Enantioselective Organocatalyzed Michael Additions of Nitroalkanes to 4-Arylidenedihydrofuran-2,3-diones and 4-Arylidenepyrrolidine-2,3-diones

Article abstract of DOI:10.1002/ejoc.202000460

Tremendous efforts have been devoted to the development of organocatalytic enantioselective Michael additions of nitroalkanes to α,β-unsaturated carbonyl compounds. However, using highly substituted electrophiles remain challenging, since the additional substituents decrease the electrophilicity. β-Arylidene-α-ketolactones and α-ketolactams are used as highly electrophilic Michael acceptors that afford the corresponding products in moderate to good yields, with high enantioselectivities. This success relies on their rigid structure that prevents deconjugation and the efficient recognition of the α-dicarbonyl motif by the hydrogen-bond donor catalyst.

Full text of DOI:10.1002/ejoc.202000460

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Enantioselective Organocatalyzed Michael Additions of
Nitroalkanes to 4-Arylidenedihydrofuran-2,3-diones and 4-
Arylidenepyrrolidine-2,3-diones
Authors: Mouhamadou Fofana, Yohan Dudognon, Laura Bertrand,
Thierry Constantieux, Jean Rodriguez, Ibrahima Ndiaye,
Damien Bonne, and Xavier Bugaut
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000460
Link to VoR: https://doi.org/10.1002/ejoc.202000460
01/2020

10.1002/ejoc.202000460
European Journal of Organic Chemistry
COMMUNICATION
Enantioselective Organocatalyzed
Michael
Additions
of
Nitroalkanes to 4-Arylidenedihydrofuran-2,3-diones and 4-
Arylidenepyrrolidine-2,3-diones
Mouhamadou Fofana,[a,b] Yohan Dudognon,[a] Laura Bertrand,[a] Thierry Constantieux,[a] Jean
Rodriguez,[a] Ibrahima Ndiaye,[b] Damien Bonne*[a] and Xavier Bugaut*[a]
[a]
Dr. Mouhamadou Fofana, Dr. Yohan Dudognon, Laura Bertrand, Prof. Dr. Thierry Constantieux, Prof. Dr. Jean Rodriguez, Dr. Damien Bonne, Dr. Xavier
Bugaut
Aix Marseille Univ, CNRS, Centrale Marseille, ISM2, Marseille, France
E-mail: damien.bonne@univ-amu.fr, xavier.bugaut@univ-amu.fr
https://ism2.univ-amu.fr/fr/annuaire/stereo/bonnedamien; https://ism2.univ-amu.fr/fr/annuaire/stereo/bugautxavier
Dr. Mouhamadou Fofana, Prof. Dr. Ibrahima Ndiaye
[b]
Département de Chimie, Faculté des Sciences et Techniques, Université Cheikh Anta Diop, Dakar, Sénégal
Supporting information for this article is given via a link at the end of the document.
Abstract: Tremendous efforts have been devoted to the development
of organocatalytic enantioselective Michael additions of nitroalkanes
to α,β-unsaturated carbonyl compounds. However, using highly
substituted electrophiles remain challenging, since the additional
substituents decrease the electrophilicity. β-Arylidene-α-ketolactones
and α-ketolactams are used as highly electrophilic Michael acceptors
that afford the corresponding products in moderate to good yields,
with high enantioselectivities. This success relies on their rigid
structure that prevents deconjugation and the efficient recognition of
the α-dicarbonyl motif by the hydrogen-bond donor catalyst.
These three strategies bring about isolated solutions but are
inherently limited in terms of potential applications.[13] In this
context, we made the hypothesis that bridging both α substituents
could help to reduce the distortion that is responsible for the low
reactivity (Scheme 1, Equation 5). Herein, we wish to disclose our
results on the enantioselective Michael addition of nitroalkanes to
β-arylidene-α-ketolactones 1[14] and α-ketolactams 2[15] catalyzed
by bifunctional hydrogen-bonding catalysts. [4e,g,h] They appeared
as especially interesting candidates for enantioselective
organocatalyzed Michael additions with their rigid α-dicarbonyl
structures that could be recognized by the hydrogen-bonding
Michael additions are among the most versatile transformations
[1]
in the toolbox of synthetic organic chemists.
The reaction
course often implies the creation of one or several stereogenic
centers, and a plethora of studies have been devoted to the
control of their absolute configurations, with organocatalysis as
the most successful method.[2] Among Michael additions, the
reaction between nitroalkanes and α,β-unsaturated carbonyl
compounds is especially appealing. This is due to the possibilities
offered to the catalysts to create specific interactions to induce
enantioselectivity and the polyfunctional nature of the
products.[3,4] Indeed, the nitro and carbonyl functionalities can be
chemoselectively proceeded to deliver valuable enantioenriched
compounds such as pyrrolidines[5] or γ-aminoalcohols.[6]
However, a limitation of this transformation is attained when highly
substituted Michael acceptors are used. Indeed, additional
substituents, especially at the α position, are deleterious to the
reactivity because of unfavorable steric interactions that tend to
hamper the conjugation between the olefin and the electron
withdrawing group (Scheme 1, Equation 1).[7] A first solution to
tackle this problem is to add a second electron-withdrawing group
either at the α or at the β position to increase the electrophilicity
(Scheme 1, Equation 2).[8-10] It is also possible to tether the
nucleophile to render the reaction intramolecular, so that the
favorable entropic factor overcomes the intrinsic low reactivity
(Scheme 1, Equation 3).[11] In addition to this, there are also
sporadic examples of the use of highly substituted aldehydes in
the presence of a chiral secondary amine, where the very strong
electron-withdrawing character of the intermediate iminium ion
warrants reasonable reactivity (Scheme 1, Equation 4).[12]
Scheme 1. Organocatalytic additions of nitroalkanes to highly substituted
Michael acceptors: challenges and solutions.
1
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000460
European Journal of Organic Chemistry
COMMUNICATION
catalyst.[16] The resulting Michael adducts were obtained in
moderate to good yields and diastereoselectivities, but with high
enantioselectivities. It should be noted that a similar reaction with
only ketolactams 2 has just been reported under Cu-catalysis.[17]
Our studies began with the reaction of β-phenylidene-α-
ketolactone 1a with 3 equivalents of nitromethane (3a) in the
presence of Takemoto bifunctional (R,R)-thiourea I in CH2Cl2 at
room temperature (Table 1, Entry 1).[4e] Michael adduct 4aa was
isolated as its enol form in encouraging yield (40%) and
enantiomeric excess (84%). Quinine-derived thiourea II[4g] or
squaramides III and IV[4h] all performed less efficiently (Entries 2-
4). The next idea was to change the solvent (CHCl3, toluene,
EtOAc, Et2O, CH3CN) and the reaction temperature (–4 °C or –
20 °C), but these modifications brought about no improvement of
the reaction outcome.[18] At that point, we noticed that the
expected product was accompanied by another compound 4aa’
resulting from the double Michael addition, and also extensive
degradation.[19] To try to solve these issues, we naturally
attempted to increase the amount of nitromethane (3a) to
outcompete the undesired pathways. Pleasingly, a gradual
increase to 10 and 20 equivalents of pronucleophile improved
both the yield and the enantiomeric excess, with 10 equivalents
standing as the best compromise (Entries 5-7). At that point of our
studies, the re-evaluation of squaramide catalyst III at 0 °C further
improved the enantiomeric excess (89% ee) at the cost of a
decrease of the yield (62%). We kept these reactions conditions
as the optimized ones to continue the study (Entry 8).
A study of the reaction scope and limitations was undertaken
(Table 2). β-Arylidene-α-ketolactones 1b-d bearing electron-
withdrawing or slightly electron-donating substituents could be
combined with nitromethane (3a) to deliver products 4ab-ad in
moderate yields but good enantiomeric excesses (Entries 1-3).
However, it was not possible to evaluate Michael acceptors
bearing more electron-donating substituents, heteroaromatics or
alkyl chains instead of the aromatic ring because they could not
be prepared. On the opposite, adding substituents on the
nitroalkane had a beneficial effect in the reaction outcome with 1a,
by increasing the stability of the resulting Michael adducts 4ba-ea
(Entries 4-7). Nitroethane (3b), phenylnitromethane (3c),
bromonitromethane (3d) and ethyl nitroacetate (3e) all delivered
the product with high yields. Diastereoselectivity was generally
moderate, with the exception of phenyl-substituted product 4ca
(Entry 5), but enantiomeric excesses reached 82 to 90%.[20]
Table 2. Scope of the Michael addition of nitroalkanes to β-arylidene-α-
ketolactones and α-ketolactams.[a]
Table 1. Optimization of the reaction conditions.
Entry
3: R1
1 or 2: X, R2
Product: yield (%),
dr, ee (%) [b]
3a: H
1b: O, 4-BrC6H4
1c: O, 4-FC6H4
1d: O, 4-MeC6H4
1a: O, Ph
4ab: 61, -, 88
1
3a: H
4ac: 54, -, 84
2
3a: H
4ad: 61, -, 90
3
3b: Me
3c: Ph
3d: Br
3e: CO2Et
3b: Me
3b: Me
3b: Me
3b: Me
3b: Me
3b: Me
3c: Ph
3c: Ph
4ba: 85, 7:1, 90
4ca: 90, 11:1, 88
4da: 85, 2.5:1, 82 and 84
4ea: 80, 1:1, 53 and 53
5ba: 95, 6:1, 97
5bb: 79, 1.2:1, 98
5bc: 89, 1.6:1, 94
5bd: 85, 2.2:1, 95
5be: 95, 1.3:1, 91
5bf: 78, 1.6:1, 93
5ca: 60, >20:1, 89
5cd: 42, 10:1, 90
4
1a: O, Ph
5
1a: O, Ph
6
1a: O, Ph
7
2a: NBn, Ph
8
Entry
x
Catalyst
Time (h)
Yield (%)[a]
ee (%)[b]
2b: NBn, 4-CNC6H4
2c: NBn, 4-NO2C6H4
2d: NBn, 4-MeOC6H4
2e: NBn, 2,4-Cl2C6H3
2f: NBn, 3-thienyl
2a: NBn, Ph
9
1
3
I
72
72
72
72
15
15
15
48
40
30
28
32
46
70
74
62
84
80
84
78
84
79
79
89
10
11
12
13
14
15
2
3
II
III
IV
I
3
3
4
3
5
10
10
20
10
6[c]
7[c]
8[c]
I
2d: NBn, 4-MeOC6H4
I
[a] Reaction conditions: nitroalkanes 3a-e (10 equiv) and β-arylidene-α-
ketolactones 1a-d or α-ketolactams 2a-f were stirred in the presence of catalyst
III (10 mol%) in CH2Cl2 at 0 °C for 48 hours. [b] Yield of analytically pure product
after flash chromatography, dr determined by 1H NMR and ee determined by
HPLC on chiral stationary phase, for the major diastereomer, or for each of them
when possible.[20]
III
[a] Yield of analytically pure product after flash chromatography. [b] ee
determined by HPLC on chiral stationary phase. [c] Reaction run at 0 °C.
2
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000460
European Journal of Organic Chemistry
COMMUNICATION
To try to expand the usefulness of the present transformation, we
then turned our attention towards the corresponding β-arylidene-
[15]
α-ketolactams, which seems easier to prepare and use.
Following the same reaction conditions, nitroalkanes 3b-c were
combined with β-arylidene-α-ketolactams 2a-f (Entries 8-15).
Products bearing diversified functional groups were obtained in
moderate to good yields, and high enantiomeric excesses
between 89 and 98%. Diastereoselectivities were variable from
nearly no selectivity to almost complete, with an improvement
when R1 is an aromatic substituent. Additionally, comparing the
optical rotation value for compound 5ba (–29.7, c 1.02, CHCl3)
with the one obtained with the Cu-catalyzed variant (+31.7, c 1.02,
CHCl3) allowed attributing the absolute and relative configurations
for the products.[17] They are also in agreement with the
stereoselection model discussed at the end of the article.
Scheme 2. Michael additions followed by C-to-O benzoyl migrations.
In conclusion, we have developed the first organocatalyzed
addition of various nitroalkanes 3 to β-arylidene-α-ketolactones 1
and α-ketolactams 2. The highly functionalized products 4 and 5
were obtained with moderate to good yields and diastereocontrol,
but
high enantioselectivities. Moreover,
the present
Moreover, 2-nitro-1-phenylethanone (3f) could be used as a more
activated pronucleophile (Scheme 2). Pleasingly, a stoichiometric
amount of this compound was sufficient to promote the Michael
addition to 1a and 2a, followed by a C-to-O benzoyl migration, to
deliver products 4fa and 5fa in high yield. Despite moderate
enantioselectivities (42% and 50% ee for 4fa and 5fa,
respectively), this observation illustrates the concept of acyl group
transfer as transient activation in organocatalysis.[21]
transformation is complementary to the Cu-catalyzed variant that
has just been published.[17] Indeed, if those conditions generally
allow attaining excellent diastereoselectivities, the applicability
has been demonstrated only for lactams and with non-
functionalized nitroalkanes. Therefore, the present transformation
brings elements of novelty by allowing the use of lactones in the
electrophilic partner, and of pronucleophilic partners bearing a
bromine atom, a phenyl ring, an ester function or a benzoyl group.
The observed reactivity and stereoselectivity provided by the
quinine-derived squaramide catalyst could be rationalized based
on DFT studies present in the literature, notably for related
additions of nitroalkanes to enones (Figure 1).[22] By taking
inspiration directly from those precedents, we can assume that
the nitroalkane interacts through double hydrogen bonding with
the squaramide unit, which allows its easy deprotonation by the
tertiary amine by stabilizing the nitronate ion. When a R1
substituent is present on the pronucleophile, it is placed on the left
side via an anti-gauche topology to escape from the steric
hindrance of the quinuclidine bicyclic system. The resulting
tertiary ammonium ion can now act as a hydrogen bond donor to
both the ketone and lactone/lactam of the electrophile to favor its
approach by the lower face. The product is formed and the
catalyst regenerated after C-C bond formation, followed by proton
transfer from the catalyst to the intermediate enolate ion. The
application of this model from the literature is in accordance with
the observed enantio- and diastereoselectivities.
Acknowledgements
We warmly thank the whole team of the Spectropole for analytical
work (www.spectropole.fr), along with Dr. Nicolas Vanthuyne and
Marion Jean for the HPLC analyses. Financial support from Aix
Marseille Université, Centrale Marseille, the CNRS and Université
Cheikh Anta Diop de Dakar (Senegal) is acknowledged.
Keywords: Enantioselectivity • Lactams • Lactones • Michael
addition • Organocatalysis
[1]
a) T. Komnenos, Justus Liebigs Ann. Chem. 1883, 218, 145; b) A.
Michael, J. Prakt. Chem. 1887, 35, 349; c) P. Perlmutter, Conjugate Addition
Reactions in Organic Synthesis, Pergamon, Oxford, 1992; d) T. Tokoroyama,
Eur. J. Org. Chem. 2010, 2009.
Figure 1. Reaction mechanism and rationalization of stereoselectivity.
3
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000460
European Journal of Organic Chemistry
COMMUNICATION
[2]
a) B. List, K. Maruoka, Asymmetric Organocatalysis Thieme, Stuttgart,
2012; b) P. I. Dalko, Comprehensive Enantioselective Organocatalysis:
Catalysts, Reactions, and Applications, Wiley-VCH, Weinheim, 2013; c)
J. L. Vicario, D. Badia, L. Carrillo, E. Reyes, Organocatalytic
Enantioselective Conjugate Addition Reactions: A Powerful Tool for the
Stereocontrolled Synthesis of Complex Molecules, RSC Publishing,
London, 2011.
J. Org. Chem. 2013, 78, 996; d) M. W. Giuliano, S. J. Maynard, A. M.
Almeida, A. G. Reidenbach, L. Guo, E. C. Ulrich, I. A. Guzei, S. H.
Gellman, J. Org. Chem. 2013, 78, 12351; e) M. W. Giuliano, S. J.
Maynard, A. M. Almeida, L. Guo, I. A. Guzei, L. C. Spencer, S. H.
Gellman, J. Am. Chem. Soc. 2014, 136, 15046; f) L. Bernardi, M. Fochi,
R. Carbone, A. Martinelli, M. E. Fox, C. J. Cobley, B. Kandagatla, S.
Oruganti, V. H. Dahanukar, A. Carlone, Chem. Eur. J. 2015, 21, 19208.
[3]
[4]
For general reviews on the reactivity of nitro compounds, see: a) N. Ono,
The Nitro Group in Organic Synthesis, Wiley-VCH, Weinheim, 2001; b)
R. Ballini, G. Bosica, D. Fiorini, A. Palmieri, M. Petrini, Chem. Rev. 2005,
105, 933.
[13] There is also
a
single report of cyclopropanation between
bromocyclopropane and trisubstituted Michael acceptors with only one
activating group: B.-L. Zhao, D.-M. Du, Eur. J. Org. Chem. 2015, 5350.
[14] a) For their preparation, see supporting information; b) no catalytic
enantioselective reaction has been reported with those substrates and
there is only a single example of Michael addition in the racemic series:
K. Matsuo, M. Adachi, T. Takagi, S. Ueno, T. Arase, F. Kuroi,
Heterocycles 2005, 65, 377.
For seminal key reports on the reactivity of nitro compounds in
enantioselective organocatalysis, see: a) S. Hanessian, V. Pham, Org.
Lett. 2000, 2, 2975; b) E. J. Corey, F.-Y. Zhang, Org. Lett. 2000, 2, 4257;
c) N. Halland, R. G. Hazell, K. A. Jørgensen, J. Org. Chem. 2002, 67,
8331; d) M. T. Allingham, A. Howard-Jones, P. J. Murphy, D. A. Thomas,
P. W. R. Caulkett, Tetrahedron Lett. 2003, 44, 8677; e) T. Okino, Y.
Hoashi, Y. Takemoto, J. Am. Chem. Soc. 2003, 125, 12672; f) S. B.
Tsogoeva, S. B. Jagtap, Z. A. Ardemasova, V. N. Kalikhevich, Eur. J.
Org. Chem. 2004, 4014; g) B. Vakulya, S. Varga, A. Csámpai, T. Soós,
Org. Lett. 2005, 7, 1967; h) J. P. Malerich, K. Hagihara, V. H. Rawal, J.
Am. Chem. Soc. 2008, 130, 14416.
[15] ) For their preparation, see supporting information. A handful of catalytic
enantioselective domino processes are known with those substrates.
See: b) S. Zhang, Y.-C. Luo, X.-Q. Hu, Z.-Y. Wang, Y.-M. Liang, P.-F.
Xu, J. Org. Chem. 2015, 80, 7288; c) Y. Lu, Y. Zhou, L. Lin, H. Zheng, K.
Fu, X. Liu, X. Feng, Chem. Commun. 2016, 52, 8255; d) J.-L. Li, K.-C.
Yang, Y. Li, Q. Li, H.-P. Zhu, B. Han, C. Peng, Y.-G. Zhi, X.-J. Gou,
Chem. Commun. 2016, 52, 10617; e) C. Wang, H. Jia, C. Zhang, Z. Gao,
L. Zhou, C. Yuan, Y. Xiao, H. Guo, J. Org. Chem. 2017, 82, 633; f) J.-L.
Li, L. Fu, J. Wu, K.-C. Yang, Q.-Z. Li, X.-J. Gou, C. Peng, B. Han, X.-D.
Shen, Chem. Commun. 2017, 53, 6875; g) Q. Li, L. Zhou, X.-D. Shen,
K.-C. Yang, X. Zhang, Q.-S. Dai, H.-J. Leng, Q.-Z. Li, J.-L. Li, Angew.
Chem. 2018, 130, 1931; Angew. Chem. Int. Ed. 2018, 57, 1913; h) Q.-Z.
Li, Y. Liu, H.-J. Leng, J.-L. Li, Synlett 2018, 29, 2601; i) Y. Wang, Y.
Chen, X. Li, Y. Mao, W. Chen, R. Zhan, H. Huang, Org. Biomol. Chem.
2019, 17, 3945; j) X. Lu, Y. Zhang, Y. Wang, Y. Chen, W. Chen, R. Zhan,
J. C. G. Zhao, H. Huang, Adv. Synth. Catal. 2019, 361, 3234; k) X. Zhao,
J. Xiong, J. An, J. Yu, L. Zhu, X. Feng, X. Jiang, Org. Chem. Front. 2019,
6, 1989.
[5]
[6]
a) M. C. Kloetzel, J. Am. Chem. Soc. 1947, 69, 2271. For recent
examples of post-functionalization after an organocatalyzed
enantioselective step, see: b) I. Urruzuno, O. Mugica, M. Oiarbide, C.
Palomo, Angew. Chem. 2017, 129, 2091; Angew. Chem. Int. Ed. 2017,
56, 2059; c) R. Ding, C. Wolf, Org. Lett. 2018, 20, 892; d) C. K. Mahato,
S. Mukherjee, M. Kundu, A. Pramanik, J. Org. Chem. 2019, 84, 1053.
For selected examples, see: a) M. Petrini, R. Ballini, G. Rosini, Synthesis
1987, 713; b) B. M. Trost, S. Hisaindee, Org. Lett. 2006, 8, 6003; c) S.-
G. Wang, X.-J. Liu, Q.-C. Zhao, C. Zheng, S.-B. Wang, S.-L. You,
Angew. Chem. 2015, 127, 15142; Angew. Chem. Int. Ed. 2015, 54,
14929.
[7]
[8]
a) For example, ethyl methacrylate is 1000 times less electrophilic than
ethyl acrylate: D. S. Allgäuer, H. Jangra, H. Asahara, Z. Li, Q. Chen, H.
Zipse, A. R. Ofial, H. Mayr, J. Am. Chem. Soc. 2017, 139, 13318. b) J.
Duschmalé, H. Wennemers, Chem. Eur. J. 2012, 18, 1111.
[16] For the use of α-dicarbonyl compounds as pronucleophiles in
organocatalysis, see: a) O. Baslé, W. Raimondi, M. M. Sanchez Duque,
D. Bonne, T. Constantieux, J. Rodriguez, Org. Lett. 2010, 12, 5246; b)
W. Raimondi, D. Bonne, J. Rodriguez, Angew. Chem. 2012, 124, 40;
Angew. Chem. Int. Ed. 2012, 51, 40; c) W. Raimondi, O. Baslé, T.
Constantieux, D. Bonne, J. Rodriguez, Adv. Synth. Catal. 2012, 354,
563; d) W. Raimondi, D. Bonne, J. Rodriguez, Chem. Commun. 2012,
48, 6763.
α position: a) T. Ooi, S. Fujioka, K. Maruoka, J. Am. Chem. Soc. 2004,
126, 11790; b) O. Bassas, J. Huuskonen, K. Rissanen, A. M. P.
Koskinen, Eur. J. Org. Chem. 2009, 1340; c) T. Inokuma, S. Sakamoto,
Y. Takemoto, Synlett 2009, 1627; d) B. Zhang, L. Cai, H. Song, Z. Wang,
Z. He, Adv. Synth. Catal. 2010, 352, 97; e) S. Piovesana, D. M. S.
Schietroma, L. G. Tulli, M. R. Monaco, M. Bella, Chem. Commun. 2010,
46, 5160; f) M. Chiarucci, M. Lombardo, C. Trombini, A. Quintavalla, Adv.
Synth. Catal. 2012, 354, 364; g) U. Das, Y.-L. Tsai, W. Lin, Org. Biomol.
Chem. 2013, 11, 44; h) D. Gavin, J. Stephens, ARKIVOC 2013, 76; i) R.
Baran, E. Veverková, A. Škvorcová, R. Šebesta, Org. Biomol. Chem.
2013, 11, 7705; j) S. Hajra, S. M. Aziz, R. Maji, RSC Adv. 2013, 3, 10185;
k) J. Duan, J. Cheng, P. Li, Org. Chem. Front. 2015, 2, 1048; l) Z. Bai, L.
Ji, Z. Ge, X. Wang, R. Li, Org. Biomol. Chem. 2015, 13, 5363; m) M.
Amireddy, K. Chen, Tetrahedron 2015, 71, 8003; n) Ż. A. Ignatiuk, M. J.
Janicki, R. W. Góra, K. Konieczny, R. Kowalczyk, Adv. Synth. Catal.
2019, 361, 1108.
[17] a) The complementary Cu-catalyzed alternative conditions were reported
during the preparation of our manuscript: Y. Huang, Z. Zha, Z. Wang,
Org. Lett. 2020, DOI: 10.1021/acs.orglett.0c00030; for other metal-
catalyzed transformations on the same substrates, see: b) X. Hu, Y.
Zhou, Y. Lu, S. Zou, L. Lin, X. Liu, X. Feng, J. Org. Chem. 2018, 83,
8679; c) Y. Huang, Y. Li, J. Sun, J. Li, Z. Zha, Z. Wang, J. Org. Chem.
2018, 83, 8464.
[18] See supporting information for further details.
[19] Even though no experimental proof could be collected, it is likely that the
product 4aa exhibits intramolecular hydrogen-bonding between the enol
function and the nitro group. This intramolecular activation could explain
why the double addition product 4aa’ is observed even in the presence
of a large excess of nitromethane:
[9]
β position: a) S.-W. Duan, H.-H. Lu, F.-G. Zhang, J. Xuan, J.-R. Chen,
W.-J. Xiao, Synthesis 2011, 1847; b) A. Quintavalla, F. Lanza, E.
Montroni, M. Lombardo, C. Trombini, J. Org. Chem. 2013, 78, 12049; c)
M. Monari, E. Montroni, A. Nitti, M. Lombardo, C. Trombini, A.
Quintavalla, Chem. Eur. J. 2015, 21, 11038.
[10] Both α and β positions: a) L. Wen, L. Yin, Q. Shen, L. Lu, ACS Catal.
2013, 3, 502; b) M. A. Horwitz, J. L. Fulton, J. S. Johnson, Org. Lett.
2017, 19, 5783.
[20] For the examples where the enantiomeric excesses were determined for
both diastereomers, values are very similar (Table 2, Entries 6 and 7).
This observation points towards an epimerization at the position α to the
nitro group in the basic reaction conditions.
[11] a) W. J. Nodes, D. R. Nutt, A. M. Chippindale, A. J. A. Cobb, J. Am.
Chem. Soc. 2009, 131, 16016; b) W. J. Nodes, K. Shankland, S.
Rajkumar, A. J. A. Cobb, Synlett 2010, 3011; c) A. Quintavalla, M.
Lombardo, S. P. Sanap, C. Trombini, Adv. Synth. Catal. 2013, 355, 938;
d) W. Al-Ani, K. Shankland, A. J. A. Cobb, Synlett 2016, 27, 17.
[12] a) J.-m. Zhang, C.-l. Lou, Z.-p. Hu, M. Yan, ARKIVOC 2009, 362; b) L.
Guo, W. Zhang, I. A. Guzei, L. C. Spencer, S. H. Gellman, Org. Lett.
2012, 14, 2582; c) F. Malihi, D. L. J. Clive, C.-C. Chang, Minaruzzaman,
[21] a) For a review, see: J. Rodriguez, A. Quintard, Synthesis 2019, 51,
1923; for recent related example, see: b) K. Mondal, S. C. Pan, J. Org.
Chem. 2018, 83, 5301; c) Y.-X. Song, D.-M. Du, Adv. Synth. Catal. 2019,
361, 5042.
[22] a) B. Kótai, G. Kardos, A. Hamza, V. Farkas, I. Pápai, T. Soós, Chem.
Eur. J. 2014, 20, 5631; b) M. N. Grayson, J. Org. Chem. 2017, 82, 4396.
4
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000460
European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents
Despite tremendous efforts towards the development of organocatalytic enantioselective Michael additions of nitroalkanes to α,β-
unsaturated carbonyl compounds, highly substituted electrophiles remain challenging. β-Arylidene-α-ketolactones and α-ketolactams
are used as highly electrophilic Michael acceptors that afford the corresponding products in moderate to good yields, with high
enantioselectivities.
Institute and/or researcher Twitter usernames: @ism2_fr, @damien_bonne, @XavierBugaut
5
This article is protected by copyright. All rights reserved.