Two chemodivergent anionic domino processes from cyclic α-nitroketones and aromatic aldehydes

Article abstract of DOI:10.1016/j.tet.2011.05.115

Treatment of cyclic α-nitroketones and aromatic 1,2-dialdehydes with DBU in tetrahydrofuran containing small amounts of water proceeded through two chemodivergent one-pot domino pathways, whose outcome depended on the ring size of the starting nitroketone. Thus, α-nitrocyclohexanone underwent diastereoselective α′-arylmethylenation reactions through a nitroaldol/aldol/reverse nitroaldol mechanism. On the other hand, α-nitrocycloheptanone and α-nitrocyclooctanone afforded 2-nitroindane-1,2-diols containing three contiguous stereocenters in a highly diastereoselective fashion through a nitroaldol/retro-Dieckmann/intramolecular nitroaldol process.

Full text of DOI:10.1016/j.tet.2011.05.115

Tetrahedron 67 (2011) 5582e5589
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Two chemodivergent anionic domino processes from cyclic
aromatic aldehydes
a-nitroketones and
*
ꢀ
ꢀ
Giorgio Giorgi, Francisco J. Arroyo, Pilar Lopez-Alvarado, J. Carlos Menendez
ꢀ
ꢀ
Departamento de Química Organica y Farmaceutica, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 April 2011
Received in revised form 27 May 2011
Accepted 29 May 2011
Available online 2 June 2011
Treatment of cyclic
small amounts of water proceeded through two chemodivergent one-pot domino pathways, whose
outcome depended on the ring size of the starting nitroketone. Thus, -nitrocyclohexanone underwent
diastereoselective
0-arylmethylenation reactions through a nitroaldol/aldol/reverse nitroaldol mecha-
nism. On the other hand, -nitrocycloheptanone and -nitrocyclooctanone afforded 2-nitroindane-1,2-
a-nitroketones and aromatic 1,2-dialdehydes with DBU in tetrahydrofuran containing
a
a
a
a
diols containing three contiguous stereocenters in a highly diastereoselective fashion through a nitro-
aldol/retro-Dieckmann/intramolecular nitroaldol process.
Ó 2011 Elsevier Ltd. All rights reserved.
O
CHO
Ar
OH
1. Introduction
DBU, THF,
r.t., 24 h
CHO
CHO
E
α
NO2
NO2
α'
Ar
+
The search for chemodivergent reactions is one of the keys for
the success of the current bid for methods able to generate mo-
lecular diversity and complexity from simple and inexpensive
starting materials, ideally in a single step. This type of chemistry is
often considered as one of the most promising paradigms of drug
discovery and has also become one of the main challenges for
current organic synthesis.1 Domino reactions, in which several
transformations are combined in a one-pot procedure so that each
individual step leads to a reactive species that undergoes further
transformations under the same reaction conditions, are particu-
larly promising as a pathway to molecular diversity and are finding
increasing applications in organic synthesis,2 including the total
synthesis of natural products.3 We describe here two chemo-
divergent, synthetically useful anionic domino processes based on
3
2
1a
Scheme 1.
These compounds have a particular value as synthetic building
blocks in view of the synthetic relevance of
-nitroketones7 and
a
their high degree of functionalization, both at the carbocyclic and
aromatic fragments. The reaction was found to be completely
regioselective in favour of the a
0 position of the starting nitroketone
and gave exclusively compounds with an E geometry at the exo-
cyclic double bond, as shown by NOE effects in compound 3a, al-
though in the case of compound 3c some E to Z isomerization during
column chromatography could not be avoided. The use of non-
symmetric starting aldehydes, namely 3-chlorophthalaldehyde
and thiophene-1,2-dicarbaldehyde, led to the isolation of mixtures
of regioisomers arising from reaction at either of the aldehyde
groups (compounds 3d, e and 3f, g, respectively). This is an in-
teresting transformation because it constitutes the first one-step
the DBU-promoted reactions between cyclic
a-nitroketones and
aromatic aldehydes, with special emphasis on 1,2-dialdehydes,
which were discovered in the course of our research into the syn-
thetic applications of a
-nitroketone anions.4
a
0-arylmethylenation of an
lated process consisting of the
compounds is also a difficult synthetic problem, which has been
a
-nitroketone. The better-studied, re-
-alkenylidenation of -dicarbonyl
g
b
2. Results and discussion
solved only rather recently. Thus, Rodriguez has shown that the
As shown in Scheme 1, treatment of a-nitrocyclohexanone 1a
reaction between cyclic
b
-ketoesters and
b
-ketoamides and alde-
-methylidene
with several aromatic 1,2-dicarbaldehyde derivatives 25 in THF
containing DBU at room temperature for 24 h afforded compounds
3 as the only products, in good to excellent yields (see also Fig. 1).6
hydes in the presence of DBU in methanol affords
g
derivatives of the starting material,8 which were subsequently
employed as starting materials for the preparation of spiro com-
pounds9 and fused heterocycles.10
In order to provide some information on the mechanism of the
above-mentioned transformation while increasing its synthetic
* Corresponding author. Tel.: þ34 91 3941840; fax: þ34 91 3941822; e-mail
ꢀ
address: josecm@farm.ucm.es (J.C. Menendez).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.05.115

G. Giorgi et al. / Tetrahedron 67 (2011) 5582e5589
5583
unexpectedly, the addition steps of these reactions were sensitive
to the nature of the substituents on the aromatic ring, and did not
take place at a synthetically feasible rate when electron-releasing
groups were present. Due to the scarcity of literature precedent
for the generation of cyclic carbonyl compounds functionalized at
a0 with chains showing extended conjugation,8b we also examined
some reactions starting from cinnamaldehyde derivatives, which
gave compounds 3jel (Scheme 3 and Table 1).
CHO
OH
α
CHO
Cl
OH
α'
NO2
NO2
Cl
3a (95%)
3b (82%)
CHO
OH
NO2
O
R2
NO2
CHO
n
+
3c (87%)
R4
CHO
OH
CHO
OH
1a
NO2
NO2
DBU, THF, rt
O
+
R2
Cl
80%, 3d/3e = 1:1
OH
NO2
Cl
3d
3e
n
R4
3
OH
OHC
OHC
Scheme 3.
NO2
NO2
+
S
S
Table 1
One-pot synthesis of a a-nitrocyclohexanone
0-arylmethylene derivatives of
3f
3g
75%, 3f/3g = 1,3:1
Compd
n
R2
R4
Time
Yield, %
3i
3j
3k
3l
0
1
1
1
H
H
NO2
H
NO2
H
H
4d
6d
5d
5d
88
60
90
85
Fig. 1. Scope and yields of the arylmethylenation reactions with o-dialdehydes.
scope, we explored some related reactions involving the use of
NO2
monofunctional aldehydes. Treatment of a-nitrocyclohexanone 1a
with benzaldehyde under the conditions used for the phthalalde-
hyde derivatives did not afford an arylmethylenation product, but
instead gave the aldol adduct 4 as a 3:3:1 mixture of diastereomers
(Scheme 2). In order for this reaction to go to completion, the use of
2 equiv of aldehyde was required, and an experiment starting from
equimolecular amounts of 1a and benzaldehyde proceeded only in
50% conversion. In an effort to adapt these conditions to the syn-
In order to rationalize our observations, the isolation of com-
pound 4 must be explained in the first place. To this end, we pro-
pose the mechanism summarized in Scheme 4. The first reaction to
take place would be a nitroaldol addition at the more reactive
a
position leading to I, which would be followed by intramolecular
thesis of
a
0-arylmethylene derivatives, we studied a number of
proton exchange, involving deprotonation of the position, and an
a
aldol reaction with a second molecule of aldehyde to give II. A final
retro-nitroaldol reaction, with loss of one molecule of aldehyde,
would explain the generation of 4. This mechanism explains the
need for at least 2 equiv of aldehyde for the reaction to go to
completion and the isolation of equimolecular amounts of 4 and 1a
in the reaction using only 1 equiv of aldehyde. TLC monitoring of
the reactions showed the formation of several intermediate spots,
but the plates were too complex to allow any mechanistic conclu-
sion other than the involvement of a multi-step mechanism. Fur-
thermore, none of the proposed intermediates could be isolated.
However, in an effort to further clarify the mechanism, we studied
the reaction between 2-benzyl-2-nitrocyclohexanone (obtained by
alkylation of 2-nitrocyclohexanone with benzyl bromide in the
presence of DBU, see Supplementary data) and o-phthalaldehyde or
p-nitrobenzaldehyde under our reaction conditions. While the
acidic conditions for the elimination of water from compound 4,
and found that its treatment, in crude state, with HCl in EtOHeH2O
at 65 ꢀC for 4 h gave compound 3h in 68% overall yield from 1a
(Scheme 2).
O
OH
O
DBU, THF,
rt, 48 h
CHO
NO2
NO2
+
1a
4 (dr 3:3:1)
HCl (37%),
EtOH, 65 °C, 4 h
O
NO2
expected
a
0-functionalization took place, in agreement with the
3h
proposed mechanism, these reactions afforded open-chain prod-
ucts generated via a retro-Dieckmann-type reaction prompted by
the high stability of the nitronate anion, with a hydroxide anion
(generated from DBU and traces of moisture in the reaction me-
dium) acting as the nucleophile. This was proved by examination of
the 13C NMR spectra of the crude reaction products, which showed
the absence of the ketone carbonyl, the presence of a carboxy
(68% from 1a)
Scheme 2.
Having in mind the objective of carrying out the arylmethyle-
nation as a one-pot transformation, we did some experimentation
with basic media for the elimination step, and discovered that the
best results were obtained by simply increasing the reaction time
between the starting a-nitroketones and aldehydes, which led to
a mild and efficient, if quite slow, DBU-promoted elimination re-
action, leading to compounds 3iel in 60e90% yields. Not
carbonyl and a 10 ppm upfield displacement of the Ca-NO2 signal,
which is now a methine according to the DEPT experiment. The
higher stability of intermediate I towards this ring opening must be
attributed to its negative charge, which means that the retro-
Dieckmann reaction would have a dianion as an intermediate.

5584
G. Giorgi et al. / Tetrahedron 67 (2011) 5582e5589
CHO
R
CHO
DBUH
DBUH
O
DBUH
R
R
H
O
R
R
DBUH
HO
O
O
O
O
O
O
Aldol
DBU
N
O
Nitroaldol
O
N+
O–
NO2
R
NO2
1a
II
I
CHO
Retro-
nitroaldol
R
O
O
N
OH
O
OH
NO2
- DBU
O
DBUH
R
R
4
Scheme 4.
In the original reactions starting from 1 equiv of phthalaldehyde
derivatives (Scheme 5), the presence of two aldehyde groups in
each molecule of the starting material would allow a mechanism
similar to the one in operation in the presence of 2 equiv of benz-
aldehyde, although in this case a cyclic intermediate (III) would be
generated and evolve to IV by a retro-nitroaldol mechanism. The
facile isolation of elimination products 3 in these reactions rather
than aldol adducts similar to 4, even for short reaction times, must
be due to the presence of the ortho aldehyde group, and can be
Indane derivatives have also served as rigid frameworks used as the
basis for the design of chiral catalysts.17 Furthermore, compounds 5
are interesting in that they contain three contiguous stereocenters,
one of which is quaternary, and were isolated in good to complete
diastereoselectivity. Although, to our knowledge, the domino pro-
cess leading to compounds 5 is unprecedented, there is an early
literature reference of the preparation of 1,3-indanediols from
phthalaldehydes and nitromethane, nitroethane or ethyl nitro-
acetate in the presence of sodium carbonate.18 The stereochemistry
of compounds 5 was determined by NOESY experiments, which
were interpreted in the light of symmetry considerations and are
summarized for the case of compound 5a. The internal symmetry of
the major reaction products was proved by the equivalence of the
explained by the likely tendency of the g-hydroxycarbonyl moiety
of IV to undergo an intramolecular cyclization leading to hemi-
acetal V, which would then be transformed into the 3a by a DBU-
induced elimination reaction.
DBU
DBU
H
DBUH
H
O
O
O
O
CHO
O
1. Nitroaldol
Retro-
nitroaldol
O
O
N
NO2
N
2. Intramolecular aldol
CHO
O
O
O
H
+
O
IV
III
DBU
HO
DBUH
O
CHO
OH
CHO
O
- DBU
O
O
O
O
NO2
NO2
H
- H2O
NO2
NO2
3a
V
Scheme 5.
0
0
0
0
0
0
Attempts to carry out the reaction between higher cyclic
-nitroketones and monofunctional aldehydes led only to complex
C1 eC3 , C4 eC7 and C5 eC6 signals and those of the corresponding
protons for all compounds except 4b and 4d, and this shows that
the hydroxy groups must be cis. The NOE correlations between the
H-10 and H-30 protons and the H-6 protons of the aliphatic chain at
C-2 confirm the proposed structure.
a
mixtures. However, when the DBU-promoted conditions were ap-
plied to the reactions between -nitrocycloheptanone or -nitro-
a
a
cyclooctanone and aromatic 1,2-dialdehydes, a remarkably abrupt
change in the reactivity pattern was observed, and indane de-
rivatives 5 were obtained (Scheme 6 and Table 2).11 This experi-
mentally simple and efficient access to highly functionalized
indane derivatives is of interest in view of the importance of indane
scaffolds in medicinal chemistry, which has made them attractive
targets for diversity-oriented synthesis.12 Thus, indane-based
structural fragments are found in many aspartic protease in-
hibitors,13 including the anti-retroviral agent indinavir, and are also
present in compounds with other activities, such as inhibition of
HIV integrase,14 melatonin receptor agonism15 and inhibition of the
Some attempts were made to use bases different from DBU for
the case of the reaction between
a-nitrocycloheptanone and
phthalaldehyde. These efforts were largely unsuccessful, with
triethylamine and K2CO3 affording small amounts of the indane
derivative 5a but requiring very long reaction times, and hydroxide
affording the nitroaldol condensation product 6 together with
small amounts of the expected product 5a. Organic bases different
from DBU were not assayed. An attempt to use 2-
acetylbenzaldehyde as the dicarbonyl component afforded only
3-hydroxy-1-indanone, from cyclization of the starting material by
an intramolecular aldol reaction.
production of the inflammation factor TNF-a 16
among others.
,

G. Giorgi et al. / Tetrahedron 67 (2011) 5582e5589
5585
The mechanism that we propose to explain the formation of
compounds 5 from -nitroketones and aromatic 1,2-dialdehydes is
O
R1
R2
CHO
CHO
a
NO2
+
depicted in Scheme 7. An initial nitroaldol reaction affords in-
termediate VI, which in the cases where n>1 undergoes a retro-
Dieckmann-type ring opening by a molecule of water from the
reaction medium, which is probably previously deprotonated to
a hydroxide anion by the alkoxide substituent in VI. The resulting
nitronate anion VII finally cyclizes to compounds 5 through a sec-
ond nitroaldol reaction, this time in intramolecular fashion. The
observed diastereoselectivity in favour of a cis arrangement for the
hydroxy and nitro groups can be explained by the initial formation
of a hydrogen bond between the nitro group and one of the hy-
droxyls, which blocks one side of the molecule and forces the
intramolecular attack of the nitronate anion to take place from the
opposite one. When hydroxide is used as the base, it disrupts this
intramolecular hydrogen bonding and allows the Henry reaction to
follow the normal course, involving elimination of hydroxide to
( )n
2
n = 2 1b
n = 3 1c
DBU (1.5 eq),
THF (H2O), rt, 24 h
H
OH
O
R1
R2
( )n
NO2
OH
OH
H
5
OH
O
N
HO
H
O
H
H
give compound 6. For the reactions starting from
a-nitro-
H
H
cyclohexanone (n¼1), VI is sufficiently stable to allow a proton shift
(or deprotonation by a second molecule of DBU) that generates an
enolate anion, which is cyclized to the previously mentioned in-
termediate III via an intramolecular nitroaldol reaction.
CO2H
CO2H
NOEs in 5a
CHO
NO2
3. Conclusion
6
Scheme 6.
In conclusion, the present study reports two unique, syntheti-
cally relevant one-pot sequences starting from aromatic 1,2-
dialdehydes and cyclic
divergent reactivities according to ring size. Thus, the first sequence
leads to -nitrocyclohexanone and
0-arylmethylene derivatives of
a-nitroketones, which show completely
Table 2
Scope, yields and diastereomeric ratios obtained in the synthesis of indanes 5
a
a
is proposed to involve an anionic domino process comprising up to
six individual steps that include inter- and intramolecular nitro-
aldol additions, ring opening through a retro-nitroaldol mechanism
and an elimination. The second reaction, proceeding through an
intermolecular nitroaldol/retro-Dieckmann/intramolecular nitro-
Compd
n
R1
R2
Yield, %
dr
4:1a
1:0
1:0
5a
5b
5c
5d
5e
5f
5g
5h
5i
2
2
2
2
2
2
3
3
3
H
H
H
CH3
H
Cl
81
CH3
CH3
Cl
96
75b
85
1:0
1:0
Cl
78
aldol sequence starting from
a-nitrocycloheptanone or a-nitro-
eCH]CHeCH]CHe
H
CH3
76
3.5:1a
3.5:1a
1:0
cyclooctanone, affords indane derivatives and leads to the
generation of two CeC and one CeO bonds in a single operation.
H
CH3
72b,c
70
eCH]CHeCH]CHe
66d
3.5:1a
The overall transformation can be considered as
a three-
component reaction, considering water as the third component.
This reaction generates three contiguous stereocenters, one of
which is quaternary, in high to complete diastereoselectivity. The
reactions described in this paper give ready access to structures
that are not easy to prepare by other synthetic methods and that
should serve as useful building blocks in medicinal chemistry,
a
The minor diastereomers could not be isolated.
Based on unrecovered starting material.
b
c
Together with 20% of the corresponding
Together with 22% of the corresponding
a
0-arylmethylenation product (3m).
d
a
0-arylmethylenation product (3n).
[n = 1]
III
3
Intramolecular
aldol
R1
R2
R1
R2
O
DBUH
OH
H2O
Retro-Dieckmann
O
O
N
OHC
CHO
R1
R2
DBUH
O
CHO
- OH
Nitroaldol
( )n
O
O
OHC
O
6
[n = 2,3]
NO2
( )n
N
O
DBUH
HO
VII
( )n
VI
H
OH
H
H
O
O
R1
R2
O
O
Intramolecular
nitroaldol
O
N
O
( )n
NO2
OH
H
O
OH
N
H
DBUH
O
O
- DBU
R
H
H
H
R
5
Scheme 7.

5586
G. Giorgi et al. / Tetrahedron 67 (2011) 5582e5589
specially bearing in mind that their high degree of functionalization
easily allows for subsequent elaboration. Finally, the synthetic
processes described here are attractive from an environmental
point of view, as they require only simple and readily available
starting materials and reagents and have water as the only side
product.
Anal. Calcd for C14H13NO4: C, 64.86; H, 5.02; N, 5.40. Found: C,
64.90; H, 4.72; N, 5.24.
4.3.2. (E)-4,5-Dichloro-2-[(2-hydroxy-3-nitrocyclohex-2-en-1-
yliden)methyl]benzaldehyde (3b). Isolated in 82% yield as pale yel-
low oil after chromatography on silica gel, eluting with a gradient
from petroleum ether to ethyl acetate. IR (NaCl) nmax: 3344, 1767
(CO), 1557 and 1350 (NO2), 1223 cmꢂ1. 1H NMR (250 MHz, CDCl3) dH
13.84 (s,1H, OH),10.11(s,1H, CHO), 8.04 (s,1H, H-10), 7.66(s,1H, H-6),
7.46 (s,1H, H-3), 2.81 (t, 2H, J¼6.3 Hz, H-400), 2.54e2.47 (m, 2H, H-600),
1.83 (q, 2H, J¼6.3 Hz, H-500) ppm. 13C NMR (63 MHz, CDCl3) dC 188.4
(CHO), 161.5 (C-200), 137.4 (C-2), 136.2 (C-1), 133.2 (C-4), 132.5 (C-5),
131.2 (C-100), 130.7 (C-6), 130.5 (C-3), 128.9 (C-10), 124.6 (C-300), 25.2
(C-600), 23.3 (C-400), 20.2 (C-500) ppm. Anal. Calcd for C14H11NO4Cl2: C,
51.21; H, 3.35; N, 4.27. Found: C, 51.32; H, 3.28; N, 4.24.
4. Experimental
4.1. General experimental information
All reagents (Aldrich, Fluka, SDS, Probus) and solvents (SDS,
Scharlau) were of commercial quality and were used as received.
Reactions were monitored by TLC on aluminium plates coated with
silica gel with fluorescent indicator (SDS CCM221254). Separations
by flash chromatography were performed on silica gel (SDS 60 ACC
40e63 mm). Melting points were measured on a Reichert 723 hot
stage microscope and are uncorrected. Infrared spectra were
recorded on a PerkineElmer Paragon 1000 FT-IR spectrophotom-
eter with all compounds examined as thin films on NaCl disks. NMR
spectra were obtained on a Bruker Avance 250 spectrometer op-
erating at 250 and 62.9 MHz for 1H and 13C NMR spectra, re-
4.3.3. (E)-3-[(2-Hydroxy-3-nitrocyclohex-2-en-1-yliden)methyl]-
naphthalene-2-carbaldehyde (3c). Obtained in 87% yield as a yellow
oil after chromatography on silica gel, eluting with a gradient from
petroleum ether to ethyl acetate.1H NMR (250 MHz, CDCl3) dH 14.23
(s,1H, OH),10.27 (s,1H, CHO), 8.42 (s,1H, H-10), 8.36 (s,1H, H-1), 8.07
(d, 1H, J¼8.4 Hz, H-8), 7.93 (d, 1H, J¼8.4 Hz, H-5), 7.82e7.58 (m, 3H,
H-4, 6, 7), 2.78 (t, 2H, J¼6.3 Hz, H-400), 2.64 (td, 2H, J¼8.4 and 1.7 Hz,
H-600), 1.79 (q, 2H, J¼6.2 Hz, H-500) ppm. 13C NMR (63 MHz, CDCl3) dC
192.2 (CHO), 164.6 (C-200), 136.4 (C-8a), 134.8 (C-100), 134.6 (C-8),
132.3 (C-6),132.1 (C-1),131.9 (C-2),130.9 (C-4a),130.1 (C-3),129.8 (C-
5),129.3 (C-7),128.0 (C-4),127.8 (C-10),125.7 (C-300), 26.1 (C-600), 24.5
(C-400), 21.3 (C-500) ppm. Anal. Calcd for C18H15NO4: C, 69.89; H, 4.89;
N, 4.53. Found: C, 69.63; H, 4.52; N, 4.41.
ꢀ
spectively (CAI de Resonancia Magnetica Nuclear, Universidad
Complutense) with the signal of the residual non-deuterated sol-
vent as an internal standard. Combustion elemental analyses were
ꢀ
determined by the CAI de Microanalisis Elemental, Universidad
Complutense, using a Leco 932 CHNS microanalyzer.
4.2. General procedure for the synthesis of phthaldehydes via
IBX oxidation
4.3.4. (E)-4-Chloro-2-[(2-hydroxy-3-nitrocyclohex-2-en-1-yliden)
methyl]benzaldehyde (3d) and (E)-5-chloro-2-[(2-hydroxy-3-
nitrocyclohex-2-en-1-yliden)methyl]-benzaldehyde (3e). Obtained
as a 1:1 mixture of regioisomers in 80% yield as a viscous yellow oil
after chromatography on silica gel, eluting with a gradient from
petroleum ether to ethyl acetate. IR (NaCl) nmax: 3367, 1765 (CO),
To a suspension of IBX (5.4 mmol) in ethyl acetate (75 ml) was
added a solution of the suitable diol19 (1.8 mmol) in acetone (5 ml).
The reaction mixture was heated at 80 ꢀC for 3.5 h, cooled and fil-
tered, and the filtered solid was washed with acetone (2ꢁ5 ml). The
combined filtrate and washings were evaporated under reduced
pressure and purified by distillation, giving the desired dialdehydes
in 66e80% yields.
1563 and 1354 (NO2), 1122 cmꢂ1 1H NMR (250 MHz, CDCl3) dH
.
13.95 (s, 1H, OH), 13.91 (s, 1H, OH), 10.18 (s, 1H, CHO), 10.14 (s, 1H,
CHO), 8.08 (s, 1H, H-10), 7.98e7.82 (m, H, 3HeAr and H-10),
7.73e7.46 (m, 4H, HeAr), 7.34e7.30 (m, 2H, HeAr), 2.83 (t, 4H,
J¼6.2 Hz, H-400), 2.74e2.65 (m, 2H, H-600), 2.57e2.45 (m, 2H, H-600),
2.10e1.93 (m, 2H, H-500), 1.89e1.73 (m, 2H, H-500) ppm. 13C NMR
(63 MHz, CDCl3) dC 191.2 (CHO), 191.0 (CHO), 163.7 (C-200), 163.5 (C-
200), 140.6, 139.8, 136.6, 135.6, 135.5 (C-4), 134.0 (C-4), 132.8 (C-5),
132.2 (C-100),132.0 (C-6),130.9 (C-3),130.4 (C-10),129.4 (C-300),126.9
(C-300), 126.7 (C-300), 124.0 (C-300), 123.2 (C-300), 30.1 (C-600), 26.5 (C-
600), 25.9 (C-400), 24.8 (C-400), 23.3 (C-500), 21.6 (C-500) ppm. Anal.
Calcd for C14H12NO4Cl: C, 57.25; H, 4.12; N, 4.77. Found: C, 57.00; H,
3.91; N, 4.73.
4.3. General procedure for the anionic domino reactions
To a solution of the starting a-nitroketone (1 mmol) in tetra-
hydrofuran (5 ml) was added DBU (1.3 mmol). The resulting solu-
tion was stirred at room temperature for 5 min, under an argon
atmosphere. A solution of the suitable dialdehyde (2 mmol) in
tetrahydrofuran (5 ml) containing one drop of water was then
added, and stirring at room temperature was maintained for 24 h,
except where indicated otherwise. Then, CH2Cl2 (20 ml) and 2 M
HCl (10 ml) were added, and the reaction mixture was separated
and extracted with CH2Cl2 (3ꢁ10 ml). The combined organic layers
were dried over anhydrous sodium sulfate and evaporated. The
residue was chromatographed on silica gel, eluting with the mobile
phase specified in each case.
4.3.5. (E)-2-[(2-Hydroxy-3-nitrocyclohex-2-en-1-yliden)methyl]-tio-
phene-3-carbaldehyde (3f) and (E)-3-[(2-hydroxy-3-nitrocyclohex-2-
en-1-yliden)methyl]-tiophene-2-carbaldehyde (3g). Obtained as
a 1.3:1 mixture of regioisomers in 75% yield as a yellow oil after
chromatography on silica gel, eluting with a gradient from petro-
leum ether to dichoromethane. Anal. Calcd for C12H11NO4S: C,
54.33; H, 4.15; N, 5.28. Found: C, 54.51; H, 4.35; N, 5.37. Spectral
data for 3f: 1H NMR (250 MHz, CDCl3) dH 13.95 (s, 1H, OH), 10.08 (d,
1H, J¼0.9 Hz, CHO), 8.59 (br s, 1H, H-10g), 8.05 (br s, 1H, H-1),
7.79e7.66 (m, 2H, H-4b,5), 7.59 (d, 1H, J¼5.3 Hz, H-4), 7.53 (d, 1H,
J¼5.3 Hz, H-5), 2.84e2.74 (m, 2H, H-400), 2.69e2.63 (m, 2H, H-6),
1.97e1.79 (m, 2H, H-5) ppm. 13C NMR (63 MHz, CDCl3) dC 182.1
(CHO), 163.0 (C-200), 147.1 (C-2), 143.5 (C-100), 134.3 (C-3), 129.8 (C-
5), 128.6 (C-4), 126.2 (C-10), 124.4 (C-300), 26.7 (C-600), 24.2 (C-400),
21.2 (C-500) ppm. Spectral data for 3g: 1H NMR (250 MHz, CDCl3) dH
14.08 (s, 1H, OH), 10.25 (s, 1H, CHO), 8.59 (br s, 1H, H-10), 7.79e7.66
4.3.1. (E)-2-[(2-Hydroxy-3-nitrocyclohex-2-en-1-yliden)methyl]
benzaldehyde (3a). Isolated in 95% yield as a pale yellow oil after
chromatography on silica gel, eluting with a gradient from petro-
leum ether to ethyl acetate. IR (NaCl) nmax: 3472, 1695 (CO), 1574
and 1355 (NO2), 1224 cmꢂ1. 1H NMR (250 MHz, CDCl3) dH 14.07 (s,
1H, OH), 10.21 (s, 1H, CHO), 8.19 (s, 1H, H-10), 7.97 (dd, 1H, J¼7.5 and
1.3 Hz, H-6), 7.67 (td, 1H, J¼7.5 and 1.4 Hz, H-4), 7.57 (td, 1H, J¼7.5
and 1.2 Hz, H-5), 7.36 (d, 1H, J¼7.5 Hz, H-3), 2.79 (t, 2H, J¼6.3 Hz, H-
400), 2.54e2.49 (m, 2H, H-600), 1.80 (q, 2H, J¼6.3 Hz, H-500) ppm. 13C
NMR (63 MHz, CDCl3) dC 191.7 (CHO),163.7 (C-200), 137.7 (C-2),134.0
(C-1), 133.5 (C-4), 133.5 (C-10), 132.3 (C-100), 131.3 (C-6), 130.1 (C-3),
128.8 (C-5), 126.0 (C-300), 26.1 (C-600), 24.5 (C-400), 21.3 (C-500) ppm.

G. Giorgi et al. / Tetrahedron 67 (2011) 5582e5589
5587
(m, 2H, H-4b,5), 2.84e2.74 (m, 2H, H-400), 2.69e2.63 (m, 2H, H-600),
1.97e1.79 (m, 2H, H-500) ppm. 13C NMR (63 MHz, CDCl3) dC 184.2
(CHO),163.4 (C-200),147.3 (C-3),143.4 (C-100),133.5 (C-2),131.8 (C-5),
128.8 (C-10), 126.7 (C-4), 123.8 (C-300), 27.0 (C-600), 24.0 (C-400), 20.9
(C-500) ppm. Anal. Calcd for C12H11NO4S: C, 54.33; H, 4.18; N, 5.28.
Found: C, 54.10; H, 3.94; N, 5.03.
etheredichloromethane to neat dichloromethane. 1H NMR (CDCl3,
250 MHz) dH 8.12 (dd, 2H, J¼8.2 and 1.2 Hz, H-200,600), 7.64 (tt, 1H,
J¼7.3 and 1.3 Hz, H-400), 7.53e7.30 (m, 2H, H-300,500), 5.36 (m, 1H, H-
10), 4.94 (m, 1H, H-6), 2.81e2.60 (m, 3H, H-3), 2.53e2.41 (m, 2H, H-
5), 1.97e1.82 (m, 2H, H-4) ppm. 13C NMR (CDCl3, 63 MHz) dC: 202.2
(C-1),140.3 (C-100),129.6 (C-300,500),128.8 (C-200,600),127.2 (C-400), 92.6
(C-2), 73.8 (C-10), 57.9 (C-6), 32.6 (C-3), 30.8 (C-4), 24.2 (C-5) ppm.
Anal. Calcd for C13H15NO4: C, 62.64; H, 6.07; N, 5.62. Found: C,
62.45; H, 5.97; N, 5.43.
4.3.6. (E)-6-(4-Nitrobenzylidene)-2-nitrocyclohex-1-enol
(3i). Isolated in 88% yield as a pale orange solid after 4 days of
reaction followed by chromatography on silica gel, eluting with
dichloromethane. Mp 117e118 ꢀC. IR (NaCl) nmax: 3380 (OH), 2932,
1558 and 1342 (NO2) cmꢂ1. 1H NMR (CDCl3, 250 MHz) dH 14.97 (s,
1H, OH), 8.30 (d, 2H, J¼8.8 Hz, H-300,500), 7.77 (s, 1H, H-10), 7.57 (d,
2H, J¼8.8 Hz, H-200,600), 2.82 (t, 2H, J¼6.2 Hz, H-3), 2.77e2.71 (m, 2H,
H-5), 1.81 (quint, 2H, J¼6.2 Hz, H-4) ppm. 13C NMR (CDCl3, 63 MHz)
dC 162.9 (C-1), 147.1 (C-400), 141.9 (C-100), 133.2 (C-10), 132.7 (C-6),
130.4 (C-200,600), 126.6 (C-2), 123.6 (C-300,500), 26.3 (C-5), 24.2 (C-3),
21.3 (C-4) ppm. Anal. Calcd for C13H12N2O5: C, 56.52; H, 4.34; N,
10.14. Found: C, 56.22; H, 4.54; N, 9.88.
4.3.11. (ꢃ)-(10S*,20S*,30R*)-6-(10,30-dihydroxy-20-nitroindan-20-yl)
hexanoic acid (5a). Isolated in 81% yield, initially as a 4:1 mixture of
diastereoisomers. Chromatography on silica gel, eluting with
a gradient from petroleum ether to dichloromethane, followed by
ethyl acetate, afforded the pure compound 5a, as a white solid. Data
for the major diastereomer of 5a: Mp 102e103 ꢀC; IR (NaCl) nmax
:
3397 (OH); 1702 (CO), 1534, 1353 (NO2) cmꢂ1. 1H NMR (250 MHz,
acetone-d6) dH: 7.44e7.34 (m, 4H, HeAr), 5.69 (s, 2H, H-10,30), 5.50
(br s, 2H, OH), 2.17e2.25 (m, 4H, H-2, 6), 1.44e1.56 (m, 2H, H-3),
1.14e1.33 (m, 4H, H-4, 5) ppm. 13C NMR (63 MHz, acetone-d6) dC
:
4.3.7. (E,E)-2-Nitro-6-(3-phenyl-20-propenylidene)-cyclohex-1-enol
(3j). Isolated in 60% yield as a pale brown solid after 6 days of re-
action followed by chromatography on silica gel, eluting with
dichloromethane. Mp, 125e126 ꢀC. IR (NaCl) nmax: 3603 (OH), 2926,
174.2 (C-1), 140.9 (C-30a,70a),129.0 (C-50,60), 123.8 (C-40,70), 105.8 (C-
20), 77.1 (C-10,30), 33.5 (C-6), 29.8 (C-2), 29.4 (C-5), 24.7 (C-3), 24.3
(C-4) ppm. Anal. Calcd for C15H19NO6: C, 58.25; H, 6.19; N, 4.53.
Found: C, 58.03; H, 6.08; N, 6.02. Data for the minor diastereomer of
5a (obtained from the initial mixture): 1H NMR (250 MHz, acetone-
1589 and 1398 (NO2), 1210 cmꢂ1. 1H NMR (CDCl3, 250 MHz)
d: 14.38
(s, 1H, OH), 7.65e745 (m, 5H, HeAr), 7.20e6.99 (m, 3H, CH]), 2.79
(t, 2H, J¼6.2 Hz, H-6), 2.73e2.66 (m, 2H, H-5), 1.88 (quint, 2H,
d6):
d
¼7.50e7.20 (m, 4H, HeAr), 5.94 and 5.00 (2s, 2H, H-10,30), 5.27
(s, 2H, 2OH), 2.30e1.80 (m, 4H, H-2,6), 1.60e1.30 (m, 6H, H-3,4,5)
J¼6.2 Hz, H-4) ppm. 13C NMR (CDCl3, 63 MHz)
d
: 165.3 (C-1), 141.2
ppm. 13C NMR (63 MHz, acetone-d6):
d
¼178.8 (C-1), 140.8 (C-3a0),
(C-100), 136.3 (C-6), 129.2 (C-30), 128.9 (C-300,500), 128.7 (C-400), 127.6
(C-20), 127.3 (C-200,600), 125.2 (C-10), 123.4 (C-2), 25.0 (C-5), 24.5 (C-
3), 21.0 (C-4) ppm. Anal. Calcd for C15H15NO3: C, 70.03; H, 5.83; N,
5.44. Found: C, 69.90; H, 5.78; N, 5.46.
137.4 (C-7a0), 130.2 (C-50), 129.4 (C-60), 125.2 (C-40), 124.3 (C-70),
35.4 (C-2), 32.3 (C-6), 29.6 (C-5), 24.1 and 23.9 (C-3,4) ppm.
4.3.12. (ꢃ)-(10S*,20S*,30R*)-6-(10,30-dihydroxy-50-methyl-20-nitro-
indan-20-yl)hexanoic acid (5b). Isolated in 96% yield as a colourless
viscous oil after chromatography on silica gel, eluting with a gra-
dient from petroleum ether to dichloromethane, followed by ethyl
acetate. 1H NMR (250 MHz, CDCl3) dH: 7.40 (d, 1H, J¼7.9 Hz, H-7),
7.31e7.29 (m, 1H, H-4), 7.22 (d, 1H, J¼7.9 Hz, H-4), 5.51e5.48 (2s,
2H, 2OH), 5.26 and 5.23 (2s, 2H, H-10, H-30), 2.40 (s, 3H, CH3),
2.42e2.28 (m, 4H, H-2, 6), 2.20e1.95 (m, 2H, H-3),1.27e1.30 (m, 2H,
H-4, 5) ppm. 13C NMR (63 MHz, CDCl3) dC 141.6 (C-30a),141.2 (C-70a),
132.0 (C-50), 126.5 (C-60), 138.6 (C-40), 137.7 (C-70), 105.8 (C-20), 77.3
(C-10), 81.5 (C-30), 33.3 (C-6), 27.9 (C-2), 26.2 (C-5), 22.2 (C-3), 21.8
(C-4), 21.8 (CH3) ppm. Anal. Calcd for C16H21NO6: C, 59.43; H, 6.55;
N, 4.33. Found: C, 59.38; H, 6.71; N, 4.19.
4.3.8. (E,E)-2-Nitro-6-[3-(2-nitrophenyl)propenylidene]-cyclohex-1-
enol (3k). Isolated in 90% yield as a red solid after 5 days of reaction
followed by chromatography on silica gel, eluting with dichloro-
methane. Mp 219e220 ꢀC. IR (NaCl) nmax: 3390 (OH), 2358, 1519 and
1342 (NO2) cmꢂ1. 1H NMR (CDCl3, 250 MHz)
d: 14.08 (s, 1H, OH), 8.03
(d, 1H, J¼8.1 Hz, H-300), 7.76 (d, 1H, J¼7.8 Hz, H-600), 7.65 (t, 1H,
J¼7.6 Hz, H-400), 7.53e7.46 (m, 3H, H-300 and H-20,30), 7.10 (dd, 1H,
J¼14.9 Hz, H-10), 2.80 (t, 2H, J¼6.1 Hz, H-6), 2.69 (m, 2H, J¼5.9 Hz, H-
5), 1.89 (quint, 2H, J¼6.1 Hz, H-4) ppm. 13C NMR (DMSO, 63 MHz)
d:
163.7 (C-1), 148.4 (C-200), 134.6 (C-6), 134.4 (C-30), 133.7 (C-500), 132.5
(C-100),131.1 (C-600),130.0 (C-400),128.9 (C-20),126.4 (C-10,300),124.9 (C-
2), 24.8 (C-5), 24.6 (C-3), 20.9 (C-4) ppm. Anal. Calcd for C15H14N2O5:
C, 59.60; H, 4.63; N, 9.27. Found: C, 59.59; H, 4.64; N, 9.42.
4.3.13. (ꢃ)-(10S*,20S*,30R*)-6-(10,30-Dihydroxy-50,60-dimethyl-20-nitro-
indan-20-yl)hexanoic acid (5c). Obtained in 75% yield (based on
unrecovered starting material) as a white solid after chromatog-
raphy on silica gel, eluting with a gradient from petroleum ether to
dichloromethane, followed by ethyl acetate. Mp 105e107 ꢀC; IR
(NaCl) nmax: 3390 (OH), 1702 (CO), 1534 and 1353 (NO2) cmꢂ1. 1H
NMR (250 MHz, acetone-d6) dH 7.17 (d, 2H, J¼7.9 Hz, H-7, 4), 5.59 (s,
2H, H-10,30), 2.29 (s, 6H, 2 CH3), 2.15e2.27 (m, 4H, H-2, 6), 1.50e1.56
(m, 2H, H-3), 1.27e1.30 (m, 4H, H-4, 5) ppm. 13C NMR (63 MHz,
acetone-d6) dC 174.1 (C-1), 138.6 (C-30a, C-70a), 137.5 (C-50, C-60),
124.8 (C-40, C-70),105.8 (C-20), 77.2 (C-10, C-30), 33.4 (C-6), 29.7 (C-2),
29.5 (C-5), 24.6 (C-3), 24.2 (C-4), 19.5 (2CH3) ppm. Anal. Calcd for
C17H23NO6: C, 60.52; H, 6.87; N, 4.15. Found: C, 60.38; H, 6.72; N,
3.99.
4.3.9. (E,E)-2-Nitro-6-[3-(4-nitrophenyl)-20-propenylidene]cyclohex-
1-enol (3l). Isolated in 85% yield as a red solid after 5 days of reaction
followed by chromatography on silica gel, eluting with dichloro-
methane. Mp 218e219 ꢀC. IR (NaCl) nmax: 3280 (OH), 2359, 1508,
1396 and 1336 (2 NO2) cmꢂ1. 1H NMR (CDCl3, 250 MHz)
d: 14.07 (s,
1H, OH), 8.26 (d, 2H, J¼8.7 Hz, H-300,500), 7.66 (d, 1H, J¼8.8 Hz, H-
200,600), 7.55e7.43 (m, 1H, H-30), 7.34e7.23 (m, 1H, H-20), 7.04 (d, 1H,
J¼15.4 Hz, H-10), 2.81 (t, 2H, J¼6.1 Hz, H-3), 2.75e2.70 (m, 2H, H-5),
1.89 (quint, 2H, J¼6.1 Hz, H-4) ppm. 13C NMR (DMSO, 175 MHz)
d:
163.7 (C-1), 147.3 (C-400), 143.4 (C-100), 138.4 (C-30), 134.8 (C-6), 132.8
(C-200,600), 128.9 (C-10), 128.8 (C-20), 126.6 (C-2), 124.4 (C-300,500), 24.9
(C-5), 24.7 (C-3), 21.0 (C-4) ppm. Anal. Calcd for C15H14N2O5: C,
59.60; H, 4.63; N, 9.27. Found: C, 59.38; H, 4.70; N, 9.82.
4.3.14. (ꢃ)-(10S*,20S*,30R*)-6-(50-Chloro-10,30-dihydroxy-20-nitro-
indan-20-yl)hexanoic acid (5d). Obtained in 85% yield as a pale
brown oil after chromatography on silica gel, eluting with a gradi-
ent from petroleum ether to dichloromethane, followed by ethyl
acetate. IR (NaCl) nmax: 3360 (OH), 1711 (CO), 1597 and 1424 (NO2)
cmꢂ1. 1H NMR (250 MHz, CDCl3) dH 7.80e7.08 (m, 3H, HeAr), 5.55
4.3.10. 6-(1-Hydroxy-1-phenylmethyl)-2-nitrocyclohexanone
(4). Obtained in 100% yield as a 3:3:1 mixture of diastereomers and
the crude product as such for the synthesis of compound 3h (see
below). One of the diastereomers could be purified by chroma-
tography on silica gel, eluting with a gradient from 1:1 petroleum

5588
G. Giorgi et al. / Tetrahedron 67 (2011) 5582e5589
(s, 1H, H-10,30), 5.33 (s, 1H, H-10,30), 2.85e2.02 (m, 4H, H-2, 6),
1.98e0.66 (m, 6H, H-3, 4, 5) ppm. 13C NMR (63 MHz, CDCl3) dC 179.4
(C-1), 140.7 (C-30a), 137.2 (C-70a), 135.1 (C-50), 129.6 (C-70), 125.2 (C-
40), 124.9 (C-60), 104.8 (C-20), 75.8 (C-10,30), 33.5 (C-6), 29.5 (C-2),
28.9 (C-5), 24.6 (C-3), 24.2 (C-4) ppm. Anal. Calcd for C15H18NO6Cl:
C, 52.41; H, 5.28; N, 4.07. Found: C, 52.23; H, 5.28; N, 4.00.
cmꢂ1. 1H NMR (250 MHz, CDCl3) dH 10.16 (s,1H, CHO), 8.01 (s,1H, H-
10), 7.96 (dd, 1H, J¼7.5 and 1.4 Hz, H-6), 7.68 (td, 1H, J¼7.4 and
1.5 Hz, H-4), 7.59 (td, 1H, J¼7.5 and 1.0 Hz, H-5), 7.31 (d, 1H,
J¼7.4 Hz, H-3), 5.91 (dd, 1H, J¼10.3 and 5.7 Hz, H-300), 2.75 (dt, 1H,
J¼14.9 and 4.0 Hz, H-800), 2.53e2.30 (m, 3H, H-400,800), 1.93e1.59 (m,
4H, H-500,600,700), 1.53e1.25 (m, 2H, H-600,700) ppm. 13C NMR (63 MHz,
CDCl3) dC 195.2 (C-200), 191.9 (CHO), 139.8 (C-100), 139.4 (C-10), 137.7
(C-2), 134.5 (C-1), 134.3 (C-4), 132.1 (C-6), 129.7 (C-3), 129.4 (C-5),
90.2 (C-300), 32.7 (C-400), 29.5 (C-700), 25.8 (C-600), 25.6 (C-800), 22.8 (C-
500) ppm. Anal. Calcd for C16H17NO4: C, 66.89; H, 5.96; N, 4.88.
Found: C, 66.61; H, 6.08; N, 4.66.
4.3.15. (ꢃ)-(10S*,20S*,30R*)-6-(50,60-Dichloro-10,30-dihydroxy-20-nitro-
indan-20-yl)hexanoic acid (5e). Obtained in 78% yield as a pale
brown oil after chromatography on silica gel, eluting with a gradi-
ent from petroleum ether to dichloromethane, followed by ethyl
acetate. 1H NMR (250 MHz, acetone-d6) dH 7.57 (s, 2H, HeAr); 5.72
(s, 2H, H-10,30), 2.27e2.11 (m, 4H, H-2, 6), 1.56e1.49 (m, 2H, H-3),
1.31e1.21 (m, 4H, H-4, 5) ppm. 13C NMR (63 MHz, acetone-d6) dC
175.0 (C-1), 142.5 (C-30a,70a); 133.2 (C-50,60), 126.8 (C-40,70), 106.6
(C-20), 77.0 (C-10,30), 34.3 (C-6), 30.6 (C-2), 30.3 (C-5), 25.5 (C-3),
25.3 (C-4) ppm. Anal. Calcd for C15H17Cl2NO6: C, 47.64; H, 4.53; N,
3.70; Found: C, 47.48; H, 4.32; N, 3.55.
4.3.18. (ꢃ)-(10S*,20S*,30R*)-7-(10,30-Dihydroxy-50,60-dimethyl-20-nitro-
indan-20-yl)heptanoic acid (5h). Obtained in 70% yield as a yellow
oil after chromatography on silica gel, eluting with a gradient from
petroleum ether to ethyl acetate. 1H NMR (250 MHz, CDCl3) dH 7.52
(s, 2H, H-40,70); 5.54 (s, 2H, H-10,30); 2.42e2.05 (m, 10H, H-2, 7, 2ꢁ
CH3); 1.59e1.54 (m, 2H, H-3); 1.37e1.12 (m, 6H, H-4, 5, 6) ppm. 13
C
NMR (63 MHz, CDCl3) dC 179.2 (C-1), 137.0 (C-30a,70a), 135.4 (C-
50,60), 125.2 (C-40,70), 104.5 (C-20), 76.9 (C-10,30), 34.1 (C-2), 30.3 (C-
7), 29.5 (C-5), 28.8 (C-4), 25.9 (C-3), 24.7 (C-6), 20.4 (CH3) ppm.
Anal. Calcd for C18H25NO6: C, 61.52; H, 7.17; N, 3.99. Found: C, 61.30;
H, 6.89; N, 3.70.
4.3.16. (ꢃ)-(10S*,20S*,30R*)-6-(10,30-Dihydroxy-20-nitro-20,30-dihydro-
1H-ciclopenta[b]naphtalen-20-yl)hexanoic acid (5f). Obtained in 76%
yield, initially as a 3.5:1 mixture of diastereoisomers. Chromatog-
raphy on silica gel, eluting with a gradient from petroleum ether to
dichloromethane, followed by ethyl acetate, afforded the pure
compound 5f, as a colourless oil. Data for the major diastereomer of
4.3.19. (ꢃ)-(10S*,20S*,30R*)-7-(10,30-Dihydroxy-20-nitro-20,30-dihydro-
1H-ciclopenta[b]naphtalen-20-yl)heptanoic acid (5i) and (E)-3-[(30-
nitro-20-oxocyclooctyliden)methyl]naphtalene-2-carbaldehyde
(3n). Compound 5i was isolated in 66% yield, initially as a 3:1
mixture of diastereoisomers. Chromatography on silica gel, eluting
with a gradient from petroleum ether to ethyl acetate, afforded the
pure compound 5i, as a yellow oil. Compound 3n (22%) was iso-
lated as a yellow solid. Data for the major diastereomer of 5i: IR
5f: IR (NaCl) nmax 3360 (OH); 1711 (CO), 1597 and 1424 (NO2) cmꢂ1
.
1H NMR (500 MHz, acetone-d6) dH 7.91 (dd, 2H, J¼6.0 and 3.2 Hz, H-
50,80), 7.85 (s, 2H, H-40,90), 7.49 (dd, 2H, J¼6.3 and 3.2 Hz, H-60,70),
5.78 (s, 2H, H-10,30), 5.59e5.56 (br s, 2H, 2OH), 2.20e2.14 (m, 4H, H-2,
6), 1.48e1.42 (m, 2H, H-3), 1.32e1.20 (m, 4H, H-4, 5) ppm. 13C NMR
(125 MHz, acetone-d6) dC 179.1 (C-1), 138.8 (C-30a,90a), 134.4 (C-
40a,80a), 128.1, 126.0 and 122.2 (C-40,50,60,70,80,90); 105.1 (C-20), 76.7
(C-10,30), 33.7 (C-6), 29.7 (C-2), 28.8 (C-5), 24.5 (C-3), 24.0 (C-4) ppm.
Anal. Calcd for C19H21NO6: C, 63.50; H, 5.89; N, 3.90. Found: C, 63.22;
H, 5.90; N, 3.83. Data for the minor diastereomer of 5f (obtained from
the initial mixture): 1H NMR (250 MHz, CDCl3) dH 8.04e7.70 (m, 4H,
H-40,50,80,90), 7.60e7.43 (m, 2H, H-60,70), 6.18 and 5.41 (2s, 2H, H-
10,30), 5.31 (s, 2H, 2OH), 2.50e2.00 (m, 4H, H-2,6), 2.80e0.79 (m, 6H,
H-3,4,5) ppm. 13C NMR (63 MHz, CDCl3) dC 179.0 (C-1), 138.1 and
136.7 (C-30a,90a), 133.9 and 133.8 (C-40a,80a), 133.6 128.6, 126.6,
126.4, 124.7 and 123.5 (C-40,90), 101.1 (C-20), 77.4 and 76.9 (C-10,30),
31.8 (C-6), 30.1 (C-2), 29.2 (C-5), 28.7 (C-3), 23.8 (C-4) ppm.
(NaCl) nmax 3415 (OH), 1722, 1711 (CO), 1536 and 1357 (NO2) cmꢂ1
.
1H NMR (250 MHz, MeOD) dH 7.92 (dd, 2H, J¼6.6 and 3.3 Hz, H-
50,80), 7.85 (s, 2H, H-40,90), 7.49 (dd, 2H, J¼6.2 and 3.2 Hz, H-60,70),
5.78 (s, 2H, H-10,30), 2.25e2.12 (m, 4H, H-2, 7), 1.54e1.48 (m, 2H,
H-3), 1.31e1.23 (m, 8H, H-4, 5, 6, 2OH) ppm. 13C NMR (63 MHz,
MeOD) dC 179.2 (C-1), 138.6 (C-30a,90a), 131.9 (C-40a,80a), 129.4,
124.9, 123.7 (C-40,50,60,70,80,90), 104.1 (C-20), 76.3 (C-10,30), 33.6 (C-
2), 29.8 (C-7), 29.2 (C-5), 28.2 (C-3), 24.2 (C-4), 24.0 (C-6) ppm.
Anal. Calcd for C20H23NO6: C, 64.33; H, 6.21; N, 3.75. Found: C,
64.30; H, 6.20; N, 3.62. Data for the minor diastereomer of 5i
(obtained from the initial mixture): 1H NMR (250 MHz, CDCl3): dH
8.10e7.80 (m, 4H, H-40,50,80,90), 7.75e7.60 (m, 2H, H-60,70), 6.20 (s,
2H, H-10,30), 5.60 (s, 2H, OH), 2.40e2.30 (m, 4H, H-2,7), 2.30e2.10
(m, 2H, H-3), 1.80e1.50 and 1.40e1.20 (2 m, 6H, H-4, 5, 6) ppm. 13C
NMR (63 MHz, CDCl3) dC 168.3 (C-1), 137.7 and 137.1 (C-30a,90a),
135.6 and 134.4 (C-40a,80a), 132.7, 131.3, 129.2, 128.6, 126.7 and
123.5 (C-40,50,60,70,80,90), 102.1 (C-20), 77.5 and 76.1 (C-10,30), 34.1 (C-
2), 29.5 (C-7), 28.7 (C-5), 24.8 (C-3), 24.5 (C-4), 23.1 (C-6) ppm.
Data for 3n: 1H NMR (250 MHz, CDCl3) dH 10.18 (s, 1H, CHO), 8.51
(s, 1H, H-10), 8.12 (s, 1H, H-1), 8.07 (d, 1H, J¼8.0 Hz, H-8), 7.93 (d,
1H, J¼7.9 Hz, H-5), 7.81e7.64 (m, 3H, H-4, 6, 7), 5.97 (m, 1H, H-300),
2.91 (dt, 1H, J¼14.8 and 4.0 Hz, H-800), 2.53e2.20 (m, 3H, H-400,800),
1.94e1.12 (m, 4H, H-500,600,700), 0.98e0.75 (m, 2H, H-600,700) ppm.
Anal. Calcd for C20H19NO4: C, 71.20; H, 5.68; N, 4.15. Found: C,
71.16; H, 5.91; N, 4.33.
4.3.17. (ꢃ)-(10S*,20S*,30R*)-7-(10,30-Dihydroxy-20-nitroindan-20-yl)
heptanoic acid (5g) and (E)-2-[(3-nitro-2-oxocyclooctyliden)methyl]
benzaldehyde (3m). Compound 5g was obtained in 72% yield, ini-
tially as a 3:1 mixture of diastereoisomers. Chromatography on
silica gel, eluting with a gradient from petroleum ether to ethyl
acetate, afforded the pure compound 5g, as a yellow oil. Compound
3m (20%) was obtained from the same column as a yellow solid.
Data for the major diastereomer of 5g: IR (NaCl) nmax 3415 (OH),1722,
1711 (CO), 1536 and 1357 (NO2) cmꢂ1. 1H NMR (250 MHz, CDCl3) dH
7.59e7.32 (m, 4H, HeAr), 5.59 (s, 2H, H-10,30), 5.00e3.41 (br s, 2H, 2
OH), 2.31 (t, 2H, J¼7.3 Hz, H-2), 2.19e2.10 (m, 2H, H-7), 1.59e1.54
(m, 2H, H-3), 1.37e1.12 (m, 6H, H-4, 5, 6) ppm. 13C NMR (63 MHz,
CDCl3) dC 179.2 (C-1), 138.6 (C-30a,70a), 129.4 (C-50,60), 123.7 (C-
40,70), 104.1 (C-20), 76.3 (C-10,30), 33.6 (C-2), 29.8 (C-7), 29.2 (C-5),
28.2 (C-4), 24.2 (C-3), 24.0 (C-6) ppm. Anal. Calcd for C16H21NO6:
59.43; H, 6.55; N, 4.33. Found: C, 59.28; H, 6.39; N, 4.20. Data for the
minor diastereomer of 5g (obtained from the initial mixture): 1H NMR
4.4. (E)-6-Benzylidene-2-nitrocyclohex-1-enol (3h)
(250 MHz, CDCl3):
d
¼7.75e7.20 (m, 4H, HeAr), 5.98 (s, 2H, 2OH),
A solution of crude 4 (700 mg, 2.8 mmol) in ethanol (2 ml) was
added 35% aqueous hydrochloric acid (0.12 ml). The reaction mix-
ture was stirred at room temperature for 48 h and was then heated
at 60 ꢀC for 4 h. The solvent was removed under reduced pressure
and the residue was chromatographed on silica gel eluting with
dichloromethane, to give compound 3h (439 mg, 68%) as a pale
5.31 and 5.21 (2s, 2H, H-10,30), 2.36e2.00 (m, 4H, H-2,7), 1.85e1.40
(m, 2H, H-3), 1.39e1.00 (m, 6H, H-4, 5, 6) ppm. 13C NMR (63 MHz,
CDCl3):
d
¼179.9 (C-1), 141.3, 137.7, 130.6, 129.7, 125.7, 124.8, 101.7
(C-20), 77.4, 76.6, 34.2 (2C); 29.5, 28.9, 24.7 (2C), 24.3 ppm. Data for
3m: IR (NaCl) nmax 2936 (OH), 1694 (CO),1594, 1556 and 1357 (NO2)

G. Giorgi et al. / Tetrahedron 67 (2011) 5582e5589
5589
brown oil. IR (NaCl) nmax: 2934, 1558 and 1342 (NO2) cmꢂ1. 1H NMR
(CDCl3, 250 MHz)
: 14.39 (s, 1H, OH), 7.80 (s, 1H, H-10), 7.45e7.29
References and notes
d
1. For reviews of diversity-oriented synthesis and its implications in the discovery
of bioactive small molecules, see: (a) Schreiber, S. L. Science 2000, 287, 1964; (b)
Spring, D. R. Org. Biomol. Chem. 2003, 1, 3867; (c) Burke, M. D.; Berger, E. M.;
Schreiber, S. L. Science 2003, 302, 5645; (d) Burke, M. D.; Schreiber, S. L. Angew.
Chem., Int. Ed. 2004, 43, 46; (e) Tan, D. S. Nat. Chem. Biol. 2005, 1, 74; (f)
Wessjohann, L. A.; Ruijter, E. Top. Curr. Chem. 2005, 243, 137; (g) Spandl, R. J.;
Bender, A.; Spring, D. R. Org. Biomol. Chem. 2008, 6, 1149; (h) Spandl, R. J.;
Thomas, G. L.; Díaz Gavilan, M.; O’Connel, K. M. G.; Spring, D. R. In ‘Linker
Strategies in Solid-Phase Organic Synthesis’; Scott, P., Ed.; Wiley: Chichester,
2009; p 241; (i) Galloway, W. R. J. D.; Spring, D. R. Expert Opin. Drug Discovery
(m, 5H, HeAr), 2.81e2.75 (m, 4H, H-400, H-600), 1.80 (quint, 2H,
J¼6.3 Hz, H-500) ppm. 13C NMR (CDCl3, 63 MHz)
d: 165.7 (C-1), 136.7
(C-100), 136.0 (C-6), 130.4 (C-10), 130.3 (C-400), 129.3 (C-300,500), 128.9
(C-200,600), 126.0 (C-2), 26.8 (C-5), 24.8 (C-3), 21.9 (C-4) ppm. Anal.
Calcd for C13H13NO3: C, 67.52; H, 5.67; N, 6.06. Found: C, 67.37; H,
5.94; N, 5.80.
ꢀ
4.5. Reaction between 2-nitrocyclohexanone and
phthalaldehyde in the presence of potassium hydroxide
ꢀ
2009, 4, 467; (j) Galloway, W. R. J. D.; Díaz Gavilan, M.; Isidro Llobet, A.; Spring,
D. R. Angew. Chem., Int. Ed. 2009, 48, 1194; (k) Galloway, W. R. J. D.; Isidro Llobet,
A.; Spring, D. R. Nat. Commun. 2010, 1, 80.
2. For selected reviews, see: (a) Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed. Engl.
1993, 32, 131; (b) Tietze, L. F. Chem. Rev. 1996, 96, 115; (c) Rodriguez, J. Synlett
1999, 505; (d) Pellisier, H. Tetrahedron 2006, 62, 1619; (e) Pellisier, H. Tetrahe-
To a solution of 2-nitrocycloheptanone (500 mg, 3.18 mmol) in
methanol containing 5% KOH (195 ml) was added phthalaldehyde
(640 mg, 4.77 mmol) and the reaction mixture was stirred at room
temperature for 29 h, poured on water (200 ml) and washed with
dichloromethane (3ꢁ30 ml). The aqueous layer was acidified with
2 M aqueous HCl and extracted with dichloromethane (3ꢁ200 ml).
The combined organic layers were dried over anhydrous sodium
sulfate and evaporated, and the residue was purified by chroma-
tography on silica gel, eluting with a gradient from 9:1 petroleum
ethereethyl acetate to neat ethyl acetate, to obtain 160 mg (16%) of
compound 5a, 300 mg (32%) of compound 6, as a yellow viscous oil
containing a 5:1 mixture of diastereomers a and b and 93 mg (22%)
of isobenzofuran-1(3H)-one as a white solid. Data for 6: IR (NaCl)
nmax: 1693, 1524, 1335 cmꢂ1. 1H NMR (CDCl3, 250 MHz) dH: 10.13 (s,
1H, CHOa),10.10 (s,1H, CHOb), 8.43 (s,1H, H-8a), 7.95 (dd,1H, J¼7.4,
1.4 Hz, H-30a), 7.88e7.85 (m, 1H, H-30b), 7.73e7.61 (m, 2H, H-40a, H-
50a), 7.58e7.50 (m, 2H, H-40b,50b), 7.33 (d, 1H, J¼7.3 Hz, H-60a),
7.24e7.21 (m, 1H, H-60b), 7.09 (s, 1H, H-8b), 2.74 (t, 2H, J¼7.0 Hz, H-
6b), 2.61 (t, 2H, J¼7.6 Hz, H-6a), 2.40 (t, 2H, J¼7.2 Hz, H-2b), 2.27 (t,
2H, J¼7.4 Hz, H-2a), 1.73e1.62 (m, 4H, H-4b,5b), 1.61e1.48 (m, 4H,
H-4a,5a), 1.33e1.23 (m, 4H, H-3ab) ppm. 13C NMR (CDCl3, 63 MHz)
dC: 192.6 (CHOb), 192.1 (CHOa), 180.1 (C-1b), 180.0 (C-1a), 153.1 (C-
7a), 152.6 (C-7b), 134.7 (C-20a), 134.5 (C-50a), 134.4 (C-50b), 134.3 (C-
10a), 133.7 (C-30ab), 133.2 (C-8a), 130.2 (C-40a,10b,20b), 129.8 (C-60a),
129.4 (C-40b), 129.2 (C-60b), 126.1 (C-8b), 33.6 (C-2b), 33.6 (C-2a),
32.5 (C-6b), 28.2 (C-3a), 27.8 (C-3b), 27.3 (C-5a), 26.5 (C-6a), 26.3
(C-5b), 24.0 (C-4b), 23.9 (C-4a) ppm. Anal. Calcd for C15H17NO5: C,
61.85; H, 5.88; N, 4.81. Found: C, 61.84; H, 6.05; N, 4.30.
ꢀ
dron 2006, 62, 2143; (f) Lieby-Muller, F.; Simon, C.; Constantieux, T.; Rodriguez,
J. QSAR Comb. Sci. 2006, 25, 432; (g) Bur, S. K.; Padwa, A. Adv. Heterocycl. Chem.
2007, 94, 1; (h) Padwa, A.; Bur, S. K. Tetrahedron 2007, 63, 5341; (i) For
a monograph, see: Tietze, L. F.; Brasche, G.; Gericke, K. M. Domino Reactions in
Organic Synthesis; Wiley-VCH: Weinheim, 2006.
3. For a review, see: Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int.
Ed. 2006, 45, 7134.
ꢀ
~
4. (a) Miranda, S.; Lopez-Alvarado, P.; Giorgi, G.; Rodríguez, J.; Avendano, C.;
ꢀ
ꢀ
Menendez, J. C. Synlett 2003, 2159; (b) Giorgi, G.; Miranda, S.; Lopez-Alvarado,
P.; Avendano, C.; Rodríguez, J.; Menendez, J. C. Org. Lett. 2005, 7, 2197; (c) Giorgi,
G.; Miranda, S.; Ruiz, M.; Rodriguez, J.; Lopez-Alvarado, P.; Menendez, J. C. Eur. J.
Org. Chem. 2011, 2101; (d) Giorgi, G.; Maiti, S.; Lopez-Alvarado, P.; Menendez, J.
C. Org. Biomol. Chem. 2011, 9, 2722.
~
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
5. For the synthesis of non-commercially available phthalaldehydes, see Ref. 16.
The last step of this method involves a double Swern oxidation, which we were
unable to reproduce. Instead, we resorted to IBX as the oxidant, as detailed in
the Experimental section.
6. No other bases were assayed.
7. For reviews of the synthetic applications of
a-nitroketones, see: (a) Fischer, R.
H.; Witz, H. M. Synthesis 1980, 261; (b) Ballini, R. Synlett 1999, 1009; (c) Ballini,
R.; Bosica, G.; Fiorini, D.; Palmieri, A. Tetrahedron 2005, 61, 8971; (d) For
a monograph on the synthetic applications of nitro compounds, see: Ono, N.
The Nitro Group in Organic Synthesis; Wiley-VCH: 2001.
8. (a) Charonnet, E.; Filippini, M. H.; Rodriguez, J. Synthesis 2001, 788; (b) Habib-
Zahmani, H.; Hacini, S.; Charonnet, E.; Rodriguez, J. Synlett 2002, 1827.
9. Habib-Zahmani, H.; Viala, J.; Hacini, S.; Rodriguez, J. Synlett 2007, 1037.
10. (a) Sotoca, E.; Constantieux, T.; Rodriguez, J. Synlett 2008, 1313; (b) Sotoca, E.;
Allais, C.; Constantieux, T.; Rodriguez, J. Org. Biomol. Chem. 2009, 7, 1911.
11. The preparation of some compounds 10 has been described in preliminary
ꢀ
ꢀ
communication form. See: Giorgi, G.; Arroyo, F. J.; Lopez-Alvarado, P.; Menen-
dez, J. C. Synlett 2010, 2465.
12. Kesavan, S.; Panek, J. S.; Porco, J. A., Jr. Org. Lett. 2007, 9, 5203.
13. For a representative example, see: Ersmark, K.; Feierberg, I.; Bjelic, S.; Hame-
link, E.; Hackett, F.; Blackman, M. J.; Hulten, J.; Samuelsson, B.; Qvist, J.; Hall-
berg, A. J. Med. Chem. 2004, 47, 110.
Acknowledgements
14. Molteni, V.; Rhodes, D.; Rubins, K.; Hansen, M.; Bushman, F. D.; Siegel, J. S. J.
Med. Chem. 2000, 43, 2031.
15. Fukatsu, K.; Uchikawa, O.; Kawada, M.; Yamano, T.; Yamashita, M.; Kato, K.;
Hirai, K.; Hinuma, S.; Miyamoto, M.; Ohkawa, S. J. Med. Chem. 2002, 45, 4212.
16. Matsui, T.; Kondo, T.; Nishita, Y.; Itadani, S.; Tsuruta, H.; Fujita, S.; Omawari, N.;
Sakai, M.; Nakazawa, S.; Ogata, A.; Mori, H.; Kamoshima, W.; Terai, K.; Ohno, H.;
Obata, T.; Nakai, H.; Toda, M. Bioorg. Med. Chem. New York 2002, 10, 3787.
17. See, for instance: (a) Hett, R.; Senanayake, C. H.; Wald, S. A. Tetrahedron Lett.
1998, 39, 1705; (b) Zhao, C.-X.; Duffey, M. O.; Taylor, S. J.; Morken, J. P. Org. Lett.
2001, 3, 1829.
We thank MEC (grant CTQ2009-12320-BQU) and UCM (Grupos
ꢀ
de Investigacion Consolidados, grant GR35/10-A-920234) for fi-
nancial support.
Supplementary data
18. Baer, H. H.; Achmatowicz, B. J. Org. Chem. 1964, 29, 3180.
19. Farooq, O. Synthesis 1994, 1035.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2011.05.115.