Stereoselective synthesis of functionalized chiral 2- nitrocyclohexanecarboxylic esters via catalytic dienamine addition to β-substituted β-nitroacrylates

Article abstract of DOI:10.1002/adsc.201301074

A metal-free stereoselective catalytic addition of in situ generated dienamine to β-nitroacrylates has been developed. Starting from simple α,β unsaturated ketones, highly functionalized chiral β-nitrocyclohexanecarboxylic esters were obtained in a single step, in good yields and up to 98% ee. By an unprecedented mechanistic pathway, starting from the synthetically readily available E-nitroacrylate, the present methodology allowed us to obtain as major product the isomer bearing a cis relative disposition between the nitro and the ester groups, which is not accessible via a classical Diels-Alder reaction.

Full text of DOI:10.1002/adsc.201301074

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DOI: 10.1002/adsc.201301074
Stereoselective Synthesis of Functionalized Chiral
2-Nitrocyclohexanecarboxylic Esters via Catalytic Dienamine
Addition to b-Substituted b-Nitroacrylates
Elisabetta Massolo,a Maurizio Benaglia,a,* Rita Annunziata,a
Alessandro Palmieri,b Giuseppe Celentano,c and Alessandra Fornid
a
Dipartimento di Chimica, Universitaꢀ degli Studi di Milano, via Golgi 19, 20133 Milano, Italy
Fax : (+39)-02-5031-4159; phone: (+39)-02-5031-4171; e-mail: maurizio.benaglia@unimi.it
Green Chemistry Group, School of Science and Technology, Chemistry Division, University of Camerino, Via S. Agostino
b
1, 62032, Camerino (MC), Italy
Dipartimento di Scienze Farmaceutiche, Universitꢁ degli Studi di Milano, Via Mangiagalli, 25, Milano, Italy
CNR-ISTM, Istituto di Scienze e Tecnologie Molecolari del CNR, via Golgi 19, Milano, Italy
c
d
Received: December 2, 2013; Published online: February 6, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201301074.
Abstract: A metal-free stereoselective catalytic addi- major product the isomer bearing a cis relative dis-
tion of in situ generated dienamine to b-nitroacry- position between the nitro and the ester groups,
lates has been developed. Starting from simple a,b- which is not accessible via a classical Diels–Alder re-
unsaturated ketones, highly functionalized chiral b- action.
nitrocyclohexanecarboxylic esters were obtained in
a single step, in good yields and up to 98% ee. By an
unprecedented mechanistic pathway, starting from Keywords: bifunctional catalysts; cyclohexanecar-
the synthetically readily available E-nitroacrylate, boxylic esters; dienamines; nitroacrylates; organoca-
the present methodology allowed us to obtain as talysis
Introduction
a viable synthetic approach for the stereoselective
synthesis of chiral b-aminocyclohexanecarboxylic
Chiral b-amino acids are a subject of extraordinary in- acids; indeed, Barluenga has already explored that
terest because of their presence in many natural prod- strategy by studying the reaction between an amino-
ucts,[1] biologically active compounds,[2] and their use diene and nitroalkenes, employing a chiral auxiliary
as starting materials for the preparation of b-lactam at the diene residue to control the absolute stereo-
antibiotics.[3] Recently they have gained new attention chemistry of the process.[8]
as constituents of b-peptides, unnatural oligomers
In the attempt to develop a catalytic methodology
characterized by a high resistance to peptide-cata- for the synthesis of functionalized cyclohexanecarbox-
lyzed hydrolysis.[4] Interestingly, it was observed that ylic acids, we have thought to take advantage of the
peptides containing cyclic amino acids tend to adopt recent progress in the field of organocatalysis,[9] where
a more regular secondary structure than those based impressive results have been obtained in the activa-
on acyclic residues.[5] Moreover, b-amino esters carry- tion of unsaturated ketones via amino catalysis.[10] Re-
ing a hydroxy function have proved to be difficult to cently Melchiorre and List have reported that Cincho-
obtain, and this is unfortunate in light of the consider- na-based primary amines can be exploited to activate
able importance of these molecules, present in many a,b-unsaturated ketones and enals,[11] and reacted
important products, like taxol, bestatin and related them via dienamine catalysis with different electro-
compounds.[6] Additionally, nitrocyclohexanones have philic partners, including nitroalkenes.
been recognized as important and flexible precursors
However, although many reports in organocatalysis
for the synthesis of some alkaloid derivatives in the have focused on the electrophilic reactivity of nitroal-
lycorine, crinine and caranine series (Figure 1).[7]
kenes (especially nitrostyrene derivatives),[12] much
The cycloaddition between nitroacrylates and prop- less is known on the use of nitroacrylates.[13] A few
erly functionalized dienes may be envisaged as years ago, in a study by Seidel on the addition of in-
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Elisabetta Massolo et al.
Figure 1. Some representative aminocyclohexanecarboxylic acid derivatives of biological interest.
Scheme 1. Organocatalytic approach to the synthesis of highly functionalized cyclohexanecarboxylic acids.
doles to nitroalkenes catalyzed by quinolium thio- mol equiv. of nitroacrylate, in the presence of a 20
amides, a single example of the reaction of 3-nitroa- mol% amount of the catalyst and 30 mol% of salicylic
crylate was described.[14] In 2008 List reported the acid (Table 1).
ACHTUNGTRENNUNG
enantioselective reduction via transfer hydrogenation
of b-nitroacrylates.[15] In 2010 the organocatalytic con- addition of a catalytic amount of an acidic additive
jugate addition of oximes to b-nitroacrylates has been
developed.[16] More recently, Wennemers successfully
accomplished a highly stereoselective addition of al-
dehydes to a-substituted b-nitroacrylates;[17] the tri-
peptide-catalyzed transformation generated all-
carbon quaternary stereocenters, thus showing the
great potential of the methodology (Scheme 1).[18]
As expected on the basis of previous studies, the
However, the catalytic direct addition of unsaturat-
ed ketones to nitroacrylates is largely underdevel-
oped;[19] therefore we decided to investigate in detail
the organocatalyzed reaction of nitroacrylates with in
situ generated dienamine.[20]
Results and Discussion
b-Alkyl-substituted b-nitroacrylates were easily pre-
pared[21] and used in reactions promoted by bifunc-
tional organocatalysts. After a preliminary investiga-
tion,[22] our attention focused on the use of Cinchona
derivatives (Figure 2).[23] The reaction between 4-
phenyl-2-butanone 1 and ethyl (E)-3-ethyl-3-nitro-
ACHTUNGTRENNUNG
Figure 2. A few selected chiral organocatalysts employed in
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Stereoselective Synthesis of Functionalized Chiral 2-Nitrocyclohexanecarboxylic
Table 1. Preliminary studies with organocatalysts A–E.
Entry Cat. Time [h] Yield [%][a] 3a/3b[b] ee [%][c]
Table 2. Optimization studies with catalyst A.
Entry
Solvent
Temp.
[8C]
Yield
[%][a]
3a/3b[b]
ee
[%][c]
1[d]
2
3
4
5
A
A
B
A
B
C
D
E
A
48
48
48
24
24
24
24
24
48
n.r.
55
57
83
75
45
71
87
57
–
–
33/67
13/87
30/70
20/80
30/70
50/50
30/70
15/85
(+) 92/87
(À) 90/93
(+) 89/85
(À) 97/95
(À) 95/92
(À) 83/90
(À) 92/96
(+) 90/93
1
2
3
4
toluene
toluene
toluene
toluene
toluene
toluene
DCM
EtOH
DMSO
water
40
60
25
5
40
40
40
40
40
40
40
40
40
55
57
72
61
57
80
80
70
41
37
40
61
50
33/67
48/52
33/67
20/80
33/67
50/50
25/75
30/70
50/50
15/85
50/50
47/53
48/52
(+) 92/87
(+) 94/81
(+) 96/93
(+) 93/92
(+) 95/90
(+) 70/75
(+) 87/83
(+) 91/70
(+) 77/76
(+) 91/87
(+) 95/70
(+) 93/78
(+) 83/72
6
5[d]
6[e]
7
7[e]
8
9[f]
8
9
10
11[f]
12[g]
13[h]
[a]
[b]
[c]
Reaction run in toluene at 408C; isolated yields after
chromatography.
toluene
toluene
toluene
Diastereoisomeric ratio determined by NMR on the
crude reaction mixture and confirmed after purification.
Enantiomeric excess determined by HPLC on a chiral
stationary phase (see the Supporting Information for de-
tails), use of cat. B–E led to the major enantiomers of 3a
and 3b with opposite configuration to those obtained
with cat. A.
Reaction performed without salicylic acid.
Reaction performed in CH2Cl2.
Reaction performed starting from ethyl (Z)-3-ethyl-3-ni-
troacrylate.
[a]
Reaction time: 48 h; isolated yields after chromatograph-
ic purification.
[b]
[c]
Diastereoisomeric ratio determined by NMR on the
crude reaction mixture and confirmed after purification.
Enantiomeric excess determined by HPLC on chiral sta-
tionary phase (see the Supporting Information for de-
tails.
Ketone/acrylate ratio 1/1.
Ketone/acrylate 1/2.
Additive: acetic acid.
Additive: 2-F-benzoic acid.
[d]
[e]
[f]
[d]
[e]
[f]
[g]
[h]
was found to be essential to promote the transforma-
tion.[24] 9-Amino
(9-deoxy)-epi-quinidine A, in the
Additive: 4-OH-benzoic acid.
ACHTUNGTRENUNG
presence of salicylic acid, was indeed able to activate
ketone 1 via dienamine, that reacted with (E)-nitro-
Interestingly, when the (Z) isomer of acrylate 2 was
ACHTUNGTRENNUNGacrylate 2 to afford the 2-nitro-3-phenyl-5-ketocyclo- employed, the same reaction products were isolated,
hexanecarboxylic ethyl ester 3 as mixture of two dia- with the same level of enantioselectivity (90% and
stereoisomers; noteworthy both isomers were ob- 93%), and a slightly increased diastereoselectivity
tained with very high enantioselectivities (92% and (3a/3b 15/85, entry 9, Table 1).
87% ee, respectively, entries 1 and 2 of Table 1).
In looking for the best experimental conditions,
When the quasi-enantiomeric quinine derivative B several parameters were investigated; a few, selected
was used, virtually identical ee values (but for the op- results of the optimization studies are shown in
posite absolute configuration) for both stereoisomers Table 2. Reaction temperature did not show any ap-
were observed, leading to the products 3a and 3b preciable influence on yield and stereoselectivity;
shown in Scheme 2, with an increased diastereoselec- however generally by operating at 258C the highest
tivity (entry 3, Table 1). Very good results were ob- ee were observed.
tained also for shorter reaction times, when enantiose-
Toluene seems to be the best solvent, but also
lectivities up to 97% were reached. A preliminary chlorinated solvents may be used without compromis-
survey of catalyst structural variations showed that ing significantly the stereoselectivity. A drop in the
neither the presence of an OH group possibly engag- enantioselection was registered by running the reac-
ed in hydrogen bond-based recognition phenomena, tion in DMSO, while in pure water interesting levels
nor the modification of the OR substituent at the of ee were recorded, although in low yields. Notewor-
quinoline ring influenced the catalyst behaviour.
thy the acidic additive seems not to have a decisive
role in determining the stereochemical outcome of
Scheme 2. Model reaction between 4-phenyl-2-butanone 1 and ethyl 3-ethyl-3-nitroacrylate 2.
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Table 3. General applicability of the catalytic approach.
Entry
n.
Cat.
Yield [%][a]
R
R’
R’’
a/b dr[b]
ee [%][c]
1
2
3
4
3
B
A
A
B
A
B
B
A
B
A
B
A
B
A
B
57
55
67
70
57
45
55
81
77
25
31
71
80
67
81
Et
Et
Pent
Pent
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Ph
Ph
Ph
Ph
4-BrC6H4
4-BrC6H4
4-BrC6H4
2-thienyl
2-thienyl
Me
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
i-Pr
i-Pr
Bn
Bn
13/87
33/67
33/67
30/70
45/55
47/53
30/70
12/88
25/75
25/75
47/53
20/80
12/88
30/70
32/68
(À) 90/93
(+) 92/87
(+) 83/86
(À) 96/94
(+) 93/81
(À) 94/92
(À) 94/98
(+) 91/90
(À) 97/98
(+) 97/87
(À) 97/93
(+) 90/84
(À) 88/92
(+) 91/77
(À) 93/90
en3
en4
4
en5
5
5
en6
6
en7
7
en8
8
en9
9
5
6
7d
8
9
10
11
12
13
14
15
Me
Ph
Ph
Ph
Ph
[a]
Reaction conditions: toluene, 48 h, 408C; isolated yields after chromatographic purification.
Diastereoisomeric ratio determined by NMR on the crude reaction mixture and confirmed after purification.
Enantiomeric excess determined by HPLC on a chiral stationary phase (see the Supporting Information for details).
Reaction performed with 10 mol% amount of catalyst and 15 mol% amount of salicylic acid.
[b]
[c]
[d]
the reaction, although the use of 4-hydroxybenzoic tion). The experimentally observed formation of the
acid instead of 2-hydroxybenzoic acid caused a de- major isomer 3b, bearing a cis disposition of the nitro
crease in the enantioselectivity for both isomers.
and the ester groups, seems to confirm a stepwise
The general applicability of the methodology was mechanism, involving a Michael addition followed by
then investigated, by employing catalysts A and B as ring closure, rather than a concerted 4+2 cycloaddi-
to direct the reaction towards the formation of the tion.[25] The proposed reaction mechanism (Figure 3)
two opposite enantiomers of each stereoisomer involves the ketone activation by the catalyst, to gen-
(Table 3).
erate the dienamine system, that can react with the
The relative configuration of the products was es- nitroacrylate in a Michael addition. The transient a,b-
tablished by NMR studies, while the absolute configu- unsaturated iminium species thus formed may be at-
ration was determined by X-ray analysis to be tacked by the in situ generated nucleophilic carb-
1R,2S,3R for the major isomer of the 4-Br phenyl de-
ACHTUNGTRENaNUNG nionic species (stabilized by the nitro group) to
rivative 5b (entry 6, Table 3, see Supporting Informa- afford the cyclohexane ring.
Figure 3. A proposed reaction mechanism.
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Stereoselective Synthesis of Functionalized Chiral 2-Nitrocyclohexanecarboxylic
Scheme 3. Synthetic transformations of chiral 2-nitro-3-aryl-5-ketocyclohexanecarboxylic esters.
Due to the steric hindrance of the a-alkyl-substitut- Conclusions
ed nitro derivative and the stabilization of the carb-
ACHTUNGTRENNUNGanionic species, the reaction rate becomes slow In conclusion, a direct metal-free catalytic stereose-
enough to allow the equilibrium between the two in- lective methodology has been developed to synthesize
termediates I and II of Figure 3. Stabilizing, electro- highly functionalized 2-nitrocyclohexanecarboxylic
static interactions between the nitro group and the esters. Molecules bearing one quaternary and two ter-
ester moiety may be hypothesized to justify the for- tiary stereocenters were assembled in a single step, in
mation of the never before observed isomer 3b as the good yields and up to 98% ee.
major reaction product.[26]
Finally, the synthetic versatility of the functional-
ized 2-nitrocyclohexanonecarboxylic ester derivatives
was briefly studied (Scheme 3). The enantiomerically
pure product 3b (easily separated by column chroma-
tography) may be selectively reduced at the carbonyl
group, to afford the corresponding alcohol 4 as
a single isomer. The reduction of the nitro group
mediated by Zn afforded the N-hydroxy-b-lactam 5.
Noteworthy the same experimental protocol on
Experimental Section
General Methods
Dry solvents were purchased and stored under nitrogen
over molecular sieves (bottles with crown caps). Reactions
were monitored by analytical thin-layer chromatography
(TLC) using silica gel 60 F254 pre-coated glass plates
(0.25 mm thickness) and visualized using UV light. Melting
isomer 3a led to a different result, affording 7, the points were determined with a Branstead Electrothermal
9100 capillary melting point apparatus. Flash chromatogra-
phy was carried out on silica gel (230–400 mesh). Proton
NMR spectra were recorded on spectrometers operating at
300 MHz (Bruker Fourier 300 or AMX 300) or at 500 MHz
(Bruker Advance 500). Proton chemical shifts are reported
in ppm (d) with the solvent reference relative to tetrame-
thylsilane (TMS) employed as the internal standard (CDCl3
d=7.26 ppm). 13C NMR spectra were recorded on 300 MHz
spectrometers (Bruker Fourier 300 or AMX 300) operating
at 75 MHz, or on 500 MHz spectrometers (Bruker Advance
500) operating at 125 MHz, with complete proton decou-
product of a Clemmensen-type reduction of the car-
bonyl group.[27]
Reduction of both the nitro and the ketone of 3b
could be accomplished with NiCl2 and NaBH4, to
afford 8, while the reaction with LiAlH4 produced the
diol 9, that could be converted to the corresponding
dihydroxy amine 11.
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Elisabetta Massolo et al.
pling. Carbon chemical shifts are reported in ppm (d) rela-
tive to TMS with the respective solvent resonance as the in-
ternal standard (CDCl3, d=77.0 ppm). Enantiomeric excess
determinations were performed under below reported con-
ditions with Agilent 1200 series HPLC. Mass spectra (MS)
were performed at CIGA (Centro Interdipartimentale
Grandi Apparecchiature), with mass spectrometer APEX II
& Xmass software (Bruker Daltonics). Optical rotations
were obtained on a polarimeter at 589 nm using 5 mL or
1 mL cell with a length of 1 dm.
(s), 45.96 (s), 42.84 (s), 40.02 (s), 25.32 (s), 13.43 (s), 8.63 (s);
HR-MS (ESI+): m/z=342.13211 [M+Na], calcd. for
+
C17H21NO5Na1 : 342.13119. IR: n=3019.98 (Ph), 1729.83
(C=O), 1654.62 (C=O), 1541.81 (NO2), 1336.43 cmÀ1 (NO2).
The enantiomeric excess was determined by HPLC [Daicel
Chiralpack AD column; eluent: 95:5 hexane/i-PrOH; flow
rate: 0.8 mLminÀ1; detection: 210 nm]: (+) enantiomer, ob-
tained with catalyst A: tR 13.15 min (minor), tR 19.35 min
(major); (À) enantiomer, obtained with catalyst B: tR
13.52 min (major), tR 20.32 min (minor); [a]2D3: À88 (ee 97%,
c 0.23, CHCl3).
Ethyl 2-ethyl-2-nitro-5-oxo-3-phenylcyclohexanecarboxy-
late (Scheme 2, compound 3b): The product was purified by
flash column chromatography on silica gel with a 95:5
Materials
Commercial grade reagents and solvents were used without
further purification. Chiral primary amine catalysts A–E
were prepared from commercially available quinine and qui-
nidine, following literature procedures (see the Supporting
Information). a,b-Unsaturated ketones were purchased
from Aldrich and used as received or synthesized following
known procedures. Nitroacrylates were prepared according
to literature procedures.[21]
hexane/ethyl acetate mixture as eluent. The product appears
as an oil. Rf =0.17 (8:2 hexane/ethyl acetate). 1H NMR
(300 MHz, CDCl3): d=7.32–7.30 (m, 3H), 7.06–7.03 (m,
2H), 4.18 (q, J=7.1 Hz, 2H), 3.36–3.41 (m, 3H), 3.33 (dd,
J=13.3, 5.5 Hz, 1H), 2.79 (dd, 1H, J=15.2, 5.3 Hz), 2.57–
2.54 (m, 1H), 2.13 (sex, J=7.5 Hz, 1H), 1.87 (sex, J=
7.5 Hz, 1H), 1.24 (t, J=7.1 Hz, 3H), 1.06 (t, J=7.6 Hz, 3H);
13C NMR (75 MHz, CDCl3): d=205.70 (s), 171.63 (s), 136.60
(s), 129.16 (s), 128.38 (s), 93.18 (s), 61.94 (s), 47.05 (s), 46.26
(s), 42.61 (s), 40.57 (s), 29.08 (s), 13.98 (s), 7.91 (s); HR-MS
General Procedure for Organocatalytic Reactions
The primary amine catalyst (0.2 equiv.) and the acidic co-
catalyst (0.3 equiv.) were dissolved in dry solvent (1M solu-
tion) under an N2 atmosphere and stirred at room tempera-
ture for 10 min. After this period, the a,b-unsaturated
ketone and the nitroacrylate were added. The reaction mix-
ture was heated to the desired temperature and stirred for
the reported time, after which solvent was removed at re-
duced pressure. Cyclohexanone derivatives were isolated by
flash column chromatography on silica gel. The diastereo-
meric ratio was determined by 1H NMR analysis on the
crude mixture; the enantiomeric ratio was determined by
HPLC on chiral stationary phase.
The absolute configuration of the major enantiomer of
ethyl 3-(4-bromophenyl)-2-ethyl-2-nitro-5-oxocyclohexane-
carboxylate (Table 3, entries 5–6–7, cis isomer b) obtained
with catalyst B (9-deoxy-9-amino-epiquinine) was deter-
mined to be 1R,2S,3R by X-ray analysis.
(ESI+):
C17H21NO5Na1 : 342.13119. IR: n=3019.01 (Ph), 1717.3ACHTUNGTRENNUNG
m/z=342.13099
[M+Na],
calcd.
for
(C=
+
O), 1653.66 (C=O), 1544.7 cmÀ1 (NO2). The enantiomeric
excess was determined by HPLC [Daicel Chiralpack AD
column; eluent: 95:5 hexane/i-PrOH; flow rate:
0.8 mLminÀ1; detection: 210 nm]: (+)-enantiomer, obtained
with catalyst A: tR 26.11 min (major), 29.29 min (minor);
(À)-enantiomer, obtained with catalyst B: tR 26.01 min
(minor), 28.83 min (major). [a]2D3: À20.58 (ee 88%, c: 0.38,
CHCl3).
Ethyl 2-ethyl-2-nitro-5-oxo-3-phenylcyclohexanecarboxy-
late (Scheme 2, compound 3a): The product was purified by
flash column chromatography on silica gel with a 95:5
Supporting Information
Experimental details for the catalytic experiments and the
synthetic modifications. Analysis and characterization of the
reaction products, NMR and HPLC traces of the products,
Plot of the X-ray structure of the 4-Br phenyl derivative,
crystallographic information file (CIF) and checkCIF report
are available in the Supporting Information.
hexane/ethyl acetate mixture as eluent. The product appears
as an oil. Rf =0.25 (8:2 hexane/ethyl acetate). 1H NMR
(300 MHz, CDCl3): d=7.33–7.29 (m, 3H), 7.12- 7.06 (m,
2H), 4.33–4.17 (m, 2H), 4.07 (dd, J=13.4, 4.2 Hz, 1H), 3.91
(dd, J=7.3, 3.4 Hz, 1H), 3.36 (dd, J=16.8, 7.3 Hz, 1H), 3.01
(dd, J=15.9, 13.4 Hz, 1H), 2.67–2.57 (m, 2H), 2.12 (hept,
J=7.5 Hz, 1H), 1.83 (sex, J=7.5 Hz, 1H), 1.31 (t, 3H, J=
7.2 Hz, 3H), 0.95 (t, 3H, J=7.3 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d=205.46 (s), 168.65 (s), 135.63 (s),
128.63 (s), 128.23 (s), 127.31 (s), 90.07 (s), 61.35 (s), 46.22
Acknowledgements
This work was supported by MIUR-PRIN (Nuovi metodi
catalitici stereoselettivi e sintesi stereoselettiva di molecole
funzionali); A.P. thanks YFIRB National Project “Metodolo-
gie di nuova generazione nella formazione di legami carbon-
io-carbonio e carbonio-eteroatomo in condizioni eco-sosteni-
bili”. M. B. thanks COST action CM9505 “ORCA” Organo-
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Stereoselective Synthesis of Functionalized Chiral 2-Nitrocyclohexanecarboxylic
catalysis. The authors thank Prof. Franco Cozzi and Roberto
Ballini for valuable discussion.
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499

FULL PAPERS
Elisabetta Massolo et al.
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[22] Explorative studies showed that under similar experi-
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presence of acidic additives.
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chemical activation of the ketone, by facilitating the
imine-enamine equilibrium, its role in determining the
stereochemical outcome of the reaction is less clear.
Although hydrogen-bond interactions with the nitro-
AHCTUNGTREGaNNUN crylate may be reasonably hypothesized, more than
a unique coordination mode are possible; further stud-
ies are needed to clarify this point.
[25] The product with a cis relative disposition between the
nitro and the ester groups in the cyclohexane ring has
never been observed in previous works with nitroal-
kenes, see refs.[11,16]
[26] Noteworthy, starting from the synthetically available E-
nitroacrylate, the present methodology allows us to
obtain as major product the cis-isomer, that is not ac-
cessible via a classical Diels–Alder reaction.
[27] The different behavior of isomers 3a and 3b is a further
demonstration of the assigned relative configuration.
The unexpected product 7 obtained in the reduction of
isomer 3a is probably due to the great difficulty in re-
ducing the scarcely accessible nitro group. Indeed hy-
drogenation reactions under different experimental
conditions or the use of other reducing agents did not
afford the corresponding amines (unreacted starting
material was recovered).
[20] In ref.[11c] a single example of a reaction with a nitro-
ACHTUNGTRENNUNGacrylate was reported.
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500
asc.wiley-vch.de
ꢂ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2014, 356, 493 – 500