Crystallization Does It All: An Alternative Strategy for Stereoselective Aza-Henry Reaction

Article abstract of DOI:10.1021/acs.orglett.9b01489

An efficient and experimentally straightforward method for the stereoselective synthesis of a variety of β-nitro-α-amino carboxylic acids via aza-Henry (nitro-Mannich) reaction of aldimines is disclosed, yielding either anti- or a rarely reported syn-configuration. The reaction operates directly on free glyoxylic acid and generates imine species in situ. Crystallization-controlled diastereoselectivity enables isolation of the target compounds in high enantio- and diastereomeric purities by a simple filtration.

Full text of DOI:10.1021/acs.orglett.9b01489

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Crystallization Does It All: An Alternative Strategy for
Stereoselective Aza-Henry Reaction
†
†
†
†
†
‡
̌
̌
́
́
̌
̌
̌
̌
Michaela Marcekova, Peter Gerza, Michal Soral, Jan Moncol, Dusan Berkes, Andrej Kolarovic,
and Pavol Jakubec*,†
†
́
Faculty of Chemical and Food Technology, Slovak University of Technology, Radlinskeho 9, 812 37 Bratislava, Slovakia
‡
́
Department of Chemistry, Faculty of Education, Trnava University, Priemyselna 4, 918 43 Trnava, Slovakia
S
* Supporting Information
ABSTRACT: An efficient and experimentally straightforward
method for the stereoselective synthesis of a variety of β-nitro-
α-amino carboxylic acids via aza-Henry (nitro-Mannich)
reaction of aldimines is disclosed, yielding either anti- or a
rarely reported syn-configuration. The reaction operates
directly on free glyoxylic acid and generates imine species in
situ. Crystallization-controlled diastereoselectivity enables
isolation of the target compounds in high enantio- and
diastereomeric purities by a simple filtration.
severalfold excess,1 thus hampering applications to more
complex and expensive nitro derivatives.
za-Henry reaction, often titled as a nitro-Mannich
1
Areaction,
belongs to a family of synthetically useful
multicomponent reactions. It allows for an effective carbon−
carbon bond formation between nitroalkanes and imines,
potentially formed in situ, and is associated with a
simultaneous construction of up to two stereogenic centers.
The resulting β-nitro-α-amino compounds bear two different
nitrogen functionalities, which allow diverse chemoselective
manipulations toward complex nitrogen-containing struc-
tures.2,3 Despite its potential usefulness, the aza-Henry reaction
remained relatively unexplored for a long time, and an
intensified interest in the method was sparked in 1998 by
Anderson’s pioneering work on diastereoselectivity of acyclic
reactions.4 Very soon it was followed by its first catalytic
enantioselective variant,5 and ever since, numerous asymmetric
protocols based on chiral auxiliaries,6 metal catalysis,7 or
organocatalysis8−10 have been reported (Scheme 1A−C). In
general, the most remarkable examples of stereoselective aza-
Henry reactions involving aldimines are based on catalytic
protocols. Nevertheless, relatively high loadings of complex
ligands or catalysts (10−20 mol %) are often required.1 In
response to that, more effort has been put into the
development of reusable supported catalysts, with several
interesting applications to the aza-Henry reaction.11
Isolation and purification of the reaction products constitute
a problem on their own and can be laborious and costly,
bringing a significant environmental burden. Selective
crystallization of the desired product followed by filtration
greatly simplifies the reaction workup and constitutes an
attractive separation option.14 Moreover, crystallization can
play a pivotal role in the overall direction of the reaction
course, as is the case in crystallization-induced diastereose-
lective transformations (CIDT).15 Recently, we have demon-
strated that reversible reactions, which yield the amino acid
functionality, are suitable for exploration as a platform for
CIDT.16 On the basis of the knowledge that amino acid
formation makes crystallization of the product presumable, we
envisioned that this concept might be further expanded to the
aza-Henry reaction (Scheme 1D).
The aza-Henry reaction can be reversible and often yields
stereoisomeric mixtures.17 Besides a simple separation, several
useful strategies toward a more effective product isolation have
been employed, e.g., a dynamic kinetic resolution cascade,18
a
selective extraction of a single diastereomer in combination
with Et3N-catalyzed epimerization of the solid residue,3c or a
base-catalyzed epimerization associated with CIDT.19 We
aimed to develop an innovative multicomponent procedure
that would take advantage of the reaction reversibility and,
under a simple reaction setup, would yield crystalline α-amino-
β-nitro acids in excellent stereoisomeric purities. As a key
design feature, we envisioned the use of glyoxylic acid.20
While impressive advancements have been made in the field
over the last two decades, some issues remain to be addressed.
The vast majority of the reported methodologies describe
syntheses of β-nitroamino structures in the anti-configuration,
and only very few efficient protocols toward syn-stereoisomers
are known.7b,12 Preformed imines bearing a protecting group,
e.g., N-Boc or N-PMP, are typically required, which brings
about an extra reaction step.13 For the sake of satisfactory
reaction yields, nitroalkanes are commonly used in a
Received: April 29, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01489
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Examples Illustrating Current State-of-the-Art
Stereoselective Aza-Henry Reactions of Aldimines
Scheme 2. Initial Studies of Aza-Henry Reaction
The efficiency and beauty of this stereoselective trans-
formation intrigued us to further explore its applicability on
sterically hindered α,α-disubstituted nitro compounds. We
were pleased to find that the reaction had a broad scope and
smoothly afforded the corresponding conformationally con-
strained amino acids 6−10 in very high stereochemical purities
and good yields (Figure 1).
At the outset of our investigation, the most simple
nitroalkane, nitromethane (1), was chosen as a model substrate
(Scheme 2).
Introductory screening experiments with four different
amine auxiliaries and 10 solvents disclosed21 that (R)-1-
phenylethylamine (3) in combination with iPrOH provided
superior results. To our delight, under the optimized
conditions, the reaction mixture gradually formed a thick
white suspension. As further revealed by HPLC analyses, a
diastereomeric composition of the mixture was changing over
time and (2S,1′R)-4, initially dominant, was gradually
transformed in favor of (2R,1′R)-4. A final filtration removed
most of the residual minor diastereomer and (2R,1′R)-4 was
obtained in excellent diastereomeric purity 99:1 and a good
yield of 59%. It is important to note that experiments
conducted with 1 equiv of (R)-3 failed to crystallize, yielding
low drs of 65:35, and thus, use of 2 equiv of (R)-3 was vital for
the success of the reaction. The stereochemistry of the
configurationally labile acid (2R,1′R)-4 was locked by a
catalytic reduction to provide a highly crystalline α,β-diamino
acid 5, suitable for X-ray crystallography (Scheme 2).
Figure 1. Reaction scope for α,α-disubstituted nitro compounds.
Notably, the use of organic solvents could have been
completely avoided in this set of reactions and water served as
a suitable medium. We succeeded in finding experimental
conditions for a selective reduction of amino acid 9 to
derivative 11, yielding crystals suitable for X-ray analysis, and
the (R)-configuration of the newly built stereogenic center was
confirmed. Elucidation of stereochemistry in structures 5
(Scheme 2) and 11 led us to an assumption that amino acids
B
DOI: 10.1021/acs.orglett.9b01489
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Figure 2. Reaction scope for α-prochiral nitro compounds. The dr composition is reported in the order of elution on HPLC.
of the whole series, i.e., 4 and 6−10, prefer to crystallize in a
(2R,1′R)-configuration. This judgment is in conclusive
accordance with our findings related to more complex
derivatives (vide infra).
iPrOH were most suitable and allowed for a fine tune up of the
reaction medium properties. The reaction progress was
carefully monitored by means of HPLC. Remarkably,
concerning the diastereomeric composition, the measured
reaction profiles exhibited two distinct patterns: it has always
been either the first (D1) or the last (D4) signal of the arisen
set of diastereomers intensity of which grew over time, thus
reflecting its gradual deposition in the form of crystals. Two
representatives of each of these groups, 13 and 16 for D1 and
20 and 28 for D4, were analyzed by X-ray crystallography. The
obtained data disclosed three stereochemical trends that
appear to be general: (a) (R)-1-phenylethylamine 3 and (R)-
1-(1-naphthyl)ethylamine induce an (R)-configuration on C2
(X-ray analyses of 5 and 11 provide an additional experimental
support, vide supra); (b) the diastereomers labeled as D1, that
are eluted first by reversed-phase HPLC, bear an anti-
configuration; (c) consequently, the diastereomers labeled as
D4, that are eluted last, exhibit a syn relationship. On the other
hand, it appears that there is no distinct structural feature of
the nitro substrates that would allow for any conclusive
Encouraged by the feasibility of crystallization-driven aza-
Henry reaction using a variety of symmetrical nitroalkanes, we
set out to evaluate the generality of this method on more
challenging nitro compounds bearing a prochiral carbon in the
α-position. As shown in Figure 2, a rich array of alkyl-, alkenyl-,
and aryl-substituted nitro derivatives were successful substrates
and underwent highly stereoselective conversions to the
corresponding salts of α-amino-β-nitro amino acids 12−27.22
Nevertheless, owing to the broad structural scope, the
previously employed reaction conditions (Scheme 2 and
Figure 1) had to be further optimized. We found out that in
terms of the product crystallinity and the overall reaction
performance, (R)-1-(1-naphthyl)ethylamine was superior to
the previously utilized phenyl-substituted analogue 3. Addi-
tional adjustment was needed for the used solvents on a case
by case basis. Generally, aqueous mixtures with MeCN or
C
DOI: 10.1021/acs.orglett.9b01489
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(2) (a) Lucet, D.; Le Gall, T.; Mioskowski, C. The Chemistry of
Vicinal Diamines. Angew. Chem., Int. Ed. 1998, 37, 2580−2627.
(b) Ballini, R.; Petrini, M. The Nitro to Carbonyl Conversion (Nef
reaction): New Perspective for a Classical Transformation. Adv. Synth.
Catal. 2015, 357, 2371−2402.
(3) For illustrative examples of aimed syntheses featuring aza-Henry
reaction as one of the key steps, see: (a) Jakubec, P.; Hawkins, A.;
Felzmann, W.; Dixon, D. J. Total Synthesis of Manzamine A and
Related Alkaloids. J. Am. Chem. Soc. 2012, 134, 17482−17485.
(b) Clark, P. G. K.; Vieira, L. C. C.; Tallant, C.; Fedorov, O.;
Singleton, D. C.; Rogers, C. M.; Monteiro, O. P.; Bennett, J. M.;
prediction of the product syn/anti-stereochemistry, and
broader crystallographic investigations might be needed. On
the basis of the obtained data, a preferential crystallization in
syn-configuration seems to be more presumable.
In summary, we have discovered a highly stereoselective
crystallization-driven aza-Henry reaction, applicable to a broad
range of substrates. The target compounds are readily isolated
by filtration. The method features imine species generated in
situ, eliminating the need for preparation of these moisture-
sensitive compounds in an extra step. In contrast with most of
the previous records, only 1 equiv of the nitro compound was
sufficient to obtain the corresponding β-nitroamines in
satisfactory yields. The method is applicable to sterically
demanding α,α-disubstituted nitro compounds as well as α-
prochiral substrates, yielding either syn- or anti-stereoisomers
in high purities. Moreover, synthesis of β-nitroamines with a
syn-configuration has scarcely been reported, and we believe
that the protocol described herein provides an attractive
synthetic tool that fills this gap and holds promise for various
future applications.
́
Baronio, R.; Muller, S.; Daniels, D. L.; Mendez, J.; Knapp, S.;
̈
Brennan, P. E.; Dixon, D. J. LP99: Discovery and Synthesis of the
First Selective BRD7/9 Broandersonmodomain Inhibitor. Angew.
Chem., Int. Ed. 2015, 54, 6217−6221. (c) Lin, L.-Z.; Fang, J.-M. Total
Synthesis of Anti-Influenza Agents Zanamivir and Zanaphosphor via
Asymmetric Aza-Henry Reaction. Org. Lett. 2016, 18, 4400−4403.
(4) Adams, H.; Anderson, J. C.; Peace, S.; Pennell, A. M. K. The
Nitro-Mannich Reaction and Its Application to the Stereoselective
Synthesis of 1,2-Diamines. J. Org. Chem. 1998, 63, 9932−9934.
̈
(5) Yamada, K.-i.; Harwood, S. J.; Groger, H.; Shibasaki, M. The
First Catalytic Asymmetric Nitro-Mannich-Type Reaction Promoted
by a New Heterobimetallic Complex. Angew. Chem., Int. Ed. 1999, 38,
3504−3506.
ASSOCIATED CONTENT
* Supporting Information
■
(6) For illustrative examples, see: (a) Ruano, J. L. G.; Topp, M.;
S
́
́
́
Lopez-Cantarero, J.; Aleman, J.; Remuin
̃
an, M. J.; Cid, M. B.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01489.
Asymmetric Aza-Henry Reactions from N-p-Tolylsulfinylimines. Org.
Lett. 2005, 7, 4407−4410. (b) Pindi, S.; Kaur, P.; Shakya, G.; Li, G.
N-Phosphinyl Imine Chemistry (I): Design and Synthesis of Novel N-
Phosphinyl Imines and their Application to Asymmetric aza-Henry
Reaction. Chem. Biol. Drug Des. 2011, 77, 20−29. (c) Yun, H.-S.; Lee,
H.-J.; Chang, D.-H.; Lee, S.-J.; Kim, S. H.; Kim, J. S.; Cho, C.-W.
Asymmetric Synthesis of Chiral 2-Alkyl-3,3-Dinitro-1-Tosylazetidines.
Bull. Korean Chem. Soc. 2015, 36, 1524−1527.
Experimental details, characterization data, copies of
NMR spectra (PDF)
Crystallographic data for 5, 11·1.5H2O, 13, 16, 20, and
28·H2O (PDF)
(7) For representative examples, see: (a) Nishiwaki, N.; Knudson, K.
Accession Codes
̈
R.; Gothelf, K. V.; Jorgensen, K. A. Catalytic Enantioselective
Addition of Nitro Compounds to Imines − A Simple Approach for
the Synthesis of Optically Active β-Nitro-α-Amino Esters. Angew.
Chem., Int. Ed. 2001, 40, 2992−2995. (b) Handa, S.; Gnanadesikan,
V.; Matsunaga, S.; Shibasaki, M. syn-Selective Catalytic Asymmetric
Nitro-Mannich Reactions Using a Heterobimetalic Cu-Sm-Schiff Base
Complex. J. Am. Chem. Soc. 2007, 129, 4900−4901. (c) Choudhary,
M. K.; Tak, R.; Kureshy, R. I.; Ansari, A.; Khan, N.-u. H.; Abdi, S. H.
R.; Bajaj, H. C. Enantioselective aza-Henry reaction for the synthesis
of (S)-levamisole using efficient recyclable chiral Cu(II)-amino
alcohol derived complexes. J. Mol. Catal. A: Chem. 2015, 409, 85−
93. (d) Dudek, A.; Mlynarski, J. Iron-Catalyzed Asymmetric Nitro-
Mannich Reaction. J. Org. Chem. 2017, 82, 11218−11224. (e) Liu, S.;
Gao, W.-C.; Miao, Y.-H.; Wang, M.-C. Dinuclear Zinc-AzePhenol
Catalyzed Asymmetric Aza-Henry Reaction of N-Boc Imines and
Nitroalkanes under Ambient Conditions. J. Org. Chem. 2019, 84,
2652−2659.
(8) Illustrative examples: (a) Fini, F.; Sgarzani, V.; Pettersen, D.;
Herrera, R. P.; Bernardi, L.; Ricci, A. Phase-Transfer-Catalyzed
Asymmetric Aza-Henry Reaction Using N-Carbamoyl Imines
Generated In Situ from α-Amido Sulfones. Angew. Chem., Int. Ed.
2005, 44, 7975−7978. (b) Wang, C.-J.; Dong, X.-Q.; Zhang, Z.-H.;
Xue, Z.-Y.; Teng, H.-L. Highly anti-Selective Asymmetric Nitro-
Mannich Reactions Catalyzed by Bifunctional Amine-Thiourea-
Bearing Multiple Hydrogen-Bonding Donors. J. Am. Chem. Soc.
2008, 130, 8606−8607. (c) Takada, K.; Nagasawa, K. Enantiose-
lective Aza-Henry Reaction with Acyclic Guanidine-Thiourea Bifunc-
tional Organocatalyst. Adv. Synth. Catal. 2009, 351, 345−347.
(d) Davis, T. A.; Wilt, J. C.; Johnston, J. N. Bifunctional Asymmetric
Catalysis: Amplification of Brønsted Basicity Can Orthogonally
Increase the Reactivity of a Chiral Brønsted Acid. J. Am. Chem. Soc.
2010, 132, 2880−2882. (e) Anderson, J. C.; Koovits, P. J. An
enantioselective tandem reduction/nitro-Mannich reaction of nitro-
alkenes using a simple thiourea organocatalyst. Chem. Sci. 2013, 4,
CCDC 1908404−1908409 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: pavol.jakubec@stuba.sk.
ORCID
́
Jan Moncol: 0000-0003-2153-9753
̌
Andrej Kolarovic: 0000-0001-8533-0743
Pavol Jakubec: 0000-0001-8872-3817
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Slovak Research and
Development Agency under Contract No. APVV-16-0258.
The crystal structures were solved with the support of the
project “University Science Park of STU Bratislava” (ITMS
Project No. 26240220084) cofounded by the European
Regional Development Fund.
REFERENCES
■
(1) For a recent review, see: Noble, A.; Anderson, J. C. Nitro-
Mannich Reaction. Chem. Rev. 2013, 113, 2887−2939.
D
DOI: 10.1021/acs.orglett.9b01489
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
2897−2901. (f) Lu, N.; Bai, F.; Fang, Y.; Wei, Z.; Cao, J.; Liang, D.;
Lin, Y.; Duan, H. Bifunctional Phase-Transfer Catalysts Catalyzed
Diastereo- and Enantioselective Aza-Henry Reaction of β,γ-Unsatu-
rated Nitroalkenes With Amidosulfones. Adv. Synth. Catal. 2017, 359,
4111−4116.
(9) For an interesting example of organocatalysis mediated by an
iridium(III) complex, see: Ma, J.; Ding, X.; Hu, Y.; Huang, Y.; Gong,
L.; Meggers, E. Metal-templated chiral Brønsted base organocatalysis.
Nat. Commun. 2014, 5, 4531.
(19) Xu, F.; Corley, E.; Zacuto, M.; Conlon, D. A.; Pipik, B.;
Humphrey, G.; Murry, J.; Tschaen, D. Asymmetric Synthesis of a
Potent, Aminopiperidine-Fused Imidazopyridine Dipeptidyl Peptidase
IV Inhibitor. J. Org. Chem. 2010, 75, 1343−1353.
(20) Glyoxylic acid is reported to react in aza-Henry reaction, in
aqueous KOH: Coghlan, P. A.; Easton, C. J. A one-pot three-
component synthesis of β-nitro-α-amino acids and their N-alkyl
derivatives. J. Chem. Soc., Perkin Trans. 1 1999, 2659−2660.
(21) Screened amines: (R)-2-phenylglycinamide, (S)-2-phenyl-
glycinol, (S)-1-(4-methoxyphenyl)ethylamine, (R)-1-phenylethyl-
amine (3); solvents: H2O, MeOH, EtOH, iPrOH, MeCN, 1,4-
dioxane, THF, Et2O, CH2Cl2, toluene.
(10) Studies related to ketimines, α-nitroesters, α-nitrophospho-
nates, or cascade reactions are beyond the scope of this article and are
not quoted in the literature survey.
́
(22) For examples of less successful α-prochiral substrates, see the
Supporting Information.
́
(11) (a) Pedrosa, R.; Andres, J. M.; Avila, D. P.; Ceballos, M.;
Pindado, R. Chiral Ureas and Thioureas Supported on Polystyrene for
Enantioselective Aza-Henry Reaction in Solvent-free conditions.
Green Chem. 2015, 17, 2217−2225. (b) Miao, Z.; Qi, C.; Wang, L.;
Wensley, A. M.; Luan, Y. The synthesis of metal-organic framework
Al-MIL-53-derived Brønsted acid catalyst and its application in the
Mannich reaction. Appl. Organomet. Chem. 2017, 31, No. e3569. For
an example of immobilized catalysts in ketimine chemistry, see:
́
̃
(c) Goldys, A. M.; Nunez, M. G.; Dixon, D. J. Creation through
Immobilization: A New Family of High Performance Heterogenous
Bifunctional Iminophosphorane (BIMP) Superbase Organocatalysts.
Org. Lett. 2014, 16, 6294−6297.
́
(12) (a) Palomo, C.; Oiarbide, M.; Laso, A.; Lopez, R. Catalytic
Enantioselective Aza-Henry Reaction with Broad Substrate Scope. J.
Am. Chem. Soc. 2005, 127, 17622−17623. (b) Wang, X.; Chen, Y.-F.;
Xu, P.-F. Diastereo- and Enantioselective Aza-MBH-Type Reaction of
Nitroalkenes to N-Tosylimines Catalyzed by Bifunctional Organo-
catalysts. Org. Lett. 2009, 11, 3310−3313. (c) Kundu, D.; Debnath, R.
K.; Majee, A.; Hajra, A. Zwitterionic-type molten salt-catalyzed syn-
selective aza-Henry reaction: solvent-free one-pot synthesis of β-
nitroamines. Tetrahedron Lett. 2009, 50, 6998−7000. (d) Wei, Y.; He,
W.; Liu, Y.; Liu, P.; Zhang, S. Highly Enantioselective Nitro-Mannich
Reaction Catalyzed by Cinchona Alkaloids and N-Benzotriazole
Derived Ammonium Salts. Org. Lett. 2012, 14, 704−707.
(13) For an illustrative example of aza-Henry reaction involving
imine formed in situ, see: Cruz-Acosta, F.; de Armas, P.; García-
Tellado, F. Chem. - Eur. J. 2013, 19, 16550−16554.
(14) (a) Tung, H.-H. Industrial Perspectives of Pharmaceutical
Crystallization. Org. Process Res. Dev. 2013, 17, 445−454. For an
appealing combination of an intermittent-flow aza-Henry reaction and
a product crystallization, see: (b) Tsukanov, S. V.; Johnson, M. D.;
May, S. A.; Rosemeyer, M.; Watkins, M. A.; Kolis, S. P.; Yates, M. H.;
Johnston, J. N. Development of an Intermittent-Flow Enantioselective
Aza-Henry Reaction Using an Arylnitromethane and Homogeneous
Brønsted Acid-Base Catalyst with Recycle. Org. Process Res. Dev. 2016,
20, 215−226.
(15) For a review on CIDT, see: Brands, K. M. J.; Davies, A. J.
Crystallization-Induced Diastereomer Transformations. Chem. Rev.
2006, 106, 2711−2733.
́
̌
́
́
́
̌
(16) Sivak, I.; Toberny, M.; Kyselicova, A.; Caletkova, O.; Berkes,
̌
D.; Jakubec, P.; Kolarovic, A. Stereoselective Synthesis of Function-
alized α-Amino Acids Isolated by Filtration. J. Org. Chem. 2018, 83,
15541−15548.
(17) (a) Anderson, J. C.; Stepney, G. J.; Mills, M. R.; Horsfall, L. R.;
Blake, A. J.; Lewis, W. Enantioselective Conjugate Addition Nitro-
Mannich Reactions: Solvent Controlled Synthesis of Acyclic anti- and
syn-β-Nitroamines with Three Contiguous Stereocenters. J. Org.
Chem. 2011, 76, 1961−1971. For a recent mechanistic study of a
retro-aza-Henry reaction, see: (b) Kallitsakis, M. G.; Tancini, P. D.;
Dixit, M.; Mpourmpakis, G.; Lykakis, I. N. Mechanistic Studies on the
Michael Addition of Amines and Hydrazines To Nitrostyrenes:
Nitroalkane Elimination via a Retro-aza-Henry-Type Process. J. Org.
Chem. 2018, 83, 1176−1184.
(18) Cheng, T.; Meng, S.; Huang, Y. A Highly Diastereoselective
and Enantioselective Synthesis of Polysubstituted Pyrrolidines via an
Organocatalytic Dynamic Kinetic Resolution Cascade. Org. Lett.
2013, 15, 1958−1961.
E
DOI: 10.1021/acs.orglett.9b01489
Org. Lett. XXXX, XXX, XXX−XXX