Cycloaddition vs. conjugative Michael-type addition of 2-ethoxy-3-morpholinobuta-1,3-diene with nitroolefins

Article abstract of DOI:10.1039/a605345i

The reactivity of the title dienamine towards conjugated nitroolefins has been investigated. With 1-nitrocyclopentene carbocyclic products largely predominated, whereas with 1-nitrocyclohexene only Michael-type products were formed. The behaviour of β-nitrostyrene was found to be dependent on the reaction conditions used.

Full text of DOI:10.1039/a605345i

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Cycloaddition vs. conjugative Michael-type addition of
-ethoxy-3-morpholinobuta-1,3-diene with nitroolefins
2
Ga sˇ per Marc,† Patrizia Nitti, Giuliana Pitacco,* Alessandro Pizzioli and
Ennio Valentin
Dipartimento di Scienze Chimiche, Università, Via L. Giorgieri 1, I-34127 Trieste, Italy
The reactivity of the title dienamine towards conjugated nitroolefins has been investigated. With
1
-nitrocyclopentene carbocyclic products largely predominated, whereas with 1-nitrocyclohexene only
M ichael-type products were formed. The behaviour of â-nitrostyrene was found to be dependent on the
reaction conditions used.
Introduction
2
-Amino 1,3-dienes are interesting building blocks for cyclo-
1
additions. However, their chemical behaviour has been little
described in the literature because, in general, they are difficult
to prepare. A few syntheses of chiral
1
a–c
1d–f
and achiral
2
-aminobuta-1,3-dienes have recently been described. For
instance, chiral systems were prepared by Wittig olefination
of an α-oxo enamine derived from butane-2,3-dione and
1
a
(
S)-methoxymethylpyrrolidine. Of the achiral systems an
interesting method makes use of catalytic aminomercuriation
1
a
of terminal alkynes.
Their reactivity with electrophilic olefins is characterized by
two different pathways. Either they behave as 4π electron
donors upon cyclization or they undergo a Michael-type reac-
tion with the formation of open-chain products. In particular,
Fig. 1
the dienamine
1 (R NH = morpholine) reacted with β-
2
nitrostyrene in THF to give, after hydrolysis, the open-chain
product 2 (Fig. 1), whereas in methanol the cyclic product 3
(
Ar = Ph) was obtained as a single diastereoisomer, after
1e
hydrolysis of the enamine intermediate. The same ketone 3
was obtained by D. Enders with high diastereoselectivity and
1
a
excellent enantiomeric excess, using the chiral dienamine 1
[
R NH = (S)-(2-methoxymethyl)pyrrolidine] and a series of 2-
2
aryl-1-nitroethenes. In contrast, because of its particular
reactivity β-nitrostyrene reacted with 2,3-dimorpholinobuta-
2
1
,3-diene 4 in a [3 + 2] carbocyclization, to yield the corres-
ponding 2-aminocyclopentanone 5, as a 3:1 mixture of two
diastereoisomers, after hydrolysis of the diastereoisomeric
morpholinocyclopentene intermediates.
Scheme 1 Reagents and conditions: i, HC(OEt) , conc. H SO , 5 ЊC; ii,
3
2
4
H SO , 100 ЊC, 760 Torr, 4 h; 80–140 ЊC, 42 Torr, 1.5 h; iii, morpholine,
2
4
TiCl , pentane, 6 h, 0 ЊC
4
Results
3
Owing to the continuing interest in nitroaliphatic compounds,
only product, provided the temperature was maintained at
we now describe both the synthesis of a new 2-aminobuta-1,3-
diene, which is simultaneously a dienol ether, and its application
in the reactions with nitroolefins. Our investigations began with
0
ЊC. Under these conditions the αβ-unsaturated ketone 8 reacts
faster than the more hindered ketone 7 and the enamine 9 can
be isolated in pure form. Although this compound is likely
to exist in an s-trans conformation, an NOE experiment
4
the synthesis of the αβ-unsaturated ketone 8 from butane-2,3-
5
dione 6 (Scheme 1). We found that when the diethyl ketal 7 was
in which the CH N protons resonating at 2.86 ppm were irradi-
2
heated at 80 ЊC, in the presence of a catalytic amount of toluene-
p-sulfonic acid, partial deprotection of the protected carbonyl
group occurred, to give the αβ-unsaturated ketone 8. Although
the ketone 8 was always contaminated by the monoacetalated
butane-2,3-dione 7 (15–20%), condensation of the mixture
ated showed a weak enhancement (3%) of the ethyl group’s
methylene resonance (3.86 ppm), thus indicating that there is
some contribution of the s-cis form to the conformational
equilibrium.
6
with morpholine under White and Weingarten conditions gave
Reaction with 1-nitrocyclopentene (NCP)
the desired 2-ethoxy-3-morpholinobuta-1,3-diene 9 as the
Addition of 1-nitrocyclopentene to the dienamine 9 in chloro-
form, at room temperature, gave a mixture of cyclic and acyclic
enamine intermediates, which could not be isolated by chroma-
†
On leave from the Faculty of Pharmacy of the University of
1
Ljubljana, Slovenia.
tography, owing to their instability towards hydrolysis. The H
J. Chem. Soc., Perkin Trans. 1, 1997
223

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NMR spectrum of the crude reaction mixture, however, clearly
showed the presence of two trisubstituted enamines 10 and 11
Table 1 Chemical shift (ppm) and multiplicity (J/Hz) for the nitro-
methine proton
(δH for their vinyl proton signal 4.59 ppm, d J 4.4 Hz and 4.66
ppm, d J 3.9 Hz) and only one dienamine derivative 12, whose
geometry was not determined (δH for its vinyl proton signal
R
4
.30 ppm, d J 9.3 Hz) (Scheme 2). Since the reaction mixture
δH 4.98
δH 4.46
dt, J 6.2, 6.2, 1.7
dt, J 8.3, 5.7, 5.7
δH 5.09
δH 4.60
dt, J 6.4, 6.4, 1.8
dt, J 8.8, 6.0, 6.0
δH 5.07
δH 4.58
dt, J 6.6, 6.6, 2.0
dt, J 7.8, 6.2, 6.2
7
,9
istic of a non-conjugated tetrasubstituted enamine, and also
by the NOE effect (11%) found for the NCH resonating at 3.17
2
ppm, when 7-H was irradiated.
Hydrolysis of the reaction mixture containing 10, 11 and 12
with aqueous hydrochloric acid gave a mixture of 6-
hydrindanone derivatives 15 and 16 along with the open-chain
ketone 17 in a trans configuration.
Compounds 15 and 16 differed in the orientation of the
1
ethoxy group, as indicated by a comparison of the H NMR
signal of their respective CHOEt resonances (3.58 ppm, ddd, J
0
1
.9, 3.0, 5.0 Hz for 15 and 3.98 ppm, ddd, J 0.9, 6.1, 12.3 Hz for
6) and by heating the mixture in the presence of an acid as a
catalyst to equilibrate it. Conversion of 15 into 16 was com-
plete, thus proving the axial orientation of the ethoxy group
in the less thermodynamically stable compound. This stereo-
chemical assignment was confirmed by NOE difference experi-
ments carried out on 16 (Fig. 2), by which also the cis fusion
between the rings was determined. It is interesting to note the
presence in 16 of a large long-range coupling between 4 -H
eq
4
Scheme 2 Reagents and conditions: i, CHCl , RT, 72 h; ii, NCP, CHCl ,
and 7a-H ( J 2.4 Hz), which indicates a diequatorial relation-
3
3
RT, 72 h; iii, aq. HCl, RT, 2 h; iv, benzene, PTSA, 80 ЊC, 15 min; v, NCP,
ship between the two protons, thus confirming the cis fusion
between the rings.
CHCl , RT, 72 h
3
Equilibration of the ketone 17, carried out in refluxing
benzene with traces of toluene-p-sulfonic acid as a catalyst,
afforded a 4:1 mixture of 17 and its cis isomer 18. Since a dif-
had a very complicated NMR spectrum, nothing can be said
about the presence in it of the tetrasubstituted enamine 13
which, however, is the product formed first from the reac-
tants. On the other hand, equilibration of a tetrasubstituted
enamine into the corresponding trisubstituted derivative is a
well known process and might be due to the presence of traces
1
3
ferentiation between 16 and 17 by a comparison of their
C
NMR spectra was not possible, their relative stereochemistry
was determined by comparing the values of chemical shift and
vicinal coupling constants of their nitromethine protons with
7
10
of acid.
those of similar compounds (Table 1).
1
Besides their identification in the reaction mixture, 10 and 11
in the equilibrium mixture were also trapped by the nitroolefin
itself. In fact, by using 1-nitrocyclopentene in excess they
underwent further reaction to yield the Michael-type adduct 14
The ratio cyclic:acyclic products was 9:1, determined by H
NMR analysis of the spectrum of the hydrolysed crude reac-
tion mixture. Approximately the same ratio was obtained after
chromatographic separation of the products.
(
Scheme 2) as a single isomer. Its stereochemistry was assigned
A repeat of the reaction between the dienamine 9 and 1-
nitrocyclopentene in 1:1 molar ratio in ethanol at 80 ЊC for 1 h
gave the same products in a similar relative ratio, no significant
differences being observed.
by means of NOE experiments (see Fig. 2). The trans configur-
ation was attributed to the 2-nitrocyclopentyl residue on the
basis of the pattern of the nitromethine proton (dt, J 7.8, 5.8,
5
.8 Hz); this will be discussed below for other derivatives con-
In contrast, reaction of 9 and 1-nitrocyclopentene in diethyl
ether at Ϫ20 ЊC gave the moisture-sensitive 1,2-oxazine N-oxide
derivative 19 (Scheme 3) which could not be isolated as a pure
compound. Its formation, however, was proved by the isolation
of the diketone 21, obtained by hydrolysis at pH 2 of the crude
reaction mixture. This result is to be ascribed to a Nef-type
reaction occurring with compound 19 by protonation of the
N-oxide oxygen, nucleophilic ring fission and attack of water
onto the electrophilic carbon atom of the nitronic group of 20
taining the same moiety.
In spite of its double nature as an enamine and an enol ether,
compound 14 was very resistant to acidic hydrolysis, at room
temperature. This is because conjugation of the nitrogen lone
pair with the double bond, which is necessary for protonation
of the enamine β carbon, cannot be achieved for steric reasons,
1
1
1
,2
8
owing to the presence of an A strain. This is also confirmed
by the value of the C᎐C stretching band, 1660 cm , character-
Ϫ1
᎐
2
24
J. Chem. Soc., Perkin Trans. 1, 1997

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(see Scheme 3). Further, the iminium group was simultaneously
hydrolysed, while the enol ether system remained unchanged.
Scheme 3 Reagents and conditions: i, NCP, diethyl ether, Ϫ20 ЊC, 24 h;
ii, aq. HCl, RT, 1 h
Fig. 2 The main data of DIFNOE measurements for compounds 14,
6 and 27
1
Reaction with 1-nitrocyclohexene
The reaction of the dienamine 9 with 1-nitrocyclohexene,
carried out in chloroform at room temperature was much
simpler, leading to the exclusive formation of the Michael-type
adducts as a mixture of cis-trans stereoisomers 22 and 23, in the
ratio of 15:85 (Scheme 4). Both isomers were assigned the E
Fig. 3
products 26 and 27 (Fig. 3), albeit in low yield (18%), along
with the already mentioned acyclic compounds 24 and 25.
Again these cyclization products differed in the configuration
of the carbon atom bearing the ethoxy group, as shown by
acidic equilibration which completely converted the 2-decalone
2
6 into 27. The stereochemical assignment is based on NOE
experiments carried out on 27 (Fig. 2).
Reaction with â-nitrostyrene
The reaction between the dienamine 9 and β-nitrostyrene,
carried out in chloroform, furnished a mixture of acyclic and
cyclic products, 28 and 29/30 respectively (Scheme 5), after
Scheme 4 Reagents and conditions: i, CHCl , RT, 72 h; ii, aq. HCl, RT,
3
2
h
configuration, by means of NOE difference experiments.
Irradiation of the enamine vinyl proton signals of 22 (4.53
ppm, d J 10.1 Hz) and 23 (4.15 ppm, d J 9.5 Hz) caused
enhancement of their respective methylene protons adjacent to
the amine nitrogen (η 13% and 9% for 22 and 23 respectively).
As for the nitrocyclohexyl moiety, the cis configuration was
assigned to 22 and the trans configuration to 23, on the basis of
the NMR values of their respective nitromethine proton signals
Scheme 5 Reagents and conditions: i, CHCl , RT, 24 h; ii, aq. HCl, RT,
2 h
3
hydrolysis. The ratio acyclic:cyclic products was 3:1. The 2-
ethoxycyclohexanone derivatives 29 and 30 were in the ratio of
4:1 in favour of the isomer with the ethoxy group in an axial
orientation. The nitro group and the phenyl group are equa-
torial in both isomers as indicated by their respective nitrome-
thine and benzylic proton signals, which showed the same
multiplicities and very close values for the vicinal coupling con-
stants. In contrast, the proton geminal to the ethoxy group was
(compound 22: 4.32 ppm, q J 4.1 Hz; compound 23: 4.00 ppm,
dt J 14.9, 14.9, 3.9 Hz).
Hydrolysis of this mixture afforded the corresponding cis
and trans ketones 24 and 25 in the ratio of 1:9, after acidic
equilibration.
A repeat of the reaction at 80 ЊC in ethanol or benzene, fol-
lowed by hydrolysis, allowed the isolation of the cyclization
J. Chem. Soc., Perkin Trans. 1, 1997
225

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a triplet (J 6.0 Hz) for compound 29 and a doublet of double
Experimental
4
3
doublets ( J 0.1, J 6.3 and 12.2 Hz) for compound 30, thus
suggesting the equatorial orientation of the former proton and
the axial orientation of the latter. Also DIFNOE measurements
carried out on 30 (Scheme 5) supported this assignment.
The same reaction performed in tetrahydrofuran at 5 ЊC led
to the same products, although in a slightly different com-
position. The ratio between the acyclic product 28 and the cyc-
lic products 29/30 was 1:1. In ethanol at room temperature only
the linear product 28 was formed, whereas in refluxing ethanol
the cyclic products were also formed, although in both cases a
considerable amount of the adduct between morpholine and
β-nitrostyrene was separated.
IR spectra were determined with a Perkin-Elmer 1320 spectro-
meter. UV spectra were obtained on a Perkin-Elmer Lambda
1
13
5
spectrophotometer. H and C NMR spectra were scanned
on a JEOL EX400 at 400 MHz and 100.4 MHz respec-
tively, using deuteriochloroform as the solvent. All chemical
shifts (δ) are reported in parts per million (ppm) and the
coupling constants (J) are quoted in Hz. Mass spectra were
determined with a VG 7070 spectrometer at 70 eV. Mps were
determined on a Büchi apparatus and are uncorrected. Thin-
layer chromatographic analyses (TLC) were performed on
Merck 60F-254 glass-backed silica gel plates with visualisation
by UV light (254 nm) or iodine. Flash chromatography was
carried out using silica gel 60 H (Merck 7385). Gas chro-
matographic analyses were performed on a C. Erba GC
Mechanism
Although a Diels–Alder process cannot be excluded a priori, a
stepwise mechanism could better explain the difference in
reactivity observed. In particular, the different behaviour of the
dienamine 9 towards 1-nitrocyclopentene and 1-nitrocyclo-
hexene might be ascribed to the different lifetime of their
respective dipolar intermediates 31 and 32 (Scheme 6). The
zwitterion 31 is likely to be more stable than 32, because of the
existence of a resonance form with a double bond external to a
8
2
000 instrument, the capillary column being OV 1701, size
5 m × 0.32 mm.
Synthesis of 3-ethoxybut-3-en-2-one 8
Triethyl orthoformate (29.7 g, 0.20 mol) was added to butane-
2,3-dione 6 (17.2 g, 0.20 mol) at 5 ЊC followed by 5 drops of
conc. H SO , added with vigorous stirring. The yellow solution
2
4
1
2a
five-membered ring. This would allow the formation of the
suitable rotamer reactive for cyclization. The intermediacy of
the nitronate form would also account for the exclusive occur-
rence of the cis fusion between the rings. The chain in fact
turned brown and it was warmed to room temperature. The
mixture was heated at 100 ЊC for 4 h in a distillation apparatus
fitted with a Vigreux column. During this period approximately
10 g of light yellow product was collected, which consisted
mainly of triethyl orthoformate. The mixture was cooled to
room temperature and the pressure was reduced to 42 Torr,
while the receiver was cooled at Ϫ40 ЊC. The temperature was
increased to 80 ЊC in 20 min. After 1 h at 80 ЊC (distillation of
yellow product slowly continued), the temperature was grad-
ually increased to 140 ЊC. The distillate (18.2 g) was collected as
a clear oil, bp 60 ЊC (42 Torr) and consisted of 80–85% of the
1
,3
would be forced into an axial conformation to avoid the A
1
2b
strain with the nitronate group. It is worth noting that the
initially formed enamine intermediate would be the tetrasubsti-
tuted systems 13 and 33, from which the trisubstituted isomers
would be generated by equilibration.
4
desired 3-ethoxybut-3-en-2-one 8, the remaining being the
compound 7. Compound 8: νmax(neat)/cm 1710 (C᎐O), 1610
Ϫ1
(
C᎐C) and 1155 (C᎐O᎐C); δ (CDCl ) 5.18 (1 H, d, J 2.4, vinyl-
᎐
H 3
H trans to OEt), 4.46 (1 H, d, J 2.4, vinyl-H cis to OEt), 3.81
2 H, q, CH CH ), 2.31 (3 H, s, COCH ) and 1.39 (3 H, t,
(
2
3
3
CH CH ); δ (CDCl ) 195.5 (s, C᎐O), 157.4 (s, EtO᎐C᎐C), 90.8
2
3
C
3
(
t, ᎐CH ), 63.4 (t, OCH CH ), 25.5 (q, CH CO) and 13.9 (q,
᎐
2 2 3 3
OCH CH ).
2
3
2
-Ethoxy-3-morpholinobuta-1,3-diene 9
3
A solution of TiCl (5.7 g, 0.030 mol) in pentane (10 cm ) was
4
added to a solution of morpholine (15.7 g, 0.15 mol) in pentane
3
(
200 cm ) under an argon atmosphere. The mixture was stirred
for 30 min at room temperature and then cooled to 0 ЊC. A
3
solution of the ketone 8 (7.0 g, 0.05 mol) in pentane (50 cm )
was added dropwise to the mixture which was then stirred for
6
h at 0 ЊC. The mixture was filtered through Celite and the
filtrate evaporated under reduced pressure. The orange oily
residue was distilled at 30 Torr to eliminate morpholine, then
at 0.05 Torr. The first fraction contained the protected ketone
Scheme 6
7
and the unchanged ketone 8. The second fraction (51–52 ЊC)
+
It is interesting to note that the preferred orientation of the
ethoxy group in our cyclohexanone derivative is axial and the
preferred orientation of the same group in the bicyclic deriv-
atives is equatorial. The former situation confirms what is
already found for 2-ethoxycyclohexanone while the latter is a
consequence of the 1,3 diaxial interaction with the nitro group
at the junction carbon atom.
was the desired dienamine 9 (5.0 g, 55%) [Found (M Ϫ 1),
182.11798. C H NO
182.11810]; νmax(neat)/cm 3045, 3020 (᎐CH ), 1600, 1580
᝽
(C H NO Ϫ H) requires m/z,
1
0
16
2
10 17 2
Ϫ1
2
(C᎐C), 1260, 1200 (C᎐O᎐C᎐, asymm. stretch), 1110 (C᎐O᎐C),
1060 (C᎐O᎐C᎐, symm. stretch) and 860, 810 (᎐CH2 wag);
λmax(EtOH)/nm 235 (εmax 4438); δ (CDCl ) 4.55 (1 H, s,
1
3
H
3
N᎐C᎐CH trans to morpholine), 4.45 (1 H, d, J 2.0, O᎐C᎐CH
trans to OEt), 4.13 (1 H, d, J 2.0, O᎐C᎐CH cis to OEt), 4.11
(1 H, s, N᎐C᎐CH cis to morpholine), 3.80 (2 H, q, J 7.0,
OCH CH ), 3.75 (4 H, t, CH OCH ), 2.86 (4 H, t, CH NCH )
A final observation regards the possibility of performing the
hydrolyses of the Michael-type enamine intermediates (pH
around 5, room temperature) leaving the vinyl ether group
untouched. Deprotection leading to the corresponding 1,2-
2
3
2
2
2
2
and 1.35 (3 H, t, J 7.0, OCH CH ); δ (CDCl ) 158.4
2
3
C
3
1
0
dicarbonyl compounds in fact occurs in refluxing benzene in
the presence of toluene-p-sulfonic acid as a catalyst and water
in traces.
(s, O᎐C᎐C), 153.1 (s, N᎐C᎐C), 91.3 (t, N᎐C᎐CH ), 85.7
2
(t, O᎐C᎐CH ), 66.7 (t, CH OCH ), 63.2 (t, OCH CH ), 49.6
2
2
2
2
3
+
(t, CH NCH ) and 14.5 (q, OCH CH ); m/z (EI) 182 (M Ϫ 1,
2
2
2
3
᝽
2
26
J. Chem. Soc., Perkin Trans. 1, 1997

View Article Online
+
4
(
4
0%), 153 (M Ϫ H Ϫ Et, 94), 138 (18), 126 (36), 115 (16), 108
(1ЈR *,2ЈS *,3aS *,7S *,7aS *)-5-Ethoxy-6-morpholino-3a-nitro-
᝽
24), 100 (60), 87 (30), 82 (16), 68 (24), 54 (36), 43 (100) and
7-(2-nitrocyclopentyl)-2,3,3a,4,7,7a-hexahydro-1H-indene 14
To a solution of the enamine 9 (0.25 g, 1.37 mmol) in dry
1 (86).
3
chloroform (10 cm ) at 0 ЊC was added 1-nitrocyclopentene
3
Reaction with 1-nitrocyclopentene
(0.31 g, 2.75 mmol) in the same solvent (10 cm ). The mixture
To a solution of the enamine 9 (0.50 g, 2.75 mmol) in dry
was kept at room temperature for 3 days. Evaporation of the
solvent left a solid which was crystallized from benzene–ligroin,
mp 221 ЊC (85% yield, after crystallization) (Found: C, 58.70;
H, 7.68; N, 10.51. C H N O requires C, 58.66; H, 7.63; N,
3
14
chloroform (10 cm ) at 0 ЊC was added 1-nitrocyclopentene
3
(
0.30 g, 2.75 mmol) in the same solvent (25 cm ). The mixture
was kept at room temperature for 3 days after which water
2
0
31
Ϫ1
3
6
3
Ϫ3
(
5 cm ) and hydrochloric acid (2 mol dm ) were added. The
10.26%); νmax(Nujol)/cm 1660 (C᎐C), 1540, 1360 (NO ) and
2
mixture was stirred for 2 h, after which the two phases were
separated and the oily residue was chromatographed with light
petroleum–ethyl acetate (gradient from 100:0 to 80:20) as
eluent to give a 1:1 mixture of compounds 15/16 (0.5 g, 80%
yield) and the linear ketone 17 (0.06 g, 10% yield).
1110 (C᎐O᎐C); δ (CDCl ) 5.18 (1 H, dt, J 8.1, 8.1, 6.1,
H
3
2
3
CHNO ), 3.61 (1 H, dq, J 9.0, J 7.1, CHCH ), 3.60 (4 H, t, J
2
3
2
3
4.5, CH OCH ), 3.42 (1 H, dq, J 9.0, J 7.1, CHCH ), 3.16 (2
2
2
3
H, dt, J 4.5, 4.5, 12.2, CH N), 3.06 (1 H, d J 14.9, 7β-H), 3.04
2
(1 H, m, 1Ј-H), 2.88 (1 H, m, 3a-H), 2.66 (2 H, dt, J 4.5, 4.5,
(
3aS *,5R *,7aS *)-5-Ethoxy-3a-nitrooctahydro-6H-inden-6-
one 15. Oil; Rf 0.35 (eluent: light petroleum–EtOAc 4:1);
δ (CDCl ) 3.58 (1 H, ddd, J 0.9, J4ax,5 3.0, J4eq,5 5.0, 5-H),
12.2, CH N), 2.62 (1 H, m, 5Ј-H cis with respect to the nitro
2
group), 2.50 (1 H, d, 14.9, 7α-H), 2.23–2.10 (3 H, m, 3α-H, 2 3Ј-
H), 2.00–1.93 (1 H, m, 2α-H), 1.83 (1 H, d, J 11.0, 4-H), 1.80–
1.46 (5 H, m, 2 1-H, 2 4Ј-H, 5Ј-H trans with respect to the nitro
group), 1.30–1.12 (2 H, m, 2β-H, 3β-H) and 1.17 (3 H, t, J 7.1,
CH CH ); δ (CDCl ) 138.8 (s), 130.3 (s), 99.0 (s), 88.6 (d), 67.9
H
3
5,7eq
3
.39, 3.40 (2 H, 2 q, J 7.1, CH CH ), 3.42–3.35 (1 H, m hidden
under CH CH , 7a-H), 3.15 (1 H, ddd, J 2.1, J4eq,5 5.0,
J4ax,4eq 15.2, 4 -H), 3.10 (1 H, dd, J
2 3
2
3
4eq,7a
6.6, J7ax,7eq 14.4, 7 -H),
ax
eq
7a,7ax
2
3
C
3
2
1
.40 (1 H, ddd, J3α,3β 13.4, J 7.4, 10.7, 3β-H), 2.30–1.80 (2 H, m,
α-H, 3α-H), 2.21 (1 H, dd, J4ax,5 3.0, J4ax,4eq 15.2, 4 -H), 2.11 (1
(2 t), 64.9 (t), 50.2 (2 t), 47.1 (d), 45.9 (d), 45.5 (d), 41.6 (t), 36.0
(t), 35.0 (t), 34.1 (t), 32.3 (t), 24.6 (t), 23.8 (t) and 15.4 (q); m/z
ax
+
H, ddd, J5,7eq 0.9, J7a,7eq 3.6, J7ax,7eq 14.4, 7 -H), 1.75–1.60 (2 H,
m, 2 2-H), 1.46–1.32 (1 H, m, 1β-H) and 1.11 (3 H, t, J 7.1,
CH CH ); δ (CDCl ) 207.3 (C-6), 91.8 (C-3a), 78.8 (C-5), 65.4
(EI) 409 (M , 2%), 407 (22), 381 (13), 378 (61), 362 (42), 332
eq
᝽
(100), 316 (32), 315 (26), 304 (22), 288 (19), 286 (29), 258 (19),
249 (26), 220 (35), 218 (29), 205 (22), 192 (19), 160 (16), 145
(13), 117 (19), 107 (19), 105 (22), 91 (35), 86 (29), 84 (22), 81
(22), 79 (35), 77 (26) and 67 (48).
2
3
C
3
(CH ), 43.4 (C-7a), 38.09 (C-7), 38.06 (C-3), 37.6 (C-4), 29.5
2
(C-1), 20.6 (C-2) and 14.9 (CH ).
3
(3aS *,5S *,7aS *)-5-Ethoxy-3a-nitrooctahydro-6H-inden-6-
one 16. Oil; Rf 0.40 (eluent: light petroleum–EtOAc 4:1);
3-Ethoxy-1-(2-oxocyclopentyl)but-3-en-2-one 21
Ϫ1
νmax(neat)/cm
1725 (C᎐O), 1530, 1360 (NO ) and 1110
The reaction between the dienamine 9 (0.25 g, 1.37 mmol) and
1-nitrocyclopentene (0.15 g, 1.37 mmol) was performed in
anhydrous ether, at Ϫ20 ЊC. Hydrolysis of the crude mixture
carried out after 2 h allowed the isolation of the diketone 21, oil
2
(
1
C᎐O᎐C); δ (CDCl ) 3.98 (1 H, ddd, J
0.9, J4eq,5 6.1, J4ax,5
H
3
5,7ax
2
3
2.3, 5-H), 3.74 (1 H, dq, J 9.0, J 7.1, CHCH ), 3.45 (1 H, dq,
3
3
2
J 9.0, J 7.1, CHCH ), 3.20 (1 H, m, 7a-H), 3.01 (1 H, ddd,
3
+
J4eq,7a 2.4, J4eq,5 6.1, J4ax,4eq 14.9, 4 -H), 2.73 (1 H, ddd, J
0.9,
(0.1 g, 37%) (Found: M , 196.10970. C H O requires m/z,
eq
5,7ax
᝽
11 16
3
Ϫ1
J7a,7ax 6.5, J7ax,7eq 14.9, 7 -H), 2.39 (1 H, dd, J7a,7eq 3.4, J7ax,7eq
196.10994); νmax(neat)/cm 1730, 1700 (C᎐O), 1605 (C᎐C) and
1230 and 1105 (C᎐O᎐C); δ (CDCl ) 5.18 (1 H, d, J 2.4, C᎐CH
ax
1
4.9, 7 -H), 2.10–1.90 (3 H, m, 1α-H, 2 3-H), 2.07 (1 H, dd,
eq
H
3
᎐
J4ax,4eq 14.9, J4ax,5 12.2, 4 -H), 1.85, 1.65 (2 H, m, 2 2-H), 1.46–
trans to OEt), 4.41 (1 H, d, J 2.4, C᎐CH cis to OEt), 3.79 (2 H,
ax
᎐
1
.32 (1 H, m, 1β-H) and 1.22 (3 H, t, J 7.1, CH CH );
q, OCH CH ), 3.19 (1 H, dd, J 3.4, 18.9, CHCO), 2.78 (1 H, dd,
2
3
2
3
δ (CDCl ) 209.3 (C-6), 94.5 (C-3a), 77.4 (C-5), 66.3 (CH ), 45.7
J 7.9, 18.9, CHCO), 2.50 (1 H, m, CHCH CO), 2.27 (3 H, m,
C
3
2
2
(C-7a), 39.7 (C-7), 38.4 (C-4), 38.1 (C-3), 29.2 (C-1), 20.4 (C-2)
ring H), 2.05 (1 H, m, ring H), 1.80 (1 H, m, ring H), 1.53 (1 H,
and 15.2 (CH ).
The mixture 15/16: m/z (EI) [Found: (M Ϫ HNO ),
dq, ring H), and 1.36 (3 H, t, OCH CH ); δ (CDCl ) 220.4 (s),
3
2
3
C
3
+
195.9 (s), 157.3 (s), 90.8 (t), 63.7 (t), 44.5 (d), 38.1 (t), 37.5 (t),
᝽
2
+
1
1
1
6
80.11518. C H O (C H NO Ϫ HNO ) requires m/z,
80.11503, 3%], 135 (M Ϫ HNO Ϫ OEt, 10), 134 (20),
23 (15), 109 (14), 106 (46), 94 (45), 80 (100), 77 (68) and
6 (32).
29.4 (t), 20.8 (t) and 14.3 (q); m/z (EI) 196 (M , 37%), 181
1
1
16
2
11 17
+
᝽
2
2
᝽
+
+
+
(M Ϫ 15, 1), 168 (M Ϫ CO, 10), 152 (M Ϫ 44, 18), 139
2
᝽
᝽
᝽
(17), 125 (55), 113 (24), 97 (100), 83 (36) and 69 (67).
trans-3-Ethoxy-1-(2-nitrocyclopentyl)but-3-en-2-one 17. Oil;
Reaction with 1-nitrocyclohexene
+
R 0.55 (eluent: light petroleum–EtOAc 4:1) [Found: (M + 1),
To a solution of the enamine 9 (0.5 g, 2.75 mmol), in dry chloro-
f
᝽
3
2
2
1
28.12324. C H NO
(C H NO + H) requires m/z,
form (10 cm ) at room temperature was added 1-nitro-
1
1
18
4
11 17
4
Ϫ1
3
28.12358]; νmax(neat)/cm 1695 (C᎐O), 1610 (C᎐C), 1540,
360 (NO ) and 1125 (C᎐O᎐C); δ (CDCl ) 5.18 (1 H, d, J 2.4,
cyclohexene (0.35 g, 2.75 mmol) in the same solvent (25 cm ).
The mixture was kept at room temperature for 3 days after
2
H
3
3
Ϫ3
C᎐CH trans to OEt), 4.60 (1 H, dt, J 8.8, 6.0, 6.0, CHNO ), 4.39
which water (5 cm ) and hydrochloric acid (2 mol dm ) were
added. After the mixture had been stirred for 2 h, the two
phases were separated and the oily residue was chromato-
graphed with light petroleum–ethyl acetate (gradient from
100:0 to 80:20) as eluent to give compounds 24 and 25 (0.45 g,
70%).
᎐
2
(
1 H, d, J 2.4, C᎐CH cis to OEt), 3.80, 3.78 (2 H, 2q,
᎐
OCH CH ) 2.90 (3 H, m, CHCH CO), 2.28 (1 H, m, ring H),
2
3
2
2
.14 (2 H, m, 2 ring H), 1.90 (1 H, m, ring H), 1.78 (1 H, m, ring
H) and 1.38 and 1.36 (4 H, t and m, CH CH and ring H);
2
3
δ (CDCl ) 195.9 (s), 157.3 (s), 90.8 (t), 90.7 (d), 63.8 (t), 41.6 (t),
C
3
4
1.4 (t), 32.0 (d), 31.5 (t), 23.8 (t) and 14.3 (q).
cis-3-Ethoxy-1-(2-nitrocyclopentyl)but-3-en-2-one 18. In the
cis- and trans-3-Ethoxy-1-(2-nitrocyclohexyl)but-3-en-2-one
+
24 and 25. Oil (Found: M , 241.13120. C H NO requires
᝽
12 19
4
1
Ϫ1
H NMR spectrum only a few signals of 18 were not super-
imposed with those of 17 in the 9:1 mixture 17/18: δ (CDCl )
m/z, 241.13141); νmax/cm 1700 (C᎐O), 1610 (C᎐C), 1540, 1360
᎐ ᎐
(NO ) and 1130 (C᎐O᎐C); δ (CDCl ) 5.17 (0.1 H, d, J 2.4,
H
3
2
H
3
5
.18 (1 H, d, J 2.4, C᎐CH), 5.09 (1 H, dt, J 1.8, 6.4, 6.4,
C᎐CH), 5.16 (0.9 H, d, J 2.4, C᎐CH), 4.75 (0.1 H, q, J 4.9,
᎐ ᎐
᎐
CHNO ) and 4.40 (1 H, d, J 2.4, C᎐CH); δ (CDCl ) 196.5 (s),
CHNO ), 4.40 (0.1 H, d, J 2.4, C᎐CH), 4.39 (0.9 H, d, J 2.4,
2
2
C
3
1
3
57.3 (s), 91.0 (t), 90.9 (d), 63.8 (t), 41.5 (t), 41.3 (t), 31.9 (d),
C᎐CH), 4.37 (0.9 H, dt, J 4.2, 10.3, 10.3, CHNO ), 3.52–3.35 (2
H, m, CH CH ), 2.75–2.46 (3 H, m, CHCH CO), 1.92–1.70
2 3 2
᎐
2
1.4 (t), 23.9 (t) and 14.2 (q).
The mixture 17/18: m/z (EI) 228 (M + 1, 0.2%), 181
+
(m, 8 H, ring H), and 1.38 (t, 3 H, CH CH ); δ (CDCl )
᝽
2 3 C 3
(M Ϫ 46, 8), 153 (11), 151 (8), 135 (9), 123 (14), 115 (10), 109
for the isomer 24 195.5 (s), 149.9 (s), 90.9 (t), 85.3 (d), 63.7
(t), 40.5 (t), 34.1 (d), 28.3 (t), 27.3 (t), 23.0 (t), 21.3 (t)
and 14.2 (q); δ (CDCl ) for the isomer 25 195.5 (s), 157.3 (s),
(28), 17 (13), 96 (11), 95 (12), 87 (12), 82 (14), 81 (52), 79 (22),
7
1 (25), 68 (14), 67 (100) and 43 (61).
C
3
J. Chem. Soc., Perkin Trans. 1, 1997
227

View Article Online
9
2
0.7 (t), 89.9 (d), 63.7 (t), 40.5 (t), 36.9 (d), 31.9 (t), 30.3 (t),
(2 d), 128.2 (d), 126.9 (2 d), 85.1 (d, C-4), 79.3 (d, C-2), 65.6 (t,
+
4.6 (t), 24.3 (t) and 14.2 (q); m/z (EI) 242 (M + 1, 2), 241
OCH ), 47.8 (d, C-5), 42.0 (t, C-6), 36.5 (t, C-3) and 15.1 (q,
᝽
2
+
(
(
(
M
, 2%), 240 (2), 196 (2), 195 (5), 193 (3), 116 (100), 106
CH ).
᝽
3
14), 96 (15), 95 (17), 89 (41), 81 (45), 80 (81), 78 (24), 69
20), 66 (34) and 60 (78).
(2S *,4R *,5S *)-2-Ethoxy-4-nitro-5-phenylcyclohexanone 30.
Further elution gave 30 (0.04 g, 5.5%), mp 127–129 ЊC; R 0.20
f
When the same reaction was carried out in refluxing ethanol
for 2 h and hydrolysed, 2-decalone derivatives 26 and 27 were
also formed. They were separated from the linear compounds
(eluent: light petroleum–EtOAc 4:1) (Found: C, 63.95; H,
6.36; N, 5.47. C H NO requires C, 63.87; H, 6.51; N, 5.32);
1
4
17
4
Ϫ1
νmax/cm 1730 (C᎐O), 1540, 1380 (NO ) and 1130 and 1100
2
2
5/26 by chromatography in 7% yield.
3R *,4aS *,8aS *)-3-Ethoxy-4a-nitrooctahydro-1H-
(C᎐O᎐C); δ (CDCl ) 7.28–7.13 (5 H, m, Ph), 5.06 (1 H, dt, J
H
3
(
3.4, 12.0, 12.0, 4-H), 3.76 (1 H, dq, OCHCH ), 3.55 (1 H, ddd, J
3
naphthalen-2-one 26. Only a few signals of the isomer 26 could
be identified in the H NMR spectrum of the 1:9 mixture with
5.6, 11.5, 12.2, 5-H), 4.05 (1 H, ddd, J 0.1, 6.3, 12.2, 2-H), 3.46
(1 H, dq, OCHCH ), 2.82 (1 H, ddd, J 3.9, 5.8, 12.2, 3 -H),
1
3
eq
2
7: δ (CDCl ) 3.64 (0.1 H, dt, J 1.0, 4.8, 4.8, 3-H), 3.39 (0.2 H,
2.65 (2 H, m, 6-H), 2.38 (1 H, apparent q, J 12.2, 3 -H) and
H
3
ax
q, CH CH ), 3.18 (0.1 H, dd, J 5.8, 15.2), 3.1 (0.1 H, m), 2.81
1.21 (3 H, t, OCH CH ); δ (CDCl ) 203.8 (s, C-1), 137.2 (s),
2
3
2
3
C
3
(0.1 H, dd, J 3.6, 9.6), 2.43 (0.1 H, dd, J 4.0, 15.2), 1.98 (0.1 H,
129.1 (2 d), 128.2 (d), 126.7 (2 d), 86.8 (d, C-4), 78.6 (d, C-2),
dd, J 4.0, 13.1) and 1.11 (0.3 H, t, CH CH ).
66.4 (t, OCH ), 47.6 (d, C-5), 43.9 (t, C-6), 36.9 (t, C-3) and 15.1
2
3
2
(
3S *,4aS *,8aS *)-3-Ethoxy-4a-nitrooctahydro-1H-
(q, CH ); m/z (EI): 191 (4%), 187 (7), 172 (55), 159 (17), 143 (43),
131 (31), 117 (100), 104 (57), 91 (59) and 77 (30).
3
+
naphthalen-2-one 27. Oil (Found: M , 241.13128. C H NO
requires m/z, 241.13141); νmax/cm 1730 (C᎐O), 1540, 1380
NO ) and 1130 and 1100 (C᎐O᎐C); δ (CDCl ) 3.99 (1 H, ddd,
᝽
12 19
4
Ϫ1
᎐
The same reaction carried out in tetrahydrofuran gave the
same products. The ratio acyclic:cyclic products was 1:1. In
ethanol under reflux for 2 h, also the cyclic compounds 29 and
30 were recovered, after hydrolysis, in the ratio of 1:1. Acidic
equilibration of the 1:1 mixture of 29 and 30, performed in
refluxing benzene, in the presence of toluene-p-sulfonic acid in
traces, changed the ratio to 4:1 in favour of the isomer 29, in
(
2
H
3
2
J
1.2, J3ax,4ax 11.9, J3ax,4eq 6.7, 3 -H), 3.79 (1 H, dq, J 9.2,
1
ax,3ax
ax
3
2
3
J 7.0, CHCH ), 3.48 (1 H, dq, J 9.2, J 7.0, CHCH ), 3.01–
.94 (2 H, m, 4 -H, 8a-H), 2.61 (1 H, ddd, J
J1ax,1eq 14.3, 1 -H), 2.37 (1 H, dd, J
4ax-H), 2.19 (1 H, dd, J1eq,8a 2.4, J1ax,1eq 14.3, 1 -H), 2.14–2.11 (1
3
3
2
1.2, J1ax,8a 5.5,
eq
1ax,3ax
11.9, J4ax,4eq 15.0,
ax
3ax,4ax
eq
1
3
H, m, 5 -H), 2.05-1.99 (1 H, m, 5 -H), 1.98–1.74 (3 H, m,
which the ethoxy group is in the axial conformation.
eq
ax
6eq-H, 7 -H, 8 -H), 1.43–1.30 (2 H, m, 6 -H, 7 -H), 1.27–1.18
ax
ax
ax
eq
(
(
(
1 H, m, 8 -H) and 1.25 (3 H, t, CH CH ); δ (CDCl ) 206.4
eq 2 3 C 3
C-2), 93.1 (C-4a), 78.0 (C-3), 66.4 (CH CH ), 42.6 (C-1), 40.9
Acknowledgements
2
3
C-8a), 37.1 (C-5), 35.6 (C-4), 29.3 (C-8), 24.7 (C-7), 22.4 (C-6)
The authors thank the Ministero dell’Università e della Ricerca
Scientifica (MURST) and the Consiglio Nazionale delle Rich-
erche (CNR, Rome) for financial support. One of the authors
+
and 15.2 (CH CH ); m/z (EI) 241 (M , 1%), 193 (2), 149 (12),
1
8
2
3
᝽
48 (15), 138 (13), 120 (36), 106 (12), 94 (100), 92 (33), 90 (13),
0 (16), 78 (39) and 66 (46).
(
G. M.) thanks the Consorzio per lo Sviluppo Internazionale of
the University of Trieste for a fellowship.
Reaction with â-nitrostyrene
To a solution of the enamine 9 (0.5 g, 2.75 mmol) in dry chloro-
3
form (10 cm ) at room temperature was added β-nitrostyrene
References
3
(
0.4 g, 2.75 mmol) in the same solvent (15 cm ). The mixture
3
1 (a) D. Enders, O. Meyer and G. Raabe, Synthesis, 1992, 1242; (b) D.
Enders, O. Meyer and G. Raabe, Synthesis, 1994, 66; (c) R. H.
Schlessinger and T. R. R. Pettus, J. Org. Chem., 1994, 59, 3246; (d)
J. Barluenga, F. Aznar, A. Martin and J. T. Vásquez, J. Am. Chem.
Soc., 1995, 117, 9419; (e) J. Barluenga, F. Aznar, M. P. Cabal and
C. Valdes, J. Chem. Soc., Perkin Trans. 1, 1990, 633; (f ) J. Barluenga,
F. Aznar, M. P. Cabal, F. H. Cano and M. C. Foces-Foces, J. Chem.
Soc., Chem. Commun., 1988, 1247.
was kept at room temperature for 24 h after which water (5 cm )
and hydrochloric acid (2 mol dm ) were added. After the mix-
Ϫ3
ture had been stirred for 2 h, separation of the two phases left
an oil which was chromatographed with light petroleum–ethyl
acetate (gradient from 100:0 up to 90:10) as eluent.
2
-Ethoxy-6-nitro-5-phenylhex-1-en-3-one 28. Mp 64 ЊC (0.40
g, 55%), R 0.45 (eluent: light petroleum–EtOAc 4:1) [Found:
f
+
2 D. Pocar, P. Trimarco, R. Destro, E. Ortoleva and M. Ballabio,
Tetrahedron, 1984, 40, 3579.
(
M
Ϫ HNO ), 216.11523. C H O (C H NO Ϫ HNO )
2 14 16 2 14 17 4 2
Ϫ1
᝽
requires m/z, 216.11503]; νmax(neat)/cm 1710 (C᎐O), 1618
C᎐C), 1600, 1485 (Ph) and 1540 (NO ); δ (CDCl ) 7.30 (2 H,
3
(a) Nitroalkanes and Nitroalkenes in Synthesis, A. G. M. Barrett ed.,
Tetrahedron, 1990, 46, 7313; (b) G. Rosini and R. Ballini, Synthesis,
1988, 833; (c) A. G. M. Barrett and G. G. Graboski, Chem. Rev.,
1986, 86, 751; (d) D. Seebach, E. V. Colvin, F. Lehr and T. Weller,
Chimia, 1979, 33, 1.
J. Quick and R. Jenkins, J. Org. Chem., 1978, 43, 2275.
D. A. Harris, J. Chem. Soc., 1950, 2247.
W. A. White and H. Weingarten, J. Org. Chem., 1967, 32, 213.
F. Johnson, L. G. Duquette, A. Whitehead and L. C. Dorman,
Tetrahedron, 1974, 30, 3241.
(
᎐
2
H
3
m, o-Ar-H), 7.25 (3 H, m, m- and p-Ar-H), 5.15 (1 H, d, J 1.4,
2
3
2
C᎐CH), 4.71 (1 H, dd, J 12.5, J 6.7, CHNO ), 4.60 (1 H, J
᎐
2
3
1
2.5, J 8.3, CHNO ), 4.38 (1 H, d, J 1.4, C᎐CH), 4.06 (1 H, br
2
4
5
6
7
quintet, CHPh), 3.77 (2 H, q, OCH CH ), 3.13 (2 H, 2 pseudo
2
3
q, CH CO) and 1.36 (3 H, t, OCH CH ); δ (CDCl ) 194.7
2
2
3
C
3
(
(
(
(
(
s, C-3), 156.9 (s, C-2), 139.0 (s), 128.8 (2 d), 127.6 (d), 127.4
2 d), 91.0 (t, C-1), 79.4 (t, C-6), 63.7 (t, OCH CH ), 40.9
2
3
t, C-4), 38.8 (d, C-5) and 14.1 (q, OCH CH ); m/z (EI) 216
8 F. Johnson, Chem. Rev., 1968, 68, 3759.
2
3
+
+
9 H. Mazarguil and A. Lattes, Bull. Soc. Chim. France, 1969, 319.
0 G. Pitacco, A. Pizzioli and E. Valentin, Synthesis, 1996, 242.
1 F. Felluga, P. Nitti, G. Pitacco and E. Valentin, Tetrahedron, 1989,
M
Ϫ HNO , 24%), 188(M Ϫ HNO Ϫ Et, 50), 187(39), 173
᝽
2
᝽
2
1
1
18), 159 (32), 145 (36), 143 (60), 131 (36), 117 (77), 104 (100),
1 (55), 78 (38) and 77 (33).
2R *,4R *,5S *)-2-Ethoxy-4-nitro-5-phenylcyclohexanone 29.
Further elution gave compound 29 (0.11 g, 15%), oil; R (eluent:
9
4
5, 5667.
(
1
2 (a) E. L. Eliel, S. H. Wilen and L. N. Mandel, Stereochemistry of
Organic Compounds, Wiley & Sons, New York, 1994, p. 769; (b)
p. 738.
3 J. A. Kresge and Y. Yin, Can. J. Chem., 1987, 65, 1753.
4 E. J. Corey and H. Estreicher, Tetrahedron Lett., 1981, 22, 603.
f
Ϫ1
light petroleum–EtOAc 4:1); νmax(neat)/cm
1720 (C᎐O),
1
1
1
7
3
3
540, 1380 (NO ) and 1130 and 1100 (C᎐O᎐C); δ (CDCl )
2
H
3
.35–7.15 (5 H, m, Ph), 5.35 (1 H, dt, J 4.0, 11.9, 11.9, 4-H),
.82 (1 H, t, J 6.0, 2-H), 3.58 (1 H, ddd, J 4.6, 11.0, 13.4, 5-H),
.51 (2 H, q, J 6.7, OCH CH ), 3.11 (1 H, t, J 13.7, 6 -H), 2.74
2
3
ax
(
1 H, dt, J 4.0, 4.0, 13.4, 3 -H), 2.52 (1 H, dd, J 4.6, 13.7,
Paper 6/05345I
Received 30th July 1996
eq
6eq-H), 2.40 (1 H, ddd, J 3.0, 11.9, 13.4, 3 -H) and 1.20 (3 H, t,
ax
J 6.7, OCH CH ); δ (CDCl ) 206.6 (s, C-1), 137.9 (s), 129.0
Accepted 23rd September 1996
2
3
C
3
2
28
J. Chem. Soc., Perkin Trans. 1, 1997