 1. Scope and yields of the reactions between cyclic nitro
ketones and acyclic enals or enones.
Entry
Compound
n
R
Time Yield [%]
tassium salt. Another problem is the low stability of α-nitro
ketones in the presence of nucleophiles owing to their easy
opening through a retro-Claisen mechanism, which gener-
ates a very stable nitronate anion. Indeed, some innovative
synthetic applications of cyclic α-nitro ketones are designed
to make use of this ring cleavage.[27] Probably for this
reason, the few existing protocols are restricted to the use
of non-nucleophilic bases such as tertiary amines or phos-
phanes in organic solvents[28] or basic alumina.[29] Conse-
quently, Michael additions of α-nitro ketones have not been
systematically studied.
Owing to the problems described for basic catalysts, we
started our study by investigating the reaction between α-
nitrocycloheptanone and methyl vinyl ketone in the pres-
ence of ytterbium triflate in aqueous solution, as pioneered
by Feringa for the case of an acyclic α-nitroester.[5] This
reaction proved to be very sluggish and after 3 d at room
temperature afforded only a 35% yield of the desired
Michael adduct, together with 49% recovered starting ma-
terial. Nevertheless, this result proved that it should be pos-
sible to achieve the desired transformation under acidic
conditions. Because the accelerating role of water in “on-
1
2
3
4
5
6
7
8
2
3
1
2
2
2
3
3
3
3
3
5
5
5
6
6
6
6
6
7
7
7
H
H
14 h
8 h
98
85
93
85
99
98
83[a]
65
65
99
68
85
76
80
77
81
80
99
99
99
4
CH3
CH2CH3
H
CH3
CH3
CH2CH3
CH2CH3
H
CH3
CH2CH3
H
H
CH3
CH3
CH2CH3
H
CH3
CH2CH3
4 d
4 d
5
6
14 h
4 d
7
7
16 h
11
8
9
8
5 d[b]
37 h
14 d
17 d
16 d
7 d[b]
16 d
8 d[b]
14 d[b]
5 d[b]
7 d[b]
7 d[b]
10
11
12
13
14
15
16
17
18
19
20
9
10
11
12
12
13
13
14
15
16
17
[a] Together with 22% of 3-hydroxy-2,7-octanedione (calculated
with respect to the enone). [b] 10% CTAB was added.
The long reaction times found in some cases prompted
water” reactions has been recently proposed to arise from us to attempt reactions heated to reflux,[32] which were as-
acid-base chemistry at the interface,[30] we decided to assay sayed for the reaction between 2-nitrocyclooctanone and
the reaction by using neat water as the reaction medium, in methyl vinyl ketone. The reaction time was reduced from
the absence of catalyst.[31] Vigorous magnetic stirring at 4 d to 16 h, but the desired product, although still the major
room temperature of aqueous emulsions or suspensions of product (3:1 in its favour), was accompanied by 3-hydroxy-
a range of α-nitrocycloalkanones 1[22] and acyclic α,β-unsat- 2,7-octanedione, which presumably arose from a hetero
urated aldehydes and ketones, including acrolein, methyl Diels–Alder reaction between two molecules of methyl vinyl
vinyl ketone and ethyl vinyl ketone, turned out to be highly ketone followed by hydrolysis of the enol ether function in
successful (Scheme 1 and Table 1). Most reactions pro- the resulting pyrane derivative (Scheme 2).[33] Owing to this
ceeded in excellent yields, and the formation of side prod- side reaction, we conducted subsequent experiments at
ucts either from retro Claisen-type reactions or further evol- room temperature.
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Michael Addition Processes from α-Nitro Ketones and Their Anions
octanone and methyl vinyl ketone in water heated to reflux,
we obtained small amounts of 3-hydroxy-2,7-octanedione
(R = Me) and 4-hydroxy-3,8-decanedione (R = Et), from a
combination of two molecules of the starting enone.
Scheme 2. Side reaction observed when heated to reflux.
The reaction with conjugated alkynals and alkynones
was also examined, and found to proceed along similar lines
(Scheme 3 and Table 2). These reactions generally gave ex-
cellent yields, although those involving 2-nitrocycloundec-
anone did not go to completion. As expected, the Michael
adducts were isolated as almost equimolecular mixtures of
Z and E diastereomers.
Scheme 4. Benzoylnitromethane as a synthetic equivalent to nitro-
methane under “on-water” reaction conditions.
The fact that the Michael reactions proceed in aqueous
media in the absence of any catalyst suggests that water
itself promotes the reaction despite the starting materials
being water-insoluble. We decided to further investigate this
aspect of our reaction, and examined the non-catalysed re-
action between α-nitrocycloheptanone and acrolein in
homogeneous solution in several organic solvents including
toluene, dichloromethane, 1,4-dioxane and ethanol. We
found that in all cases the reaction failed to take place and
the starting nitro ketone was recovered. This behaviour is
characteristic of “on-water” processes, but it is unusual to
observe such a clear-cut difference between aqueous and
non-aqueous media. To discard the possibility of self-catal-
ysis owing to the acidity of the nitro ketones, we performed
an experiment that involved stirring 2-nitrocyclooctanone
and acrolein in the absence of solvent, which led only to
recovered starting materials after 18 h at room temperature
(the “on-water” reaction was complete after 14 h at room
temperature, see Table 1, Entry 5).
Scheme 3. Michael reactions of cyclic nitro ketones with alkynals
or alkynones.
Table 2. Scope and yields of the reactions between cyclic nitro
ketones and alkynals or alkynones.
Entry Compound
n
R
Time [d] Yield [%] E/Z
1
2
3
4
5
6
7
18
19
20
21
22
23
24
2
3
5
5
6
6
7
CH3
H
H
CH3
H
CH3
CH3
6
5
5
6
5
6
6
99
99
95
99
1:1
1:1
1.2:1
1.3:1
50 (100)[a] 1.2:1
55 (86)[a]
99[b]
1.4:1
1.5:1
[a] Yields in parentheses are based on recovered starting nitrocy-
cloalkanone. [b] This reaction was carried out in the presence of
10% CTAB.
Next, we studied two representative reactions starting
The reactions between α-nitro ketones and α,β-unsatu-
from benzoylnitromethane, a commercially available acyclic rated ketones, although clean and high yielding, were slow,
α-nitro ketone, which has been recently employed as the and we set out to finding conditions to accelerate them
nucleophile in asymmetric Michael addition reactions per- (Scheme 5 and Table 3). We first assayed the reactions in
formed in the presence of chiral thiourea organocata- phosphate buffer at pH 7.4 on the rather slow reaction be-
lysts.[34] This compound proved to be less reactive than its tween 2-nitrocyclooctanone and methyl vinyl ketone. A sig-
cyclic counterparts and required heating to reflux. As nificant acceleration was observed (2 d versus 4 d), but the
shown in Scheme 4, the Michael adduct was not isolated yield decreased from 99% to 84% owing to the formation
and instead we obtained compounds 25 and 26 from its of significant amounts of 3-hydroxy-2,7-octanedione, the
retro Claisen-type degradation by water, together with previously mentioned side product. The fact that nitroalk-
benzoic acid. Thus, the starting nitro ketone can be consid- anes have been shown to react as nucleophiles in aqueous
ered to behave as a synthetic equivalent to nitromethane sodium hydroxide, normally in the presence of cationic sur-
and has some literature precedent.[34a,34b] Interestingly, our factants,[36,37] led us to attempt the use of aqueous NaOH,
preparation of 25 (90% yield after 4 h heating to reflux) in the reaction between 2-nitrocycloheptanone and methyl
performs very favourably relative to the results found pre- vinyl ketone as a model. Unfortunately, a complex mixture
viously for the reaction between nitromethane and methyl was obtained, in which the only identifiable component was
vinyl ketone in water, which has been found to proceed in 7-nitroheptanoic acid that resulted from opening of the
60% yield after 48 h at 40 °C.[35,36] As side products of these starting nitro ketone by the hydroxide anion. The use of
reactions, and in agreement with the result of the previously dilute aqueous potassium carbonate solutions[38] was more
mentioned Michael addition reaction between 2-nitrocyclo- satisfactory. Although an initial experiment involving a
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J. C. Menéndez et al.
FULL PAPER
long reaction time gave only the ring-opened product
(Table 3, Entry 1), we found that the desired reaction was
quite fast (Table 3, Entries 2–4), and that optimal condi-
tions (0.07 m potassium carbonate, room temp., 30 min, en-
try 3) led to 92% yield of compound 4, without detection
of the open-chain derivative. These conditions seem to be
of general value for unsaturated ketones, as shown by the
preparation of 5 in 80% yield after 1 h (Table 3, Entry 6).
In addition, aldehydes gave better results in the absence of
base; see, Table 3, Entry 5 relative to Table 1, Entry 2. When
less-reactive Michael acceptors, such as unsaturated esters,
nitriles or sulfones, were investigated, the reactions “on-
water” were too slow for practical purposes and the per-
formance of the newly-developed basic conditions was ex-
amined. The reaction between 2-nitrocycloheptanone and
ethyl acrylate afforded only a 30% yield of compound 27
under our standard conditions (water, room temperature;
Table 3, Entry 7), which could be increased to 40% by heat-
ing the reaction to reflux (Table 3, Entry 8), and to 49%
in a dilute potassium carbonate aqueous solution (Table 3,
Entry 9). The latter method was also employed to obtain
compounds 28 and 29 from acrylonitrile and phenyl vinyl
sulfone in 60 and 77% yields, respectively (Table 3, En-
tries 10 and 11).
Scheme 6. Michael additions of α-nitro cycloalkanones to 2-cyclo-
pentenone.
Table 4. Scope and yields of the Michael additions with 2-cyclo-
pentenone.
Entry Compound
n
Time [d]
Yield [%]
1
2
3
4
30
31
32
33
2
3
5
7
1
3
5
6
72
73
77
83
Similarly, benzoylnitromethane reacted with 2-cyclopent-
enone or 2-cyclohexenone to give compounds 34 and 35,
respectively, again as equimolecular mixtures of both pos-
sible diastereomers (Scheme 7).
Scheme 7. Michael addition reactions of benzoylnitromethane to 2-
cyclopentenone and 2-cyclohexenone in dilute aqueous potassium
carbonate solutions.
Scheme 5. Reactions of α-nitrocycloheptanone with acyclic
Michael acceptors in dilute aqueous bases.
The reactions performed in the presence of base took
place in suspension, which in principle is compatible with
an “on-water” mechanism. However, we have verified that
the isolated potassium nitronate salt is freely soluble in
water, and it is likely that in these cases the Michael ad-
dition reactions take place in the aqueous phase (i.e., “in-
water”[39]), with the insoluble neutral fraction acting as a
reservoir from which the nitronate anion in the aqueous
phase is replenished.
Table 3. Scope and yields of the reactions between α-nitrocyclo-
heptanone and α,β-unsaturated ketones, esters, nitriles and sulfones
in dilute aqueous basic solutions.
Entry Michael
adduct
Z
Conditions
Yield
[%]
[a]
1
2
3
4
5
6
7
8
–
4
4
4
5
COMe aq. KHCO3 (0.07 m), r.t., 48 h
COMe aq. KHCO3 (0.07 m), r.t., 3 h
COMe aq. K2CO3 (0.07 m), r.t., 30 min
COMe aq. K2CO3 (0.035 m), r.t., 4 h
76
92
65
80
55
30
40
49
60
77
Conclusions
COEt
CHO
aq. K2CO3 (0.07 m), r.t., 1 h
aq. K2CO3 (0.07 m), r.t., 30 min
In conclusion, we have developed two methodologies for
performing Michael addition reactions of α-nitro ketones
to a variety of α,β-unsaturated carbonyl derivatives. First,
we have shown that these reactions can be performed in
good to excellent yields at room temperature, without any
added catalyst. The “on-water” character of these reactions
makes them unique among Michael reactions and was illus-
trated by the fact that they took place in suspension or
3
27
27
27
28
29
CO2Me H2O, r.t., 7 d
CO2Me H2O, reflux, 24 h
CO2Me aq. K2CO3 (0.07 m), r.t., 45 min
9
10
11
CN
aq. K2CO3 (0.07 m), r.t., 3 h
SO2Ph
aq. K2CO3 (0.07 m), CTAB, r.t., 3 h
[a] 7-Nitroheptanoic acid (90%) was obtained.
These new conditions also allowed us to carry out reac- emulsion at a much increased rate relative to the same
tions with cyclic enones, which had failed to take place in transformations performed in organic solvents or in the ab-
water alone. Thus, several representative cyclic nitro ketones sence of solvent. A second protocol, which used very dilute
were treated with 2-cyclopentenone to give compounds 30– aqueous solutions of potassium carbonate as the reaction
33 in good yields, as 1:1 mixtures of both possible dia- media, extended the scope of the method to cyclic enones
stereomers (Scheme 6 and Table 4).
and unsaturated esters, nitriles and sulfones, and probably
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Michael Addition Processes from α-Nitro Ketones and Their Anions
1-H), 2.80–1.40 (m, 14 H, H-2,3,3Ј–7Ј) ppm. 13C NMR (63 MHz,
CDCl3): δC = 202.5 (C-2Ј), 199.7 (C-1), 98.4 (C-1Ј), 41.2 (C-3Ј),
38.3 (C-2), 35.1 (C-5Ј), 29.3 (C-7Ј), 28.6 (C-6Ј), 25.5 (C-4Ј), 24.4
(C-3) ppm. C10H15NO4 (213.23): calcd. C 56.33, H 7.09, N 6.57;
found C 56.59, H 7.29, N 6.49.
proceeded through an “in-water” mechanism. Both types of
reactions were normally very clean; thus, in some cases the
Michael adducts were obtained in a pure state without the
need for chromatographic separation and others were puri-
fied by simple filtration through a pad of silica gel. These
features lead us to the conclusion that our protocol consti-
tutes a new approach to a class of compounds of great sig-
nificance in synthetic and medicinal chemistry, which is an
environmentally benign and efficient alternative to previous
procedures.
2-Nitro-2-(3Ј-oxobutyl)cycloheptanone (4): Yield 93%, as a pale yel-
low oil (Procedure I). IR (NaCl): ν
= 1715 (C=O), 1545 and
˜
max
1358 (NO2) cm–1. 1H NMR (250 MHz, CDCl3): δH = 2.70–2.15 (m,
7 H, 3,7,1Ј,2Ј-H), 2.10 (s, 3 H, CH3), 1.95–1.40 (m, 7 H, 3–6-
H) ppm. 13C NMR (63 MHz, CDCl3): δC = 206.3 (C-3Ј), 202.6 (C-
1), 98.7 (C-2), 41.3 (C-7), 37.6 (C-2Ј), 35.3 (C-5), 30.3 (C-3), 29.9
(CH3), 29.4 (C-4), 25.6 (C-6), 24.5 (C-1Ј) ppm. C11H17NO4
(227.26): calcd. C 58.14, H 7.54, N 6.16; found C 58.33, H 7.58, N
6.11.
Experimental Section
2-Nitro-2-(3Ј-oxopentyl)cycloheptanone (5): Yield 85%, as a pale
General Information: All reagents and solvents were of commercial
quality and were used as received. Reactions were monitored by
thin layer chromatography, on aluminium plates coated with silica
gel with fluorescent indicator. Melting points were measured with
a Reichert hot stage microscope. Infrared spectra were recorded
with a Perkin–Elmer 1000 FT-IR spectrophotometer, with all com-
pounds examined as thin films on NaCl disks. NMR spectra were
obtained with Bruker Avance spectrometers operating at 250 or
500 MHz for 1H and 63 or 125 MHz for 13C and maintained by the
CAI de Resonancia Magnética Nuclear, Universidad Complutense.
Combustion microanalyses were performed by the CAI de Micro-
análisis Elemental, Universidad Complutense.
yellow oil (Procedure I). IR (NaCl): ν
= 1715 (C=O), 1547 and
˜
max
1348 (NO2) cm–1. 1H NMR (250 MHz, CDCl3): δH = 2.70–1.30 (m,
14 H, 3,7,1Ј,2Ј-H), 2.35 (q, J = 7.1 Hz, 2 H, 4Ј-H), 0.94 (t, J =
7.1 Hz, 3 H, 5Ј-H) ppm. 13C NMR (63 MHz, CDCl3): δC = 209.5
(C-3Ј), 203.1 (C-1), 99.4 (C-2), 41.7 (C-7), 36.7 (C-4Ј), 36.3 (C-2Ј),
35.6 (C-5), 30.7 (C-3), 29.8 (C-4), 26.1 (C-6), 24.9 (C-1Ј), 8.1 (C-
5Ј) ppm. C12H19NO4 (241.29): calcd. C 59.73, H 7.94, N 6.57;
found C 59.92, H 8.03, N 6.47.
3-(1Ј-Nitro-2Ј-oxocycloooctyl)propanal (6): Yield 99%, as a pale yel-
low oil (Procedure I). IR (NaCl): ν
= 1723 (C=O), 1542 and
˜
max
1342 (NO2) cm–1. H NMR (250 MHz, CDCl3): δH = 9.51 (s, 1 H,
1-H), 2.60–1.10 (m, 16 H, 2,3,3Ј–8Ј-H) ppm. 13C NMR (63 MHz,
CDCl3): δC = 204.7 (C-2Ј), 199.4 (C-1), 97.2 (C-1Ј), 38.3 (C-2), 38.1
(C-3Ј), 31.7 (C-5Ј), 28.3 (C-6Ј), 25.2 (C-8Ј), 24.2 (C-4Ј), 23.9 (C-
7Ј), 21.8 (C-3) ppm. C11H17NO4 (227.26): calcd. C 58.14, H 7.54,
N 6.16; found C 57.82, H 7.31, N 5.98.
1
General Procedures for the Michael Reactions
Procedure I: To a vigorously stirred dispersion of the starting α-
nitrocycloalkanone (0.96 mmol) in tap water (pH 6.9, 5 mL) was
added the suitable Michael acceptor (2.4 mmol, 2.5 equiv.). It was
necessary to add CTAB (10%) for compounds 14–17 and 24 and
in the case of compounds 8, 12, and 13 this addition significantly
decreased the reaction time, as summarized in Table 1. The mixture
was stirred at room temperature for the time specified in Table 1
and the aqueous phase was then extracted with ethyl acetate (3ϫ
10 mL). The combined organic layers were dried with anhydrous
sodium sulfate and evaporated, yielding the corresponding Michael
adducts. In some cases the residue was filtered through a pad of
silica gel, eluting with the solvent mixture specified.
2-Nitro-2-(3Ј-oxobutyl)cyclooctanone (7): Yield 98%, as a colourless
oil (Procedure I). IR (NaCl): ν
= 1719 (C=O), 1543 and 1359
˜
max
(NO2) cm–1. 1H NMR (250 MHz, CDCl3): δH = 2.41–1.85 (m, 8
H, 3,8,1Ј,2Ј-H), 1.81 (s, 3 H, CH3), 1.55–0.48 (m, 8 H, 4–7-H) ppm.
13C NMR (63 MHz, CDCl3): δC = 206.7 (C-3Ј), 205.4 (C-1), 97.9
(C-2), 38.5 (C-2Ј), 38.1 (C-8), 32.2 (C-6), 30.2 (CH3), 28.9 (C-5),
25.6 (C-3), 24.5 (C-7), 24.4 (C-4), 22.8 (C-1Ј) ppm. C12H19NO4
(241.29): calcd. C 59.75, H 7.88, N 5.81; found C 59.51, H 7.59, N
5.77.
Procedure II: To a vigorously stirred dispersion of the starting α-
nitrocycloalkanone (0.96 mmol) in tap water (5 mL) with K2CO3
(0.66 g, 0.48 mmol) and CTAB (10%) in the cases of compounds
22–24, the corresponding Michael acceptor (2.4 mmol, 2 equiv.)
was added. The mixture was stirred at room temperature for the
time specified in Table 3 and Table 4 before the aqueous phase was
extracted with ethyl acetate (3ϫ 10 mL). The combined organic
layers were dried with anhydrous sodium sulfate and evaporated,
yielding the Michael adducts. Compound 8 was isolated by fil-
tration. In the other cases the products were filtered through a pad
of silica gel, eluting with the solvent or solvent mixture specified.
2-Nitro-2-(3Ј-oxopentyl)cyclooctanone (8): Yield 65%, as a pale yel-
low oil (Procedure I). The product obtained in the experiment car-
ried out with CTAB (10%) was filtered through a pad of silica gel,
eluting with ethyl acetate. IR (NaCl): ν
= 2937, 1716 (C=O),
˜
max
1541 and 1341 (NO2) cm–1. 1H NMR (250 MHz, CDCl3): δH
=
2.73–2.16 (m, 10 H, 3,8,1Ј,2Ј,4Ј-H), 2.00–1.75 (m, 2 H, 7-H), 1.73–
1.52 (m, 4 H, 4–6-H), 1.50–1.33 (m, 1 H, 5-H), 1.25–1.07 (m, 1 H,
4-H), 1.05 (t, J = 7.3 Hz, 3 H, 5Ј-H) ppm. 13C NMR (63 MHz,
CDCl3): δC = 209.4 (C-3Ј), 205.4 (C-1), 98.1 (C-2), 38.8 (C-2Ј), 36.9
(C-8), 36.4 (C-4Ј), 32.6 (C-6), 29.0 (C-5), 28.2 (C-3), 25.8 (C-7),
24.5 (C-4), 22.9 (C-1Ј), 8.1 (CH3) ppm. C13H21NO4 (255.31): calcd.
C 61.16, H 8.29, N 5.49; found C 60.49, H 8.03, N 5.81.
3-(1Ј-Nitro-2Ј-oxocyclohexyl)propanal (2): Yield 98%, as a pale yel-
low oil (Procedure I). IR (NaCl): ν
= 2950, 1727 (C=O), 1547
˜
max
3-(1Ј-Nitro-2Ј-oxocyclodecyl)propanal (9): Yield 99%, as a pale yel-
and 1358 (NO2) cm–1. H NMR (250 MHz, CDCl3): δH = 9.76 (s,
1 H, 1-H), 2.90–1.50 (m, 12 H, 2,3,3Ј–6Ј-H) ppm. 13C NMR
(63 MHz, CDCl3): δC = 200.3 (C-2Ј), 199.3 (C-1), 95.8 (C-1Ј), 39.5
(C-3Ј), 38.1 (C-2), 36.9 (C-6Ј), 27.2 (C-4Ј), 26.5 (C-3), 21.2 (C-
5Ј) ppm. C9H13NO4 (199.21): calcd. C 54.26, H 6.58, N 7.03; found
C 54.00, H 6.49, N 7.06.
1
low oil (Procedure I). IR (NaCl): ν
= 1725 (C=O), 1544 and
˜
max
1
1353 (NO2) cm–1. H NMR (250 MHz, CDCl3): δH = 9.68 (s, 1 H,
1-H), 2.86–1.19 (m, 20 H, 2,3,3Ј–10Ј-H) ppm. 13C NMR (63 MHz,
CDCl3): δC = 202.7 (C-2Ј), 199.9 (C-1), 100.5 (C-1Ј), 38.4 (C-2),
35.6 (C-3Ј), 30.9 (C-10Ј), 26.8, 25.6, 25.5, 24.8, 24.6 (C-4Ј-8Ј), 23.2
(C-3), 20.2 (C-9Ј) ppm. C13H21NO4 (255.31): calcd. C 61.17, H
8.23, N 5.49; found C 61.45, H 7.92, N 5.35.
3-(1Ј-Nitro-2Ј-oxocycloheptyl)propanal (3): Yield 85%, as a pale yel-
low oil (Procedure I). IR (NaCl): ν
= 1721 (C=O), 1542 and
2-Nitro-2-(3Ј-oxobutyl)cyclodecanone (10): Yield 68%, as a white
solid (Procedure I). The product was filtered through a pad of silica
˜
max
1347 (NO2) cm–1. H NMR (250 MHz, CDCl3): δH = 9.77 (s, 1 H,
1
Eur. J. Org. Chem. 2013, 1327–1336
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1331

J. C. Menéndez et al.
FULL PAPER
gel, eluting with ethyl acetate/petroleum ether, m.p. 80.5 °C. IR
(C-11Ј) ppm. C15H25NO4 (283.37): calcd. C 63.60, H 8.83, N 4.95;
found C 63.24, H 8.59, N 4.80.
(KBr): ν
= 2932, 1718 (C=O), 1540 and 1356 (NO2) cm–1. 1H
˜
max
NMR (250 MHz, CDCl3): δH = 2.85 (ddd, J = 18.0 and 10.3 and
3.3 Hz, 1 H, 10-H), 2.68–2.40 (m, 5 H, 10,1Ј,2Ј-H), 2.34–2.01 (m,
6 H, 3,9,4Ј-H), 1.78–1.22 (m, 11 H, 4–9-H) ppm. 13C NMR
(63 MHz, CDCl3): δC = 205.9 (C-3Ј), 202.3 (C-1), 100.3 (C-2), 37.5
(C-2Ј), 35.3 (C-10), 30.8 (C-3), 29.9, 28.1, 25.1 (2 C), 24.4 (C-5–9),
24.2 (C-1Ј), 22.7 (C-4), 19.8 (CH3) ppm. C14H23NO4 (269.34):
calcd. C 62.43, H 8.61, N 5.20; found C 62.35, H 8.29, N 5.26.
2-Nitro-2-(3Ј-oxobutyl)cyclododecanone (16): Yield 99%, as
colourless solid (Procedure I). The product was filtered through a
pad of silica gel eluting with a gradient from petroleum ether to
a
ethyl acetate, m.p. 149.1 °C. IR (KBr): ν
= 2933, 1723 (C=O),
˜
max
1541 and 1350 (NO2) cm–1. 1H NMR (250 MHz, CDCl3): δH
=
2.83 (ddd, J = 18.4 and 11.8 and 2.4 Hz, 1 H, 12-H), 2.56–2.05 (m,
9 H, 3,12,1Ј,2Ј,4Ј-H), 1.50–0.87 (m, 17 H, 3–11-H) ppm. 13C NMR
(63 MHz, CDCl3): δC = 205.8 (C-3Ј), 200.9 (C-1), 100.0 (C-2), 37.2
(C-2Ј), 32.5 (C-12), 30.3 (C-3), 29.8 (CH3), 26.7, 26.2, 26.1, 23.1,
22.4, 21.8, 21.7 (C-5–11), 21.2 (C-1Ј), 19.0 (C-4) ppm. C16H27NO4
(297.39): calcd. C 64.62, H 9.15, N 4.71; found C 64.26, H 8.76, N
4.77.
2-Nitro-2-(3Ј-oxopentyl)cyclodecanone (11): Yield 85%, as a yellow
oil (Procedure I). The product was filtered through a pad of silica
gel, eluting with ethyl acetate. IR (NaCl): νmax = 2935, 1719 (C=O),
˜
1
1542, 1355 (NO2) cm–1. H NMR (250 MHz, CDCl3): δH = 2.90–
1.15 (m, 22 H, 3–10,1Ј,2Ј,4Ј-H), 1.09 (t, J = 6.4 Hz, 3 H, 5Ј-H) ppm.
13C NMR (63 MHz, CDCl3): δC = 209.2 (C-3Ј), 202.8 (C-1), 100.8
(C-2), 36.6 (C-2Ј), 36.4 (C-10), 35.8 (C-4Ј), 31.2 (C-3), 28.7, 25.6
(2 C), 24.8, 24.7 (C-5–9), 23.2 (C-1Ј), 20.3 (C-4), 8.1 (CH3) ppm.
C15H25NO4 (283.37): calcd. C 63.58, H 8.89, N 4.94; found C
63.36, H 8.53, N 5.07.
2-Nitro-2-(3Ј-oxopentyl)cyclododecanone (17): Yield 99%, as a
white solid (Procedure I). The product was filtered through a pad
of silica gel, eluting with a gradient from petroleum ether to ethyl
acetate, m.p. 68.0 °C. IR (NaCl): ν
= 2935, 1724 (C=O), 1538
˜
max
and 1368 (NO2) cm–1. 1H NMR (250 MHz, CDCl3): δH = 2.80
(ddd, J = 18.5 and 11.7 and 2.6 Hz, 1 H, 12-H), 2.51–2.18 (m, 8
H, 3,12,1Ј,2Ј,4Ј-H), 2.13–2.00 (m, 2 H, 3,11-H), 1.46–0.85 (m, 15 H,
4–11-H), 1.00 (t, J = 7.2 Hz, 3 H, 5Ј-H) ppm. 13C NMR (63 MHz,
CDCl3): δC = 208.9 (C-3Ј), 201.3 (C-1), 100.6 (C-2), 36.3 (C-4Ј),
36.2 (C-2Ј), 32.9 (C-12), 30.6 (C-3), 27.3, 26.7, 26.5, 23.6, 22.9, 22.3,
22.1 (C-5–11), 21.7 (C-1Ј), 19.4 (C-4), 8.0 (CH3) ppm. C17H29NO4
(311.42): calcd. C 65.57, H 9.39, N 4.50; found C 65.39, H 9.00, N
4.54.
3-(1Ј-Nitro-2Ј-oxocycloundecyl)propanal (12): Yield 76%, as a yel-
low oil (Procedure I, with the addition of 10% CTAB). The product
was filtered through a pad of silica gel, eluting with ethyl acetate/
petroleum ether. IR (NaCl): ν
= 2930, 1727 (C=O), 1542 and
˜
max
1345 (NO2) cm–1. H NMR (250 MHz, CDCl3): δH = 9.74 (s, 1 H,
1-H), 2.66–2.13 (m, 7 H, 2,3,3Ј,11Ј-H), 2.05–1.83 (m, 1 H, 11Ј-H),
1.81–1.09 (m, 14 H, 4Ј-10Ј-H) ppm. 13C NMR (63 MHz, CDCl3):
δC = 202.1 (C-2Ј), 199.1 (C-1), 99.9 (C-1Ј), 37.9 (C-2), 36.7 (C-3Ј),
29.4 (C-11Ј), 26.9, 26.3, 26.2, 26.1, 25.4, 22.6 (C-4Ј-9Ј), 21.9 (C-3),
20.8 (C-10Ј) ppm. C14H23NO4 (269.34): calcd. C 62.43, H 8.61, N
5.20; found C 62.40, H 8.34, N 5.09.
1
4-(1Ј-Nitro-2Ј-oxocyclooctyl)-3-buten-2-one (18): Yield 99%, as a
yellow oil containing a 1.2:1 diastereomeric mixture (Procedure I).
The product was filtered through a pad of silica gel, eluting with a
gradient from petroleum ether to ethyl acetate. The diastereomeric
2-Nitro-2-(3Ј-oxobutyl)cycloundecanone (13): Yield 81%, as a white
solid (Procedure I). The product was filtered through a pad of silica
ratio after this purification was 1 :0.65 . IR (NaCl): ν = 2948,
˜
max
E
Z
1733 (C=O), 1717 (C=O), 1557 and 1343 (NO2) cm–1. 1H NMR
(CDCl3, 250 MHz): δH = 7.19 (d, J = 16.4 Hz, 1 H, H-4E), 6.58 (d,
J = 12.3 Hz, 1 H, H-4Z), 6.53 (d, J = 12.3 Hz, 1 H, H-3Z), 6.29 (d,
J = 16.4 Hz, 1 H, H-3E), 3.25–2.98 (m, 2 H, H-3ЈZ), 2.83–2.62 (m,
3 H, H3ЈE, 8ЈE), 2.61–2.45 (m, 3 H, H-8ЈE, 8ЈZ), 2.43–2.30 (m, 4 H,
H-4ЈE, CH3E), 2.25 (s, 3 H, CH3Z), 2.08–0.80 (m, 15 H, 4ЈZ–7ЈZ-H,
4ЈE–7ЈE-H) ppm. 13C NMR (CDCl3, 63 MHz): δC = 203.1 (C-2ЈZ),
202.6 (C-2ЈE), 198.1 (C-2E), 196.8 (C-2Z), 137.1 (C-4E), 134.4 (C-
4Z), 133.1 (C-3E), 131.4 (C-3Z), 97.8 (C-1ЈZ), 97.5 (C-1ЈE), 38.0 (C-
3ЈE), 35.6 (C-3ЈZ), 32.3 (C-8ЈE), 32.0 (C-8ЈZ), 30.9 (CH3Z), 29.3Z,
28.2E, 27.6 (CH3E), 25.4 (2 CZ, E), 24.3Z, 24.2E (C-4Ј-6Ј), 23.3 (C-
7ЈZ), 22.3 (C-7ЈE) ppm. C12H17NO4 (239.27): calcd. C 60.24, H
7.16, N 5.85; found C 60.49, H 6.94, N 6.24.
gel, eluting with ethyl acetate, m.p. 118 °C. IR (KBr): νmax = 2931,
˜
1722 (C=O), 1541 and 1348 (NO2) cm–1. 1H NMR (250 MHz,
CDCl3): δH = 2.72–2.20 (m, 8 H, 3,11,1Ј,2Ј-H), 2.16 (s, 3 H, 4Ј-H),
2.03–1.85 (m, 1 H, 10-H), 1.76–1.08 (m, 13 H, 4–10-H) ppm. 13C
NMR (63 MHz, CDCl3): δC = 205.8 (C-3Ј), 202.2 (C-1), 100.2 (C-
2), 37.4 (C-2Ј), 36.8 (C-11), 29.9 (CH3), 29.6 (C-3), 27.1, 27.0, 26.3,
26.2, 26.1, 22.7 (C-5–10), 21.9 (C-1Ј), 20.9 (C-4) ppm. C15H25NO4
(283.37): calcd. C 63.58, H 8.89, N 4.94; found C 63.12, H 8.52, N
4.99.
2-Nitro-2-(3Ј-oxopentyl)cycloundecanone (14): Yield 80%, as a yel-
low oil (Procedure I). The product was filtered through a pad of
silica gel, eluting with a gradient from petroleum ether to ethyl
acetate. IR (NaCl): ν
= 2933, 1721 (C=O), 1542 and 1345
˜
max
3-(1Ј-Nitro-2Ј-oxocyclooctyl)propenal (19): Yield 99%, as a yellow
oil containing a 1:1 diastereomer mixture (Procedure I). The prod-
uct was filtered through a pad of silica gel, eluting with a gradient
from petroleum ether to ethyl acetate. The diastereomer ratio after
(NO2) cm–1. 1H NMR (250 MHz, CDCl3): δH = 2.78–2.20 (m, 8
H, 11,1Ј,2Ј,4Ј-H), 2.09–1.13 (m, 16 H, 3–10-H), 1.06 (t, J = 6.5 Hz,
3 H, 5Ј-H) ppm. 13C NMR (63 MHz, CDCl3): δC = 208.6 (C-3Ј),
202.2 (C-1), 100.2 (C-2), 37.4 (C-2Ј), 36.8 (C-11), 36.0 (C-4Ј), 35.9
(C-3), 27.1, 27.0, 26.3, 26.2, 26.1, 22.7 (C-5–10), 21.9 (C-1Ј), 20.9
(C-4), 7.6 (CH3) ppm. C16H27NO4 (297.39): calcd. C 64.62, H 9.15,
N 4.71; found C 62.84, H 8.92, N 4.76.
this purification was 1.6 :1 . IR (NaCl): νmax = 2934, 1724 (C=O),
˜
E
Z
1697 (C=O), 1552 and 1341 (NO2) cm–1. 1H NMR (CDCl3,
250 MHz): δH = 9.80 (dd, J = 6.9 and 1.1 Hz, 1 H, H-1Z), 9.68
(dd, J = 7.3 and 1.1 Hz, 1 H, H-1E), 7.30 (d, J = 16.2 Hz, 1 H, H-
3E), 6.79 (d, J = 12.3 Hz, 1 H, H-3Z), 6.39–6.29 (m, 2 H, H-2Z,E),
3.12–2.97 (m, 1 H, H-3ЈZ), 2.90–2.30 (m, 7 H, H-3ЈZ, 8ЈZ, H-3ЈE,
8ЈE), 2.09–0.80 (m, 16 H, 4ЈZ,E–7ЈZ,E-H) ppm. 13C NMR (CDCl3,
3-(1Ј-Nitro-2Ј-oxocyclododecyl)propanal (15): Yield 99%, as a pale
yellow oil (Procedure I). The product was filtered through a pad of
silica gel, eluting with a gradient from petroleum ether to ethyl
acetate. IR (NaCl): νmax = 1728 (C=O), 1543 and 1345 (NO2) cm–1. 63 MHz): δC = 202.3 (C-2ЈE), 202.2 (C-2ЈZ), 192.0 (C-1E), 189.6 (C-
˜
1H NMR (250 MHz, CDCl3): δH = 9.71 (s, 1 H, 1-H), 2.81–2.74
(m, 1 H, 3Ј-H), 2.54–2.03 (m, 9 H, 1,2,3Ј,4Ј,12Ј-H), 1.34–0.94 (m,
14 H, 5Ј–11Ј-H) ppm. 13C NMR (63 MHz, CDCl3): δC = 201.2 (C-
2Ј), 199.6 (C-1), 100.3 (C-1Ј), 38.1 (C-2), 32.9 (C-3Ј), 30.6 (C-12Ј),
1Z), 146.0 (C-3E), 137.1 (C-3Z), 135.1 (C-2Z), 134.4 (C-2E), 97.4 (C-
1ЈE), 97.1 (C-1ЈZ), 38.1E, 37.3Z, 35.0Z, 32.4E, 28.6Z, 28.2E, 25.5 (2
CZ,E), 24.2E, 24.1Z, 22.5Z, 22.3E (C-3Ј-8Ј) ppm. C11H15NO4
(225.24): calcd. C 58.66, H 6.71, N 6.22; found C 58.92, H 6.60, N
26.7, 26.5, 25.6, 23.6, 22.9, 22.3, 22.1 (C-5Ј-11Ј), 21.7 (C-3), 19.5 6.35.
1332
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 1327–1336

Michael Addition Processes from α-Nitro Ketones and Their Anions
3-(1Ј-Nitro-2Ј-oxocyclodecyl)propenal (20): Yield 95%, as a yellow
oil containing a 1:1 diastereomer mixture (Procedure I). The prod-
uct was filtered through a pad of silica gel, eluting with a gradient
from petroleum ether to ethyl acetate. Data for the trans dia-
(250 MHz, CDCl3): δH = 7.26 (d, J = 16.5 Hz, 1 H, 4E-H), 6.81 (d,
J = 12.2 Hz, 1 H, 4Z-H), 6.51 (d, J = 12.2 Hz, 1 H, 3Z-H), 6.22 (d,
J = 16.5 Hz, 1 H, 3E-H), 3.08–2.09 (m, 14 H, 3ЈZ–11ЈZ-H, 3ЈE–
11ЈE-H, CH3Z, CH3E) 2.00–1.02 (m, 28 H, 4ЈZ–10ЈZ-H, 4ЈE–10ЈE-
H) ppm. Data of the major diastereomer: 13C NMR (63 MHz,
stereomer: IR (NaCl): νmax = 2934, 1733 (C=O), 1699 (C=O), 1558
˜
and 1362 (NO2) cm–1. 1H NMR (250 MHz, CDCl3): δH = 9.68 (dd, CDCl3): δC = 200.4 (C-2Ј), 196.8 (C-2), 138.4 (C-4), 132.4 (C-3),
J = 7.2 and 0.7 Hz, 1 H, H-1), 7.32 (d, J = 16.9 Hz, 1 H, C-3),
6.29 (ddd, J = 16.2, 7.2 and 0.7 Hz, 1 H, H-2), 3.00–2.83 (m, 2 H,
H-3Ј), 2.78–2.60 (m, 3 H, 4Ј,10Ј-H), 2.58–2.35 (m, 2 H, 4Ј,9Ј-H),
2.24–1.95 (m, 3 H, 8Ј,9Ј-H), 1.90–1.20 (m, 6 H, 5Ј–7Ј-H) ppm. 13C
NMR (63 MHz, CDCl3): δC = 200.5 (C-2Ј), 192.4 (C-1), 147.8 (C-
3), 134.4 (C-2), 100.4 (C-1Ј), 36.0 (C-3Ј), 32.1 (C-10Ј), 25.7, 25.6,
24.4, 24.3, 23.1 (C-4Ј-8Ј), 20.2 (C-9Ј) ppm. C13H19NO4 (253.30):
calcd. C 61.64, H 7.56, N 5.53; found C 61.51, H 7.47, N 5.60.
Data for the Z diastereomer (assigned from the initial mixture): 1H
NMR (250 MHz, CDCl3): δH = 9.75 (dd, J = 6.5 Hz, 1 H, 1-H),
6.90 (d, J = 12.2 Hz, 1 H, C-3), 6.35–6-21 (m, 1 H, 2-H), 3.00–0.75
(m, 16 H, 3Ј-10Ј-H) ppm. 13C NMR (63 MHz, CDCl3): δC = 204.7
(C-2Ј), 189.9 (C-1), 139.7 (C-3), 133.5 (C-2), 99.9 (C-1Ј), 35.7 (C-
3Ј), 31.7 (C-10Ј), 27.3, 27.1, 25.4, 25.3, 23.7 (C-4Ј-8Ј), 21.8 (C-
9Ј) ppm.
99.5 (C-1Ј), 36.8 (C-3Ј), 32.2 (C-11Ј), 27.7 (CH3), 27.0, 26.2, 26.1,
26.0, 23.2, 21.9 (C-4Ј-9Ј), 21.0 (C-10Ј) ppm. C15H23NO4 (281.35):
calcd. C 64.03, H 8.24, N 4.98; found C 64.23, H 8.28, N 4.90.
4-(1Ј-Nitro-2Ј-oxocyclododecyl)-3-buten-2-one (24): Yield 99%, as a
yellow solid containing a 1.5:1 mixture of diastereomers (Procedure
I). The product was filtered through a pad of silica gel, eluting with
petroleum ether/ethyl acetate, m.p. 132.3 °C. IR (NaCl): ν
=
˜
max
2933, 1731 (C=O) 1694 (C=O), 1551 and 1350 (NO2) cm–1. 1H
NMR (250 MHz, CDCl3): δH = 7.26 (d, J = 16.6 Hz, 1 H, 4E-H),
6.80 (d, J = 12.2 Hz, 1 H, 4Z-H), 6.49 (d, J = 12.2 Hz, 1 H, 3Z-H),
6.18 (d, J = 16.5 Hz, 1 H, 3E-H), 3.25–3.08 (m, 1 H, 3ЈZ-H), 2.90–
2.70 (m, 1 H, 3ЈE-H), 2.62–2.38 (m, 5 H, 3Z,3ЈE-H, 12ЈZ,E-H), 2.34–
2.26 (m, 4 H, 12ЈE-H, CH3), 2.23–2.19 (m, 4 H, 4ЈE-H, CH3), 2.15–
2.01 (m, 3 H, 4ЈZ,4ЈE-H), 1.50–0.80 (m, 28 H, 5Ј–11ЈZ-H,5Ј–11ЈE-
H) ppm. 13C NMR (63 MHz, CDCl3): δC = 199.1 (C-2ЈE), 198.5
(C-2ЈZ), 196.7 (C-2E), 196.4 (C-2Z), 135.6 (C-4E), 132.3 (C-4Z),
131.5 (C-3E), 129.4 (C-3Z), 99.1 (C-1ЈE), 98.5 (C-1ЈZ), 32.9 (C-3ЈE),
32.8 (C-12ЈE), 32.3 (C-3ЈZ), 30.4 (C-12ЈZ), 27.3 (CH3E), 26.6
(CH3Z), 26.2E, 26.0Z, 25.9E, 25.8Z, 23.1E, 22.8Z, 22.3E, 22.1Z, 21.8E,
21.7E, 21.5Z, 21.3Z, 21.1E, 21.0Z (C-4Ј-10Ј), 19.1 (C-11ЈZ), 19.0 (C-
11ЈE) ppm. C16H25NO4 (295.38): calcd. C 65.06, H 8.53, N 4.74;
found C 64.93, H 8.40, N 4.70.
4-(1Ј-Nitro-2Ј-oxocyclodecyl)-3-buten-2-one (21): Yield 99%, as a
yellow oil containing a 1.3E:1Z mixture of diastereomers (Procedure
I). The product was filtered through a pad of silica gel, eluting with
a gradient from petroleum ether to ethyl acetate. IR (NaCl): ν
˜
max
1
= 2932, 1727 (C=O), 1701 (C=O), 1551 and 1356 (NO2) cm–1. H
NMR (CDCl3, 250 MHz): δH = 7.22 (d, J = 16.4 Hz, 1 H, H-1ЈE),
6.73 (d, J = 12.2 Hz, 1 H, H-1ЈZ), 6.49 (d, J = 12.2 Hz, 1 H, H-
2ЈZ), 6.26 (d, J = 16.4 Hz, 1 H, H-2ЈE), 3.28–3.16 (m, 1 H, H-3ЈZ),
3.05–2.34 (m, 11 H, H-3ЈZ, H-4ЈZ, H-10ЈZ, H-3ЈE, H-4ЈE, H-10ЈE),
2.35 (s, 3 H, CH3E), 2.24 (s, 3 H, CH3Z), 2.18–1.92 and 1.85–1.62
(2m, 20 H, 5ЈZ–9ЈZ-H, 5ЈE–9ЈE-H) ppm. 13C NMR (CDCl3,
63 MHz): δC = 200.9 (C-2ЈE), 200.8 (C-2ЈZ), 198.5 (C-2Z), 197.3 (C-
2E), 139.0 (C-4E), 136.4 (C-4Z), 133.1 (C-3E), 130.3 (C-3Z), 100.5
(C-1ЈE), 99.6 (C-1ЈZ), 36.2 (C-3ЈE), 34.0 (C-3ЈZ), 33.1 (C-10ЈZ), 32.1
(C-10ЈE), 31.4 (CH3Z), 28.1 (CH3E), 25.8E, 25.7Z, 25.6E, 25.0Z,
24.5E, 24.4E, 24.3Z, 24.0Z, 23.1 (2 C, C-4ЈZ–8ЈZ, C-4ЈE–8ЈE), 20.7
(C-9ЈZ), 20.2 (C-9ЈE) ppm. C14H21NO4 (267.32): calcd. C 62.90, H
7.92, N 5.24; found C 62.74, H 7.66, N 5.62.
Methyl 3-(1Ј-Nitro-2Ј-oxocycloheptyl)propanoate (27): Yield 30%,
as a pale yellow oil (Procedure I, room temp.), 40% (Procedure I,
reflux), or 49% (Procedure II). IR (NaCl): ν
= 1732 (C=O),
˜
max
1549 and 1347 (NO2) cm–1. 1H NMR (250 MHz, CDCl3): δH
=
3.66 (s, 3 H, OCH3), 2.75–2.20 (m, 7 H, 2,3,3Ј,7Ј-H), 1.95–1.35 (m,
7 H, 4Ј–7Ј-H) ppm. 13C NMR (63 MHz, CDCl3): δC = 202.2 (C-
2Ј), 172.3 (C-1), 98.5 (C-1Ј), 51.8 (CO2CH3), 41.1 (C-3Ј), 34.6 (C-
2), 31.5 (C-5Ј), 29.3 (C-7Ј), 28.3 (C-6Ј), 25.6 (C-4Ј), 24.4 (C-3) ppm.
C11H17NO5 (243.26): calcd. C 54.31, H 7.04, N 5.76; found C
54.12, H 7.23, N 5.79.
3-(1Ј-Nitro-2Ј-oxocycloheptyl)propanonitrile (28): Yield 60%, as a
pale yellow oil (Procedure II). IR (NaCl): ν
= 2251 (CN), 1726
˜
3-(1Ј-Nitro-2Ј-oxocycloundecyl)propenal (22): Yield 100% (based on
50% recovered starting material), as a yellow oil containing a 1.2:1
mixture of diastereomers (Procedure I). The product was filtered
through a pad of silica gel, eluting with a gradient from petroleum
max
(C=O), 1556 and 1348 (NO2) cm–1. H NMR (250 MHz, CDCl3):
δH = 2.80–2.20 (m, 7 H, 1,2,3Ј,7Ј-H), 1.95–1.50 (m, 7 H, 4Ј–7Ј-
H) ppm. 13C NMR (63 MHz, CDCl3): δC = 202.1 (C-2Ј), 118.6 (C-
1), 97.8 (C-1Ј), 41.7 (C-3Ј), 35.1 (C-2), 32.7 (C-5Ј), 29.5 (C-7Ј), 25.9
(C-6Ј), 24.8 (C-4Ј), 13.0 (C-3) ppm. C10H14N2O3 (210.23): calcd. C
57.14, H 6.66, N 13.33; found C 57.25, H 6.56, N 13.24.
1
ether to ethyl acetate. Data for the E diastereomer: IR (NaCl): ν
˜
max
1
= 2932, 1729 (C=O), 1699 (C=O), 1550 and 1359 (NO2) cm–1. H
NMR (250 MHz, CDCl3): δH = 9.68 (d, J = 7.3 Hz, 1 H, 1-H),
7.35 (d, J = 16.3 Hz, 1 H, 3-H), 6.25 (dd, J = 16.2, 7.3 Hz, 1 H, 2-
H), 3.00–2.01 (m, 6 H, 3Ј,4Ј,11Ј-H), 2.00–0.94 (m, 12 H, 5Ј–10Ј-
H) ppm. 13C NMR (63 MHz, CDCl3): δC = 200.1 (C-2Ј), 191.8 (C-
1), 147.1 (C-3), 133.7 (C-2), 99.4 (C-1Ј), 36.7 (C-3Ј), 32.1 (C-11Ј),
27.0, 26.2, 26.1, 26.0, 23.2, 21.9 (C-4Ј-9Ј), 20.9 (C-10Ј) ppm.
C14H21NO4 (267.32): calcd. C 62.90, H 7.92, N 5.24; found C
62.68, H 9.19, N 6.47. Data for the Z diastereomer (assigned from
2-Nitro-2-(2Ј-phenylsulfonylethyl)cycloheptanone (29): Yield 77%,
as a white solid, obtained by filtration of the reaction mixture (Pro-
cedure II), m.p. 123–125 °C. IR (NaCl): ν
= 1721 (C=O), 1548
˜
max
and 1347 (NO2), 1305 (SO2) cm–1. 1H NMR (250 MHz, CDCl3):
δH = 7.90–7.40 (m, 5 H, Ar-H), 3.25–2.85 (m, 2 H, 2Ј-H), 2.65–
2.15 (m, 4 H, 7,1Ј-H), 1.90–1.25 (m, 8 H, 3–6-H) ppm. 13C NMR
(63 MHz, CDCl3): δC = 202.2 (C-1), 138.7 (C-1ЈЈ), 134.6 (C-4ЈЈ),
129.9 (C-3ЈЈ, 5ЈЈ), 128.4 (C-2ЈЈ, 6ЈЈ), 97.9 (C-2), 51.4 (C-2Ј), 41.6 (C-
7), 35.4 (C-5), 30.1 (C-3), 29.6 (C-4), 25.9 (C-6), 24.8 (C-1Ј) ppm.
C15H19NO5S (325.38): calcd. C 55.37, H 5.89, N 4.30; found C
55.09, H 5.79, N 4.18.
1
the initial mixture): H NMR (250 MHz, CDCl3): δH = 9.77 (dd,
J = 6.5 Hz, 1 H, 1-H), 7.04 (d, J = 12.2 Hz, 1 H, 3-H), 6.28 (dd, J
= 12.2 and 6.5 Hz, 1 H, 2-H), 2.95–0.59 (m, 18 H, 3Ј–11Ј-H) ppm.
4-(1Ј-Nitro-2Ј-oxocycloundecyl)-3-buten-2-one (23): Yield 86%
(based on 36% recovered starting material) as a yellow oil com-
posed of a 1.4:1 mixture of diastereomers (Procedure I). The prod-
uct was filtered through a pad of silica gel, eluting with a gradient
2-Nitro-2-(3Ј-oxo-1Ј-cyclopentyl)cycloheptanone (30): Yield 72%, as
a colourless oil containing a 1:1 mixture of diastereomers a/b (Pro-
cedure II). The product was filtered through a pad of silica gel,
eluting with a gradient from petroleum ether to ethyl acetate. IR
from petroleum ether to ethyl acetate. IR (NaCl): ν
= 2932,
˜
max
1728 (C=O), 1686 (C=O), 1550 and 1358 (NO2) cm–1. 1H NMR (NaCl): ν
= 2933, 1745 (C=O), 1730 (C=O), 1713 (C=O), 1537
˜
max
Eur. J. Org. Chem. 2013, 1327–1336
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1333

J. C. Menéndez et al.
FULL PAPER
and 1346 (NO2) cm–1. 1H NMR (250 MHz, CDCl3): δH = 3.13–
2.90 (m, 2 H, 7ab-H), 2.75–2.60 (m, 2 H, 7ab-H), 2.58–2.25 and
1), 214.7 (C-1), 187.5 (C-2Ј), 187.1 (C-2Ј), 134.9 (2 C-1ЈЈ), 134.1
(C-4ЈЈ), 133.8 (C-4ЈЈ), 129.1 (C-2ЈЈ,6ЈЈ), 128.6 (C-3ЈЈ,5ЈЈ), 91.4 (C-
2.24–1.95 (2m, 16 H, 3,6,2Ј,4Јab-H), 1.90–1.40 (m, 14 H, 1Ј), 91.1 (C-1Ј), 41.2 (C-2), 40.8 (C-2), 37.7 (C-5), 37.4 (C-3), 37.7
4,5,1Ј,5Јab-H) ppm. 13C NMR (63 MHz, CDCl3): δC = 215.2 (C-
(C-5), 37.2 (C-3), 25.9 (C-4), 25.5 (C-4) ppm. C13H13NO4 (247.25):
3Ј), 215.1 (C-3Ј), 201.4 (C-1), 201.3 (C-1), 99.9 (C-2), 99.8 (C-2), calcd. C 63.15, H 5.30, N 5.67; found C 63.01, H 5.34, N 5.63.
42.9 (C-1Ј), 42.8 (C-1Ј), 41.3 (C-2Ј), 41.1 (C-2Ј), 39.8 (C-4Ј), 39.6
(C-4Ј), 38.0 (C-7), 37.9 (C-7), 32.3 (2 C), 28.9, 28.8, 25.2, 25.1, 24.3,
24.2 (2 C), 23.8 (C-3–6,5Ј) ppm. C12H17NO4 (239.27): calcd. C
65.25, H 7.11, N 5.85; found C 65.23, H 7.01, N 5.80.
3-(1Ј-Nitro-2Ј-oxo-2ЈЈ-phenylethyl)cyclohexanone (35): Yield 70%,
as a brown solid. The product was filtered through a pad of silica
gel, eluting with a gradient from petroleum ether to ethyl acetate
to give a 5:1 mixture of diastereomers a/b. Data for the major dia-
stereomer: M.p. 123.6 °C. IR (KBr): νmax = 1715 (C=O), 1557 and
˜
2-Nitro-2-(3Ј-oxo-1Ј-cyclopentyl)cyclooctanone (31): Yield 73%, as
a colourless oil containing a 1:1 mixture of diastereomers (Pro-
cedure II). The product was filtered through a pad of silica gel,
eluting with a gradient from petroleum ether to ethyl acetate. IR
1
1362 (NO2) cm–1. H NMR (CDCl3, 250 MHz): δH = 7.99 (d, J =
7.4 Hz, 2 H, 2ЈЈ,6ЈЈ-H), 7.69 (t, J = 7.3 Hz, 1 H, 4ЈЈ-H), 7.57–7.51
(m, 2 H, 3ЈЈ,5ЈЈ-H), 6.07 (d, J = 6.0 Hz, 1 H, 1Ј-H), 3.15–2.88 (m,
1 H, 2-H), 2.60–2.21 (m, 4 H, 2,3,6-H), 2.18–2.03, 1.97–1.81, 1.80–
1.62 and 1.56–1.38 (4m, 4 H, 4,5-H) ppm. 13C NMR (CDCl3,
63 MHz): δC = 207.6 (C-1), 187.3 (C-2Ј), 135.0 (C-1ЈЈ), 134.3 (C-
4ЈЈ), 129.2 (C-2ЈЈ, 6ЈЈ), 128.7 (C-3ЈЈ, 5ЈЈ), 91.7 (C-1Ј), 43.0 (C-2),
40.7 (C-6), 39.0 (C-3), 27.8 (C-4), 24.6 (C-5) ppm. C14H15NO4
(261.28): calcd. C 64.36, H 5.74, N 5.36; found C 64.24, H 5.70, N
5.31.
(NaCl): ν
= 2933, 1747 (C=O), 1723 (C=O), 1537 and 1339
˜
max
(NO2) cm–1. 1H NMR (250 MHz, CDCl3): δH = 3.15–2.90 (m, 2
H, 8ab-H), 2.79–2.10 (m, 14 H, 3,8,2Ј,4Јab-H), 1.93–1.52, 1.50–
1.24 and 1.11–0.90 (3m, 22 H, 4–7-H, 1Ј,5Јab-H) ppm. 13C NMR
(63 MHz, CDCl3): δC = 215.5 (C-3Ј), 215.0 (C-3Ј), 204.5 (C-1),
204.3 (C-1), 99.7 (C-2), 99.0 (C-2), 40.5 (C-2Ј), 40.0 (2 C-1Ј), 39.4
(C-2Ј), 38.9 (C-4Ј), 38.7 (C-4Ј), 38.5 (C-8), 37.9 (C-8), 31.6, 30.8,
27.8, 27.6, 25.4, 25.3, 25.2, 24.3, 24.2, 23.7, 21.9 (2 C, C-3–
7,5Ј) ppm. C13H19NO4 (253.30): calcd. C 61.66, H 7.50, N 5.53;
found C 61.54, H 7.38, N 5.50.
General Procedure for the Michael Reaction Between Benzoyl-
nitromethane and Enones: To a vigorously-stirred dispersion of
benzoylnitromethane (0.158 g, 0.96 mmol) in tap water (pH = 6.9,
5 mL) the corresponding Michael acceptor was added (2.4 mmol,
2.5 equiv.). The mixture was stirred and heated to reflux for 4 h
and the aqueous phase was then extracted with CH2Cl2 (3ϫ
10 mL). The combined organic layers were then extracted with a
saturated solution of NaHCO3 (3ϫ 15 mL) and dried with anhy-
drous sodium sulfate and the solvent evaporated. The product was
filtered through a pad of silica gel, eluting with a gradient from
petroleum ether to ethyl acetate, yielding compounds 25 and 26.
2-Nitro-2-(3Ј-oxo-1Ј-cyclopentyl)cyclodecanone (32): Yield 77%, as
a colourless oil containing a 1:1 mixture of diastereomers a/b (Pro-
cedure II). The product was filtered through a pad of silica gel,
eluting with a gradient from petroleum ether to ethyl acetate. IR
1
(NaCl): ν
= 2932, 1724 (C=O), 1538 and 1337 (NO2) cm–1. H
˜
max
NMR (250 MHz, CDCl3): δH = 3.11–3.01 (m, 2 H, 10ab-H), 2.89–
2.55 (m, 6 H, 3,10,2Јab-H), 2.52–1.70 (m, 18 H, 3,4,9,1Ј,2Ј,4Јab-
H), 1.69–1.32 (m, 20 H, 5–8-H, 5Јab-H) ppm. 13C NMR (63 MHz,
CDCl3): δC = 215.7 (C-3Јb), 215.0 (C-3Јa), 202.3 (C-1b), 202.1 (C-
1a), 102.3 (C-2b), 101.9 (C-2a), 40.7 (C-1Јa), 40.5 (C-1Јb), 40.3 (C-
2Јb), 39.4 (C-2Јa), 38.6 (C-4Јa), 38.0 (C-4Јb), 36.2 (C-10a), 36.0 (C-
10b), 31.2a, 30.3b, 25.8a, 25.7b, 25.3b, 25.2a, 24.9b, 24.8b, 24.7a,
24.5a, 23.9a, 23.7b, 22.9a, 22.7b, 19.3a, 19.2b (C-3–9,5Ј) ppm.
C15H23NO4 (281.35): calcd. C 64.05, H 8.18, N 4.98; found C
63.93, H 8.09, N 4.90.
1
5-Nitro-2-pentanone (25): Yield 90%, as a colourless oil. H NMR
(250 MHz, CDCl3): δH = 4.45 (t, J = 6.5 Hz, 2 H, 5-H), 2.63 (t, J
= 6.7 Hz, 2 H, 3-H), 2.27 (t, J = 6.6 Hz, 2 H, 4-H), 2.20 (s, 3 H,
1-H) ppm.
6-Nitro-3-hexanone (26): Yield 70%, as a colourless oil. IR (NaCl):
ν
= 1714 (C=O), 1552 and 1377 (NO2) cm–1. 1H NMR
˜
max
(250 MHz, CDCl3): δH = 4.45 (t, J = 6.2 Hz, 2 H, 6-H), 2.56 (t, J
= 6.7 Hz, 2 H, 4-H), 2.46 (q, J = 7.4 Hz, 2 H, 2-H), 2.27 (quint, J
= 6.7 Hz, 2 H, 5-H), 1.07 (t, J = 7.3 Hz, 3 H, 1-H) ppm. 13C NMR
(63 MHz, CDCl3): δC = 209.2 (C-3), 74.5 (C-6), 37.8 (C-4), 35.9
(C-2), 21.0 (C-5), 7.6 (C-1) ppm. C6H11NO3 (145.16): calcd. C
49.65, H 7.64, N 9.65; found C 49.80, H 7.89, N 9.60.
2-Nitro-2-(3Ј-oxo-1Ј-cyclopentyl)cyclodecanone (33): Yield 83% as a
colourless oil containing a 1:1 mixture of diastereomers (Procedure
II). The product was filtered through a pad of silica gel, eluting
with a gradient from petroleum ether to ethyl acetate to give a 5:1
mixture of diastereomers a/b. IR (NaCl): νmax = 2933, 1747 (C=O),
˜
1723 (C=O), 1537 and 1336 (NO2) cm–1. 1H NMR (250 MHz,
CDCl3): δH = 3.23–3.04 (m, 2 H, 12ab-H), 2.84–2.70 (m, 2 H, 12ab-
H), 2.63–1.83 (m, 18 H, 3,11,1Ј,2Ј,4Јab-H), 1.58–0.94 (m, 32 H, 4–
10-H, 5Јab-H) ppm. 13C NM ppm. 13C NMR (63 MHz, CDCl3):
δC = 215.7 (C-3Јa), 214.8 (C-3Јb), 200.8 (C-1a), 200.5 (C-1b), 102.2
(C-2a), 101.7 (C-2b), 40.1 (C-2Јa), 38.9 (C-1Јb), 38.8 (C-2Јb), 38.5
(C-1Јa), 37.9 (C-4Јa), 33.6 (C-4Јb), 33.2 (C-12a), 31.8 (C-12b),
30.2a, 26.3a, 26.1a, 24.5b, 23.2b, 23.1 (2 Ca), 22.5b, 22.4a, 21.8a,
21.6a, 21.4b, 21.3a, 18.3a ppm; (6 carbons relating to the b dia-
stereomer are not observed in the 13C NMR spectrum).
C17H27NO4 (309.40): calcd. C 66.01, H 8.73, N 4.53; found C
65.89, H 8.68, N 4.40.
Side Products from Heating to Reflux: When the reactions between
2-nitrocyclooctanone or benzoylnitromethane and methyl or ethyl
vinyl ketone were performed under reflux conditions the expected
Michael adducts were accompanied by the side products described
below.
3-Hydroxy-2,7-octanedione: Isolated from the reactions between 2-
nitrocyclooctanone and methyl vinyl ketone under reflux condi-
tions (22% with respect to the enone) or in phosphate buffer at pH
7.4 (13%), and also from the reaction between benzoylnitrometh-
ane and methyl vinyl ketone (10%). IR (NaCl): νmax = 3466 (OH),
˜
1
1713 (CO) cm–1. H NMR (250 MHz, CDCl3): δH = 4.11 (dd, J =
7.3 and 6.7 Hz, 1 H, 3-H); 3.55 (s, 1 H, OH); 2.45 (t, J = 6.7 Hz,
2 H, 6-H); 2.15 and 2.06 (2s, 2ϫ3 H, 2 COCH3); 1.80–1.40 (m, 4
H, 4,5-H) ppm.
3-(1Ј-Nitro-2Ј-oxo-2Ј-phenylethyl)cyclopentanone (34): Yield 72%,
as a colourless oil containing a 1:1 mixture of diastereomers. IR
1
(NaCl): ν
= 2918, 1745 (C=O), 1548 and 1358 (NO2) cm–1. H
˜
max
NMR (CDCl3, 250 MHz): δH = 8.05–7.96 (m, 4 H, H-Ar), 7.71– 4-Hydroxy-3,8-decanedione: Isolated from the reaction between
7.63 (m, 2 H, H-Ar), 7.60–7.45 (m, 4 H, H-Ar), 6.13–6.05 (m, 2 H, benzoylnitromethane and ethyl vinyl ketone. Yield 16%, as a
1Ј-H), 3.42–3.20 (m, 4 H, 2-H), 2.90–2.65 (m, 2 H, 3-H), 2.59–1.55 colourless oil. IR (NaCl): ν = 3457 (OH), 1711 (C=O), 1104
˜
max
(m, 8 H, 4, 5-H) ppm. 13C NMR (CDCl3, 63 MHz): δC = 214.8 (C- (C–O) cm–1. 1H NMR (250 MHz, CDCl3): δH = 4.22–4.18 (m, 1
1334
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 1327–1336

Michael Addition Processes from α-Nitro Ketones and Their Anions
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H, 4-H), 4.00–3.00 (br. s, 1 H, OH), 2.74–2.40 (m, 6 H, 2,7,9-H),
1.92–1.51 (m, 4 H, 5,6-H), 1.17–1.09 (m, 6 H, 1,10-H) ppm. 13C
NMR (63 MHz, CDCl3): δC = 212.6 (C-8), 211.2 (C-3), 75.9 (C-4),
41.4 (C-7), 35.8 (C-9), 32.9 (C-2), 31.0 (C-5), 18.9 (C-6), 7.7 (C-1),
7.5 (C-10) ppm. C10H18O3 (186.25): calcd. C 64.49, H 9.74; found
C 64.30, H 9.50.
[18]
[19]
For a preliminary communication on part of this work, see:
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Supporting Information (see footnote on the first page of this arti-
cle): Copies of 1H NMR and 13C NMR spectra of all compounds).
Acknowledgments
Financial support from the Spanish Ministerio de Economía y
Competitividad, formerly named Ministerio de Ciencia e Innova-
ción (MICINN) (grant numbers CTQ2009-12320-BQU and
CTQ2012-33272-BQU) and Universidad Complutense (grant
number GR35/10-A-920234) is gratefully acknowledged.
[20]
[21]
[22]
[23]
[24]
[25]
[26]
[27]
[1] For selected monographs on the use of water as a reaction me-
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Received: October 26, 2012
Published Online: January 24, 2013
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