Synthesis, structure, and E-Z isomerization of β-(hetero)aryl-α- nitro-α,β-enals

Article abstract of DOI:10.1021/jo702731b

(Chemical Equation Presented) The first general methodology for the gram-scale preparation of previously overlooked β-(hetero)aryl-α- nitro-α,β-enals (3) is reported. Condensation of (hetero)aromatic aldehydes with 2-nitroethanol gave the E-isomers of uncommon β-(hetero)aryl-α-hydroxymethyl-α,β-unsatured-nitroalkenes (2), as determined by NOE and X-ray studies. α-Nitro-α,β-enals 3 were subsequently obtained by hypervalent iodine oxidation of 2 as E-Z-mixtures in solid form. They showed varied stability and solvent-dependent thermal-promoted and photopromoted E-Z interconversion. Starting with furfural, experimental conditions were developed to prepare the corresponding nitroenal 3a enriched in either the E or the Z isomer: E-3a/Z-3a ≈ 90/10 and 20/80, respectively. In contrast with other structurally related compounds, nitroenals 3 have their (hetero)aryl-vinyl unit and their formyl and nitro groups all in a planar arrangement, both in solid form and in solution; accordingly, they are colored compounds with predicted high dipole moments. As deduced from solution-NMR and X-ray data, the C=C and the C=O double bonds in 3 are exclusively s-cis-oriented; this disposition corresponds in fact to the DFT-computed most stable conformer.

Full text of DOI:10.1021/jo702731b

Synthesis, Structure, and E-Z Isomerization of
-(Hetero)aryl-r-nitro-r,ꢀ-enals
ꢀ
†
,¶
¶
‡
§
Patricia Martínez-Bescos, Fernando Cagide-Fagín, Luis F. Roa, Juan Carlos Ortiz-Lara,
⊥
|
Krzysztof Kierus, Lidia Ozores-Viturro, Marta Fernández-González, and Ricardo Alonso*
Departamento de Química Orgánica, UniVersidad de Santiago de Compostela,
1
5782 Santiago de Compostela, Spain
qoraa@usc.es
ReceiVed December 21, 2007
The first general methodology for the gram-scale preparation of previously overlooked ꢀ-(hetero)aryl-
R-nitro-R,ꢀ-enals (3) is reported. Condensation of (hetero)aromatic aldehydes with 2-nitroethanol gave
the E-isomers of uncommon ꢀ-(hetero)aryl-R-hydroxymethyl-R,ꢀ-unsatured-nitroalkenes (2), as determined
by NOE and X-ray studies. R-Nitro-R,ꢀ-enals 3 were subsequently obtained by hypervalent iodine oxidation
of 2 as E-Z-mixtures in solid form. They showed varied stability and solvent-dependent thermal-promoted
and photopromoted E-Z interconversion. Starting with furfural, experimental conditions were developed
to prepare the corresponding nitroenal 3a enriched in either the E or the Z isomer: E-3a/Z-3a ≈ 90/10
and 20/80, respectively. In contrast with other structurally related compounds, nitroenals 3 have their
(
hetero)aryl-vinyl unit and their formyl and nitro groups all in a planar arrangement, both in solid form
and in solution; accordingly, they are colored compounds with predicted high dipole moments. As deduced
from solution-NMR and X-ray data, the CdC and the CdO double bonds in 3 are exclusively s-cis-
oriented; this disposition corresponds in fact to the DFT-computed most stable conformer.
3
Introduction
-(Hetero)aryl-R-nitro-R,ꢀ-enals (ArCHdC(NO2)CHO, 3)
enal 3l had been named in a patent (see below); also, there
were no precedents for the use of ꢀ-(hetero)aryl-R-nitro-R,ꢀ-
enals (3) in synthesis.
ꢀ
densely combine a (hetero)aromatic ring, a CdC double bond,
a nitro group and a formyl group to form an extended π system,
where three functionalities of demonstrated utility in synthesis,
namely, a (hetero)arylvinyl unit, an R,ꢀ-unsaturated nitroalkene,
and an R,ꢀ-enal, intimately coexist sharing a common double
bond. Attractive as this combination of structural and functional
features could be, ꢀ-(hetero)aryl-R-nitro-R,ꢀ-enals have never-
theless been essentially overlooked and their properties and
synthetic potential unexplored. In fact, at the outset of our study,
Before our work in the area, procedures to prepare ꢀ-(het-
ero)aryl-R-nitro-R,ꢀ-enals 3 were limited to those reported for
a and 3i-k. Preparation of 3a, 3i, and 3j involved N2O4-
promoted nitration of the corresponding ꢀ-furyl-R,ꢀ-enal precur-
sors: 3-(2-furyl)propenal (7a) for both 3a and 3i, and 3-(5-
methyl-2-furyl)propenal (7i) for 3j. Nitration of 7a took place
at the formyl R-position to give 3a in 17% yield, and
concurrently, to some extent, in the furane ring, thus also giving
3
1a
1b
dinitrocompound 3i. Blockade of the furyl-ring most-activated
C5 position with a methyl group, as in 7i, allowed the nitration
to be more selective, rendering 3j in 53% yield. In turn, 3k
1
only three ꢀ-furyl-analogues (3a, 3i, and 3j) and an azulene
2
derivative (3k) had been prepared, and a ꢀ-aryl-R-nitro-R,ꢀ-
1c
was prepared in 36% yield by condensation of guaiazulene (5-
*
To whom correspondence should be addressed. Phone: +34 981547085.
Fax: +34 981595012.
(1) (a) Sitkin, A. I.; Klimenko, V. I.; Fridman, A. L. Zh. Org. Khim. 1975,
11, 2452. (b) Klimenko, V. I.; Sitkin, A. I.; Fridman, A. L. Vses. Nauchn. Konf.
Khim. Tekhnol. FuranoVykh Soedin., [Tezisy Dokl.], 3rd, Riga, USSR 1978, 116.
(c) Sitkin, A. I.; Klimenko, V. I.; Fridman, A. L. Khim. Geterotsikl. Soedin.
1977, 1604.
†
Current address: ALCOA, San Ciprián, Lugo, Spain.
Both authors contributed equally to this work.
Current address: División Académica de Ciencias Básicas, Universidad
¶
‡
Juárez Autónoma de Tabasco, 86690 Cunduacán, Tabasco, Mexico.
§
Current address: Sintenovo, Mexico.
Current address: Laboratorios Lesvi, Avda. Barcelona, 69 08970 Sant Joan
(2) Kirby, E. C.; Reid, D. H. J. Chem. Soc. 1961, 3579.
(3) Goldmann, S. Bechem, M. Ger. Offen. DE 4222770 A1, 1994. Neither
details nor references regarding preparation, properties, and use of 3l, are
explicitly given.
⊥
Despí, Barcelona, Spain.
|
Current address: Department of Chemistry, Oxford University, UK.
1
0.1021/jo702731b CCC: $40.75  2008 American Chemical Society
J. Org. Chem. 2008, 73, 3745–3753 3745
Published on Web 04/23/2008

Martínez-Bescos et al.
SCHEME 1. First Reported Use of ꢀ-(Hetero)aryl-r-
nitro-r,ꢀ-enals (3) in Synthesis: Total Synthesis of
rac-7-Deoxy-2-epi-Pancratistatin Tetraacetate (rac-6b)
a
a
See refs 9 and 12.
isopropyl-3,8-dimethylazulene) with nitromalondialdehyde in the
Our interest in R-nitroenals 3 originated from the need to
efficiently prepare aminocyclitol units. In particular, we judged
3 potential annulation partners of protected dihydroxyacetone
4 for the one-step formation of nitrocyclitols 5, on their way to
the antitumoral natural product pancratistatin (6a) and their
2
presence of perchloric acid.
4
Looking for general, safer (N2O4, HClO4, and nitromalon-
5
dialdehyde free), more selective, and higher yielding syntheses
of enals 3, we judged 3-(hetero)aryl-2-nitroprop-2-en-1-ols
11
2
to be suitable precursors (see structures above). The
analogues (Scheme 1). The implementation of this annulation,
and its successful application to a short, one-batch, 0.8 g scale
synthesis of rac-7-deoxy-2-epi-pancratistatin tetraacetate (rac-
6b) clearly established, for the first time, that ꢀ-(hetero)aryl-
R-nitro-R,ꢀ-enals 3 are useful building blocks in organic
hydroxyl group in 2, being allylic, should be easily oxidized
under mild conditions, thus minimizing chances for side
reactions and presumably facilitating the isolation of the
resulting nitroenals 3.
12
Unexpectedly, we also found compounds 2 to be rare, with
only two examples described in the literature: 2a (Ar ) 2-furyl)
synthesis. Further study of the properties and the value of this
type of compounds by the scientific community requires them
to be readily available. We herein satisfy such a requisite by
disclosing procedures for the gram-scale preparation of 3 from
commercially available (hetero)aromatic aldehydes. These pro-
cedures additionally supply the rare and interesting 2-nitroprop-
2-en-1-ols 2. We also report on the particular structural
characteristics of 2 and 3, as deduced from NMR, X-ray, and
UV data and supported by theoretical calculations, as well as
on the stability and E/Z interconversion of nitroenals 3.
6
7a
in an article in 1958, and 2m (Ar ) Ph) in a patent in 1982
see structure above). Compound 2a was obtained as a byproduct
when 2-(1-methoxy-2-nitroethyl)furan (8), contaminated with
-(2-nitrovinyl)furan (9), was heated with 33% HCHO-MeOH.
This result was suggestive of the preparation of intermediates
by hydroxymethylation of nitrovinylarenes, e.g., 2a from 9,
(
2
2
through a Morita-Baylis-Hillman (MBH) reaction. However,
in spite of the fact that the MBH reaction had been widely
8
studied we found no single report of its application to
nitrovinylarenes. After we had prepared compounds 2 (and
nitroenals 3 there from) by condensation of aldehydes with
nitroethanol (vide infra) and while proceeding to patent-
Results and Discussion
Synthesis of ꢀ-(Hetero)aryl-r-nitro-r,ꢀ-enals (3). Having
selected 2-nitropropenols 2 as precursors of nitroenals 3, we
decided to explore, in light of the literature precedents depicted
above, the preparation of 2 by condensation of 2-nitroethanol
with commercially available (hetero)aromatic aldehydes. We
first looked for conditions where the addition of 2-nitroethanol
to the aldehyde could concurrently take place with the dehydra-
tion of the diol so formed, to directly render the desired
9
protection, it was demonstrated that the synthesis of 2 by
R-hydroxymethylation of conjugated nitroalkenes via the
1
0
Morita-Baylis-Hillman reaction was indeed feasible.
7
b
(
4) Nitrogen tetroxide (or dinitrogen tetroxide, N
and corrosive oxidizer: http://encyclopedia.airliquide.com/sds/en/090_AL_EN.pdf.
5) (a) Nitromalonaldehyde itself is unstable; its sodium salt, widely used as
2 4
O ) is a powerful, highly toxic,
(
a synthetic equivalent, is, in crude form, impact-sensitive and thermally unstable,
and should be handled as a potentially explosive material: Fanta, P. E.; Stein,
R. A. Chem. ReV. 1960, 60, 261. (b) For a new synthetic equivalent of
nitromalonaldehyde, see: Nishiwaki, N.; Ogihara, T.; Takami, T.; Tamura, M.;
Ariga, M. J. Org. Chem. 2004, 69, 8382.
2
-nitropropenols 2. In our hands, use of aluminiumphosphate
13
oxynitrides (ALPON) did not induce any transformation of
5
-methoxypiperonal when heated with 2-nitroethanol (1equiv)
(
6) Saikachi, H.; Hoshida, H. Yakugaku Zasshi 1958, 78, 917–20; CAN 52:
1
13630, AN 1958:113630.
(11) Pancratistatins comprise a family of antitumoral natural products; for
(
7) (a) Eian, G. L.; Trend, J. E. EP Patent 46083, 1982. (b) In ref 7a,
the most recent reviews, see: (a) Chapleur, Y.; Chretien, F.; Ahmed, S. I.; Khaldi,
M. Curr. Org. Synth. 2006, 3, 341. (b) Rinner, U.; Hudlicky, T. Synlett 2005,
365. See also: (c) Wilson, R. M.; Danishefsky, S. J. Chem. Soc. ReV. 2007, 36,
1207. For the pharmacological potential and biological mode of action of
pancratistatins, see: (d) Pandey, S.; Kekre, N.; Naderi, J.; McNulty, J. Artif.
Cells Blood Substit. Immobil. Biotechnol. 2005, 33, 279. (e) McLachlan, A.;
Kekre, N.; McNulty, J.; Pandey, S. Apoptosis 2005, 10, 619. (f) Kekre, N.; Griffin,
C.; McNulty, J.; Pandey, S. Cancer Chemother. Pharmacol. 2005, 56, 29.
(12) Ortiz, J. C.; Ozores, L.; Cagide-Fagin, F.; Alonso, R. Chem. Commun.
2006, 4239.
nitrocinnamylalcohol (2-nitro-3-phenylprop-2-en-1-ol, 2m) was prepared from
benzaldehyde and 2-nitroethanol; neither isomer configuration nor yields are given
for 2m.
(
8) For reviews, see: (a) Basavaiah, D. Rao, A. J. Satyanarayana, T. Chem.
ReV. 2003, 103, 811. (b) Ciganek, E. In Organic Reactions; Paquette, L. A.,
Ed.; John Wiley & Sons: New York, 1997; Vol. 51, p 201.
(
9) Alonso Alonso, R.; Ozores Viturro, L.; Cagide Fagin, F.; Ortiz Lara,
J. C. ES 2245603 A1; priority date June, 25th, 2004; WO 2006003227.
10) (a) Rastogi, N.; Namboothiri, I. N. N.; Cojocaru, M. Tetrahedron Lett.
004, 45, 4745. (b) Mohan, R.; Rastogi, N.; Namboothiri, I. N. N.; Mobin, S. M.;
Panda, D. Bioorg. Med. Chem. 2006, 14, 8073.
(
2
(13) Climent, M. J.; Corma, A.; Guil-Lopez, R.; Iborra, S.; Primo, J. Catal.
Lett. 1999, 59, 33.
3
746 J. Org. Chem. Vol. 73, No. 10, 2008

Sunthesis of ꢀ-(Hetero)aryl-R-nitro-R,ꢀ-enals
TABLE 1. Two-Step Synthesis of ꢀ-(Hetero)aryl-r-nitro-r,ꢀ-enals (3) from (Hetero)aromatic Aldehydes (1) through 2-Nitroprop-2-en-1-ol
a
Intermediates 2
a
b
c
d
e
For detailed procedures, see the Experimental Section. Amount of 1 in grams. Reaction time in h. I Isolated yields. Chemical displacement for
f
g
h
proton H in ppm. Multiplicity. H-H′ coupling constant in Hz. Hidden by the signals of major E-3d. The yield was essentially quantitative; minor
amounts of the starting aldehyde 1 and/or some derivatives of the oxidation reagents were sometimes detected. Method C did not work because of the
insolubility of 1f in the reaction mixture. Z-2g was also obtained (11%).
j
k
in toluene at 75 °C for 12 h. Higher temperatures caused
decomposition. Alternatively, heating 0.5 g of furfural (1a) with
2b and 2c in 91% and 63% yields, respectively (entries 2 and
3). It was less effective for thiophen-2-carbaldehyde (1d) (19%,
entry 4) and ineffective for the substituted benzaldehydes 1e-h.
For these, method A was followed. Better overall yields were
obtained when the reactions were worked up before complete
conversion of the starting aldehydes, which were then separated
from the desired 2-nitropropenols 2e-h by chromatography
(15–43% yields for 2e-h, 40–84% when recovered aldehyde
is taken into account, gram scale, entries 5–8). Attempts to
increase yields by extending reaction times led to decomposition
of 2 with formation of a black gum. Addition of free-radical
inhibitors (2,6-di-tert-butyl-4-methylphenol, TEMPO and ben-
zoquinone) to the reaction mixture had no significant beneficial
effect. Although method A allowed us to prepare gram quantities
of 2e-h, we finally found that the addition of an aqueous
solution of NaOH (10.5 M) to a cooled solution of the starting
aldehyde and 2-nitroethanol in methanol, followed by treatment
3
equiv each of 2-nitroethanol and AcONH4, in acetic acid (1.25
M in 1a) at 75 °C, gave 2a in 55% yield after chromatography
(
Table 1, entry 1, method A).
A stepwise process, where the Henry reaction was first
performed by adding furfural to a solution of 2-nitroethanol in
0% aqueous potassium hydroxide at –15 °C and the dehydra-
2
tion was subsequently carried out with 18% hydrochloric acid,
gave improved results (94% of 2a, 5–10 g scale, no chroma-
1
4
tography, Table 1, entry 1, method B).
Method B was also suitable for the condensation of 2-nitro-
ethanol with furan-3-carbaldehyde (1b) and benzo[b]furan-2-
carbaldehyde (1c), to yield the corresponding 2-nitropropenols
(
14) For details, see the Experimental Section and/or the Supporting
Information.
J. Org. Chem. Vol. 73, No. 10, 2008 3747

Martínez-Bescos et al.
a
b
a,
c
SCHEME 2. Selected NOEs (CDCl
3
, 400 MHz) for E-2g
TABLE 2. Crystallographic Structures for 2a, 2d, 3d, and
d
Z-10
with 25% aqueous HCl (method C), was more efficient and
experimentally more convenient (Table 1).
With 2-nitropropenols 2 in hand, we next studied their
conversion into nitroenals 3. Attempted oxidation of the allylic
hydroxyl group in 2a with MnO2 did not take place [2a was
unaltered on treatment with activated MnO2 (6 equiv, Fluka
6
3548) in refluxing CH2Cl2 for 2 h]. Although the reaction
proceeded with Cr(VI) oxidants, we isolated 3a in low yields
e.g., 18% with PCC (4 equiv), 0.1 g scale, 0.06 M in CH2Cl2,
[
Sieves 3 Å (0.5 g), 1 h at rt]. Better results were obtained with
t-
either Dess-Martin periodinane [DMP (1 equiv), BuOH (1
equiv), 1.7 g scale, 0.1 M in CH3CN, 1 h at rt] or with
2
-iodoxybenzoic acid [IBX (1 equiv), 1.38 g scale, 6–10 h,
1
5
refluxing suspension in AcOEt], which gave nitroenal 3a as
a yellow solid in 78% and 82% yield, respectively, after
chromatography (Table 1, entry 1). Oxidation of 2b-h pro-
ceeded as for 2a to give the desired nitroenals 3b-h in good
yields (Table 1, entries 2–8).
Stability and Characterization of 2-Nitropropenols 2.
2-Nitroprop-2-en-1-ols (ArCHC(NO2)CH2OH, 2) were obtained
as single geometric isomers in the form of yellow or orange
stable solids. The configuration of the double bond proved to
be E, as deduced from NOE studies on 2g, which showed
enhancements of the methylene signal (δ 4.74) on saturation
of the aromatic protons at δ 7.17 and 7.22, and vice versa
a
b
c
1
6
This work, see refs 14 and 17. See also ref 18. E-3d:Z-3d ) 8:2
(
Scheme 2).
d e
in the crystal. From ref 17b. See ref 19.
Similarly, the X-rays of 2a and 2d (yellow crystals from
17,18
EtOAc)
showed a trans-arrangement of the nitro group with
the furyl- and the thienyl-ring, respectively (Table 2, entries 1
and 2). They also showed the entire π system to be almost
planar with CdCsNsO dihedral absolute values of about 4°
and 10° for 2a and 2d, respectively. The nitro group is a bit
twisted with one of its oxygen atoms tilted toward the hydroxyl
group. For 2d, the -N(O)O· · ·HO distance of about 2.86 Å
suggests an intramolecular stabilizing interaction between the
nitro and the hydroxyl groups in the crystal.
DFT [B3LYP/6-31G(d), gas phase] calculations also showed
the E-isomers of 2a and 2d (E-2a and E-2d) to be more stable
than their corresponding Z-isomers (Z-2a and Z-2d), by at least
1
9
(
15) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. (b) Tojo,
G.; Fernández, M. In Basic Reactions in Organic Synthesis, Oxidation of Alcohols
to Aldehydes and Ketones; Springer: New York, 2006; Chapter 3. (c) Caution!
IBX and DMP are explosive under impact or heating >200 °C: Plumb, J. B.;
Harper, D. J. Chem. Eng. News 1990, 68 (29), 3; see also comments in ref 15b,
pp 203 and 183, respectively, and references cited therein.
20
(
16) For the particular case of 2g, minor quantities of the Z-isomer were
obtained when following protocol C. Z-2g showed enhancement of the methylene
signal (δ 4.81) on saturation of H3 at δ 8.27:
2
.5 and 1.9 kcal/mol, respectively (Table 3). For E-2a, the s3–4-
cis conformer is predicted to be more stable than the s3–4-trans
by 1.1 kcal/mol. This is in line with the X-ray of E-2a (Table
2
, entry 1), where only the s3–4-cis conformer is found. E-2d
follows a similar trend: the s3–4-cis conformer found in the
crystal (Table 2, entry 2) is also more stable than the s3–4-trans
in the gas phase, in this case by just 0.3 kcal/mol (Table 3).
Stability and Characterization of ꢀ-(Hetero)aryl-r-nitro-
r,ꢀ-enals 3. Nitroenals 3 were obtained as colored (yellow to
orange or red) solids of varied stability. Furylnitroenals 3a and 3b
showed the highest stability: they could be chromatographed on
silica gel and stored with no appreciable decomposition for at least
one month at room temperature and for more than six months at
(
17) (a) Crystallographic data for 2a [EtOAc, C
7 7 4
H NO , M ) 169.14,
orthorhombic, a ) 4.2404(10) Å, b ) 22.1197(6) Å, c ) 7.9235(2) Å, V )
3
7
7 7 1 3 1
31.38 (3) Å , T ) 100 (2) K, space group Cc, Z ) 4], 2d [EtOAc, C H N O S ,
M ) 185.2, monoclinic, a ) 11.4493(1) Å, b ) 5.0645(1) Å, c ) 13.6414(1)
3
Å, V ) 760.419 (17) Å , T ) 100 (2) K, space group P21/n, Z ) 4], and 3d
[C H N O S , M ) 183.2, monoclinic, a ) 8.4333(3) Å, b ) 5.3908(2) Å, c )
7 5 1 3 1
3
1
6.6554(6) Å, V ) 7736.10 (5) Å , T ) 100 (2) K, space group P21/n, Z ) 4],
have been deposited with the Cambridge Crystallographic Data Centre as CCDC
41192, 641193, and 641194, respectively, and can be obtained free of charge
6
at www.ccdc.cam.ac.uk/data_request/cif. (b) Panfilova, L. V.; Antipin, M. Y.;
(19) Crystallographic structures in Table 2 were prepared by using ORTEP-3
for Windows (Farrugia, L. J. J. Appl. Crystallogr. 1997, 30, 565. ) and Mercury
1.4.2.
Churkin, Y. D.; Struchkov, Y. T. Khim. Geterotsikl. Soedin. 1979, 9, 1201.
(
2 2
18) For crystallographic data of 2d [CH Cl -petroleum ether ) 1–3, T )
2
93(2) K], see also ref 10b.
(20) See computational details in the Experimental Section.
3
748 J. Org. Chem. Vol. 73, No. 10, 2008

Sunthesis of ꢀ-(Hetero)aryl-R-nitro-R,ꢀ-enals
TABLE 3. B3LYP/6-31G(d) Relative Gibbs Free Energies (E,
kcal/mol) and Dipole Moments (µ, Debyes) for
TABLE 4. B3LYP/6-31G(d) Relative Gibbs Free Energies (E,
a
kcal/mol) and Dipole Moments (µ, Debyes) for Nitroenals 3a and
a, b,c
b
Hetero(aryl)nitroprop-2-en-1-ols E-2a, Z-2a, E-2d, and Z-2d
3d and Enal 7a
a
For details, see the Experimental Section and the Supporting Infor-
b
mation. A total of four conformers were found in every case (E-3a, E-3d,
Z-3a, Z-3d, and E-7a) around C1-C2 (s1,2-cis-enal and s1,2-trans-enal
conformers) and C3-C4 (s3,4-trans and s3,4-cis conformers) bonds.
a
For details, see the Experimental Section and the Supporting Infor-
b
mation. For every s3,4-conformer (s3,4-trans and s3,4-cis) of 2-nitro-
were both considerably more stable than their corresponding
s1–2-trans-enal analogues (Table 4). The s1–2-cis-enal conformers
were also more stable for Z-3a and for both geometric isomers
of 3d, E-3d, and Z-3d as well (Table 4).
propenols E-2a, Z-2a, E-2d, and Z-2d, only the most stable conformer
around O-C1 and C1-C2 bonds is represented (GaussView). For a more
complete set of conformers, see the Supporting Information.
c
–
20 °C. A quick silica gel chromatography was also feasible for
the purification of 3c and 3d. However, ꢀ-aryl R-nitro-R,ꢀ-enals
e-h decomposed on attempted chromatography. Accordingly,
Additionally, an X-ray study showed that in fact 3d exists in
the solid state as the s1–2-cis-enal conformer for both geometric
isomers E-3d and Z-3d (Table 2, entries 3 and 4). The X-ray
also showed that their whole molecular structures in the crystal
are essentially planar with CCNO dihedral absolute values of
6° and 8° for the E- and the Z-isomers, respectively. This also
looks to be the case in solution, at least in chloroform, where
the UV spectra of a 3d sample (E/Z ) 81/19) showed its long-
3
they were isolated from the reaction mixture of 2e-h with IBX
by cooling in the appropriate media, filtration, and solvent
evaporation; in some cases they were additionally purified by
14
precipitation.
Nitroenals 3 were isolated as E-Z mixtures, as clearly seen in
1
-1
their H NMR spectra that showed a characteristic set of signals
wave absorption band, λmax, at 388 nm (ελ ) 13797 cm
max
-
1
for every geometric isomer. In particular, proton H3 appeared as
a doublet at δ 8.3–8.7 coupled with H1 with JH3-H1 ≈ 1.5–2.6 Hz
for one isomer, and as a singlet at δ 7.2–8.5 for the other isomer
mol , Table 5, entry 1). Its good agreement with the value
(380 nm) calculated by adding the tabulated bathochromic shift
2
2
for a formyl group (30 nm) to the experimental λmax of (E)-
2
3
(Table 1, columns 5 and 6, respectively). The coupled lower field
2-(2-nitrovinyl)thiophene (11, 350 nm, entry 6) looks to
appropriately reflect additive effects of the nitro and the formyl
groups, i.e., a planar arrangement of both groups with the
2-vinylthiophene unit in 3d.
signals of H3 were attributed to the s1–2-cis-enal conformers of
21
nitroenals E-3 (represented at the top of Table 1), where H3 would
be deshielded by the vicinal cis-disposed nitro group and its
resonance split by H1 because of the relative spatial W-arrangement
of both protons. On the other hand, the singlets observed for H3
at higher fields were expected for, and consequently attributed to,
the s1–2-cis-enal conformers of Z-3.
The UV of nitroenal 3a (E/Z ) 95:5) was similar to that of
the thienyl analogue 3d. Its long-wave absorption band λmax at
-
1
-1
384 nm (ελmax ) 20623 cm mol , CHCl3, Table 5, entry 2)
again matched the expected values for a fully planar conjugated
system: 378 or 376 nm, calculated by adding the tabulated
bathochromic shifts for a formyl (30 nm) or a nitro group (60
nm) to the experimental λmax values for either the (E)-2-(2-
Further support for this assignation came from B3LYP/6-
3
1G(d) studies, which showed that the two C3-C4 conformers
(
the s3–4-trans and the s3–4-cis) found for the s1–2-cis-enal E-3a
(
21) Through this work, the C1-C2 conformers of nitroenals 3 having the
C1dO and the C2dC3 bonds cis- and trans-disposed are preferably termed
1,2-cis-enals and s1,2-trans-enals, respectively, even when the substituents of
(22) Pretsch, E.; Bühlmann, P.; Affolter, C.; Herrera A.; Martínez, R.
Structure Determination of Organic Compounds; Springer: New York, 2002; p
385.
s
higher priority (the O atom of the carbonyl group at C1, and the nitro group at
C2) are s1,2-trans-disposed in the first case and s1,2-cis-disposed in the second
one.
(23) Berestovitskaya, V. M.; Aboskalova, N. I.; Ishmaeva, E. A.; Bakhareva,
S. V.; Berkova, G. A.; Vereshchagina, Ya. A.; Fel’gendler, A. V.; Fattakhova,
G. R. Russ. J. Gen. Chem. 2001, 71, 1942.
J. Org. Chem. Vol. 73, No. 10, 2008 3749

Martínez-Bescos et al.
a
a
b
c
c
TABLE 5. Experimental UV Data for 3d, 3a, 7a, 9, Z-10, and
c
1
1
FIGURE 1. Thermal E-Z isomerization of nitroenal 3a in DMF-d
7
at
0
°C.
E-Z interconversion of E- and Z-Enriched 3-(Furan-2-
yl)-2-nitroacrylaldehyde (3a). The formation of nitroenals 3
as E/Z mixtures (E/Z ≈ 6/1 to 1/1) by oxidation of pure
E-isomers of their hydroxymethyl precursors 2 with IBX in
refluxing ethyl acetate revealed that the double bond was
undergoing isomerization under the reaction conditions. Due
to the important role that the double bond geometry of nitroenals
3
could play in the outcome of their reactions (e.g., on their
1
2
reported annulation with dioxanone 4, or on their potential
behavior as dienophiles, Michael acceptors, etc), we decided
to examine the isomerization process in more detail. For our
studies, we chose the particularly stable nitroenal 3a. Starting
from a small sample of 3a enriched in the chromatographically
slightly faster E-isomer (E/Z ) 95/5, silica gel, EtOAc/Hex )
1/4), we studied the variation of its E/Z composition with time
a
b
c
d
e
This work. Reference 24. Reference 23. λmax in nm. ꢀλmax in
cm- mol
1
-1
.
1
in different solvents. H NMR showed that E-Z isomerization
nitrovinyl)furan (9, λmax ) 348 nm) or the (E)-3-(furan-2-
was not taking place in CDCl3 (ε ) 4.70) at 0 °C, and that it
was very slow, at higher temperatures reaching E/Z values of
93/7, 91/8, and 89/11 after successive hours at 25, 40, and 55
°C, respectively.
2
4
yl)acrylaldehyde (7a, λmax ) 316 nm, CH2Cl2), respectively.
The X-ray of Z-3d shows an antiparallel stacking of its
molecules along the direction normal to the [1,0,0] plane (Table
2
, entry 4), what probably reflects the high polarity of
E-Z isomerization of 3a was quicker in CH3CN (ε ) 6.02).
From the initial E/Z ) 95/5 mixture, ratios of 90/10 and 73/27
were observed after 1 h at 0 °C and a subsequent hour at 25
°C, respectively. The process was even quicker in DMF (ε )
36.7), where a similar isomer ratio (74/26) was reached after
only 5 min at 0 °C, and a constant 20/80 E/Z plateau was
reached after 150 min at the same temperature (Figure 1).
Light-promoted isomerization (300-W tungsten-filament lamp)
was more effective: 1 h of irradiation at 25 °C in CDCl3 was
sufficient to convert the initial 95/5 into a 58/42 E/Z ratio. Again,
isomerization was quicker in more polar CH3CN: irradiation
for 1 h at 25 °C changed the initial 95/5 into a 28/72 E/Z ratio
(the same change needed 4 h of irradiation in CDCl3 under the
same conditions). A second hour of irradiation in CH3CN at 25
°C led to 3a with the Z isomer already prevailing: E/Z ratio )
15/85; essentially no change was observed on further irradiation.
On the basis of the isomerization data, in particular in the
slow isomerization at low T in CDCl3, we could prepared
enriched samples of E-3a (E/Z ) 90:10) by oxidation of 2a
with DMP in either CHCl3 or CH2Cl2 as solvents at 0 °C or at
rt. Workup conditions were shown to be critical; while the use
of aqueous base, aqueous thiosulfate, and other reducing agents
compounds 3, where the planar π-system would be strongly
polarized by the combined action of two strong electron-
withdrawing substituents located at one end, and an electron-
rich heteroaromatic system at the other end. Calculated dipole
moments for nitroenals 3a and 3d (∼5.7 and 5.5 D, respectively,
Table 4), which are higher than that for simpler enals, e.g., 2-(2-
furyl)propenal (7a, 4.2–5.3 D), and nitroolefines, e.g. 2-(2-furyl)-
nitroethylene (9, 4.7 D), are in line with this expectation.
Notably, the preferred s1–2-cis-enal conformation and the fully
planar geometry shown by ꢀ-(hetero)aryl-R-nitro-R,ꢀ-enals 3,
as discussed above, do not directly apply to similar compounds,
even if structurally very similar. In particular, nitroenone Z-10
(
Table 5, entry 5), with just a methyl group instead of the
formyl-attached hydrogen of nitroenal 3d, is neither fully planar
nor has a s1–2-cis-enal but a s1–2-trans-enal preferred conforma-
tion. Actually, λmax for nitroenone Z-10 appears at only 325
2
3
nm (CH3CN). This wavelength value, even lower than that for
(
E)-2-(2-nitrovinyl)thiophene (11, Table 5, entry 6, λmax ) 350
nm), is reasonable for a conformation where the nitro group is
not coplanar with the thiophenylbutenone-conjugated system.
This is in fact the case in the solid state, as shown in the X-ray
of Z-10, where the nitro group is nearly perpendicular (93.3°)
to the 3-thienylpropenal planar conjugated system (Table 2, entry
1
5
produced appreciable E-Z isomerization, a quick filtration
of the reaction mixture through a thin layer of KHCO3 packed
between two layers of silica gel in a column reproducibly
afforded 3a with a E/Z ratio of 90:10 at the 1.2 g scale.
Taking advantage of the quick photopromoted E-Z isomer-
ization in acetonitrile, we were also able to prepare enriched
1
7b
5
). The substitution of the formyl hydrogen atom in 3d by a
methyl group, as in Z-10, also makes the s1–2 conformation
change: while the CdC and the CdO groups in R-nitroenal 3d
are cis-disposed, they prefer to be trans in R-nitroenone Z-10.
3
750 J. Org. Chem. Vol. 73, No. 10, 2008

Sunthesis of ꢀ-(Hetero)aryl-R-nitro-R,ꢀ-enals
Z-3a at the 120 mg scale (E/Z ratio ) 35/65) by direct irradiation
of 3a in CH3CN with a tungsten lamp for 4 h, followed by
solvent evaporation and flash chromatography. Similar results
(E)-3-(Furan-2-yl)-2-nitroprop-2-en-1-ol (2a, Table 1, entry
26,27
1
(
8
).
Obtained by methods A [0.5 g, 55% after chromatography
20% EtOAc/hexane)] and B (10.75 g, 94%) as a yellow solid (mp
3 °C).
E)-3-(Furan-3-yl)-2-nitroprop-2-en-1-ol (2b, Table 1, entry
(
E/Z ratio ) 32/68) where obtained by heating the nitroenal in
(
).
acetone for 5 h at 55 °C, and then evaporation of solvent at
low temperature.
26,27
2
(
7
Obtained by methods A [0.09 g, 26% after chromatography
40% EtOAc/hexane)] and B (1.81 g, 91%) as a yellow solid (mp
4 °C).
E)-3-(Benzofuran-2-yl)-2-nitroprop-2-en-1-ol (2c, Table 1,
In summary, hitherto largely overlooked conjugated 2-nitro-
prop-2-en-1-ols 2 and ꢀ-(hetero)aryl-R-nitro-R,ꢀ-enals 3 can
now be prepared at the gram scale from (hetero)arylaldehydes
(
26
entry 3). Obtained by method B[0.16 g, 63% after chromatog-
raphy (30% EtOAc/hexane)] as a yellow solid (mp ) 98 °C).
(E)-2-Nitro-3-(thiophen-2-yl)prop-2-en-1-ol (2d, Table 1, en-
2
5
through safe procedures. Condensation of (hetero)arylalde-
2
6,27
hydes with nitroethanol under different conditions renders 2 in
try 4).
Obtained by method B [0.12 g, 14% after chromatog-
1
6
raphy (10% EtOAc/hexane)] as a yellow solid (mp 97 °C).
the form of their E-isomers. Oxidation of E-2 with IBX then
easily gives 2-nitroenals 3. Nitroenals 3 were demonstrated to
undergo easy isomerization, which was quicker in more polar
solvents and when light-promoted. Study of this E-Z isomer-
ization allowed the conditions to preferentially obtain nitroenal
(
E)-3-(Benzo[d][1,3]dioxol-5-yl)-2-nitroprop-2-en-1-ol (2e, Table
2
6,27
1
, entry 5).
Obtained by methods A [0.71 g, 43% after
chromatography (25% EtOAc/hexane)] and C (0.77 g, 52%) as an
orange solid [mp (Et O/hexane) 89–93 °C].
E)-3-(4-Methoxybenzo[d][1,3]dioxol-6-yl)-2-nitroprop-2-en-
2
(
2
6
3
a enriched in either the Z or the E isomer to be determined.
1-ol (2f, Table 1, entry 6). Obtained by method A [0.88 g,
18% after chromatography (two columns, eluted with CH Cl
and 20% EtOAc/hexane, respectively)] as a yellow solid [mp
Et O) 101–103 °C].
E)-3-(3,4-Dimethoxyphenyl)-2-nitroprop-2-en-1-ol (2g, Table
The strong absorptions at high wavelengths that nitroenals 3
display in solution are compatible with them being colored and
with a planar fully conjugated structure. This feature is indeed
revealed in the solid state, where not only the formyl, but also
the nitro group is virtually coplanar with the (hetero)aryl-vinyl
group. Importantly, the enal in 3 has an s1,2-cis disposition, both
in solution and in the crystal. These particular features of 3 are
expected to manifest themselves in the form of new properties
and reactivity that can now be studied with the help of the
synthetic methodology reported here. Work in this direction is
being carried out in our laboratory; new results will be reported
in due course.
2
2
(
2
(
26,27
1
, entry 7).
Obtained by methods A [2.19 g, 23% after
chromatography (20% EtOAc/hexane)] and C (0.832 g, 52%) as
an yellow solid, [mp (Et O/hexane) 90–93 °C].
2
(E)-3-(4-Bromophenyl)-2-nitroprop-2-en-1-ol (2h, Table 1,
2
6
entry 8). Obtained by methods A [0.064 g, 15% after chroma-
tography (20% EtOAc/hexane)] and C (0.58 g, 34%) as a pale
yellow solid [mp (Et
E/Z)-ꢀ-(Hetero)aryl-r-nitro-r,ꢀ-enals (3). General procedure
for the oxidation of E-3-(hetero)aryl-2-nitroprop-2-en-1-ols (2).
2
O) 73–75 °C].
(
2
5
2
-Iodoxybenzoic acid (IBX) (2 mmol) was added to a solution
of the corresponding 2-nitropropenol 2 (1 mmol) in EtOAc (6 mL).
The suspension was refluxed for 6–8 h, then allowed to cool to
2
8
rt. EtOAc was then removed in the rotavapor with no heating,
using a water bath at rt (the magnetic stirring bar kept in the mixture
helped to prevent bumping during this operation). The residue was
Experimental Section
E-3-(Hetero)aryl-2-nitroprop-2-en-1-ols (2). General Methods
magnetically stirred with Et
bath (-78 °C; around 20 mL of Et
reaction scale; use of Et O stabilized with 2,6-di-tert-butyl-4-
methylphenol (BTH) proved to be adequate; use of Et O stabilized
2
O while cooling with a dry ice-acetone
(
A, B, and C) for the Condensation of (Hetero)aromatic
Aldehydes with 2-Nitroethanol: Method A: A solution of the
aldehyde (1 mmol), 2-nitroethanol (97%, 3 mmol), and NH AcO
3 mmol) in AcOH (6.5 mL) was heated at 75 °C for the specified
time (0–15 h). The reaction mixture was diluted with water (65
mL) and the product was extracted with Et
2
O were used for a 200 mg
2
4
2
(
with ethanol led sometimes to nitroenal decomposition). Once the
entire solid was liberated from the walls of the flask (sometimes
with the help of a spatula) and was freely floating, the suspension
was filtered through a sintered glass funnel (porosity grade 5). The
2
O (3 × 10 mL). Method
B: 2-Nitroethanol (97%, 5 mL, 67.6 mmol, 0.83 equiv) was added
dropwise to 20% aqueous KOH (35 mL) at –16 °C. After 20 min,
the aldehyde (81.24 mmol) was added dropwise and the reaction
mixture was allowed to reach 0 °C and stirred for 9 h. The reaction
mixture was then transferred to an extraction funnel previously
charged with a mixture of crushed ice (82 g) and 37% aqueous
HCl (82 mL, previously cooled to –20 °C) and extracted with cold
solid was washed with additional cold (-78 °C) Et O. Nitroenals
2
3 were obtained as solids after solvent rotaevaporation with no
heating, using a water bath at rt. Further purification was carried
out either by crystallization-precipitation with appropriate solvents
2 2
(usually Et O or Et O followed by the addition of n-hexane or
n-pentane) or by flash chromatography, as indicated. Complete
characterization details for nitroenals 3a-e are given below; when
(
-20 °C) Et
2
O (6 × 100 mL). Method C: Aqueous NaOH (0.7
1
the H NMR data obtained for the E-Z mixture are separately
mL, 10.5 M) was added to a solution of the aldehyde (6.7 mmol)
and 2-nitroethanol (9.25 mmol, 1.38 equiv) in MeOH (1.7 mL) at
assigned to E-3 and to Z-3, integral values are normalized to one
proton (1 H) for every geometric isomer.
0
°C. After 10 h at 0 °C and 4 h at rt, 25% aqueous HCl (13 mL)
2
6,29
3-(Furan-2-yl)-2-nitroacrylaldehyde (3a, Table 1, entry 1).
was added. After 20 min, the reaction was extracted with CH Cl .
2
2
3
a was prepared according to the general procedure from 2a (1.3
In every method (A, B, and C), the organic extracts were
collected and dried (anhydrous Na SO ) and the solvents rotae-
vaporated. Flash chromatography (method A), washing or precipita-
tion of the residue (hexane, Et O, or Et O/hexane), followed by
g, 7.87 mmol) and IBX (4.4 g, 15.7 mmol) in EtOAc (40 mL) and
purified by flash chromatography (20% EtOAc/hexane): 1.08 g,
2
4
-1
82%, yellow solid, mp 86 °C. IR (KBr) cm 3138, 3000, 1686,
1
3
1572, 1502, 1456, 1313, 784. H NMR (CDCl , 300 MHz, E-3a/
2
2
filtration or percolation through silica gel (20–25% EtOAc/hexane,
methods B and C) afforded 2-nitropropenols E-2.
(25) Preparation of 3 involves final oxidation with IBX. While caution should
always be exercised when dealing with this reagent, we have routinely prepared
and used it in batches of as much as 25 g without a single incident. See ref 15.
(
26) For spectra and/or complete characterization data see the Supporting
Information.
(27) See also ref 10b.
(
24) Lasseuguette, E.; Gandini, A.; Timpe, H.-J. J. Photochem. Photobiol.,
A 2005, 174, 222.
J. Org. Chem. Vol. 73, No. 10, 2008 3751

Martínez-Bescos et al.
Z-3a ) 2/1) E-3a δ 10.40 (d, J ) 2.6 Hz, 1H), 8.47 (d, J ) 3.8
Hz, 1H), 8.37 (d, J ) 2.6 Hz, 1H), 7.93 (d, J ) 1.7 Hz, 1H), 6.78
2.4 Hz, 1H), 8.33 (d, J ) 2.4 Hz, 1H), 7.93 (d, J ) 1.8 Hz, 1H),
7.55 (dd, J ) 8.2 Hz, J ) 1.8 Hz, 1H), 6.94 (d, J ) 8.2 Hz, 1H),
6.13 (s, 2H), Z-3e δ 9.50 (s, 1H), 7.23 (s, 1H), 7.16 (dd, J ) 8.2
(
dd, J ) 3.8 Hz, J ) 1.7 Hz, 1H), Z-3a δ 9.83 (s, 1H), 7.83 (d, J
)
)
1.7 Hz, 1H), 7.72 (d, J ) 3.8 Hz, 1H), 7.53 (s, 1H), 6.74 (dd, J
Hz, J ) 1.8 Hz, 1H), 7.06 (d, J ) 1.8 Hz, 1H), 6.90 (d, J ) 8.2
1
3
13
3.8 Hz, J ) 1.7 Hz, 1H); C NMR (CDCl
3
, 75 MHz, E-3a/Z-
Hz, 1H), 6.09 (s, 2H); C NMR (CDCl
3
, 75 MHz) δ 183.9, 181.6,
3
a ) 2/1) δ 183.4, 182.0, 152.0, 150.5, 147.3, 146.5, 140.2, 139.2,
154.0, 152.7, 148.9, 148.4, 145.8, 145.1, 142.4, 139.0, 133.6, 130.0,
123.6, 122.7, 111.9, 109.1, 109.0, 108.9, 102.6, 102.4. LRMS (CI )
m/z (%) 222 [100, (M + H) ]. HRMS (CI ) calcd. for C10
(M + H) , 222.0402, found 222.0399).
+
+
1
29.8, 128.2, 126.0, 125.2, 115.3, 114.8. LRMS (CI ) m/z (%) 167
+
+
+
[
100, (M + H) ]. Anal. Calcd for C
7
H
5
NO
4
: C, 50.31; H, 3.02; N,
H
7
NO
5
+
8
.38; O, 38.29. Found: C, 49.98; H, 2.95; N, 8.18; O, 38.89.
-(Furan-3-yl)-2-nitroacrylaldehyde (3b, Table 1, entry 2).
bwas prepared according to the general procedure from 2b (0.52
3
3-(4-Methoxybenzo[d][1,3]dioxol-6-yl)-2-nitroacrylaldehyde
(3f, Table 1, entry 6). 3f was prepared according to the general
procedure from 2f (0.87 g, 3.46 mmol) and IBX (1.94 g, 6.93 mmol)
in EtOAc (11 mL) at 80 °C for 10 h and isolated as a red solid
3
g, 3.05 mmol) and IBX (1.70 g, 6.1 mmol) in EtOAc (15.3 mL)
and purified by flash chromatography (20% EtOAc/hexane): 0.47 g,
9
1
6%, yellow solid, mp 53 °C. IR (KBr) 3440, 3142, 1694, 1642,
1
3
(0.80 g, 92%), mp 109–111 °C. H NMR (CDCl , 300 MHz, E-3f/
1
599, 1531, 1323, 1160, 868. H NMR (CDCl
3
, 400 MHz, E-3b/
Z-3f ≈ 1/1) E-3f δ 10.24 (d, J ) 2.4 Hz, 1H), 8.30 (d, J ) 2.4 Hz,
1H), 7.42 (d, J ) 1.6 Hz, 1H), 6.79 (d, J ) 1.6 Hz, 1H), 6.14 (s,
2H), 3.99 (s, 3H), Z-3f δ 9.49 (s, 1H), 7.59 (d, J ) 1.5 Hz, 1H),
7.20 (s, 1H), 6.81 (d, J ) 1.5 Hz, 1H), 6.10 (s, 2H), 3.92 (s, 3H).
Z-3b ) 1.8/1) E-3b δ 10.33 (d, J ) 2.4 Hz, 1H), 8.70 (m, 1H),
8
.31 (d, J ) 2.4 Hz, 1H), 7.59 (m, 1H), 7.09 (m, 1H), Z-3b δ 9.76
(
s, 1H), 8.21 (m, 1H), 7.56 (m, 1H), 7.50 (s, 1H), 6.77 (m, 1H);
1
3
13
C NMR (CDCl
3
, 100 MHz, E-3b/Z-3b ) 1.8/1) δ 184.2, 182.1,
C NMR (CDCl , 75 MHz) δ 183.9, 181.5, 149.8, 149.2, 145.8,
3
1
1
53.9, 152.2, 145.6, 145.0, 143.5, 142.2, 135.4, 130.7, 118.3, 118.0,
143.8, 143.5, 142.8, 142.1, 141.8, 140.6, 138.9, 123.6, 122.8, 115.9,
113.2, 108.0, 104.7, 103.0, 102.8, 56.71, 56.68. HRMS (ESI -TOF-
MS) calcd. for C H NO (M + H) 252.0508, found 252.0503.
+
+
+
12.9, 110.3. LRMS (CI ) m/z (%) 168 [96, (M + H) ]. Anal.
NO : C, 50.31; H, 3.02; N, 8.38; O, 38.29. Found:
C, 50.46; H, 3.25; N, 8.14; O, 38.15.
-(Benzofuran-2-yl)-2-nitroacrylaldehyde (3c, Table 1, entry
). 3c was prepared according to the general procedure from 2c
39.6 mg, 0.18 mmol) and IBX (0.10 g, 0.36 mmol) in EtOAc (0.9
mL) and purified by flash chromatography (20% EtOAc/hexane):
Calcd for C
7
H
5
4
+
1
1
10
6
3-(3,4-Dimethoxyphenyl)-2-nitroacrylaldehyde (3g, Table 1,
entry 7). 3g was prepared according to the general procedure from
2g (1.44 g, 6.02 mmol) and IBX (3.37 g, 12.04 mmol) and isolated
by precipitation with Et O or Et O/hexane: 1.39 g, 97%, orange
3
3
(
2
2
1
solid, [mp (Et O) 99–103 °C].
2
H NMR (CDCl , 300 MHz, E-3g/
3
3
1
7.2 mg, 95%, yellow solid, mp 92 °C dec. IR (KBr) 3040, 2926,
691, 1680, 1630, 1609, 1529, 1319, 1261, 1115, 755. H NMR
Z-3g ≈ 1/1) E-3g δ 10.28 (d, J ) 2.5 Hz, 1H), 8.38 (d, J ) 2.5
Hz, 1H), 8.15 (d, J ) 1.9 Hz, 1H), 7.64 (dd, J ) 1.9 Hz, J ) 8.5
Hz, 1H), 6.98 (d, J ) 8.5 Hz, 1H), 4.01 (s, 3H), 3.99 (s, 3H), Z-3g
δ 9.53 (s, 1H), 7.29 (s, 1H), 7.26 (dd, J ) 8.5 Hz, J ) 1.9 Hz,
1H), 7.11 (d, J ) 1.9 Hz, 1H), 6.94 (d, J ) 8.5 Hz, 1H), 3.97 (s,
1
(
CDCl
3
, 250 MHz, E-3c/Z-3c ≈ 1/1) δ 10.47 (d, J ) 1.5 Hz, 1H,
CHO E-3c), 9.69 (s, 1H, CHO Z-3c), 8.51 (s, 1H), 8.36 (d, J ) 1.5
Hz, 1H), 7.80–7.28 (m, 10H); C NMR (CDCl
1
1
1
1
3
3
, 62.5 MHz) δ
83.2, 181.4, 158.0, 157.2, 147.5, 146.7, 143.1, 141.9, 130.5, 130.3,
29.8, 128.0, 127.7, 125.1, 124.6, 124.4, 123.8, 123.2 (2C), 120.8,
3H), 3.88 (s, 3H). 13C NMR (CDCl , 75 MHz) δ 184.2, 181.7,
3
155.5, 154.1, 149.4, 148.9, 146.2, 142.2, 141.7, 139.4, 132.0, 128.0,
122.5, 121.4, 115.1, 112.3, 111.2, 110.9, 56.2, 56.1, 56.0, 55.9.
+
+
12.2, 112.1. LRMS (CI ) m/z (%) 218 [100, (M + H) ]. HRMS
+
+
+
+
+
(
ESI ) calcd for C11
Anal. Calcd for C11
Found: C, 59.62; H, 3.37; N, 6.06; O, 30.94.
-Nitro-3-(thiophen-2-yl)acrylaldehyde (3d, Table 1, entry
). 3d was prepared according to the general procedure from 2d
0.50 g, 2.70 mmol) and IBX (1.51 g, 5.39 mmol) in EtOAc (13.5
mL), purified by flash chromatography (20% EtOAc/hexane), and
crystallized from CHCl : 0.40 g, 80%, yellow crystalline solid, mp
H
8
NO
4
(M + H) 218.0448, found 218.0446.
LRMS (CI ) m/z (%) 238 [100, (M + H) ], 222 [14, (M - CH ) ],
3
+
+
+
H
7
NO
4
: C, 60.83; H, 3.25; N, 6.45; O, 29.47.
208 [34, (M - OH)
for C H N O (M + H)
], 191 [40, (M - NO )
]. HRMS (CI
) calcd
2
+
1
1
12
1
5
238.0715, found 238.0715.
2
3-(4-Bromophenyl)-2-nitroacrylaldehyde (3h, Table 1, entry
8). 3h was prepared according to the general procedure from 2h
(0.100 g, 0.39 mmol) and IBX (0.22 g, 0.75 mmol) and isolated
2
4
(
by precipitation with Et O/n-pentane: 0.088 g, 94%, pale yellow
1
3
2
3
solid, [mp (Et O/n-pentane) 61–62 °C]. H NMR (CDCl , 300 MHz,
1
1
13 °C. IR (KBr) 3437, 3084, 1680, 1564, 1410, 1296, 754. H
E-3h/Z-3h ) 1/2.3) E-3h δ 10.16 (d, J ) 2.2 Hz, 1H), 8.31 (d, J
) 2.2 Hz, 1H, H3), 7.83 (d, J ) 8.4 Hz, 2H), 7.64 (d, J ) 8.4 Hz,
2H), Z-3h δ 9.53 (s, 1H), 7.64 (d, J ) 8.5 Hz, 2H), 7.39 (d, J )
NMR (CDCl , 250 MHz, E-3d/Z-3d ) 6/1) E-3d δ 10.40 (d, J )
3
2
.5 Hz, 1H), 8.73 (d, J ) 2.5 Hz, 1H), 8.04 (dt, J ) 1 Hz, J ) 5
Hz, 1H), 8.00 (dd, J ) 1 Hz, J ) 4 Hz, 1H), 7.35 (dd, J ) 4 Hz,
J ) 5 Hz, 1H), Z-3d δ 10.07 (s, 1H), 8.09 (dt, J ) 1 Hz, J ) 5 Hz,
8.5 Hz, 2H), 7.30 (s, 1H, H3). 13C NMR (CDCl , 75 MHz) δ 183.2,
3
181.3, 146.9, 143.9, 137.5 134.4, 132.9, 132.4, 132.0, 131.6, 129.6,
2
7
1
1
1
H), 8.1–7.9 (1H, H3, hidden by protons of the major E isomer),
128.6, 127.7, 127.4. LRMS (EI) m/z (%) 256 [80, (M + H)
+
].
.91 (dd, J ) 1 Hz, J ) 4 Hz, 1H), 7.32 (dd, J ) 4 Hz, J ) 5 Hz,
HRMS (CI)
254.9478.
+
calcd for C H BrNO (M + H)
+
254.9475, found
9
6
3
13
H); C NMR (CDCl , 62.5 MHz, E-3d/Z-3d ) 6/1) E-3d δ 184.5,
3
45.8, 142.0, 138.9, 138.0, 133.4, 129.2, Z-3d δ 183.2, 144.9, 134.2,
Computational Details. All calculations were performed using
30
28.8, three C resonances, two of them quaternary, did not appear
the Gaussian 03 software package. Geometries and energies were
optimized at the B3LYP level and the 6–31G(d) basis set. Frequency
calculations, performed to confirm the nature of the stationary
points, showed no imaginary frequencies for every minima. All
geometries were optimized without constraints; all reported energies
are Gibbs free energies at 298 K and 1 atm.
in the spectrum due to the small proportion of the Z-isomer present
+
+
in the E-Z mixture. LRMS(CI ) m/z (%) 184 [M + H] . HRMS
+
+
+
(
ESI ) calcd for C
7
H
6
NO
3
S (M + H) 184.0063, found 184.0060.
S: C, 45.90; H, 2.75; N, 7.65; S, 17.50;
Anal. Calcd for C
7
H
7
NO
3
O, 26.20. Found: C, 45.9623; H, 2.7395; N, 7.6386; S, 17.4936;
O, 26.17.
3
-(Benzo[d][1,3]dioxol-5-yl)-2-nitroacrylaldehyde (3e, Table
, entry 5). 3e was prepared according to the general procedure
from 2e (0.27 g, 1.22 mmol) and IBX (0.69 g, 2.45 mmol), and
isolated by precipitation with Et O/hexane: 0.27 g, 99%, red solid,
mp (Et
O) 92–97 °C]. IR (film) νmax 3534, 2990, 1503 cm- . H
NMR (CDCl
, 300 MHz, E-3e/Z-3e ≈ 1/1) E-3e δ 10.24 (d, J )
Acknowledgment. This work was supported by the Spanish
Ministries of Science and Technology (Project BQU2002-
1176) and Education and Science (Project CTQ2005-02338)
in collaboration with ERDF, the Xunta de Galicia (through
Project PGIDIT05BTF20901PR). P. M-B., F. C.-F., J. C.O.,
K. K., L. O.-V., and M. F.-G. acknowledge support from the
Xunta de Galicia in the form of contracts. L.F.R. acknowledges
1
0
2
1
1
[
2
3
(
28) At this stage, a simplified workup protocol, which simply involved
addition of n-hexane (6.5 mL), cooling to 0° C, filtration, and solvent
rotaevaporation at rt, was alternatively used in a number of cases.
(29) See also ref 1.
3
752 J. Org. Chem. Vol. 73, No. 10, 2008

Sunthesis of ꢀ-(Hetero)aryl-R-nitro-R,ꢀ-enals
of 2a, 2d, 3a, and 3d, H NMR, 13C NMR, and DEPT spectra
for 2a-h and 3a-h, and CIF files for nitropropenols 2a and
2d and for nitroenal 3d. This material is available free of charge
via the Internet at http://pubs.acs.org.
1
the University of Santiago for a fellowship. We are also grateful
to the Supercomputing Centre of Galicia (CESGA) for comput-
ing facilities and computational time.
Supporting Information Available: E-Z isomerization
studies for 3a, selective preparation of E- and Z-enriched
nitroenal 3a, UV data for 3a and 3d, analytical and spectroscopic
data for 2a-h, relative DFT Gibbs free energies for conformers
JO702731B
(30) Frisch, M. J.; et al. Gaussian 03, revision C.O1; Gaussian, Inc.:
Wallingford, CT, 2004. See the Supporting Information for the full citation.
J. Org. Chem. Vol. 73, No. 10, 2008 3753